WorldWideScience

Sample records for factor peroxisome proliferator-activated

  1. Germ cell nuclear factor directly represses the transcription of peroxisome proliferator-activated receptor delta gene

    Institute of Scientific and Technical Information of China (English)

    Chengqiang He; Naizheng Ding; Jie Kang

    2008-01-01

    Germ cell nuclear factor (GCNF) is a transcription factor that can repress gene transcription and plays an important role during spermatogenesis. Peroxisome proliferator-activated receptor delta (PPARδ) is a nuclear hormone receptor belonging to the steroid receptor superfamily.It can activate the expression of many genes,including those involved in lipid metabolism.In this report,we showed that GCNF specifically interacts with PPARδ promoter.Overexpression of GCNF in African green monkey SV40 transformed kidney fibroblast COS7 cells and mouse embryo fibroblast NIH 3T3 cells represses the activity of PPARδ promoter.The mutation of GCNF response element in PPARδ promoter relieves the repression in NIH 3T3 cells and mouse testis.Moreover,we showed that GCNF in nuclear extracts of mouse testis is able to bind to PPARδ promoter directly.We also found that GCNF and PPARδ mRNA were expressed with different patterns in mouse testis by in situ hybridization.These results suggested that GCNF might be a negative regulator of PPARδ gene expression through its direct interaction with PPARδ promoter in mouse testis.

  2. Expression of peroxisome proliferator-activated receptor and CCAAT/enhancer binding protein transcription factors in cultured human sebocytes.

    Science.gov (United States)

    Chen, WenChieh; Yang, Chao-Chun; Sheu, Hamm-Ming; Seltmann, Holger; Zouboulis, Christos C

    2003-09-01

    Lipid synthesis and accumulation represent a major step in sebocyte differentiation and it may be of importance for sebocytes to express two families of transcription factors, CCAAT/enhancer binding proteins (c/EBPs) and peroxisome proliferator-activated receptors (PPARs), which were found to play a crucial role in the differentiation of adipocytes. Using the immortalized human sebaceous gland cell line SZ95 we examined the expression of the molecules before and after treatment with testosterone, 5alpha-dihydrotestosterone, dexamethasone, 17beta-estradiol and genistein, at 6, 12, 24, and 48 h, respectively. Reverse transcription-PCR analysis showed expression of peroxisome proliferator-activated receptors -alpha, -delta, -gamma1, -gamma2 and CCAAT/enhancer binding proteins-alpha, -beta, -gamma-delta in native SZ95 sebocytes. In western blot studies, high levels of CCAAT/enhancer binding proteins-alpha and -beta, and peroxisome proliferator-activated receptors-gamma were expressed at 6, 24, and 12 h, respectively. Immunostaining of the cultured sebocytes showed the CCAAT/enhancer binding proteins-alpha and -beta mainly localized within nuclei, whereas peroxisome proliferator-activated receptors-gamma in the cytoplasm. Strong staining of sebocytes was immunohistochemically revealed in the basal layer of sebaceous glands in human scalp and sebaceous nevus. Genistein down-regulated the expression of CCAAT/enhancer binding proteins-alpha and -beta, and peroxisome proliferator-activated receptors-gamma on the protein level. Treatment with linoleic acid for 48 h induced further differentiation of sebocytes leading to abundant lipid synthesis.

  3. Troglitazone inhibits cell proliferation by attenuation of epidermal growth factor receptor signaling independent of peroxisome proliferator-activated receptor γ

    Institute of Scientific and Technical Information of China (English)

    Xiaoqi Li; Xuanming Yang; Youli Xu; Xuejun Jiang; Xin Li; Fajun Nan; Hong Tang

    2009-01-01

    Peroxisome proliferator-activated receptors (PPAR) belong to the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Recent results have shown that agonists of PPARy, such as troglitazone (TGZ), can inhibit cell proliferation and promote cell differentiation independent of PPARγ. In the present study, we provide evidence that TGZ may bind directly to EGFR and trigger its signaling and internalization independent of PPARγ. Detailed studies revealed that prolonged incubation with TGZ effectively attenuated EGFR signaling by target-ing the receptor to the endo-lysosomal degradation machinery. Although the extracellular signal-regulated kinase-signaling pathway was transiently activated by TGZ in EGFR overexpressing cancer cells, inhibition of EGF-induced Akt phosphorylation most likely accounted for the growth arrest of tumor cells caused by TGZ at pharmacologically achievable concentrations. Therefore, we have provided a new line of evidence indicating that TGZ inhibits cell pro-liferation by promoting EGFR degradation and attenuating Akt phosphorylation.

  4. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    Directory of Open Access Journals (Sweden)

    Sander Kersten

    2008-01-01

    Full Text Available Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that mediates the effect of dietary fatty acids and certain drugs on plasma lipoproteins are the peroxisome proliferator activated receptors (PPARs. Three PPAR isotypes can be distinguished, all of which have a major role in regulating lipoprotein metabolism. PPARα is the molecular target for the fibrate class of drugs. Activation of PPARα in mice and humans markedly reduces hepatic triglyceride production and promotes plasma triglyceride clearance, leading to a clinically significant reduction in plasma triglyceride levels. In addition, plasma high-density lipoprotein (HDL-cholesterol levels are increased upon PPARα activation in humans. PPARγ is the molecular target for the thiazolidinedione class of drugs. Activation of PPARγ in mice and human is generally associated with a modest increase in plasma HDL-cholesterol and a decrease in plasma triglycerides. The latter effect is caused by an increase in lipoprotein lipase-dependent plasma triglyceride clearance. Analogous to PPARα, activation of PPARβ/δ leads to increased plasma HDL-cholesterol and decreased plasma triglyceride levels. In this paper, a fresh perspective on the relation between PPARs and lipoprotein metabolism is presented. The emphasis is on the physiological role of PPARs and the mechanisms underlying the effect of synthetic PPAR agonists on plasma lipoprotein levels.

  5. Acyl-CoA esters antagonize the effects of ligands on peroxisome proliferator-activated receptor alpha conformation, DNA binding, and interaction with Co-factors

    DEFF Research Database (Denmark)

    Elholm, M; Dam, I; Jorgensen, C;

    2001-01-01

    The peroxisome proliferator-activated receptor alpha (PPARalpha) is a ligand-activated transcription factor and a key regulator of lipid homeostasis. Numerous fatty acids and eicosanoids serve as ligands and activators for PPARalpha. Here we demonstrate that S-hexadecyl-CoA, a nonhydrolyzable...

  6. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    NARCIS (Netherlands)

    Rakhshandehroo, M.; Knoch, B.; Müller, M.R.; Kersten, A.H.

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPAR alpha serves as a molecular target for hypolip

  7. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    NARCIS (Netherlands)

    Rakhshandehroo, M.; Knoch, B.; Müller, M.R.; Kersten, A.H.

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPAR alpha serves as a molecular target for

  8. Peroxisome Proliferator-Activated Receptor γ Induces the Expression of Tissue Factor Pathway Inhibitor-1 (TFPI-1) in Human Macrophages

    Science.gov (United States)

    Copin, C.; Derudas, B.; Marx, N.

    2016-01-01

    Tissue factor (TF) is the initiator of the blood coagulation cascade after interaction with the activated factor VII (FVIIa). Moreover, the TF/FVIIa complex also activates intracellular signalling pathways leading to the production of inflammatory cytokines. The TF/FVIIa complex is inhibited by the tissue factor pathway inhibitor-1 (TFPI-1). Peroxisome proliferator-activated receptor gamma (PPARγ) is a transcription factor that, together with PPARα and PPARβ/δ, controls macrophage functions. However, whether PPARγ activation modulates the expression of TFP1-1 in human macrophages is not known. Here we report that PPARγ activation increases the expression of TFPI-1 in human macrophages in vitro as well as in vivo in circulating peripheral blood mononuclear cells. The induction of TFPI-1 expression by PPARγ ligands, an effect shared by the activation of PPARα and PPARβ/δ, occurs also in proinflammatory M1 and in anti-inflammatory M2 polarized macrophages. As a functional consequence, treatment with PPARγ ligands significantly reduces the inflammatory response induced by FVIIa, as measured by variations in the IL-8, MMP-2, and MCP-1 expression. These data identify a novel role for PPARγ in the control of TF the pathway. PMID:28115923

  9. Berberine regulates peroxisome proliferator-activated receptors and positive transcription elongation factor b expression in diabetic adipocytes.

    Science.gov (United States)

    Zhou, Jiyin; Zhou, Shiwen

    2010-12-15

    Berberine has hypoglycemic and hypolipidemic effects on diabetic rats. This study investigated the relationship between hypoglycemic and hypolipidemic effects of berberine and peroxisome proliferator-activated receptors (PPARs) and positive transcription elongation factor b (P-TEFb) (including cyclin-dependent kinase 9 (CDK9) and cyclin T1) in white adipose tissue of diabetic rats and RNA interference-treated 3T3-L1 cells. Berberine promoted differentiation and inhibited lipid accumulation of 3T3-L1 cells, further decreased PPARα/δ/γ, CDK9 and cyclin T1 mRNA and protein expression and decreased tumor necrosis factor α content in supernatants of both control and RNA interference-treated 3T3-L1 cells. After a 16-week induction with 35 mg/kg streptozotocin (i.p.) and high-carbohydrate/high-fat diet, diabetic rats were treated with 75, 150 and 300 mg/kg berberine and 100 mg/kg fenofibrate or 4 mg/kg rosiglitazone for another 16 weeks. Berberine decreased white adipose tissue to body weight ratio and adipocyte size and increased adipocyte number. Berberine upregulated PPARα/δ/γ, CDK9 and cyclin T1 mRNA and protein expression in adipose tissue, decreased tumor necrosis factor α and free fatty acid content and increased lipoprotein lipase activity in serum and adipose tissue. Berberine modulated metabolic related PPARs expression and differentiation related P-TEFb expression in adipocytes, which are associated with its hypoglycemic and hypolipidemic effects.

  10. The cardiovascular effects of peroxisome proliferator-activated receptor agonists.

    Science.gov (United States)

    Friedland, Sayuri N; Leong, Aaron; Filion, Kristian B; Genest, Jacques; Lega, Iliana C; Mottillo, Salvatore; Poirier, Paul; Reoch, Jennifer; Eisenberg, Mark J

    2012-02-01

    Although peroxisome proliferator-activated receptor agonists are prescribed to improve cardiovascular risk factors, their cardiovascular safety is controversial. We therefore reviewed the literature to identify landmark randomized controlled trials evaluating the effect of peroxisome proliferator-activated receptor gamma agonists (pioglitazone and rosiglitazone), alpha agonists (fenofibrate and gemfibrozil), and pan agonists (bezafibrate, muraglitazar, ragaglitazar, tesaglitazar, and aleglitazar) on cardiovascular outcomes. Pioglitazone may modestly reduce cardiovascular events but also may increase the risk of bladder cancer. Rosiglitazone increases the risk of myocardial infarction and has been withdrawn in European and restricted in the United States. Fibrates improve cardiovascular outcomes only in select subgroups: fenofibrate in diabetic patients with metabolic syndrome, gemfibrozil in patients with dyslipidemia, and bezafibrate in patients with diabetes or metabolic syndrome. The cardiovascular safety of the new pan agonist aleglitazar, currently in phase II trials, remains to be determined. The heterogenous effects of peroxisome proliferator-activated receptor agonists to date highlight the importance of postmarketing surveillance. The critical question of why peroxisome proliferator-activated receptor agonists seem to improve cardiovascular risk factors without significantly improving cardiovascular outcomes requires further investigation.

  11. Peroxisome proliferator-activated receptors for hypertension

    Institute of Scientific and Technical Information of China (English)

    Daisuke; Usuda; Tsugiyasu; Kanda

    2014-01-01

    Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes(α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin Ⅱ receptor blockers, should be studied.This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases.

  12. Peroxisome proliferator-activated receptors for hypertension

    Science.gov (United States)

    Usuda, Daisuke; Kanda, Tsugiyasu

    2014-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily, which is composed of four members encoded by distinct genes (α, β, γ, and δ). The genes undergo transactivation or transrepression under specific mechanisms that lead to the induction or repression of target gene expression. As is the case with other nuclear receptors, all four PPAR isoforms contain five or six structural regions in four functional domains; namely, A/B, C, D, and E/F. PPARs have many functions, particularly functions involving control of vascular tone, inflammation, and energy homeostasis, and are, therefore, important targets for hypertension, obesity, obesity-induced inflammation, and metabolic syndrome in general. Hence, PPARs also represent drug targets, and PPARα and PPARγ agonists are used clinically in the treatment of dyslipidemia and type 2 diabetes mellitus, respectively. Because of their pleiotropic effects, they have been identified as active in a number of diseases and are targets for the development of a broad range of therapies for a variety of diseases. It is likely that the range of PPARγ agonist therapeutic actions will result in novel approaches to lifestyle and other diseases. The combination of PPARs with reagents or with other cardiovascular drugs, such as diuretics and angiotensin II receptor blockers, should be studied. This article provides a review of PPAR isoform characteristics, a discussion of progress in our understanding of the biological actions of PPARs, and a summary of PPAR agonist development for patient management. We also include a summary of the experimental and clinical evidence obtained from animal studies and clinical trials conducted to evaluate the usefulness and effectiveness of PPAR agonists in the treatment of lifestyle-related diseases. PMID:25228953

  13. Peroxisome proliferator-activated receptor-gamma agonists suppress tissue factor overexpression in rat balloon injury model with paclitaxel infusion.

    Directory of Open Access Journals (Sweden)

    Jun-Bean Park

    Full Text Available The role and underlying mechanisms of rosiglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ agonist, on myocardial infarction are poorly understood. We investigated the effects of this PPAR-γ agonist on the expression of tissue factor (TF, a primary molecule for thrombosis, and elucidated its underlying mechanisms. The PPAR-γ agonist inhibited TF expression in response to TNF-α in human umbilical vein endothelial cells, human monocytic leukemia cell line, and human umbilical arterial smooth muscle cells. The overexpression of TF was mediated by increased phosphorylation of mitogen-activated protein kinase (MAPK, which was blocked by the PPAR-γ agonist. The effective MAPK differed depending on each cell type. Luciferase and ChIP assays showed that transcription factor, activator protein-1 (AP-1, was a pivotal target of the PPAR-γ agonist to lower TF transcription. Intriguingly, two main drugs for drug-eluting stent, paclitaxel or rapamycin, significantly exaggerated thrombin-induced TF expression, which was also effectively blocked by the PPAR-γ agonist in all cell types. This PPAR-γ agonist did not impair TF pathway inhibitor (TFPI in three cell types. In rat balloon injury model (Sprague-Dawley rats, n = 10/group with continuous paclitaxel infusion, the PPAR-γ agonist attenuated TF expression by 70±5% (n = 4; P<0.0001 in injured vasculature. Taken together, rosiglitazone reduced TF expression in three critical cell types involved in vascular thrombus formation via MAPK and AP-1 inhibitions. Also, this PPAR-γ agonist reversed the paclitaxel-induced aggravation of TF expression, which suggests a possibility that the benefits might outweigh its risks in a group of patients with paclitaxel-eluting stent implanted.

  14. Peroxisome-proliferator-activated receptors γ and β/δ mediate vascular endothelial growth factor production in colorectal tumor cells.

    Science.gov (United States)

    Röhrl, Clemens; Kaindl, Ulrike; Koneczny, Inga; Hudec, Xenia; Baron, David M; König, Jürgen S; Marian, Brigitte

    2011-01-01

    Peroxisome-proliferator-activated receptors (PPARs) are nuclear receptors for fatty acids and their derivatives. PPAR subtypes PPARγ and PPARβ/δ are suspected to modulate cancer development in the colon, but their exact role is still discussed controversially. The present study investigated the impact of PPARγ and PPARβ/δ on vascular endothelial growth factor (VEGF) and cyclooxygenase 2 (COX-2) expressions induced by synthetic and physiological agonists in the colorectal tumor cell lines SW480 and HT29 using reporter gene assays, qRT-PCR and ELISA. Activation of both PPARγ and PPARβ/δ induced expression of VEGF mRNA and protein in a PPAR-dependent way. The PPARγ agonists ciglitazone and PGJ(2) were the most effective inducers with up to ninefold and threefold increases in VEGF mRNA in SW480 and HT29 cultures, respectively. VEGF secretion was doubled in both cell lines. The PPARβ/δ agonists GW501516 and PGI(2) caused stimulations of only 1.5-fold in both cell lines. In addition, all PPAR agonists induced COX-2 mRNA and secretion of the COX-2 product PGE(2) in HT29 cells. However, this effect was not blocked by knock-down of PPAR expression nor was it essential for VEGF expression as shown by the lack of effect of the COX-2 inhibitor SC236. In summary, our results identify both PPARγ and PPARβ/δ as an alternative COX-independent mechanism of VEGF induction in colorectal tumor cells.

  15. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    OpenAIRE

    Maryam Rakhshandehroo; Bianca Knoch; Michael Müller; Sander Kersten

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPAR alpha) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPAR alpha serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPAR alpha binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPAR alpha governs biologi...

  16. Hypoxia-inducible factor-1α increased the expression of peroxisome proliferator activated receptor α in lung cancer cell A549

    Institute of Scientific and Technical Information of China (English)

    张惠兰; 张珍祥; 徐永健

    2004-01-01

    @@ Hypoxia plays a fundamental role in many pathologic processes. Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric basic helix-loop-helix-per-aryl hydrocarbon receptor ARNT-sim (PAS) domain protein, consisting of α and β subunits and is precisely regulated by cellular oxygen levels.1 The peroxisome proliferator-activated receptors (PPARs) are family nuclear hormone-binding proteins with increasing diverse functions as transcriptional regulators, owning three subtypes (α, β, and γ).2 PPARα plays a critical physiological role as lipid sensors and regulators of proliferation.3 Hypoxia can elicit up-regulation of PPAR-α expression.4 Herein, we report the results of an investigation on the correlation of HIF-1α and PPARα.

  17. Peroxisome proliferator-activated receptor alpha target genes.

    Science.gov (United States)

    Rakhshandehroo, Maryam; Knoch, Bianca; Müller, Michael; Kersten, Sander

    2010-01-01

    The peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.

  18. Peroxisome Proliferator-Activated Receptor Alpha Target Genes

    Directory of Open Access Journals (Sweden)

    Maryam Rakhshandehroo

    2010-01-01

    Full Text Available The peroxisome proliferator-activated receptor alpha (PPARα is a ligand-activated transcription factor involved in the regulation of a variety of processes, ranging from inflammation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid-derived compounds. PPARα governs biological processes by altering the expression of a large number of target genes. Accordingly, the specific role of PPARα is directly related to the biological function of its target genes. Here, we present an overview of the involvement of PPARα in lipid metabolism and other pathways through a detailed analysis of the different known or putative PPARα target genes. The emphasis is on gene regulation by PPARα in liver although many of the results likely apply to other organs and tissues as well.

  19. [Peroxisome proliferator-activated receptors (PPAR). Antiproliferative properties].

    Science.gov (United States)

    Hojka, Anna; Rapak, Andrzej

    2011-06-21

    Peroxisome proliferator-activated receptors (PPAR) are transcription factors that belong to the hormone nuclear receptor superfamily. Their main role is control of fatty acid metabolism and to maintain glucose homeostasis. Isotype γ of PPAR can also be implicated in proliferation and cellular differentiation of both normal and cancer cells. Compounds that are PPARγ ligands have a negative influence on cancer cells and can induce apoptosis, inhibit proliferation or induce cellular differentiation of these cells. This review summarizes general information about PPAR and focuses on anticancer activities of PPARγ ligands and their use in combined therapy. Combination treatment using PPARγ ligands and other agents, especially retinoids and specific kinase inhibitors, may be an effective strategy for chemoprevention and treatment of some cancers.

  20. Peroxisome proliferator-activated receptors and renal diseases.

    Science.gov (United States)

    Wu, Jing; Chen, Lihong; Zhang, Dongjuan; Huo, Ming; Zhang, Xiaoyan; Pu, Dan; Guan, Youfei

    2009-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. Three isoforms of PPAR, i.e., PPAR-a, -d, and -?, have been identified and are differentially expressed in various tissues, including the kidney. The target genes of PPARs are involved in diverse biological processes, including adipogenesis, lipid metabolism, insulin sensitivity, inflammatory response, reproduction, and cell growth and differentiation. PPARs have been reported to protect against renal injury through indirect systemic effects and/or direct renal effects in diabetic nephropathy, glomerulonephritis, renal cell carcinoma, acute renal failure and chronic renal disease. In this review, we summarize the role of the three identified PPAR isoforms, PPARa, -d, and -?, in renal physiology and discuss the renoprotective effects of PPAR ligands in various kidney diseases.

  1. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    NARCIS (Netherlands)

    Kersten, A.H.

    2008-01-01

    Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that

  2. Peroxisome Proliferator Activated Receptors and Lipoprotein Metabolism

    NARCIS (Netherlands)

    Kersten, A.H.

    2008-01-01

    Plasma lipoproteins are responsible for carrying triglycerides and cholesterol in the blood and ensuring their delivery to target organs. Regulation of lipoprotein metabolism takes place at numerous levels including via changes in gene transcription. An important group of transcription factors that

  3. Inhibition of tumor necrosis factor-alpha-induced interleukin-6 expression by telmisartan through cross-talk of peroxisome proliferator-activated receptor-gamma with nuclear factor kappaB and CCAAT/enhancer-binding protein-beta.

    Science.gov (United States)

    Tian, Qingping; Miyazaki, Ryohei; Ichiki, Toshihiro; Imayama, Ikuyo; Inanaga, Keita; Ohtsubo, Hideki; Yano, Kotaro; Takeda, Kotaro; Sunagawa, Kenji

    2009-05-01

    Telmisartan, an angiotensin II type 1 receptor antagonist, was reported to be a partial agonist of peroxisome proliferator-activated receptor-gamma. Although peroxisome proliferator-activated receptor-gamma activators have been shown to have an anti-inflammatory effect, such as inhibition of cytokine production, it has not been determined whether telmisartan has such effects. We examined whether telmisartan inhibits expression of interleukin-6 (IL-6), a proinflammatory cytokine, in vascular smooth muscle cells. Telmisartan, but not valsartan, attenuated IL-6 mRNA expression induced by tumor necrosis factor-alpha (TNF-alpha). Telmisartan decreased TNF-alpha-induced IL-6 mRNA and protein expression in a dose-dependent manner. Because suppression of IL-6 mRNA expression was prevented by pretreatment with GW9662, a specific peroxisome proliferator-activated receptor-gamma antagonist, peroxisome proliferator-activated receptor-gamma may be involved in the process. Telmisartan suppressed IL-6 gene promoter activity induced by TNF-alpha. Deletion analysis suggested that the DNA segment between -150 bp and -27 bp of the IL-6 gene promoter that contains nuclear factor kappaB and CCAAT/enhancer-binding protein-beta sites was responsible for telmisartan suppression. Telmisartan attenuated TNF-alpha-induced nuclear factor kappaB- and CCAAT/enhancer-binding protein-beta-dependent gene transcription and DNA binding. Telmisartan also attenuated serum IL-6 level in TNF-alpha-infused mice and IL-6 production from rat aorta stimulated with TNF-alpha ex vivo. These data suggest that telmisartan may attenuate inflammatory process induced by TNF-alpha in addition to the blockade of angiotensin II type 1 receptor. Because both TNF-alpha and angiotensin II play important roles in atherogenesis through enhancement of vascular inflammation, telmisartan may be beneficial for treatment of not only hypertension but also vascular inflammatory change.

  4. Regulation of lipid metabolism and peroxisome proliferator-activated receptors in rainbow trout adipose tissue by lipolytic and antilipolytic endocrine factors.

    Science.gov (United States)

    Cruz-Garcia, L; Sánchez-Gurmaches, J; Monroy, M; Gutiérrez, J; Navarro, I

    2015-04-01

    The aim of this study was to determine the effects of growth hormone (GH) and insulin-like growth factor (IGF)-I on glycerol release and the regulation of IGF-I and IGF-II expression by GH in isolated rainbow trout adipocytes. Cells were also incubated with GH, tumor necrosis factor α (TNFα), or insulin to analyze the gene expression of peroxisome proliferator-activated receptors (PPARs) and lipid metabolism markers: hormone sensitive lipase, fatty acid synthase (FAS), and lipoprotein lipase. Complimentary in vivo experiments were performed by intraperitoneally administering insulin, TNFα, or lipopolysaccharide and subjecting the animals to fasting and refeeding periods. The results showed that IGF-I had an antilipolytic effect and GH had a lipolytic effect; the latter occurred independently of IGF modulation and in conjunction with a reduction in PPARα expression in adipocytes. The anabolic action of insulin was demonstrated through its upregulation of lipogenic genes such as lipoprotein lipase, FAS, and PPARγ, whereas GH, by contrast, inhibited FAS expression in adipose tissue. The gene transcription levels of PPARs changed differentially during fasting and refeeding, and the TNFα and/or lipopolysaccharide administration suggested that the regulation of PPARs helps maintain metabolic adipose tissue homeostasis in rainbow trout. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Quantitative trait mapping reveals a regulatory axis involving peroxisome proliferator-activated receptors, PRDM16, transforming growth factor-β2 and FLT3 in hematopoiesis.

    Science.gov (United States)

    Avagyan, Serine; Aguilo, Francesca; Kamezaki, Kenjiro; Snoeck, Hans-Willem

    2011-12-01

    Hematopoiesis is the process whereby BM HSCs renew to maintain their number or to differentiate into committed progenitors to generate all blood cells. One approach to gain mechanistic insight into this complex process is the investigation of quantitative genetic variation in hematopoietic function among inbred mouse strains. We previously showed that TGF-β2 is a genetically determined positive regulator of hematopoiesis. In the presence of unknown nonprotein serum factors TGF-β2, but not TGF-β1 or -β3, enhances progenitor proliferation in vitro, an effect that is subject to mouse strain-dependent variation mapping to a locus on chr.4, Tb2r1. TGF-β2-deficient mice show hematopoietic defects, demonstrating the physiologic role of this cytokine. Here, we show that TGF-β2 specifically and predominantly cell autonomously enhances signaling by FLT3 in vitro and in vivo. A coding polymorphism in Prdm16 (PR-domain-containing 16) underlies Tb2r1 and differentially regulates transcriptional activity of peroxisome proliferator-activated receptor-γ (PPARγ), identifying lipid PPAR ligands as the serum factors required for regulation of FLT3 signaling by TGF-β2. We furthermore show that PPARγ agonists play a FLT3-dependent role in stress responses of progenitor cells. These observations identify a novel regulatory axis that includes PPARs, Prdm16, and TGF-β2 in hematopoiesis.

  6. The activation of peroxisome proliferator-activated receptor γ is regulated by Krüppel-like transcription factors 6 & 9 under steatotic conditions.

    Science.gov (United States)

    Escalona-Nandez, Ivonne; Guerrero-Escalera, Dafne; Estanes-Hernández, Alma; Ortíz-Ortega, Victor; Tovar, Armando R; Pérez-Monter, Carlos

    2015-03-20

    Liver steatosis is characterised by lipid droplet deposition in hepatocytes that can leads to an inflammatory and fibrotic phenotype. Peroxisome proliferator-activated receptors (PPARs) play key roles in energetic homeostasis by regulating lipid metabolism in hepatic tissue. In adipose tissue PPARγ regulates the adipocyte differentiation by promoting the expression of lipid-associated genes. Within the liver PPARγ is up-regulated under steatotic conditions; however, which transcription factors participate in its expression is not completely understood. Krüppel-like transcription factors (KLFs) regulate various cellular mechanisms, such as cell proliferation and differentiation. KLFs are key components of adipogenesis by regulating the expression of PPARγ and other proteins such as the C-terminal enhancer binding protein (C/EBP). Here, we demonstrate that the transcript levels of Klf6, Klf9 and Pparγ are increased in response to a steatotic insult in vitro. Chromatin immunoprecipitation (ChIp) experiments showed that klf6 and klf9 are actively recruited to the Pparγ promoter region under these conditions. Accordingly, the loss-of-function experiments reduced cytoplasmic triglyceride accumulation. Here, we demonstrated that KLF6 and KLF9 proteins directly regulate PPARγ expression under steatotic conditions. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease

    Science.gov (United States)

    Azhar, Salman

    2011-01-01

    Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/β and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID:20932114

  8. Peroxisome Proliferator-Activated Receptor α Reduces Endothelin-1-Caused Cardiomyocyte Hypertrophy by Inhibiting Nuclear Factor-κB and Adiponectin

    Directory of Open Access Journals (Sweden)

    Hsu-Lung Jen

    2016-01-01

    Full Text Available Peroxisome proliferator-activated receptor α (PPARα plays a role in the pathogenesis of cardiac hypertrophy, although its underlying mechanism remains unclear. The purpose of this study was to evaluate the effect of PPARα activation on endothelin-1- (ET-1- caused cardiomyocyte hypertrophy and explore its underlying mechanisms. Human cardiomyocytes (HCMs were cultured with or without ET-1, whereafter the inhibitory effects of fenofibrate, a PPARα activator, on cell size and adiponectin protein were tested. We examined the activation of extracellular signal-regulated kinase (ERK and p38 proteins caused by ET-1 and the inhibition of the ERK and p38 pathways on ET-1-induced cell size and adiponectin expression. Moreover, we investigated the interaction of PPARα with adiponectin and nuclear factor-κB (NF-κB by electrophoretic mobility shift assays and coimmunoprecipitation. ET-1 treatment significantly increased cell size, suppressed PPARα expression, and enhanced the expression of adiponectin. Pretreatment with fenofibrate inhibited the increase in cell size and enhancement of adiponectin expression. ET-1 significantly activated the ERK and p38 pathways, whereas PD98059 and SB205380, respectively, inhibited them. Our results suggest that activated PPARα can decrease activation of adiponectin and NF-κB and inhibit ET-1-induced cardiomyocyte hypertrophy.

  9. Peroxisome proliferator-activated receptors and cancer: challenges and opportunities.

    Science.gov (United States)

    Youssef, Jihan; Badr, Mostafa

    2011-09-01

    Peroxisome proliferator-activated receptors (PPARs), members of the nuclear hormone receptor superfamily, function as transcription factors and modulators of gene expression. These actions allow PPARs to regulate a variety of biological processes and to play a significant role in several diseases and conditions. The current literature describes frequently opposing and paradoxical roles for the three PPAR isotypes, PPARα, PPARβ/δ and PPARγ, in cancer. While some studies have implicated PPARs in the promotion and development of cancer, others, in contrast, have presented evidence for a protective role for these receptors against cancer. In some tissues, the expression level of these receptors and/or their activation correlates with a positive outcome against cancer, while, in other tissue types, their expression and activation have the opposite effect. These disparate findings raise the possibility of (i) PPAR receptor-independent effects, including effects on receptors other than PPARs by the utilized ligands; (ii) cancer stage-specific effect; and/or (iii) differences in essential ligand-related pharmacokinetic considerations. In this review, we highlight the latest available studies on the role of the various PPAR isotypes in cancer in several major organs and present challenges as well as promising opportunities in the field. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

  10. Biology and therapeutic applications of peroxisome proliferator- activated receptors.

    Science.gov (United States)

    Menendez-Gutierrez, Maria P; Roszer, Tamas; Ricote, Mercedes

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand dependent transcription factors. The three mammalian PPARs are key regulators of fatty acid and lipoprotein metabolism, glucose homeostasis, cellular proliferation/ differentiation and the immune response. PPARs are therefore important targets in the treatment of metabolic disorders such as insulin resistance and type 2 diabetes mellitus, and are also of interest in relation to chronic inflammatory diseases such as atherosclerosis, arthritis, chronic pulmonary inflammation, pancreatitis, inflammatory bowel disease, and psoriasis. Recent advances have attributed novel functions to PPARs in blood pressure regulation, neuroinflammation, nerve-cell protection, inflammatory pain reduction, and the hypothalamic control of metabolism. The abundant pleiotropic actions of PPARs suggest that PPAR agonists have enormous therapeutic potential. However, current PPAR-based therapies often have undesired side effects due to the concomitant activation of PPARs in non-target cells. There is therefore growing interest in the development of cell-specific PPAR agonists and improvement of the clinical use of PPAR ligands. This review gives an overview of PPAR functions and discusses the current and potential medical implications of PPAR ligands in various pathologies, ranging from metabolic disorders to cardiovascular disease, chronic inflammation, neurodegenerative disorders and cancer.

  11. Peroxisome proliferator-activated receptor gamma recruits the positive transcription elongation factor b complex to activate transcription and promote adipogenesis

    DEFF Research Database (Denmark)

    Iankova, Irena; Petersen, Rasmus K; Annicotte, Jean-Sébastien

    2006-01-01

    Positive transcription elongation factor b (P-TEFb) phosphorylates the C-terminal domain of RNA polymerase II, facilitating transcriptional elongation. In addition to its participation in general transcription, P-TEFb is recruited to specific promoters by some transcription factors such as c-Myc...

  12. The adipogenic acetyltransferase Tip60 targets activation function 1 of peroxisome proliferator-activated receptor gamma

    DEFF Research Database (Denmark)

    van Beekum, Olivier; Brenkman, Arjan B; Grøntved, Lars

    2008-01-01

    The transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) plays a key role in the regulation of lipid and glucose metabolism in adipocytes, by regulating their differentiation, maintenance, and function. The transcriptional activity of PPARgamma is dictated by the set ...

  13. Peroxisome proliferators-activated receptor (PPAR) regulation in cardiac metabolism and disease

    NARCIS (Netherlands)

    el Azzouzi, H.|info:eu-repo/dai/nl/304072796

    2009-01-01

    Peroxisome proliferators-activated receptors (PPARs) are members of the nuclear receptor family of ligand activated transcription factors and consist of the three isoforms, PPAR, PPAR/ and PPAR. Considerable evidence has established the importance of PPARs in myocardial lipid homeostasis and

  14. Peroxisome Proliferator-Activated Receptor : alpha Protects against Obesity-Induced Hepatic Inflammation

    NARCIS (Netherlands)

    Stienstra, R.; Mandard, S.J.; Patsouris, D.A.; Maass, C.; Kersten, A.H.; Müller, M.R.

    2007-01-01

    Recently it has become evident that obesity is associated with low-grade chronic inflammation. The transcription factor peroxisome proliferator-activated receptor (PPAR) has been shown to have a strong antiinflammatory action in liver. However, the role of PPAR in obesity-induced inflammation is

  15. The peroxisome proliferator-activated receptor alpha regulates amino acid metabolism

    NARCIS (Netherlands)

    Kersten, S.; Mandard, S.; Escher, P.; Gonzalez, F.J.; Tafuri, S.; Desvergne, B.; Wahli, W.

    2001-01-01

    The peroxisome proliferator-activated receptor is a ligand-activated transcription factor that plays an important role in the regulation of lipid homeostasis. PPAR mediates the effects of fibrates, which are potent hypolipidemic drugs, on gene expression. To better understand the biological effects

  16. Peroxisome proliferators-activated receptor (PPAR) regulation in cardiac metabolism and disease

    NARCIS (Netherlands)

    el Azzouzi, H.

    2009-01-01

    Peroxisome proliferators-activated receptors (PPARs) are members of the nuclear receptor family of ligand activated transcription factors and consist of the three isoforms, PPAR, PPAR/ and PPAR. Considerable evidence has established the importance of PPARs in myocardial lipid homeostasis and car

  17. The activation of peroxisome proliferator-activated receptor γ is regulated by Krüppel-like transcription factors 6 & 9 under steatotic conditions

    Energy Technology Data Exchange (ETDEWEB)

    Escalona-Nandez, Ivonne; Guerrero-Escalera, Dafne; Estanes-Hernández, Alma [Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15 Sección XVI, Tlalpan, 14000, México, D.F. (Mexico); Ortíz-Ortega, Victor; Tovar, Armando R. [Departamento de Fisiología de la Nutrición, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15 Sección XVI, Tlalpan, 14000, México, D.F. (Mexico); Pérez-Monter, Carlos, E-mail: carlos.perezm@incmnsz.mx [Departamento de Gastroenterología, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Vasco de Quiroga 15 Sección XVI, Tlalpan, 14000, México, D.F. (Mexico)

    2015-03-20

    Liver steatosis is characterised by lipid droplet deposition in hepatocytes that can leads to an inflammatory and fibrotic phenotype. Peroxisome proliferator-activated receptors (PPARs) play key roles in energetic homeostasis by regulating lipid metabolism in hepatic tissue. In adipose tissue PPARγ regulates the adipocyte differentiation by promoting the expression of lipid-associated genes. Within the liver PPARγ is up-regulated under steatotic conditions; however, which transcription factors participate in its expression is not completely understood. Krüppel-like transcription factors (KLFs) regulate various cellular mechanisms, such as cell proliferation and differentiation. KLFs are key components of adipogenesis by regulating the expression of PPARγ and other proteins such as the C-terminal enhancer binding protein (C/EBP). Here, we demonstrate that the transcript levels of Klf6, Klf9 and Pparγ are increased in response to a steatotic insult in vitro. Chromatin immunoprecipitation (ChIp) experiments showed that klf6 and klf9 are actively recruited to the Pparγ promoter region under these conditions. Accordingly, the loss-of-function experiments reduced cytoplasmic triglyceride accumulation. Here, we demonstrated that KLF6 and KLF9 proteins directly regulate PPARγ expression under steatotic conditions. - Highlights: • Palmitic acid promotes expression of KlF6 & KLF9 in HepG2 cells. • KLF6 and KLF9 promote the expression of PPARγ in response to palmitic acid. • Binding of KLF6 and KLF9 to the PPARγ promoter promotes steatosis in HepG2 cells. • KLF6 and KLF9 loss-of function diminishes the steatosis in HepG2 cells.

  18. Fish condition factor, peroxisome proliferator activated receptors and biotransformation responses in Sarotherodon melanotheron from a contaminated freshwater dam (Awba Dam) in Ibadan, Nigeria.

    Science.gov (United States)

    Adeogun, Aina O; Ibor, Oju R; Onoja, Anyebe B; Arukwe, Augustine

    2016-10-01

    The relationship between condition factor (CF), peroxisome proliferator-activated receptors (PPARs), phase 1 biotransformation (CYP1A isoforms) and contaminant burden has been studied in Sarotherodon melanotheron from a contaminated tropical freshwater dam (Awba Dam) and compared to a reference site (Modete Dam) in Southwest, Nigeria. A total of 89 fish (57 males and 32 females) was collected from Awba Dam and 95 fish (48 males and 47 females) from the reference site. In general, fish sampled from Awba Dam were bigger than reference site. Sediment samples were also collected from both sites for contaminant analysis. Expression of ppar and cyp1 isoforms was analyzed using validated real-time PCR, while CYP1A and PPAR protein levels were analyzed using immunochemical method with specific antibodies. CYP-mediated catalytic responses (EROD, MROD and BROD) were performed by biochemical methods. We observed significant increases in ppar and cyp1 isoforms mRNA in both male and female fish from Awba Dam, compared to the reference site. Catalytic activities of EROD, MROD and BROD paralleled cyp1 transcript levels. Sex-related differences in PPAR and CYP1A protein levels were also observed, showing higher CYP1A proteins in males, compared with females, and higher PPAR proteins in females compared with males. Principal component analysis (PCA) biplot showed positive relationships between biological responses (ppar isoforms), condition factor (CF) and sediment PCBs, PAHs, OCPs and heavy metal concentrations. The present study shows that S. melanotheron inhabiting Awba Dam are severely affected by different classes of environmental contaminants that target metabolic processes (PPAR) and biotransformation pathways (CYP1A) in male and female fish, compared to a reference site. Interestingly, fish from Awba Dam were exhibiting good growth (evidence by high CF values) that paralleled increases in the transcriptional activation of ppar and cyp1 isoforms, despite the high

  19. Association of peroxisome proliferator-activated receptorγ gene Pro12Ala and C161T polymorphisms with cardiovascular risk factors in maintenance hemodialysis patients.

    Science.gov (United States)

    Liu, Feng; Mei, Xiaobin; Zhang, Yingying; Qi, Hualin; Wang, Jun; Wang, Yi; Jiang, Wei; Zhang, Xintian; Yan, Haidong; Zhuang, Shougang

    2014-11-01

    The Pro12Ala and C161T polymorphisms in peroxisome proliferator-activated receptor γ (PPARγ) have been shown to be associated with carotid artery atherosclerosis. It remains unclear whether these two polymorphisms are associated with risk factors for cardiovascular disease (CVD) in hemodialysis (HD) patients. Therefore, the PPARγ genotypes in 99 HD patients and 149 controls were determined, and clinical characteristics among the different genotypes were compared. We found that the frequency of the Pro12Ala and C161T polymorphisms in HD patients was similar to that in healthy controls, but C161T polymorphism and T allele frequencies in HD patients with CVD were lower than that in HD patients without CVD. Carotid artery plaque (CAP) and carotid intima-media thickness (CIMT) in HD patients with CT + TT or Pro12Ala genotypes were also less than that in patients with CCor Pro12Pro genotypes, respectively. HD patients with CT + TT genotype had lower serum C reactive protein (CRP) levels, as well as higher triceps skin fold (TSF) thickness, mid arm circumference (MAC) and mean mid arm circumference (MMAC) than HD patients with CC genotype (P Pro12Ala-CT161 subgroup was less than the Pro12Pro-CC161 and Pro12Pro-CT161 subgroup, and, CAP amounts of the Pro12Ala-CT161 subgroup was less than the Pro12Pro-CC161 subgroup. Our results indicate that the Pro12Ala and C161T polymorphisms were associated with some important risk factors for CVD in HD patients in the Han Chinese population.

  20. Peroxisome proliferator-activated receptor-gamma Pro12Ala polymorphism could be a risk factor for gastric cancer.

    Science.gov (United States)

    Zhao, Jing; Zhi, Zheng; Song, Guangyao; Wang, Juan; Wang, Chao; Ma, Huijuan; Yu, Xian; Sui, Aixia; Zhang, Hongtao

    2015-01-01

    Due to the strong inhibitory effects of PPARγ gene on the growth of cancer cells, the role of Pro12Ala polymorphism in PPARγ gene has been extensively investigated in cancer recently. However, the results were inconsistent according to cancer type. The aim of this study was to comprehensively evaluate the PPARγ Pro12Ala polymorphism and gastric cancer susceptibility. Search strategies were conducted in Pubmed, Medline (Ovid), Chinese biomedical database (CBM), China national knowledge infrastructure (CNKI), VIP, and Wanfang database, covering all publications, with the last search up to November 01, 2014. The strength of association between PPARγ Pro12Ala polymorphism and gastric cancer risk was assessed by OR with 95%CI. A total of 546 cases and 827 controls in 5 case-control studies were included in this meta-analysis. The results indicated that the variant G allele carriers (CG+GG) had a 2.31 times higher risk for gastric cancer when compared with the homozygote CC (odds ratio (OR)=2.31, 95% confidence interval (CI)=1.67- 3.21 for CG+GG vs. CC). In the subgroup analysis by ethnicity, significantly elevated risks were both found in Asians (OR=2.56, 95% CI=1.42-4.64) and Caucasians (OR=2.20, 95% CI=1.48-3.25). Similarly, in the subgroup analysis by H. pylori status, a significantly increased risk was identified in H. pylori (+) populations (OR=3.68, 95%CI=2.07-6.52), but not in H. pylori(-) populations (OR=1.17, 95%CI=0.58-2.39). This pooled analysis suggested that the PPARγ Pro12Ala polymorphism could be an independent predictive risk factor for gastric cancer especially in H. pylori infected populations in Asians and Caucasians. Nevertheless, prospectively designed cohort studies are needed to further investigate gene-gene and gene-environment interactions to confirm the combined effects of PPARγ Pro12Ala polymorphisms and H. pylori infection on gastric cancer risk.

  1. Tenascin-x facilitates myocardial fibrosis and cardiac remodeling through transforming growth factor-β1 and peroxisome proliferator-activated receptor γ in alcoholic cardiomyopathy

    Institute of Scientific and Technical Information of China (English)

    JING Ling; ZHOU Li-jun; ZHANG Feng-min; LI Wei-min; SANG Ying

    2011-01-01

    Background Tenascin-x, an extracellular matrix glycoprotein exclusively expressed in fibroblasts, can mediate fibrosis in the presence of collagen. Therefore, we have investigated its potential role in facilitating myocardial fibrosis and cardiac remodeling via the transforming growth factor-lβ1 and peroxisome proliferator-activated receptor γ(TGFβ1-PPARγ) pathway in alcoholic cardiomyopathy (ACM).Methods Experimental animals were divided into control (group A) and tenascin-x knock-out groups (group B)receiving alcohol. Six months post treatment, cardiac ejections fraction (EF), fractional shortening (FS), left ventricle end-diastole internal diameter (LVEDd) and collagen column fraction (CVF) were observed. Tenascin-x, smad-3, TGFβ1,smad-7 and PPARγ protein expression levels were detected by Western blotting.Results Six months post treatment, EF and FS values were higher in group B than in group A (P <0.05 and P <0.01,respectively), while LVEDd and CVF were lower in group B (P <0.05 and P <0.01, respectively). Tenascin-x, smad-3 and TGFβ1 protein expression levels were higher in group A, while smad-7 and PPARY levels were lower than in group B (P<0.01), as measured by immunohistochemistry and Western blotting. Tenascin-x protein expression was negatively correlated with EF, FS, smad-7 and PPARγ, and positively correlated with LVEDd, CVF, smad-3, and TGFβ1 (P <0.001).Conclusion Tenascin-x is an initiator of myocardial fibrosis and ACM development via upregulation of TGFβ1 and downregulation of PPARγ.

  2. Molecular characterisation of tumour necrosis factor alpha and its potential connection with lipoprotein lipase and peroxisome proliferator-activated receptors in blunt snout bream (Megalobrama amblycephala).

    Science.gov (United States)

    Zhou, Man; Mi, Hai-Feng; Liu, Wen-Bin; Wu, Ye-Yang; Wang, Kai-Zhou; Jiang, Guang-Zhen

    2017-08-01

    Tumour necrosis factor alpha (TNF-α) is one kind of cytokines which is related to inflammation and lipid metabolism. TNF-α cDNA was cloned from the liver of blunt snout bream (Megalobrama amblycephala) through real-time polymerase chain reaction (PCR) and rapid amplification of cDNA ends (RACE) methods. The full-length cDNA of TNF-α covered 1467 bp, with an open reading frame (ORF) of 723 bp, which encodes 240 amino acids. It possessed the TNF family signature IIIPDDGIYFVYSQ. After the lipopolysaccharide (LPS) challenge test, a graded tissue-specific expression pattern of TNF-α was observed and there was high expression abundance in the kidney, brain and liver. After 8 weeks feeding trial, liver samples, two groups fed with 6% and 11% lipid levels, were collected. The results showed that, for fish fed with high-fat diet, the triglyceride of serum and lipid content of liver were elevated. Furthermore, TNF-α and peroxisome proliferator-activated receptors (PPARα, β) mRNA expression of fish fed 11% lipid diet were significantly up-regulated (p PPARγ mRNA expression of fish fed 11% lipid lever diet were significantly decreased compared to those of fish fed 6% (p < 0.05). The differences between the various expression of related genes in the high and low fat groups demonstrated that TNF-α played a key role in lipid metabolism, which may have an influence on fat metabolism through reducing fat synthesis and strengthening the β-oxidation of fatty acid. These discrepancies warrant further research.

  3. Peroxisome proliferator-activated receptors and biotransformation responses in relation to condition factor and contaminant burden in tilapia species from Ogun River, Nigeria.

    Science.gov (United States)

    Adeogun, Aina O; Ibor, Oju R; Regoli, Francesco; Arukwe, Augustine

    2016-01-01

    A major development in fishery science has been the Fulton's condition factor (CF) as a reliable physiological index of fish growth and health status (Fulton 1902). As a general rule, CF-value greater than 1 (>1) should be regarded as an indicator for good growth and health. Therefore, exposure of fish to contaminants in the environment will be expected to produce a reduction in scope for growth, since energy for growth will be allocated to overcome stressful conditions. In the present study, we hypothesized that tilapia species from Ogun River (Nigeria) are experiencing severe contaminant-induced obesogen effects leading to high CF (≥ 2) in fish with pathological alterations. The environmental obesogen hypothesis has related the interaction between environmental pollutants and PPAR isoform activation In this respect, peroxisome proliferator-activated receptors (PPARs) and biotransformation responses in relation to contaminant burden were investigated in a total of 1074 specimens of Tilapias species (Tilapia guineensis, Sarotherodon galileaus and Oreochromis niloticus) collected from three areas with different degrees of anthropogenic contamination and from a putative control site along the Ogun River. Liver mRNA expression of cytochrome cyp1 isoforms (cyp1a, 1b and 1c) and PPAR isoforms (ppar-α, β and γ) were analyzed using validated real-time PCR. Fish were also analyzed for CF and muscle contaminant burden (aliphatic and polycyclic aromatic hydrocarbons, organochlorine pesticides, and polychlorinated biphenyls). A significant increase in mRNA expression of cyp1- and ppar isoforms was observed in fish from polluted areas, and these results paralleled data on PCBs and PAHs tissue concentrations. Further, cyp1 isoforms showed clear sex-related differences, with higher mRNA expression in male fish than in females. Principal component analysis revealed a relationship between cyp1 isoforms, ppar-α, β, PCBs and PAHs and these interactions may suggest a crosstalk

  4. Blocking the peroxisome proliferator-activated receptor (PPAR): an overview.

    Science.gov (United States)

    Ammazzalorso, Alessandra; De Filippis, Barbara; Giampietro, Letizia; Amoroso, Rosa

    2013-10-01

    Peroxisome proliferator-activated receptors (PPARs) have been studied extensively over the last few decades and have been assessed as molecular targets for the development of drugs against metabolic disorders. A rapid increase in understanding of the physiology and pharmacology of these receptors has occurred, together with the identification of novel chemical structures that are able to activate the various PPAR subtypes. More recent evidence suggests that moderate activation of these receptors could be favorable in pathological situations due to a decrease in the side effects brought about by PPAR agonists. PPAR partial agonists and antagonists are interesting tools that are currently used to better elucidate the biological processes modulated by this family of nuclear receptors. Herein we present an overview of the various molecular structures that are able to block each of the PPAR subtypes, with a focus on promising therapeutic applications. Copyright © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

    OpenAIRE

    Fang Yan; Qi Wang; Chao Xu; Mingfeng Cao; Xiaoming Zhou; Tingting Wang; Chunxiao Yu; Fei Jing; Wenbin Chen; Ling Gao; Jiajun Zhao

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs ...

  6. [The role of peroxisome proliferator-activated receptor-γ/nuclear factor-ΚB transduction pathway on coagulation disorders induced by sepsis].

    Science.gov (United States)

    Sun, Yizhu; Wang, Jing; Yu, Luxin; Dai, Lin

    2015-06-01

    To determine the role of activated status of peroxisome proliferator-activated receptorγ/nuclear factor-ΚB (PPAR-γ/NF-ΚB ) in coagulation disorders induced by sepsis. Forty male Sprague-Dawley (SD) rats were randomly divided into four groups, n=10 in each group: control group, lipopolysaccharide (LPS) challenged group, rosiglitazone (ROSI, selective agonist of PPAR-γ) pretreatment group, and GW9662 (PPAR-γ antagonist) pretreatment group. The sepsis model was reproduced by injection of 6 mg/kg LPS via sublingual vein, and the rats in control group were injected with 2 mL/kg normal saline. The rats in ROSI pretreatment group were given 0.3 mg/kg ROSI by sublingual venous injection followed by injection of LPS 30 minutes later; and in GW9662 pretreatment group rats were given 0.3 mg/kg GW9662 by sublingual venous injection followed by 0.3 mg/kg ROSI 15 minutes later, followed by injection of LPS 30 minutes later. Blood was collected at 4 hours after LPS administration, and the expressions of PPAR-γ and NF-ΚBp65 in peripheral blood mononuclear cell (PBMC) were determined with immunocytocheminal technique and graph analysis. Plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and D-dimer were determined simultaneously. (1) PPAR-γ/NF-ΚB pathway: the expressions of PPAR-γ and NF-ΚBp65 were lowered in control group, and they were expressed in cytoplasm. In LPS challenged group the expression of PPAR-γ (gray value) was slightly increased but with no significant difference as compared with control group (111.01±4.06 vs. 98.46±5.99, P>0.05). In ROSI pretreatment group the expression of PPAR-γ (gray value) was significantly higher than that in LPS challenged group (214.38±5.79 vs. 111.01±4.06, P0.05). In LPS challenged group the expression of NF-ΚBp65 (gray value) was significantly higher than that in control group (249.48±6.86 vs. 105.81±10.19, P0.05). (2) Coagulation: compared with control group, PT and APTT were

  7. Role of Peroxisome Proliferator-Activated Receptors in Inflammation Control

    Directory of Open Access Journals (Sweden)

    Jihan Youssef

    2004-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs were discovered over a decade ago, and were classified as orphan members of the nuclear receptor superfamily. To date, three PPAR subtypes have been discovered and characterized (PPARα, β/δ, γ. Different PPAR subtypes have been shown to play crucial roles in important diseases and conditions such as obesity, diabetes, atherosclerosis, cancer, and fertility. Among the most studied roles of PPARs is their involvement in inflammatory processes. Numerous studies have revealed that agonists of PPARα and PPARγ exert anti-inflammatory effects both in vitro and in vivo. Using the carrageenan-induced paw edema model of inflammation, a recent study in our laboratories showed that these agonists hinder the initiation phase, but not the late phase of the inflammatory process. Furthermore, in the same experimental model, we recently also observed that activation of PPARδ exerted an anti-inflammatory effect. Despite the fact that exclusive dependence of these effects on PPARs has been questioned, the bulk of evidence suggests that all three PPAR subtypes, PPARα,δ,γ, play a significant role in controlling inflammatory responses. Whether these subtypes act via a common mechanism or are independent of each other remains to be elucidated. However, due to the intensity of research efforts in this area, it is anticipated that these efforts will result in the development of PPAR ligands as therapeutic agents for the treatment of inflammatory diseases.

  8. Effects related to gene-gene interactions of peroxisome proliferator-activated receptor on essential hypertension

    Institute of Scientific and Technical Information of China (English)

    俞浩

    2013-01-01

    Objective To explore the impact of the gene-gene interaction among the single nucleotide polymorphisms(SNPs) of peroxisome proliferator-activated receptorα/δ/γ on essential hypertension(EH).Methods

  9. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors

    Science.gov (United States)

    Lu, Changxue; Cheng, Sheue-Yann

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis. PMID:19741045

  10. Immunohistochemical characterization of peroxisome proliferator-activated receptors in canine normal testis and testicular tumours.

    Science.gov (United States)

    Sozmen, M; Kabak, Y B; Gulbahar, M Y; Gacar, A; Karayigit, M O; Guvenc, T; Yarim, M

    2013-07-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Recent studies have demonstrated that PPARs regulate lipid metabolism and are expressed in various cancers. The aim of the present study was to investigate the expression of PPAR-α, -β and -γ in normal canine testicular tissue and canine testicular tumours (CTTs). Expression of PPAR-α, -β and -γ was greater (P PPARs were therefore induced in CTTs and they may play a role in the biology of these tumours. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. The role of peroxisome proliferator-activated receptors in carcinogenesis and chemoprevention.

    Science.gov (United States)

    Peters, Jeffrey M; Shah, Yatrik M; Gonzalez, Frank J

    2012-02-09

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that are involved in regulating glucose and lipid homeostasis, inflammation, proliferation and differentiation. Although all of these functions might contribute to the influence of PPARs in carcinogenesis, there is a distinct need for a review of the literature and additional experimentation to determine the potential for targeting PPARs for cancer therapy and cancer chemoprevention. As PPAR agonists include drugs that are used for the treatment of metabolic diseases, a more complete understanding of the roles of PPARs in cancer will aid in determining any increased cancer risk for patients undergoing therapy with PPAR agonists.

  12. Thyroid hormone receptors regulate adipogenesis and carcinogenesis via crosstalk signaling with peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Lu, Changxue; Cheng, Sheue-Yann

    2010-03-01

    Peroxisome proliferator-activated receptors (PPARs) and thyroid hormone receptors (TRs) are members of the nuclear receptor superfamily. They are ligand-dependent transcription factors that interact with their cognate hormone response elements in the promoters to regulate respective target gene expression to modulate cellular functions. While the transcription activity of each is regulated by their respective ligands, recent studies indicate that via multiple mechanisms PPARs and TRs crosstalk to affect diverse biological functions. Here, we review recent advances in the understanding of the molecular mechanisms and biological impact of crosstalk between these two important nuclear receptors, focusing on their roles in adipogenesis and carcinogenesis.

  13. Peroxisome Proliferator-Activated Receptor : Mediates the Effects of High-Fat Diet on Hepatic Gene Expression

    NARCIS (Netherlands)

    Patsouris, D.A.; Reddy, J.K.; Müller, M.R.; Kersten, A.H.

    2006-01-01

    Peroxisome proliferator-activated receptors (PPARs) are transcription factors involved in the regulation of numerous metabolic processes. The PPAR isotype is abundant in liver and activated by fasting. However, it is not very clear what other nutritional conditions activate PPAR. To examine whether

  14. Peroxisome Proliferator-Activated Receptor ß/ (PPARß/) but Not PPAR Serves as a Plasma Free Fatty Acid Sensor in Liver

    NARCIS (Netherlands)

    Sanderson, L.; Degerhardt, T.; Desvergne, B.; Koppen, A.; Kalkhoven, E.; Müller, M.R.; Kersten, A.H.

    2009-01-01

    Peroxisome proliferator-activated receptor alpha (PPAR alpha) is an important transcription factor in liver that can be activated physiologically by fasting or pharmacologically by using high-affinity synthetic agonists. Here we initially set out to elucidate the similarities in gene induction

  15. Molecular Mechanism of Peroxisome Proliferator-Activated Receptor alpha Activation by WY14643: a New Mode of Ligand Recognition and Receptor Stabilization

    NARCIS (Netherlands)

    Bernardes, Amanda; Telles de Souza, Paulo C; Muniz, João R C; Ricci, Clarisse G; Ayers, Stephen D; Parekh, Nili M; Godoy, André S; Trivella, Daniela B B; Reinach, Peter; Webb, Paul; Skaf, Munir S; Polikarpov, Igor

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of a superfamily of nuclear transcription factors. They are involved in mediating numerous physiological effects in humans, including glucose and lipid metabolism. PPAR alpha ligands effectively treat dyslipidemia and have significant

  16. Pro12Ala gene polymorphism in the peroxisome proliferator-activated receptor gamma as a risk factor for the onset of type 2 diabetes mellitus in the Serbian population

    Directory of Open Access Journals (Sweden)

    Šoškić Sanja

    2010-01-01

    Full Text Available The peroxisome proliferator-activated receptor gamma (PPARγ is a gene candidate for the onset of type 2 diabetes mellitus (T2DM. We investigated the association of the PPARγ Pro12Ala gene with the onset of T2DM for the first time in the Serbian population. The study population consisted of 197 controls and 163 T2DM patients. The 12Ala allele tended to be more frequent in the group of T2DM patients (0.11 compared to the control subjects (0.09. The results from this study indicate that the PPARγ2 12Ala allele presents a non-significant risk factor for T2DM development in the Serbian population.

  17. Energy-sensing Factors Coactivator Peroxisome Proliferator-activated Receptor gamma Coactivator 1-alpha (PGC-1 alpha) and AMP-activated Protein Kinase Control Expression of Inflammatory Mediators in Liver INDUCTION OF INTERLEUKIN 1 RECEPTOR ANTAGONIST

    NARCIS (Netherlands)

    Buler, M.; Aatsinki, S.M.; Skoumal, R.; Komka, Z.; Toth, M.; Kerkela, R.; Georgiadi, A.; Kersten, A.H.; Hakkola, J.

    2012-01-01

    Obesity and insulin resistance are associated with chronic, low grade inflammation. Moreover, regulation of energy metabolism and immunity are highly integrated. We hypothesized that energy-sensitive coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 alpha) and A

  18. Role of peroxisome proliferator-activated receptors gene polymorphisms in type 2 diabetes and metabolic syndrome.

    Science.gov (United States)

    Dong, Chen; Zhou, Hui; Shen, Chong; Yu, Lu-Gang; Ding, Yi; Zhang, Yong-Hong; Guo, Zhi-Rong

    2015-05-15

    Metabolic syndrome (MetS) and type 2 diabetes mellitus (T2DM) are the serious public health problems worldwide. Moreover, it is estimated that MetS patients have about five-fold greater risk of the T2DM development compared with people without the syndrome. Peroxisome proliferator-activated receptors are a subgroup of the nuclear hormone receptor superfamily of ligand-activated transcription factors which play an important role in the pathogenesis of MetS and T2DM. All three members of the peroxisome proliferator-activated receptor (PPAR) nuclear receptor subfamily, PPARα, PPARβ/δ and PPARγ are critical in regulating insulin sensitivity, adipogenesis, lipid metabolism, and blood pressure. Recently, more and more studies indicated that the gene polymorphism of PPARs, such as Leu(162)Val and Val(227)Ala of PPARα, +294T > C of PPARβ/δ, Pro(12)Ala and C1431T of PPARγ, are significantly associated with the onset and progressing of MetS and T2DM in different population worldwide. Furthermore, a large body of evidence demonstrated that the glucose metabolism and lipid metabolism were influenced by gene-gene interaction among PPARs genes. However, given the complexity pathogenesis of metabolic disease, it is unlikely that genetic variation of a single locus would provide an adequate explanation of inter-individual differences which results in diverse clinical syndromes. Thus, gene-gene interactions and gene-environment interactions associated with T2DM and MetS need future comprehensive studies.

  19. Peroxisome proliferator-activated receptor gamma in bladder cancer: a promising therapeutic target.

    Science.gov (United States)

    Mansure, Jose J; Nassim, Roland; Kassouf, Wassim

    2009-04-01

    Peroxisome Proliferator-Activated Receptors (PPARs) are ligand-activated intracellular transcription factors, members of the nuclear hormone receptor superfamily. The PPAR subfamily consist of three subtypes encoded by distinct genes denoted PPARalpha, PPARbeta/delta, and PPARgamma. The peroxisome proliferator-activated receptor gamma (PPARgamma) is the most extensively studied subtype of the PPARs. Over the last decade, research on PPARgamma unveiled its role in important biological processes, including lipid biosynthesis, glucose metabolism, anti-inflammatory response, and atherosclerosis. Recently, PPARgamma has been shown to be expressed in many cancers including, lung, prostate, bladder, colon, breast, duodenal, thyroid, and has been demonstrated to potentially play an important role in carcinogenesis. In bladder cancer, PPARgamma ligands such as troglitazone and 15d-PGJ2 have shown to inhibit tumor growth. We have recently published the first report to show that a new class of PPARgamma agonists, PPARgamma-active C-DIMs, which are more potent than the previous generation of drugs, exhibit anti-tumorigenic activity against bladder cancer cells in vitro and bladder tumors in vivo. The following review will discuss the molecular structure of PPARgamma, its function and its role in cancer biology and how it is emerging as a promising therapeutic target in bladder cancer.

  20. Peroxisome Proliferator-Activated Receptor (PPAR): Balance for Survival in Parasitic Infections

    Science.gov (United States)

    Chan, Marion M.; Evans, Kyle W.; Moore, Andrea R.; Fong, Dunne

    2010-01-01

    Parasitic infections induce a magnitude of host responses. At the opposite ends of the spectrum are those that ensure the host's needs to eliminate the invaders and to minimize damage to its own tissues. This review analyzes how parasites would manipulate immunity by activating the immunosuppressive nuclear factor, peroxisome proliferator-activated receptors (PPARs) with type 2 cytokines and free fatty acids from arachidonic acid metabolism. PPARs limit the action of type 1 immunity, in which classically activated macrophages act through the production of proinflammatory signals, to spare the parasites. They also favor the development of alternately activated macrophages which control inflammation so the host would not be destroyed. Possibly, the nuclear factors hold a pivotal role in the establishment of chronic infection by delicately balancing the pro- and anti-inflammatory signaling mechanisms and their ligands may be used as combination therapeutics to limit host pathology. PMID:20169106

  1. Ligands and Regulatory Modes of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Avians.

    Science.gov (United States)

    Navidshad, Bahman; Royan, M

    2015-01-01

    Nutrient and gene interaction is an important aspect of poultry metabolism that determines performance capacity. New technological tools in biochemistry and biotechnology make it possible to explore the molecular base of phenotypic characteristics of poultry production. Fats act as energy deposits in the poultry body and are an essential constituent of animal cell membranes. From a functional standpoint, it has been suggested that ingested lipids change liver fatty acid synthesis and other lipogenic enzymes by regulating mRNA synthesis. Nuclear hormone receptors are ligand-activated transcription factors that control several genes involved in lipid metabolism. The peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors. Three separate PPAR genes have been identified; they are known as α, δ, and γ. The most important metabolic effect of PPARγ in chicken is its task in adipogenesis. Reviewing the ligands of chicken PPARγ gene can be useful to a better understanding of PPARγ regulatory functions.

  2. Telmisartan attenuates peritoneal fibrosis via peroxisome proliferator-activated receptor-γ activation in rats.

    Science.gov (United States)

    Su, Xuesong; Yu, Rui; Yang, Xu; Zhou, Guangyu; Wang, Yanqiu; Li, Li; Li, Detian

    2015-06-01

    Peritoneal dialysis (PD) is an effective treatment for patients with end-stage renal diseases, but long-term continuous PD causes peritoneal fibrosis (PF). This study aims to evaluate the anti-fibrotic effect of telmisartan on a rat model of PF and to investigate the underlying mechanisms. Five-sixths kidney nephrectomy and PD were used to establish the PF rat model. Glucose (2.5%) was used to establish an in vitro model in rat peritoneal mesothelial cells (PMC). Haematoxylin-eosin staining was used to examine the structural alterations. Masson's trichrome staining was used to observe the tissue fibrosis in peritoneal membrane of rats. Real-time polymerase chain reaction was used to measure messenger RNA expressions of profibrotic factors. Western blotting was used to determine protein expressions of profibrotic factors, peroxisome proliferator-activated receptor-γ, and mitogen-activated protein kinases (MAPK). Results demonstrated that administration of telmisartan dose-dependently attenuated the thickening of the peritoneal membrane and the fibrosis induced by long-term PD fluid exposure in rats. In addition, telmisartan treatment inhibited the upregulation of profibrotic factors induced by PD in the peritoneum of rats and by high-concentration glucose in PMC. Telmisartan was also effective in inhibiting PD and high-concentration, glucose-induced phosphorylation of MAPK in the peritoneum and PMC. Furthermore, peroxisome proliferator-activated receptor-γ (PPARγ) inhibitor GW9662 blocked these protective effects of telmisartan in PMC. The results suggest that telmisartan is effective in attenuating PD-induced PF, and this effect may be associated with the inhibition of profibrotic factor expression and MAPK phosphorylation via PPARγ activation. © 2015 Wiley Publishing Asia Pty Ltd.

  3. The role and regulation of the peroxisome proliferator activated receptor alpha in human liver.

    Science.gov (United States)

    Kersten, Sander; Stienstra, Rinke

    2017-05-01

    The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that is abundantly expressed in liver. PPARα is activated by fatty acids and various other lipid species, as well as by a class of chemicals referred to as peroxisome proliferators. Studies in mice have shown that PPARα serves as the master regulator of hepatic lipid metabolism during fasting. In addition, PPARα suppresses inflammation and the acute phase response. Comparatively little is known about PPARα in human liver. Here, an overview is provided of the role and regulation of PPARα in human liver. The main outcomes are: 1) the level of PPARA mRNA expression in human and mouse liver is similar. 2) Expression of PPARA in human liver is reduced in patients with non-alcoholic steatohepatitis or infected with the hepatitis C virus. 3) PPARα in human liver is able to effectively induce the expression of numerous genes involved in numerous lipid metabolic pathways, including microsomal, peroxisomal and mitochondrial fatty acid oxidation, fatty acid binding and activation, fatty acid elongation and desaturation, synthesis and breakdown of triglycerides and lipid droplets, lipoprotein metabolism, gluconeogenesis, bile acid metabolism, and various other metabolic pathways and genes. 4) PPARα activation in human liver causes the down-regulation of a large number of genes involved in various immunity-related pathways. 5) Peroxisome proliferators do not promote tumour formation in human liver as opposed to mouse liver because of structural and functional differences between human and mouse PPARα. 6) In addition to helping to correct dyslipidemia, PPARα agonists may hold promise as a therapy for patients with cholestatic liver diseases, non-alcoholic fatty liver disease, and/or type 2 diabetes. Copyright © 2017 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

  4. Peroxisome Proliferator-Activated Receptor Modulation during Metabolic Diseases and Cancers: Master and Minions

    Science.gov (United States)

    Nigro, Angela; La Rosa, Valentina Lucia; Rossetti, Paola; Rapisarda, Agnese Maria Chiara; Condorelli, Rosita Angela; Corrado, Francesco; Buscema, Massimo

    2016-01-01

    The prevalence of obesity and metabolic diseases (such as type 2 diabetes mellitus, dyslipidaemia, and cardiovascular diseases) has increased in the last decade, in both industrialized and developing countries. This also coincided with our observation of a similar increase in the prevalence of cancers. The aetiology of these diseases is very complex and involves genetic, nutritional, and environmental factors. Much evidence indicates the central role undertaken by peroxisome proliferator-activated receptors (PPARs) in the development of these disorders. Due to the fact that their ligands could become crucial in future target-therapies, PPARs have therefore become the focal point of much research. Based on this evidence, this narrative review was written with the purpose of outlining the effects of PPARs, their actions, and their prospective uses in metabolic diseases and cancers. PMID:28115924

  5. Peroxisome proliferator-activated receptors as molecular targets in relation to obesity and type 2 diabetes.

    Science.gov (United States)

    Seda, Ondørej; Sedová, Lucie

    2007-06-01

    The three isotypes of peroxisome proliferator-activated receptors (PPARs) are currently perceived as major regulatory nodes (or hubs) of metabolic pathway networks, linking most prevalent diseases including Type 2 diabetes, obesity, dyslipidemia and atherosclerosis. The integrative functions of PPARs are also reflected in their ecogenetic profile, when the variants underlying pharmacogenetic interactions were also shown to modulate the effect of lifestyle factors. Despite their extensive clinical use, there are many outstanding issues, especially concerning their safety. Critical pharmacogenomic assessment is warranted for the new potent ligands of multiple PPAR isoforms as many have displayed serious side-effects in a limited number of treated subjects. Nevertheless, the advent of genomic, transcriptomic and system biology-level approaches, integrating knowledge from model systems and human biology, should greatly facilitate the transition to individualized PPAR-based therapies.

  6. The peroxisome proliferator-activated receptor: A family of nuclear receptors role in various diseases

    Directory of Open Access Journals (Sweden)

    Sandeep Tyagi

    2011-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ causes insulin sensitization and enhances glucose metabolism, whereas activation of PPAR- β/δ enhances fatty acids metabolism. Thus, PPAR family of nuclear receptors plays a major regulatory role in energy homeostasis and metabolic function. The present review critically analyzes the protective and detrimental effect of PPAR agonists in dyslipidemia, diabetes, adipocyte differentiation, inflammation, cancer, lung diseases, neurodegenerative disorders, fertility or reproduction, pain, and obesity.

  7. Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases

    Directory of Open Access Journals (Sweden)

    Su Zhang

    2015-01-01

    Full Text Available Peroxisome proliferator-activated receptor γ (PPAR γ, a member of the nuclear receptor superfamily, is a ligand-activated transcription factor that plays an important role in the control of a variety of physiological processes. The last decade has witnessed an increasing interest for the role played by the agonists of PPAR γ in antiangiogenesis, antifibrosis, anti-inflammation effects and in controlling oxidative stress response in various organs. As the pathologic mechanisms of major blinding diseases, such as age-related macular degeneration (AMD, diabetic retinopathy (DR, keratitis, and optic neuropathy, often involve neoangiogenesis and inflammation- and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR γ to improve or prevent these vision threatening eye diseases. In this paper we describe what is known about the role of PPAR γ in the ocular pathophysiological processes and PPAR γ agonists as novel adjuvants in the treatment of eye diseases.

  8. MicroRNAs and Peroxisome Proliferator-Activated Receptors Governing the Differentiation of Mesenchymal Stem Cells.

    Science.gov (United States)

    Huang, Chenglong; Gou, Shiran; Wang, Lei; Huang, Kui; Liu, Lin; Zhao, Wenjie; Zheng, Lige; Xiao, Jingang

    2016-01-01

    Mesenchymal stem cells (MSCs) have the self-renewal ability and the ability to produce multiple differentiation. Elucidating the genetic circuits that govern MSC self-renewal and differentiation is necessary to improve our comprehension of MSCs and their role in regenerative medicine. microRNAs (miRNAs) play important roles in the regulation of transcription, and are strongly linked with MSCs regarding the maintenance of pluripotency properties. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the nuclear hormonereceptor family. Interestingly, PPARs not only regulate glucose metabolism and lipidhomeostasis, but also contribute to cell proliferation, cell differentiation, and cell apoptosis. The aim of the present review was to provide an insight into the roles of miRNAs and PPARs in the differentiation of MSCs. Understanding the miRNA signature interactions in conjunction with the role of PPARs is critical for the development of improved strategies to regulate the differentiation of MSCs.

  9. Peroxisome proliferator-activated receptors modulate cardiac dysfunction in diabetic cardiomyopathy.

    Science.gov (United States)

    Lee, T-I; Kao, Y-H; Chen, Y-C; Huang, J-H; Hsiao, F-C; Chen, Y-J

    2013-06-01

    Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among patients with diabetes mellitus (DM). Chronic inflammation and derangement of myocardial energy and lipid homeostasis are common features of DM. The transcription factors of peroxisome proliferator-activated receptors (PPARs) belong to the nuclear receptor superfamily, which are important in regulating energy and lipid homeostasis. There are three PPAR isoforms, α, γ, and δ, and their roles have been increasingly recognized to be important in CVD. These three isoforms are expressed in the heart and play pivotal roles in myocardial lipid metabolism, as well as glucose and energy homeostasis, and contribute to extra metabolic roles with effects on inflammation and oxidative stress. Moreover, regulation of PPARs may have significant effects on cardiac electrical activity and arrhythmogenesis. This review describes the roles of PPARs and their agonists in DM cardiomyopathy, inflammation, and cardiac electrophysiology. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  10. Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions

    Science.gov (United States)

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear family of ligand activated transcriptional factors and comprise three different isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ. The main role of PPARs is to regulate the expression of genes involved in lipid and glucose metabolism. Several studies have demonstrated that PPAR agonists improve dyslipidemia and glucose control in animals, supporting their potential as a promising therapeutic option to treat diabetes and dyslipidemia. However, substantial differences exist in the therapeutic or adverse effects of specific drug candidates, and clinical studies have yielded inconsistent data on their cardioprotective effects. This review summarizes the current knowledge regarding the molecular function of PPARs and the mechanisms of the PPAR regulation by posttranslational modification in the heart. We also describe the results and lessons learned from important clinical trials on PPAR agonists and discuss the potential future directions for this class of drugs. PMID:26587015

  11. Healing the diabetic heart: modulation of cardiometabolic syndrome through peroxisome proliferator activated receptors (PPARs).

    Science.gov (United States)

    Huang, Tom Hsun-Wei; Roufogalis, Basil D

    2012-06-01

    Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen regarding the safety of the thiazolidinedione PPAR-γ agonist family as a whole. This review discusses the current concern with PPAR-γ agonists by exploring if PPARs can still be considered worth pursuing as a viable target for cardiovascular diseases. We examine current research focusing on identifying ligands that are dual and pan-PPAR agonists, selective PPAR-γ modulators, PPAR-β/δ agonists and that are of natural origin.

  12. Exercise reduces adipose tissue via cannabinoid receptor type 1 which is regulated by peroxisome proliferator-activated receptor-delta

    DEFF Research Database (Denmark)

    Yan, Zhen Cheng; Liu, Dao Yan; Zhang, Li Li

    2007-01-01

    Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...... or a high-fat diet without and with regular endurance exercise. Exercise in rats on high-fat diet significantly reduced visceral fat mass, blood pressure, and adipocyte size (each p......Obesity is one major cardiovascular risk factor. We tested effects of endurance exercise on cannabinoid receptor type 1 (CB1) and peroxisome proliferator-activated receptor-delta (PPAR-delta)-dependent pathways in adipose tissue. Male Wistar rats were randomly assigned to standard laboratory chow...

  13. Peroxisome proliferator-activated receptor delta activation leads to increased transintestinal cholesterol efflux

    NARCIS (Netherlands)

    Vrins, Carlos L. J.; van der Velde, Astrid E.; van den Oever, Karin; Levels, Johannes H. M.; Huet, Stephane; Elferink, Ronald P. J. Oude; Kuipers, Folkert; Groen, Albert K.

    2009-01-01

    Peroxisome proliferator-activated receptor delta (PPAR delta) is involved in regulation of energy homeostasis. Activation of PPAR delta markedly increases fecal neutral sterol secretion, the last step in reverse cholesterol transport. This phenomenon can neither be explained by increased hepatobilia

  14. Association of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathy

    NARCIS (Netherlands)

    Tariq, K.; Malik, S.B.; Ali, S.H.; Maqsood, S.E.; Azam, A.; Muslim, I.; Khan, M.S.; Azam, M.; Waheed, N.K.; Qamar, R.

    2013-01-01

    PURPOSE: The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to

  15. Inhibition of Nuclear Transcription Factor-κB and Activation of Peroxisome Proliferator-Activated Receptors in HepG2 Cells by Cucurbitane-Type Triterpene Glycosides from Momordica charantia

    Science.gov (United States)

    Nhiem, Nguyen Xuan; Yen, Pham Hai; Ngan, Nguyen Thi Thanh; Quang, Tran Hong; Kiem, Phan Van; Minh, Chau Van; Tai, Bui Huu; Cuong, Nguyen Xuan; Song, Seok Bean

    2012-01-01

    Abstract Momordica charantia: is used to treat various diseases, including inflammatory conditions. Previous reports indicated that the extract of this plant inhibits activation of nuclear transcription factor-κB (NF-κB) but activates peroxisome proliferator-activated receptor (PPAR). Additionally, cucurbitane-type triterpene glycosides are the main bioactive components of the fruit of M. charantia. Therefore, we investigated the anti-inflammatory activity of 17 cucurbitane-type triterpene glycosides (1–17) isolated from this plant. Their inhibition of NF-κB and activation of PPAR activities in HepG2 cells were measured using luciferase reporter and PPAR subtype transactivation assays. Compounds 6 and 8 were found to inhibit NF-κB activation stimulated by tumor necrosis factor-α (TNFα) in a dose-dependent manner. With 50% inhibition concentration (IC50) values of 0.4 μM, compounds 6 and 8 were more potent inhibitors than the positive control, sulfasalazine (IC50=0.9 μM). Compounds 4, 6, and 8 also inhibited TNFα-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 mRNA. However, only compound 13 significantly increased PPARγ transactivation. PMID:22248180

  16. Inhibition of nuclear transcription factor-κB and activation of peroxisome proliferator-activated receptors in HepG2 cells by cucurbitane-type triterpene glycosides from Momordica charantia.

    Science.gov (United States)

    Nhiem, Nguyen Xuan; Yen, Pham Hai; Ngan, Nguyen Thi Thanh; Quang, Tran Hong; Kiem, Phan Van; Minh, Chau Van; Tai, Bui Huu; Cuong, Nguyen Xuan; Song, Seok Bean; Kim, Young Ho

    2012-04-01

    Momordica charantia is used to treat various diseases, including inflammatory conditions. Previous reports indicated that the extract of this plant inhibits activation of nuclear transcription factor-κB (NF-κB) but activates peroxisome proliferator-activated receptor (PPAR). Additionally, cucurbitane-type triterpene glycosides are the main bioactive components of the fruit of M. charantia. Therefore, we investigated the anti-inflammatory activity of 17 cucurbitane-type triterpene glycosides (1-17) isolated from this plant. Their inhibition of NF-κB and activation of PPAR activities in HepG2 cells were measured using luciferase reporter and PPAR subtype transactivation assays. Compounds 6 and 8 were found to inhibit NF-κB activation stimulated by tumor necrosis factor-α (TNFα) in a dose-dependent manner. With 50% inhibition concentration (IC(50)) values of 0.4 μM, compounds 6 and 8 were more potent inhibitors than the positive control, sulfasalazine (IC(50)=0.9 μM). Compounds 4, 6, and 8 also inhibited TNFα-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 mRNA. However, only compound 13 significantly increased PPARγ transactivation.

  17. ChREBP Mediates Glucose Repression of Peroxisome Proliferator-activated Receptor {alpha} Expression in Pancreatic {beta}-Cells

    DEFF Research Database (Denmark)

    Boergesen, Michael; Poulsen, Lars la Cour; Schmidt, Søren Fisker;

    2011-01-01

    Chronic exposure to elevated levels of glucose and fatty acids leads to dysfunction of pancreatic β-cells by mechanisms that are only partly understood. The transcription factor peroxisome proliferator-activated receptor α (PPARα) is an important regulator of genes involved in fatty acid metaboli...... of glucose repression of PPARα gene expression in pancreatic β-cells, suggesting that ChREBP may be important for glucose suppression of the fatty acid oxidation capacity of β-cells....

  18. Haplotypes of the porcine peroxisome proliferator-activated receptor delta gene are associated with backfat thickness

    Directory of Open Access Journals (Sweden)

    Blöcker Helmut

    2009-11-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor delta belongs to the nuclear receptor superfamily of ligand-inducible transcription factors. It is a key regulator of lipid metabolism. The peroxisome proliferator-activated receptor delta gene (PPARD has been assigned to a region on porcine chromosome 7, which harbours a quantitative trait locus for backfat. Thus, PPARD is considered a functional and positional candidate gene for backfat thickness. The purpose of this study was to test this candidate gene hypothesis in a cross of breeds that were highly divergent in lipid deposition characteristics. Results Screening for genetic variation in porcine PPARD revealed only silent mutations. Nevertheless, significant associations between PPARD haplotypes and backfat thickness were observed in the F2 generation of the Mangalitsa × Piétrain cross as well as a commercial German Landrace population. Haplotype 5 is associated with increased backfat in F2 Mangalitsa × Piétrain pigs, whereas haplotype 4 is associated with lower backfat thickness in the German Landrace population. Haplotype 4 and 5 carry the same alleles at all but one SNP. Interestingly, the opposite effects of PPARD haplotypes 4 and 5 on backfat thickness are reflected by opposite effects of these two haplotypes on PPAR-δ mRNA levels. Haplotype 4 significantly increases PPAR-δ mRNA levels, whereas haplotype 5 decreases mRNA levels of PPAR-δ. Conclusion This study provides evidence for an association between PPARD and backfat thickness. The association is substantiated by mRNA quantification. Further studies are required to clarify, whether the observed associations are caused by PPARD or are the result of linkage disequilibrium with a causal variant in a neighbouring gene.

  19. Oxidative stress and inflammation modulate peroxisome proliferator-activated receptors with regional discrepancy in diabetic heart.

    Science.gov (United States)

    Lee, Ting-I; Kao, Yu-Hsun; Chen, Yao-Chang; Pan, Nan-Hung; Chen, Yi-Jen

    2010-08-01

    Peroxisome proliferator-activated receptors (PPARs) play a pivotal role in myocardial lipid and glucose homeostasis. We investigated the effects of diabetes on PPAR isoforms in different cardiac regions and explored whether proinflammatory cytokines or oxidative stress modulate PPARs in diabetic hearts. Male Wistar rats were separated into control, diabetes and ascorbate-treated diabetes groups. Real-time PCR and Western blot analysis were performed on PPAR isoforms, tumour necrosis factor (TNF)-alpha and interleukin (IL)-6, from left and right atria and ventricles. Nicotinamide adenine dinucleotide phosphate [NAD(P)H] oxidase activity was quantified through photometric measurements. In control hearts, PPAR-alpha was most expressed, and PPAR-gamma least expressed in mRNA and protein levels. Diabetes decreased the protein and mRNA levels of PPAR-alpha and PPAR-delta. Ascorbate attenuated the diabetes-induced down-regulations of PPAR-alpha and PPAR-delta proteins in all cardiac regions and down-regulation of PPAR-alpha mRNA in the left atrium. In PPAR-gamma, the protein and mRNA levels were increased in diabetic atria and ventricles, which were decreased by ascorbate. Moreover, diabetes increased the TNF-alpha and IL-6 protein levels, and NAD(P)H oxidase activities in atria and ventricles. Ascorbate attenuated the increase of TNF-alpha, IL-6 protein levels and NAD(P)H oxidase activity in the atria, but only attenuated the increase of NAD(P)H oxidase activities in the ventricles. Peroxisome proliferator-activated receptor isoforms are differentially expressed in the atria and ventricles. Diabetes can modulate PPARs through increased inflammatory cytokines and oxidative stress, which are attenuated by ascorbate treatment.

  20. Dietary and nutritional manipulation of the nuclear transcription factors peroxisome proliferator-activated receptor and sterol regulatory element-binding proteins as a tool for reversing the primary diseases of premature death and delaying aging.

    Science.gov (United States)

    Kurtak, Karen A

    2014-04-01

    Evolution over 2.1 billion years has equipped us with a biochemical pathway that has the power to literally reverse the primary disease etiologies that have become the leading causes of death and aging in the developed world. Activation of the peroxisome proliferator-activated receptor (PPAR) pathway arrests inflammatory signaling throughout the body, reverses damage to tissues, reverses insulin resistance, and can even dissolve beta-amyloid plaque in the brain. It has played a critical role in the evolution of the metazoans and the successful migration of humans to all corners of the Earth. For two decades, various pharmaceuticals have been designed to activate the PPAR pathway but have consistently fallen short of expectations. There is nothing wrong with these drugs. The problem has been the standard "healthy" diet creating mixed signals that render the drugs ineffective. This article explores the ongoing dance between the two primary nuclear receptors that mediate gene regulation of fatty acids. It discusses their interaction with sirtuins and telomerase, optimization of their obligate heterodimers, and why manipulation of dietary and nutritional factors, like the ketogenic diet, is the most effective means of activation. These are effective tools that we can start implementing now to slow, and in some cases reverse, the diseases of aging.

  1. Interaction between Calpain 5, Peroxisome proliferator-activated receptor-gamma and Peroxisome proliferator-activated receptor-delta genes: a polygenic approach to obesity

    Directory of Open Access Journals (Sweden)

    Ruiz Agustín

    2008-07-01

    Full Text Available Abstract Context Obesity is a multifactorial disorder, that is, a disease determined by the combined effect of genes and environment. In this context, polygenic approaches are needed. Objective To investigate the possibility of the existence of a crosstalk between the CALPAIN 10 homologue CALPAIN 5 and nuclear receptors of the peroxisome proliferator-activated receptors family. Design Cross-sectional, genetic association study and gene-gene interaction analysis. Subjects The study sample comprise 1953 individuals, 725 obese (defined as body mass index ≥ 30 and 1228 non obese subjects. Results In the monogenic analysis, only the peroxisome proliferator-activated receptor delta (PPARD gene was associated with obesity (OR = 1.43 [1.04–1.97], p = 0.027. In addition, we have found a significant interaction between CAPN5 and PPARD genes (p = 0.038 that reduces the risk for obesity in a 55%. Conclusion Our results suggest that CAPN5 and PPARD gene products may also interact in vivo.

  2. Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation

    DEFF Research Database (Denmark)

    Krogsdam, Anne-M; Nielsen, Curt A F; Neve, Søren

    2002-01-01

    delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well......The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains...

  3. Nuclear receptor corepressor-dependent repression of peroxisome-proliferator-activated receptor delta-mediated transactivation

    DEFF Research Database (Denmark)

    Krogsdam, Anne-M; Nielsen, Curt A F; Neve, Søren

    2002-01-01

    delta-RXR alpha heterodimer bound to an acyl-CoA oxidase (ACO)-type peroxisome-proliferator response element recruited a glutathione S-transferase-NCoR fusion protein in a ligand-independent manner. Contrasting with most other nuclear receptors, PPAR delta was found to interact equally well......The nuclear receptor corepressor (NCoR) was isolated as a peroxisome-proliferator-activated receptor (PPAR) delta interacting protein using the yeast two-hybrid system. NCoR interacted strongly with the ligand-binding domain of PPAR delta, whereas interactions with the ligand-binding domains...

  4. Association of the Genetic Polymorphisms in Transcription Factor 7-Like 2 and Peroxisome Proliferator-Activated Receptors-γ2 with Type 2 Diabetes Mellitus and Its Interaction with Obesity Status in Emirati Population

    Directory of Open Access Journals (Sweden)

    Habiba Al-Safar

    2015-01-01

    Full Text Available Background. Transcription factor 7-like 2 gene (TCF7L2 and peroxisome proliferator-activated receptors-γ2 (PPAR-γ2 have a profound effect on the incidence of type 2 diabetes mellitus (T2DM and had previously been found to be associated with T2DM risk in various ppopulations. However, studies in the Arab population are inconsistent. We conducted a case control study to confirm the association of variants rs10885409 of TCF7L2 and Pro12Ala (rs1801282 of PPAR-γ2 with risk of T2DM and related complications in Emirati population of Arab origin. We also investigated the interaction of these associations with obesity status. Methods. DNA was extracted from the saliva samples of 272 T2DM patients and 216 nondiabetic Emiratis. Genotyping for rs10885409 (TCF7L2 and rs1801282 (PPAR-γ2 P12A variants was accomplished with a TaqMan assay. The subgroups were constituted according to obesity status. Results. In the nonobese group, the rs10885409 C allele in the recessive model was significantly associated with the incidence of T2DM (OR 1.975 [95% CI 1.127–3.461], P=0.017, but this association was not observed in the obese group or when BMI was not considered. PPAR-γ2 risk allele Pro12 frequency (0.96 was similar in the groups tested and more than 90% population was homozygous for this allele. Conclusions. Our case-control study is the first of its kind in Emiratis which establishes TCF7L2 rs10885409 C allele as a T2DM risk factor in Emiratis and this association is modulated by obesity status. We also confirmed that Pro12Ala mutation in PPAR-γ2 is not associated with T2DM risk in this population.

  5. Peroxisome proliferator activated receptors at the crossroad of obesity, diabetes, and pancreatic cancer.

    Science.gov (United States)

    Polvani, Simone; Tarocchi, Mirko; Tempesti, Sara; Bencini, Lapo; Galli, Andrea

    2016-02-28

    Pancreatic ductal adenocarcinoma (PDAC) is the fourth cause of cancer death with an overall survival of 5% at five years. The development of PDAC is characteristically associated to the accumulation of distinctive genetic mutations and is preceded by the exposure to several risk factors. Epidemiology has demonstrated that PDAC risk factors may be non-modifiable risks (sex, age, presence of genetic mutations, ethnicity) and modifiable and co-morbidity factors related to the specific habits and lifestyle. Recently it has become evident that obesity and diabetes are two important modifiable risk factors for PDAC. Obesity and diabetes are complex systemic and intertwined diseases and, over the years, experimental evidence indicate that insulin-resistance, alteration of adipokines, especially leptin and adiponectin, oxidative stress and inflammation may play a role in PDAC. Peroxisome proliferator activated receptor-γ (PPARγ) is a nuclear receptor transcription factor that is implicated in the regulation of metabolism, differentiation and inflammation. PPARγ is a key regulator of adipocytes differentiation, regulates insulin and adipokines production and secretion, may modulate inflammation, and it is implicated in PDAC. PPARγ agonists are used in the treatment of diabetes and oxidative stress-associated diseases and have been evaluated for the treatment of PDAC. PPARγ is at the cross-road of diabetes, obesity, and PDAC and it is an interesting target to pharmacologically prevent PDAC in obese and diabetic patients.

  6. Increased peroxisome proliferator-activated receptor-gamma activity reduces imatinib uptake and efficacy in chronic myeloid leukemia mononuclear cells.

    Science.gov (United States)

    Wang, Jueqiong; Lu, Liu; Kok, Chung H; Saunders, Verity A; Goyne, Jarrad M; Dang, Phuong; Leclercq, Tamara M; Hughes, Timothy P; White, Deborah L

    2017-02-02

    Imatinib is actively transported by OCT-1 influx transporter, and low OCT-1 activity in diagnostic chronic myeloid leukemia blood mononuclear cells is significantly associated with poor molecular response to imatinib. Here we report that, in diagnostic chronic myeloid leukemia mononuclear cells and BCR-ABL1+ cell lines, peroxisome proliferator-activated receptor gamma agonists (GW1929, rosiglitazone, pioglitazone) significantly decrease OCT-1 activity; conversely, peroxisome proliferator-activated receptor gamma antagonists (GW9662, T0070907) increase OCT-1 activity. Importantly, these effects can lead to corresponding changes in sensitivity to Bcr-Abl kinase inhibition. Results were confirmed in peroxisome proliferator-activated receptor gamma-transduced K562 cells. Furthermore, we identified a strong negative correlation between OCT-1 activity and peroxisome proliferator-activated receptor gamma transcriptional activity in diagnostic chronic myeloid leukemia patients (n=84; preceptor gamma activation has a negative impact on the intracellular uptake of imatinib and consequent Bcr-Abl kinase inhibition. The inter-patient variability of peroxisome proliferator-activated receptor gamma activation likely accounts for the heterogeneity observed in patient OCT-1 activity at diagnosis. Recently, the peroxisome proliferator-activated receptor gamma agonist pioglitazone was reported to act synergistically with imatinib targeting the residual chronic myeloid leukemia stem cell pool. Our findings suggest that peroxisome proliferator-activated receptor gamma ligands have differential effects on circulating mononuclear cells compared to stem cells. Since the effect of peroxisome proliferator-activated receptor gamma activation on imatinib uptake in mononuclear cells may counteract the clinical benefit of this activation in stem cells, caution should be applied when combining these therapies, especially in patients with high peroxisome proliferator-activated receptor gamma

  7. Peroxisome Proliferator Activated Receptor A Ligands as Anticancer Drugs Targeting Mitochondrial Metabolism

    OpenAIRE

    Grabacka, Maja; Pierzchalska, Malgorzata; Reiss, Krzysztof

    2013-01-01

    Tumor cells show metabolic features distinctive from normal tissues, with characteristically enhanced aerobic glycolysis, glutaminolysis and lipid synthesis. Peroxisome proliferator activated receptor α (PPAR α) is activated by nutrients (fatty acids and their derivatives) and influences these metabolic pathways acting antagonistically to oncogenic Akt and c-Myc. Therefore PPAR α can be regarded as a candidate target molecule in supplementary anticancer pharmacotherapy as well as dietary ther...

  8. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma

    OpenAIRE

    Zhang, G.Y.; Ahmed, N; Riley, C; Oliva, K; Barker, G.; Quinn, M A; Rice, G E

    2004-01-01

    The peroxisome proliferator-activated receptors (PPARs) belong to a subclass of nuclear hormone receptor that executes important cellular transcriptional functions. Previous studies have demonstrated the expression of PPAR? in several tumours including colon, breast, bladder, prostate, lung and stomach. This study demonstrates the relative expression of PPAR? in normal ovaries and different pathological grades of ovarian tumours of serous, mucinous, endometrioid, clear cell and mixed subtypes...

  9. Evaluation of single nucleotide polymorphisms of Pro12Ala in peroxisome proliferator-activated receptor-γ and Gly308Ala in tumor necrosis factor-α genes in obese Asian Indians: a population-based study.

    Science.gov (United States)

    Bhagat, Namita; Agrawal, Mukta; Luthra, Kalpana; Vikram, Naval K; Misra, Anoop; Gupta, Rajeev

    2010-10-11

    A population-based case control study was performed to determine the associations of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARG) and Gly308Ala polymorphism in tumor necrosis factor-α (TNFA) genes in obese subjects. Of 1,400 eligible subjects, ≧20 years, we recruited only 1,127. For extreme phenotype case-control design, we evaluated 201 subjects with body mass index (BMI) ≧30 kg/m(2) (Group 1) and 143 with BMI Pro12Ala polymorphism in PPARG was found in 15 (7.5%) subjects in Group 1 and 3 (2.1%) subjects in Group 2 (P = 0.028), and heterozygous Gly308Ala polymorphism in TNFA was found in 19 (9.5%) in Group 1 and 7 (4.9%) in Group 2 (P = 0.115). Presence of heterozygous polymorphism in PPARG and TNFA-predicted obesity with univariate odds ratio ([OR], 95% confidence intervals) of 2.25 (1.32-3.84, P = 0.003) and 1.48 (1.10-1.99, P = 0.009) and with multivariate OR 1.74 (1.03-2.93, P = 0.038) and 1.46 (1.05-2.03, P = 0.024), respectively. The addition of dietary and physical activity variables did not result in significant change. Obese Asian Indians have greater prevalence of heterozygous polymorphisms of Pro12Ala in PPARG and Gly308Ala in TNFA genes.

  10. Peroxisome proliferator-activated receptors as targets to treat non-alcoholic fatty liver disease.

    Science.gov (United States)

    Souza-Mello, Vanessa

    2015-05-18

    Lately, the world has faced tremendous progress in the understanding of non-alcoholic fatty liver disease (NAFLD) pathogenesis due to rising obesity rates. Peroxisome proliferator-activated receptors (PPARs) are transcription factors that modulate the expression of genes involved in lipid metabolism, energy homeostasis and inflammation, being altered in diet-induced obesity. Experimental evidences show that PPAR-alpha is the master regulator of hepatic beta-oxidation (mitochondrial and peroxisomal) and microsomal omega-oxidation, being markedly decreased by high-fat (HF) intake. PPAR-beta/delta is crucial to the regulation of forkhead box-containing protein O subfamily-1 expression and, hence, the modulation of enzymes that trigger hepatic gluconeogenesis. In addition, PPAR-beta/delta can activate hepatic stellate cells aiming to the hepatic recovery from chronic insult. On the contrary, PPAR-gamma upregulation by HF diets maximizes NAFLD through the induction of lipogenic factors, which are implicated in the fatty acid synthesis. Excessive dietary sugars also upregulate PPAR-gamma, triggering de novo lipogenesis and the consequent lipid droplets deposition within hepatocytes. Targeting PPARs to treat NAFLD seems a fruitful approach as PPAR-alpha agonist elicits expressive decrease in hepatic steatosis by increasing mitochondrial beta-oxidation, besides reduced lipogenesis. PPAR-beta/delta ameliorates hepatic insulin resistance by decreasing hepatic gluconeogenesis at postprandial stage. Total PPAR-gamma activation can exert noxious effects by stimulating hepatic lipogenesis. However, partial PPAR-gamma activation leads to benefits, mainly mediated by increased adiponectin expression and decreased insulin resistance. Further studies are necessary aiming at translational approaches useful to treat NAFLD in humans worldwide by targeting PPARs.

  11. Peroxisome proliferator-activated receptor gamma as modulator of inflammation in pulmonary sarcoidosis

    Directory of Open Access Journals (Sweden)

    Pejčić Tatjana

    2013-01-01

    Full Text Available Peroxisome proliferator-activated receptor (PPAR includes the family of ligand-activated transcription factors which belong to the group of nuclear hormone receptors and are connected to retinoid, glucocorticoid and thyroid hormone receptors. There are three subtypes of PPARs: PPARα (also known as NR1C3, PPARγ (known as NR1C1 and PPARδ (known as PPARβ or NR1C2. All of them take part in the metabolism, cell proliferation and immune response. PPARγ and PPARα are identified as important immunomodulators and potentially represent an anti-inflammatory target for respiratory diseases. PPARγ deficiency in the lungs has been observed in the inflammatory diseases such as asthma, pulmonary alveolar proteinosis, fibrosis and sarcoidosis, as well as in the animal models of the lung inflammation. A small number of papers concerned with PPARγ in sarcoidosis point to the lowered activity of this factor in the alveolar macrophages and a lowered gene expression for the PPARγ, while the activity is preserved in healthy individuals. At the same time, an increased activity of the nuclear factor kappa B (NF-kB in the bronchoalveolar lavage has been recorded in patients with sarcoidosis. The reason for the decrease in the production of PPARγ in sarcoidosis remains unknown. Several possible mechanisms are mentioned: genetic defect with lowered production, down-regulation due to the increased values of IFN-γ or an increased decomposition of PPARγ. Further investigation will explain the mechanisms regarding the decreased production of PPARγ in sarcoidosis.

  12. Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases

    Directory of Open Access Journals (Sweden)

    Francisco A. Monsalve

    2013-01-01

    Full Text Available Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR-α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR-α and PPAR-γ are mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR-β/δ function is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis.

  13. Translational Insights Into Peroxisome Proliferator-Activated Receptors in Experimental Acute Pancreatitis.

    Science.gov (United States)

    Huang, Wei; Szatmary, Peter; Wan, Meihua; Bharucha, Shameena; Awais, Muhammad; Tang, Wenfu; Criddle, David N; Xia, Qing; Sutton, Robert

    2016-02-01

    Acute pancreatitis (AP) is an inflammatory disorder of the exocrine pancreas frequently associated with metabolic causes, contributing factors, or consequences, including hypertriglyceridemia, obesity, and disorders of intermediary metabolism, respectively. To date, there is no specific therapy for this disease. Future optimal therapy should correct both inflammatory and metabolic components of the disease. Peroxisome proliferator-activated receptors (PPARs) are lipid-sensing nuclear receptors that control inflammatory and metabolic pathways via ligand-dependent and ligand-independent mechanisms. There are 3 known subtypes, PPAR-α, PPAR-β/δ, and PPAR-γ, which are differentially expressed in various tissues. The PPARs interact closely with other transcription factors such as nuclear factor κB and signal tranducers and activators of transcription that have pivotal roles in the pathobiology of AP. In this comprehensive review, we summarize the role of PPARs in AP, highlighting important in vitro and in vivo experimental findings. Finally, we propose future research directions as well as potential translational use of PPAR agonists in the treatment of AP.

  14. Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases

    Science.gov (United States)

    Monsalve, Francisco A.; Pyarasani, Radha D.; Delgado-Lopez, Fernando; Moore-Carrasco, Rodrigo

    2013-01-01

    Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs) may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR-α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR-α and PPAR-γ are mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR-β/δ function is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis. PMID:23781121

  15. Peroxisome Proliferator-Activated Receptor and Vitamin D Receptor Signaling Pathways in Cancer Cells

    Energy Technology Data Exchange (ETDEWEB)

    Matsuda, Satoru, E-mail: smatsuda@cc.nara-wu.ac.jp; Kitagishi, Yasuko [Department of Food Science and Nutrition, Nara Women’s University, Kita-Uoya Nishimachi, Nara 630-8506 (Japan)

    2013-10-21

    Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of nuclear hormone receptors, which respond to specific ligands such as polyunsaturated fatty acids by altering gene expression. Three subtypes of this receptor have been discovered, each evolving to achieve different biological functions. Like other nuclear receptors, the transcriptional activity of PPARs is affected not only by ligand-stimulation, but also by cross-talk with other molecules. For example, both PPARs and the RXRs are ligand-activated transcription factors that coordinately regulate gene expression. In addition, PPARs and vitamin D receptor (VDR) signaling pathways regulate a multitude of genes that are of importance for cellular functions including cell proliferation and cell differentiation. Interaction of the PPARs and VDR signaling pathways has been shown at the level of molecular cross-regulation of their transcription factor. A variety of ligands influencing the PPARs and VDR signaling pathways have been shown to reveal chemopreventive potential by mediating tumor suppressive activities in human cancers. Use of these compounds may represent a potential novel strategy to prevent cancers. This review summarizes the roles of the PPARs and the VDR in pathogenesis and progression of cancer.

  16. Metabolic syndrome and type 2 diabetes mellitus: focus on peroxisome proliferator activated receptors (PPAR

    Directory of Open Access Journals (Sweden)

    Fisman Enrique Z

    2003-03-01

    Full Text Available Abstract The metabolic syndrome is a highly prevalent clinical entity. The recent Adult Treatment Panel (ATP III guidelines have called specific attention to the importance of targeting the cardiovascular risk factors of the metabolic syndrome as a method of risk reduction therapy. The main factors characteristic of this syndrome are abdominal obesity, atherogenic dyslipidemia, elevated blood pressure, insulin resistance (with or without glucose intolerance, prothrombotic and proinflammatory states. An insulin resistance following nuclear peroxisome proliferator activated receptors (PPAR deactivation (mainly obesity-related is the key phase of metabolic syndrome initiation. Afterwards, there are 2 principal pathways of metabolic syndrome development: 1 with preserved pancreatic beta cells function and insulin hypersecretion which can compensate for insulin resistance. This pathway leads mainly to the macrovascular complications of metabolic syndrome; 2 with massive damage of pancreatic beta cells leading to progressively decrease of insulin secretion and to hyperglycemia (e.g. overt type 2 diabetes. This pathway leads to both microvascular and macrovascular complications. We suggest that a PPAR-based appraisal of metabolic syndrome and type 2 diabetes may improve our understanding of these diseases and set a basis for a comprehensive approach in their treatment.

  17. Maternal nutrition influences angiogenesis in the placenta through peroxisome proliferator activated receptors: A novel hypothesis.

    Science.gov (United States)

    Meher, Akshaya; Sundrani, Deepali; Joshi, Sadhana

    2015-10-01

    Placental angiogenesis is critical to maintain adequate blood flow during gestation, and any alterations in this process can result in an adverse pregnancy. Growing evidence indicates that suboptimal maternal nutrition can alter placental development. Although the underlying mechanisms are not clear, maternal nutrition likely influences the expression of genes involved in placental development through regulation of various transcription factors such as peroxisome proliferator-activated receptors (PPARs), which can be activated by ligands including long-chain polyunsaturated fatty acids. Indeed, several studies demonstrated a role for PPAR in implantation, trophoblast differentiation, and angiogenesis. Alterations in maternal nutrition during pregnancy can affect the expression of PPARs via epigenetic mechanisms or through homocysteine, which is known to compete for PPARs. This review discusses the role of maternal nutrition-particularly micronutrients like folate, vitamin B12 , and omega-3 fatty acids-in modulating the activity of PPARs during placentation and angiogenesis, which affects placental and fetal growth. Additional animal and human studies need to be undertaken to elucidate the molecular mechanisms through which maternal nutrition regulates PPARs, specifically to determine whether PPARs affect placental angiogenesis directly through angiogenic factors or indirectly by modulating trophoblast differentiation. © 2015 Wiley Periodicals, Inc.

  18. [The role of peroxisome proliferator-activated receptors γ (PPARγ) in obesity and insulin resistance].

    Science.gov (United States)

    Chmielewska-Kassassir, Małgorzata; Woźniak, Lucyna A; Ogrodniczek, Paweł; Wójcik, Marzena

    2013-12-11

    Obesity, defined as abnormal or excessive fat accumulation, is currently believed to be a major public health problem worldwide. Over the past 20 years, the prevalence of obesity has increased rapidly in both industrialized and developing countries, resulting in a considerably increased risk of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Although the exact pathophysiological mechanisms underlying these diseases remain unclear, clinical and epidemiological studies support the existence of a relationship between obesity-induced inflammation and insulin resistance linked with the development and progression of metabolic diseases. Adipokines, produced and released by adipose tissue, are considered as factors linking obesity-induced inflammation with insulin resistance, and their regulation through peroxisome proliferator-activated receptors γ (PPARγ also known as NR1C3) is essential in these processes. PPARγ are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily which directly regulate the expression of a large number of genes involved in adipocyte differentiation, lipid and carbohydrate metabolism as well as adipokine synthesis; thereby they are implicated in various metabolic disorders, including obesity, insulin resistance, dyslipidemia, and hypertension. This review summarizes the current literature on a functional relationship of PPARγ with obesity and insulin resistance and, moreover, highlights the significance of synthetic ligands of these receptors in the mentioned metabolic disorders.

  19. Peroxisome Proliferator-Activated Receptor-γ: Master Regulator of Adipogenesis and Obesity.

    Science.gov (United States)

    Shao, Xiaoru; Wang, Meiqi; Wei, Xueqin; Deng, Shuwen; Fu, Na; Peng, Qiang; Jiang, Yan; Ye, Ling; Xie, Jiamin; Lin, Yunfeng

    2016-01-01

    Obesity, which is a key risk for the development of hyperglycemia, hypertension, hyperlipidemia and insulin resistance and is totally referred to as the metabolic disorders, has aroused people's great attention because of its alarming increase rate around the world. It is widely known that the occurrence of obesity can be attributed to both environmental and genetic factors. Peroxisome proliferators-activated receptor (PPAR), a member of ligand-dependent receptor, is one of the important genetic factors. PPAR includes three isoforms: PPAR-α, PPAR- β and PPAR- γ, all of which are exerting critical influences on the maintenance of the metabolism of saccharides, lipids and proteins. PPAR-γ is of great importance in the regulation of adipogenesis; in addition, it is essential in the prevention of adiposis and the treatment of 2-diabetes mellitus. In this review, we focus on giving a brief introduction about PPAR family, the indispensible function of PPAR-γ in adipogenesis and the inseparable relationship between PPAR-γ and obesity, deriving from the understanding of how these receptors activated will provide windows of opportunities for the treatment of obesity and associated metabolism syndromes.

  20. Association between peroxisome proliferator-activated receptor gene single nucleotide polymorphisms and arterial stiffness in adult Chinese population

    Institute of Scientific and Technical Information of China (English)

    许如意

    2013-01-01

    Objective To analyze the association between single nucleotide polymorphisms(SNPs) of peroxisome proliferator-activated receptor(PPAR)and arterial stiffness in adult Chinese population(>50 years).Methods

  1. Sulfonylureas and glinides exhibit peroxisome proliferator-activated receptor gamma activity: A combined virtual screening and biological assay approach

    NARCIS (Netherlands)

    Scarsi, M.; Podvinec, M.; Roth, A.; Hug, H.; Kersten, A.H.; Albrecht, H.; Schwede, T.; Meyer, U.A.; Rucker, C.

    2007-01-01

    Most drugs currently employed in the treatment of type 2 diabetes either target the sulfonylurea receptor stimulating insulin release (sulfonylureas, glinides), or target the peroxisome proliferator-activated receptor (PPAR) improving insulin resistance (thiazolidinediones). Our work shows that sulf

  2. Structural insights into human peroxisome proliferator activated receptor delta (PPAR-delta selective ligand binding.

    Directory of Open Access Journals (Sweden)

    Fernanda A H Batista

    Full Text Available Peroxisome proliferator activated receptors (PPARs δ, α and γ are closely related transcription factors that exert distinct effects on fatty acid and glucose metabolism, cardiac disease, inflammatory response and other processes. Several groups developed PPAR subtype specific modulators to trigger desirable effects of particular PPARs without harmful side effects associated with activation of other subtypes. Presently, however, many compounds that bind to one of the PPARs cross-react with others and rational strategies to obtain highly selective PPAR modulators are far from clear. GW0742 is a synthetic ligand that binds PPARδ more than 300-fold more tightly than PPARα or PPARγ but the structural basis of PPARδ:GW0742 interactions and reasons for strong selectivity are not clear. Here we report the crystal structure of the PPARδ:GW0742 complex. Comparisons of the PPARδ:GW0742 complex with published structures of PPARs in complex with α and γ selective agonists and pan agonists suggests that two residues (Val312 and Ile328 in the buried hormone binding pocket play special roles in PPARδ selective binding and experimental and computational analysis of effects of mutations in these residues confirms this and suggests that bulky substituents that line the PPARα and γ ligand binding pockets as structural barriers for GW0742 binding. This analysis suggests general strategies for selective PPARδ ligand design.

  3. Peroxisome Proliferator-Activated Receptor γ Activity is Required for Appropriate Cardiomyocyte Differentiation

    Directory of Open Access Journals (Sweden)

    Maryam Peymani

    2016-07-01

    Full Text Available Objective Peroxisome proliferator-activated receptor γ (PPARγ is a member of the PPAR nuclear receptor superfamily. Although PPARγ acts as a master transcription factor in adipocyte differentiation, it is also associated with a variety of cell functions including carbohydrate and lipid metabolism, glucose homeostasis, cell proliferation and cell differentiation. This study aimed to assess the expression level of PPARγ in order to address its role in cardiac cell differentiation of mouse embryonic stem cells (mESCs. Materials and Methods In this an intervening study, mESCs were subjected to cardiac differentiation. Total RNA was extracted from the cells and quantitative real time polymerase chain reaction (qPCR was carried out to estimate level of gene expression. Furthermore, the requirement of PPARγ in cardiac differentiation of mESCs, during cardiac progenitor cells (CPCs formation, was examined by applying the respective agonist and antagonist. Results The obtained data revealed an elevation in the expression level of PPARγ during spontaneous formation of CPCs and cardiomyocytes. Our results indicated that during CPC formation, PPARγ inactivation via treatment with GW9662 (GW reduced expression of CPC and cardiac markers. Conclusion We conclude that PPARγ modulation has an effective role on cardiac differentiation of mESCs at the early stage of cardiomyogenesis.

  4. Peroxisome proliferator-activated receptor gamma overexpression suppresses proliferation of human colon cancer cells

    Energy Technology Data Exchange (ETDEWEB)

    Tsukahara, Tamotsu, E-mail: ttamotsu@shinshu-u.ac.jp [Department of Integrative Physiology and Bio-System Control, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan); Haniu, Hisao [Department of Orthopaedic Surgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano 390-8621 (Japan)

    2012-08-03

    Highlights: Black-Right-Pointing-Pointer We examined the correlation between PPAR{gamma} expression and cell proliferation. Black-Right-Pointing-Pointer PPAR{gamma} overexpression reduces cell viability. Black-Right-Pointing-Pointer We show the synergistic effect of cell growth inhibition by a PPAR{gamma} agonist. -- Abstract: Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) plays an important role in the differentiation of intestinal cells and tissues. Our previous reports indicate that PPAR{gamma} is expressed at considerable levels in human colon cancer cells. This suggests that PPAR{gamma} expression may be an important factor for cell growth regulation in colon cancer. In this study, we investigated PPAR{gamma} expression in 4 human colon cancer cell lines, HT-29, LOVO, DLD-1, and Caco-2. Real-time polymerase chain reaction (PCR) and Western blot analysis revealed that the relative levels of PPAR{gamma} mRNA and protein in these cells were in the order HT-29 > LOVO > Caco-2 > DLD-1. We also found that PPAR{gamma} overexpression promoted cell growth inhibition in PPAR{gamma} lower-expressing cell lines (Caco-2 and DLD-1), but not in higher-expressing cells (HT-29 and LOVO). We observed a correlation between the level of PPAR{gamma} expression and the cells' sensitivity for proliferation.

  5. Structural basis for iloprost as a dual peroxisome proliferator-activated receptor alpha/delta agonist.

    Science.gov (United States)

    Jin, Lihua; Lin, Shengchen; Rong, Hui; Zheng, Songyang; Jin, Shikan; Wang, Rui; Li, Yong

    2011-09-09

    Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPARα ligand-binding domain and PPARδ ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPARα/δ by this prostacyclin analog. In addition to conserved contacts for all PPARα ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPARα/δ interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.

  6. Structural Basis for Iloprost as a Dual Peroxisome Proliferator-activated Receptor α/δ Agonist*

    Science.gov (United States)

    Jin, Lihua; Lin, Shengchen; Rong, Hui; Zheng, Songyang; Jin, Shikan; Wang, Rui; Li, Yong

    2011-01-01

    Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPARα ligand-binding domain and PPARδ ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPARα/δ by this prostacyclin analog. In addition to conserved contacts for all PPARα ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPARα/δ interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs. PMID:21775429

  7. Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress.

    Science.gov (United States)

    Cho, Nobuo; Momose, Yu

    2008-01-01

    An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARgamma as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARgamma agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARgamma-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARgamma including the significance of PPARgamma as a drug target, describes the current status of a wide variety of novel PPARgamma ligands including PPAR dual and pan agonists and selective PPARgamma modulators (SPPARgammaMs), and highlights new approaches for identifying agents targeting PPARgamma in the treatment of type 2 diabetes.

  8. A role for Peroxisome Proliferator-Activated Receptor Beta in T cell development

    Science.gov (United States)

    Mothe-Satney, Isabelle; Murdaca, Joseph; Sibille, Brigitte; Rousseau, Anne-Sophie; Squillace, Raphaëlle; Le Menn, Gwenaëlle; Rekima, Akila; Larbret, Frederic; Pelé, Juline; Verhasselt, Valérie; Grimaldi, Paul A.; Neels, Jaap G.

    2016-01-01

    Metabolism plays an important role in T cell biology and changes in metabolism drive T cell differentiation and fate. Most research on the role of metabolism in T lymphocytes focuses on mature T cells while only few studies have investigated the role of metabolism in T cell development. In this study, we report that activation or overexpression of the transcription factor Peroxisome Proliferator-Activated Receptor β (PPARβ) increases fatty acid oxidation in T cells. Furthermore, using both in vivo and in vitro models, we demonstrate that PPARβ activation/overexpression inhibits thymic T cell development by decreasing proliferation of CD4−CD8− double-negative stage 4 (DN4) thymocytes. These results support a model where PPARβ activation/overexpression favours fatty acid- instead of glucose-oxidation in developing T cells, thereby hampering the proliferative burst normally occurring at the DN4 stage of T cell development. As a consequence, the αβ T cells that are derived from DN4 thymocytes are dramatically decreased in peripheral lymphoid tissues, while the γδ T cell population remains untouched. This is the first report of a direct role for a member of the PPAR family of nuclear receptors in the development of T cells. PMID:27680392

  9. Structural Basis for Iloprost as a Dual Peroxisome Proliferator-activated Receptor [alpha/delta] Agonist

    Energy Technology Data Exchange (ETDEWEB)

    Jin, Lihua; Lin, Shengchen; Rong, Hui; Zheng, Songyang; Jin, Shikan; Wang, Rui; Li, Yong (Pitt); (Xiamen)

    2012-03-15

    Iloprost is a prostacyclin analog that has been used to treat many vascular conditions. Peroxisome proliferator-activated receptors (PPARs) are ligand-regulated transcription factors with various important biological effects such as metabolic and cardiovascular physiology. Here, we report the crystal structures of the PPAR{alpha} ligand-binding domain and PPAR{delta} ligand-binding domain bound to iloprost, thus providing unambiguous evidence for the direct interaction between iloprost and PPARs and a structural basis for the recognition of PPAR{alpha}/{delta} by this prostacyclin analog. In addition to conserved contacts for all PPAR{alpha} ligands, iloprost also initiates several specific interactions with PPARs using its unique structural groups. Structural and functional studies of receptor-ligand interactions reveal strong functional correlations of the iloprost-PPAR{alpha}/{delta} interactions as well as the molecular basis of PPAR subtype selectivity toward iloprost ligand. As such, the structural mechanism may provide a more rational template for designing novel compounds targeting PPARs with more favorable pharmacologic impact based on existing iloprost drugs.

  10. Activation of peroxisome proliferator-activated receptor alpha in rat spinal cord after peripheral noxious stimulation.

    Science.gov (United States)

    Benani, A; Heurtaux, T; Netter, P; Minn, A

    2004-10-07

    Following recurrent noxious stimulation, both functional modification and structural reorganization such as activation of the arachidonate cascade or axon sprouting occur in the central nervous system (CNS). It has been recently proposed that these alterations observed during chronic pain state were supported by an intensification of the lipid metabolism. In this regard, it has been shown that mRNA coding for several fatty acid metabolizing enzymes are up-regulated in the rat lumbar spinal cord in response to persistent nociception induced by a peripheral inflammation. As peroxisome proliferators-activated receptor (PPAR) could mediate such effects, we therefore investigated the activation of this transcription factor in the rat spinal cord following subcutaneous injection of complete Freund's adjuvant (CFA) into a hind paw. In this study, we compared the DNA-binding activity of nuclear proteins extracted from healthy and inflamed rats toward a PPAR response element. Using electrophoretic mobility-shift assay (EMSA), we found that only the PPARalpha isoform was activated in the rat spinal cord after CFA injection. This activation occurred rapidly, as early as 30 min post-CFA injection, and was persistent up to 10 h, reaching a maximum at 6h after CFA injection. In view of the consequences of PPARalpha activation in other tissues, these results suggest that fatty acid utilization is enhanced in the CNS during chronic pain state. Although the physiopathological relevance of PPARalpha activation during hyperalgesia needs further investigation, we provided here a new player in the molecular modeling of pain pathways.

  11. Pioglitazone, a Peroxisome Proliferator-Activated Receptor γ Agonist, Suppresses Rat Prostate Carcinogenesis

    Science.gov (United States)

    Suzuki, Shugo; Mori, Yukiko; Nagano, Aya; Naiki-Ito, Aya; Kato, Hiroyuki; Nagayasu, Yuko; Kobayashi, Mizuho; Kuno, Toshiya; Takahashi, Satoru

    2016-01-01

    Pioglitazone (PGZ), a peroxisome proliferator-activated receptor γ agonist, which is known as a type 2 diabetes drug, inhibits cell proliferation in various cancer cell lines, including prostate carcinomas. This study focused on the effect of PGZ on prostate carcinogenesis using a transgenic rat for an adenocarcinoma of prostate (TRAP) model. Adenocarcinoma lesions as a percentage of overall lesions in the ventral prostate were significantly reduced by PGZ treatment in a dose-dependent manner. The number of adenocarcinomas per given area in the ventral prostate was also significantly reduced by PGZ treatment. The Ki67 labeling index in the ventral prostate was also significantly reduced by PGZ. Decreased cyclin D1 expression in addition to the inactivation of both p38 mitogen-activated protein kinase (MAPK) and nuclear factor (NF)κB were detected in PGZ-treated TRAP rat groups. In LNCaP, a human androgen-dependent prostate cancer cell line, PGZ also inhibited cyclin D1 expression and the activation of both p38 MAPK and NFκB. The suppression of cultured cell growth was mainly regulated by the NFκB pathway as detected using specific inhibitors in both LNCaP and PC3, a human androgen-independent prostate cancer cell line. These data suggest that PGZ possesses a chemopreventive potential for prostate cancer. PMID:27973395

  12. Phospholipase A2-modified low-density lipoprotein activates macrophage peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Namgaladze, Dmitry; Morbitzer, Daniel; von Knethen, Andreas; Brüne, Bernhard

    2010-02-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors modulating metabolic and inflammatory responses of phagocytes to stimuli such as fatty acids and their metabolites. We studied the role of PPARs in macrophages exposed to low-density lipoprotein (LDL) modified by secretory phospholipase A(2) (PLA). By analyzing PPAR ligand-binding domain luciferase reporter activation, we observed that PLA-LDL transactivates PPARalpha and PPARdelta, but not PPARgamma. We confirmed that PLA-LDL induced PPAR response element reporter activation by endogenous PPARalpha and PPARdelta in human THP-1 macrophages. By using THP-1 cells with a stable knockdown of PPARalpha and PPARdelta, we showed that PLA-LDL-activated PPARdelta altered macrophage gene expression related to lipid metabolism and lipid droplet formation. Although PPARalpha/delta silencing did not affect cholesterol and triglyceride accumulation in PLA-LDL-treated macrophages, PPARdelta activation by PLA-LDL attenuated macrophage inflammatory gene expression induced by interferon gamma and lipopolysaccharide. PPARdelta activation by PLA-LDL does not influence lipid accumulation in PLA-LDL-treated macrophages. However, it attenuates macrophage inflammatory responses, thus contributing to an anti-inflammatory cell phenotype.

  13. The peroxisome proliferator-activated receptors under epigenetic control in placental metabolism and fetal development.

    Science.gov (United States)

    Lendvai, Ágnes; Deutsch, Manuel J; Plösch, Torsten; Ensenauer, Regina

    2016-05-15

    The placental metabolism can adapt to the environment throughout pregnancy to both the demands of the fetus and the signals from the mother. Such adaption processes include epigenetic mechanisms, which alter gene expression and may influence the offspring's health. These mechanisms are linked to the diversity of prenatal environmental exposures, including maternal under- or overnutrition or gestational diabetes. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that contribute to the developmental plasticity of the placenta by regulating lipid and glucose metabolism pathways, including lipogenesis, steroidogenesis, glucose transporters, and placental signaling pathways, thus representing a link between energy metabolism and reproduction. Among the PPAR isoforms, PPARγ appears to be the main modulator of mammalian placentation. Certain fatty acids and lipid-derived moieties are the natural activating PPAR ligands. By controlling the amounts of maternal nutrients that go across to the fetus, the PPARs play an important regulatory role in placenta metabolism, thereby adapting to the maternal nutritional status. As demonstrated in animal studies, maternal nutrition during gestation can exert long-term influences on the PPAR methylation pattern in offspring organs. This review underlines the current state of knowledge on the relationship between environmental factors and the epigenetic regulation of the PPARs in placenta metabolism and offspring development. Copyright © 2016 the American Physiological Society.

  14. The peroxisome proliferator-activated receptors in cardiovascular diseases: experimental benefits and clinical challenges.

    Science.gov (United States)

    Cheang, Wai San; Tian, Xiao Yu; Wong, Wing Tak; Huang, Yu

    2015-12-01

    The peroxisome proliferator-activated receptors, PPARα, PPARβ/δ and PPARγ, are ligand-activated transcriptional factors belonging to the nuclear receptors superfamily and they are known to play important roles in glucose and lipid metabolism. Experimental studies in animal models of metabolic diseases have also revealed that activation of PPARs protects against the vascular complications of diabetes, hypertension, atherosclerosis, myocardial infarction and stroke, through exerting their anti-inflammatory, anti-atherogenic and antioxidant effects. In clinical trials and post-market surveillance, agonists of PPARs have been shown to effectively prevent cardiovascular events. However, adverse effects, particularly for PPARγ agonists, are also observed with the use of investigational PPAR agonists and even some approved drugs. Further exploration of underlying mechanisms is needed to develop novel ways of PPAR activation without causing serious side effects. This article reviews the cardiovascular effects of PPARs, with emphasis on the therapeutic potential of PPAR agonists in combating metabolic vascular diseases. © 2014 The British Pharmacological Society.

  15. Therapeutic modulators of peroxisome proliferator-activated receptors (PPAR): a patent review (2008-present).

    Science.gov (United States)

    Lamers, Christina; Schubert-Zsilavecz, Manfred; Merk, Daniel

    2012-07-01

    Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. The three known subtypes PPARα, PPARγ and PPARδ have different tissue distribution and play a key role as regulators of glucose and lipid homeostasis as well as in cell proliferation, differentiation and inflammatory responses. They have gained a lot of interest as pharmaceutical targets over the last years and with the antidiabetic thiazolidindiones (TZDs) and the hypolipidemic fibrates, two classes of drugs had entered the market. Early observations of severe adverse events changed the situation in the recent past. Herein the authors summarize recent (2008-present) patent applications concerning PPAR ligands claimed for the use in metabolic disorders as well as patents indicating new applications for modulators of the PPAR subtypes. Looking at the recent patent activity regarding novel compounds, there have not been real innovations. As major applications for therapeutic PPAR ligands cancer therapy, skin-related disorders and systemic anti-inflammatory therapies might arise in the mid-term future. The known PPAR targeting drugs might see a repurposing for novel indications.

  16. Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

    Science.gov (United States)

    Mandard, Stéphane; Patsouris, David

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγ ability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARα and PPARβ/δ against the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits. PMID:23577023

  17. Peroxisome proliferator-activated receptors as transcriptional nodal points and therapeutic targets.

    Science.gov (United States)

    Brown, Jonathan D; Plutzky, Jorge

    2007-01-30

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in the transcriptional regulation of key metabolic pathways such as lipid metabolism, adipogenesis, and insulin sensitivity. More recent work implicates all 3 PPAR isotypes (alpha, gamma, and delta, also known as beta or beta/delta) in inflammatory and atherosclerotic pathways. Because these nuclear receptors are activated by extracellular signals and control multiple gene targets, PPARs can be seen as nodes that control multiple inputs and outputs involved in energy balance, providing insight into how metabolism and the vasculature may be integrated. The ongoing clinical use of fibrates, which activate PPARalpha, and thiazolidinediones, which activate PPARgamma, establishes these receptors as viable drug targets, whereas considerable in vitro animal model and human surrogate marker studies suggest that PPAR activation may limit inflammation and atherosclerosis. Together, these various observations have stimulated intense interest in PPARs as therapeutic targets and led to large-scale cardiovascular end-point trials with PPAR agonists. The first of these studies has generated mixed results that require careful review, especially in anticipation of additional clinical trial data and ongoing attempts to develop novel PPAR modulators. Such analysis of the existing PPAR data, the appropriate use of currently approved PPAR agonists, and continued progress in PPAR therapeutics will be predicated on a better understanding of PPAR biology.

  18. Peroxisome proliferator-activated receptor family and its relationship to renal complications of the metabolic syndrome.

    Science.gov (United States)

    Guan, Youfei

    2004-11-01

    Peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Three PPAR isoforms, designated PPARalpha, -beta/delta, and -gamma, have been identified and attracted enormous attention as a result of the key role that these receptors play in regulating adipogenesis, lipid metabolism, insulin sensitivity, inflammation, and BP. Growing evidence points to a causative relationship between PPAR activity and the metabolic syndrome, including insulin resistance, glucose intolerance or type 2 diabetes, obesity, dyslipidemia, hypertension, atherosclerosis, and albuminuria. Importantly, both PPAR-alpha activators, such as the fibric acid class of hypolipidemic drugs, and PPAR-gamma agonists, including antidiabetic thiazolidinediones, have been proved to be effective for improving diverse aspects of the metabolic syndrome. All three PPAR isoforms seem to play important roles in the development of diabetic nephropathy in type 2 diabetes. Accumulating data suggesting that PPAR may serve as potential therapeutic targets for treating the metabolic syndrome and its related renal complications have begun to emerge. This article reviews the literature pertaining to the action, ligand selectivity, and physiologic role of PPAR. Particular emphasis is placed on their pathogenic roles in the metabolic syndrome and the therapeutic utility of PPAR modulators in the treatment of diabetic nephropathy.

  19. Peroxisome proliferator-activated receptors: bridging metabolic syndrome with molecular nutrition.

    Science.gov (United States)

    Guri, Amir J; Hontecillas, Raquel; Bassaganya-Riera, Josep

    2006-12-01

    Over recent years, obesity rates and the onset of obesity-induced chronic diseases have risen dramatically. The more we learn about the physiological and morphological changes that occur during obesity, the more it is becoming clear that obesity-related disorders can be traced back to adipocyte hypertrophy and inflammation at white adipose tissue (WAT). To combat this problem, the body has developed a regulatory system specifically designed at mediating the systemic response to obesity, utilizing free fatty acids (FFAs) and their metabolites as nutrient messengers to signal adaptations from peripheral tissues. These messages are predominantly interceded through the peroxisome proliferator-activated receptors (PPARs), a family of ligand-induced transcription factors that serve as a net of lipid sensors throughout the body. Understanding how and why nutrients, nutrient derivatives and metabolites exert their physiological effects are the key goals in the study of molecular nutrition. By learning about the mechanisms and tissue-specific effects of endogenous PPAR ligands and expanding our knowledge of the body's integrated homeostatic system, we will significantly increase our odds of designing safe and effective preventive and therapeutic interventions that keep us one step ahead of obesity-related diseases.

  20. Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

    Directory of Open Access Journals (Sweden)

    Stéphane Mandard

    2013-01-01

    Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγ ability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARα and PPARβ/δ against the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig. In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits.

  1. [The role of peroxisome proliferator-activated receptors (PPAR) in carcinogenesis].

    Science.gov (United States)

    Knapp, Paweł; Jarzabek, Katarzyna; Błachnio, Agnieszka; Zbroch, Tomasz

    2006-08-01

    Peroxisome proliferators-activated receptors are members of the nuclear hormone receptor superfamily of ligand-activated transcription factors. The PPAR subfamily consists of three members: PPAR-alpha, PPAR-sigma (NUC-1 or beta) and PPAR-gamma. PPARs regulate gene expression by binding, as heterodimers with retinoid X receptors (RXR), to specific response elements (PPREs) in the promoter regions of target genes. The prostaglandin 12 especially, all arachidonic acid metabolites and polyunsaturated fatty acids are naturally occuring PPAR ligands. Synthetic PPAR ligands are thiazolidinediones (TZDs--rosiglitazone, pioglitazone, troglitazone). Activation of nuclear hormone receptors has been identified as an approach to induce differentiation and inhibit proliferation of cancer lines. The anti-proliferative, pro-differentiation effects of PPAR activators (TZDs) suggest that these compounds might be useful in slowing the proliferation of un-differentiated tumour cells. TZDs inhibit proliferation of human breast, prostate and colon cancers, both in vitro and in tumours derived from these cells implanted into rodents. Furthermore, recent studies show that PPAR-gamma ligands are potent inhibitors of angiogenesis, a process essential for solid-tumour growth and metastasis. In conclusion, the evidence to date suggests that activation of PPAR should suppress tumour growth and development. This represents an exciting novel therapeutic application of TZDs. In present paper, structural features of PPARs, their gene transcription mechanisms and recent developments in the discovery of their biological functions are reviewed.

  2. Role of adipokines and peroxisome proliferator-activated receptors in nonalcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Vettickattuparambil; George; Giby; Thekkuttuparambil; Ananthanarayanan; Ajith

    2014-01-01

    Intrahepatic fat deposition has been demonstrated in patients with nonalcoholic fatty liver disease(NAFLD). Genetic and environmental factors are important for the development of NAFLD. Diseases such as obesity, diabetes, and hypertension have been found to be closely associated with the incidence of NAFLD. Evi-dence suggests that obesity and insulin resistance are the major factors that contribute to the development of NAFLD. In comparing the factors that contribute to the buildup of excess calories in obesity, an imbalance of energy homeostasis can be considered as the basis. Among the peripheral signals that are generated to regulate the uptake of food, signals from adipose tissue are of major relevance and involve the maintenance of energy homeostasis through processes such as lipo-genesis, lipolysis, and oxidation of fatty acids. Advances in research on adipose tissue suggest an integral role played by adipokines in NAFLD. Cytokines secreted by adipocytes, such as tumor necrosis factor-α, transform-ing growth factor-β, and interleukin-6, are implicated in NAFLD. Other adipokines, such as leptin and adiponectin and, to a lesser extent, resistin and retinol binding protein-4 are also involved. Leptin and adiponectin can augment the oxidation of fatty acid in liver by activating the nuclear receptor super-family of transcription fac-tors, namely peroxisome proliferator-activated receptor(PPAR)-α. Recent studies have proposed downregula-tion of PPAR-α in cases of hepatic steatosis. This re-view discusses the role of adipokines and PPARs with regard to hepatic energy metabolism and progression of NAFLD.

  3. Functional interaction of hepatic nuclear factor-4 and peroxisome proliferator-activated receptor-gamma coactivator 1alpha in CYP7A1 regulation is inhibited by a key lipogenic activator, sterol regulatory element-binding protein-1c.

    Science.gov (United States)

    Ponugoti, Bhaskar; Fang, Sungsoon; Kemper, Jongsook Kim

    2007-11-01

    Insulin inhibits transcription of cholesterol 7alpha-hydroxylase (Cyp7a1), a key gene in bile acid synthesis, and the hepatic nuclear factor-4 (HNF-4) site in the promoter was identified as a negative insulin response sequence. Using a fasting/feeding protocol in mice and insulin treatment in HepG2 cells, we explored the inhibition mechanisms. Expression of sterol regulatory element-binding protein-1c (SREBP-1c), an insulin-induced lipogenic factor, inversely correlated with Cyp7a1 expression in mouse liver. Interaction of HNF-4 with its coactivator, peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), was observed in livers of fasted mice and was reduced after feeding. Conversely, HNF-4 interaction with SREBP-1c was increased after feeding. In vitro studies suggested that SREBP-1c competed with PGC-1alpha for direct interaction with the AF2 domain of HNF-4. Reporter assays showed that SREBP-1c, but not of a SREBP-1c mutant lacking the HNF-4 interacting domain, inhibited HNF-4/PGC-1alpha transactivation of Cyp7a1. SREBP-1c also inhibited PGC-1alpha-coactivation of estrogen receptor, constitutive androstane receptor, pregnane X receptor, and farnesoid X receptor, implying inhibition of HNF-4 by SREBP-1c could extend to other nuclear receptors. In chromatin immunoprecipitation studies, HNF-4 binding to the promoter was not altered, but PGC-1alpha was dissociated, SREBP-1c and histone deacetylase-2 (HDAC2) were recruited, and acetylation of histone H3 was decreased upon feeding. Adenovirus-mediated expression of a SREBP-1c dominant-negative mutant, which blocks the interaction of SREBP-1c and HNF-4, partially but significantly reversed the inhibition of Cyp7a1 after feeding. Our data show that SREBP-1c functions as a non-DNA-binding inhibitor and mediates, in part, suppression of Cyp7a1 by blocking functional interaction of HNF-4 and PGC-1alpha. This mechanism may be relevant to known repression of many other HNF-4 target genes upon

  4. Transcriptomic signatures of peroxisome proliferator-activated receptor a (PPARa) in different mouse liver models identify novel aspects of its biology

    NARCIS (Netherlands)

    Szalowska, E.; Tesfay, H.A.; Hijum, van S.A.F.T.; Kersten, A.H.

    2014-01-01

    Background The peroxisome proliferator-activated receptor alpha (PPARa) is a ligand-activated transcription factor that regulates lipid catabolism and inflammation and is hepatocarcinogenic in rodents. It is presumed that the functions of PPARa in liver depend on cross-talk between parenchymal (hepa

  5. Peroxisome Proliferator-Activated Receptor-alpha Gene Level Differently Affects Lipid Metabolism and Inflammation in Apolipoprotein E2 Knock-In Mice

    NARCIS (Netherlands)

    Lalloyer, Fanny; Wouters, Kristiaan; Baron, Morgane; Caron, Sandrine; Vallez, Emmanuelle; Vanhoutte, Jonathan; Bauge, Eric; Shiri-Sverdlov, Ronit; Hofker, Marten; Staels, Bart; Tailleux, Anne

    Objective-Peroxisome proliferator-activated receptor-alpha (PPAR alpha) is a ligand-activated transcription factor that controls lipid metabolism and inflammation. PPAR alpha is activated by fibrates, hypolipidemic drugs used in the treatment of dyslipidemia. Previous studies assessing the influence

  6. Peroxisome proliferator-activated receptor alpha improves pancreatic adaptation to insulin resistance in obese mice and reduces lipotoxicity in human islets

    NARCIS (Netherlands)

    Lalloyer, Fanny; Vandewalle, Brigitte; Percevault, Frederic; Torpier, Gerard; Kerr-Conte, Julie; Oosterveer, Maaike; Paumelle, Rejane; Fruchart, Jean-Charles; Kuipers, Folkert; Pattou, Francois; Fievet, Catherine; Staels, Bart

    Peroxisome proliferator-activated receptor (PPAR) alpha is a transcription factor controlling lipid and glucose homeostasis. PPAR alpha-deficient (-/-) mice are protected from high-fat diet-induced insulin resistance. However, the impact of PPAR alpha in the pathophysiological setting of

  7. Leptin deficiency unmasks the deleterious effects of impaired peroxisome proliferator-activated receptor γ function (P465L PPARγ) in mice

    NARCIS (Netherlands)

    Gray, S.L.; Dalla Nora, E.; Grosse, J.; Manieri, M.; Stoeger, T.; Medina-Gomez, G.; Burling, K.; Wattler, S.; Russ, A.; Yeo, G.S.H.; Chatterjee, V.K.; O'Rahilly, S.; Voshol, P.J.; Cinti, S.; Vidal-Puig, A.

    2006-01-01

    Peroxisome proliferator-activated receptor (PPAR)γ is a key transcription factor facilitating fat deposition in adipose tissue through its proadipogenic and lipogenic actions. Human patients with dominant-negative mutations in PPARγ display lipodystrophy and extreme insulin resistance. For this

  8. Association between peroxisome proliferator-activated receptor-γcoactivator-1α gene polymorphisms and type 2 diabetes in southern Chinese population: role of altered interaction with myocyte enhancer factor 2C

    Institute of Scientific and Technical Information of China (English)

    ZHANG Shao-ling; LU Wen-sheng; YAN Li; WU Mu-chao; XU Ming-tong; CHEN Li-hong; CHENG Hua

    2007-01-01

    Background Some single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor-Y coactivator (PGC)-1α gene have been reported to be associated with type 2 diabetes in different populations, and studies on Chinese patients yielded controversial results. The objective of this case-control study was to explore the relationship between SNPs of PGC-1a and type 2 diabetes in the southern Chinese population and to determine whether the common variants: Gly482Ser and Thr394Thr, in the PGC-1α gene have any impacts on interaction with myocyte enhancer factor (MEF) 2C.Methods The SNPs in all exons of the PGC-1α gene was investigated in 50 type 2 diabetic patients using polymerase chain reaction-single strand conformational polymorphism (PCR-SSCP) and direct sequencing. Thereafter, 263 type 2diabetic patients and 282 healthy controls were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). A bacterial two-hybrid system and site-directed mutagenesis were used to investigate whether Gly482Ser and Thr394Thr variants in the PGC-1α gene alter the interaction with MEF2C.Results Three frequent SNPs (Thr394Thr, Gly482Ser and Thr528Thr) were found in exons of the PGC-1α gene. Only the Gly482Ser variant had a different distribution between diabetic patients and healthy subjects, with the 482Ser allele more frequent in patients than in controls (40.1% vs 29.3%, P<0.01). Even in controls, the 482Ser(A) carriers were more likely to have higher levels of total cholesterol and low-density lipoprotein cholesterol than the 482Gly(G) carriers. The 394A-482G-528A haplotype was associated with protection from diabetes, while the 394A-482A-528A was associated with the susceptibility to diabetes. The bacterial two-hybrid system and site-directed mutagenesis revealed that the 482Ser variant was less efficient than the 482Gly variant to interact with MEF2C, whereas the 394Thr (A) had a synergic effect on the interaction between

  9. Evaluation of single nucleotide polymorphisms of Pro12Ala in peroxisome proliferator-activated receptor-γ and Gly308Ala in tumor necrosis factor-α genes in obese Asian Indians: a population-based study

    Directory of Open Access Journals (Sweden)

    Gupta R

    2010-10-01

    Full Text Available Namita Bhagat1,2, Mukta Agrawal1, Kalpana Luthra3, Naval K Vikram4, Anoop Misra4, Rajeev Gupta21Department of Home Science, University of Rajasthan, Jaipur, Rajasthan, India; 2Department of Medicine, Fortis Escorts Hospital, Jaipur, Rajasthan, India; 3Department of Biochemistry, All India Institute of Medical Sciences, New Delhi, India; 4Department of Medicine, All India Institute of Medical Sciences, New Delhi, IndiaBackground: A population-based case control study was performed to determine the associations of Pro12Ala polymorphism in peroxisome proliferator-activated receptor-γ (PPARG and Gly308Ala polymorphism in tumor necrosis factor-α (TNFA genes in obese subjects.Patients and methods: Of 1,400 eligible subjects, ≥20 years, we recruited only 1,127. For extreme phenotype case-control design, we evaluated 201 subjects with body mass index (BMI ≥30 kg/m2 (Group 1 and 143 with BMI <20 kg/m2 (Group 2. Clinical, anthropometric, biochemical, and nutritional details and polymorphisms were estimated.Results: In Group 1, the dietary intake of calories and fats was higher, physical activity was lower, and prevalence of truncal obesity, hypertension, high total cholesterol, low high-density lipoprotein cholesterol, and diabetes was greater than in Group 2. There were no homozygous polymorphisms of either gene. Heterozygous Pro12Ala polymorphism in PPARG was found in 15 (7.5% subjects in Group 1 and 3 (2.1% subjects in Group 2 (P = 0.028, and heterozygous Gly308Ala polymorphism in TNFA was found in 19 (9.5% in Group 1 and 7 (4.9% in Group 2 (P = 0.115. Presence of heterozygous polymorphism in PPARG and TNFA-predicted obesity with univariate odds ratio ([OR], 95% confidence intervals of 2.25 (1.32–3.84, P = 0.003 and 1.48 (1.10–1.99, P = 0.009 and with multivariate OR 1.74 (1.03–2.93, P = 0.038 and 1.46 (1.05–2.03, P = 0.024, respectively. The addition of dietary and physical activity variables did not result in significant change

  10. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta

    National Research Council Canada - National Science Library

    Muoio, Deborah M; MacLean, Paul S; Lang, David B; Li, Shi; Houmard, Joseph A; Way, James M; Winegar, Deborah A; Corton, J Christopher; Dohm, G Lynis; Kraus, William E

    2002-01-01

    Ablation of peroxisome proliferator activated receptor (PPAR) alpha, a lipid-activated transcription factor that regulates expression of beta-oxidative genes, results in profound metabolic abnormalities in liver and heart...

  11. Peroxisome proliferator-activated receptors in chronic inflammation and colorectal cancer

    Science.gov (United States)

    Wang, Dingzhi; DuBois, Raymond N.

    2010-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily and have been implicated in a variety of physiological and pathological processes, such as nutrient metabolism, energy homeostasis, inflammation and cancer. In this review, we highlight breakthroughs in our understanding of the potential roles of PPARs in inflammatory bowel disease and colorectal cancer. These PPAR receptors might hold the key to some of the questions pertinent to the pathophysiology of inflammatory diseases and colorectal cancer and could possibly serve as drug targets for new anti-inflammatory therapeutic and anti-cancer agents. PMID:20951925

  12. Peroxisome proliferator-activated receptors and atherogenesis: regulators of gene expression in vascular cells.

    Science.gov (United States)

    Marx, Nikolaus; Duez, Hélène; Fruchart, Jean-Charles; Staels, Bart

    2004-05-14

    A large body of data gathered over the past couple of years has identified the peroxisome proliferator-activated receptors (PPAR) alpha, gamma, and beta/delta as transcription factors exerting modulatory actions in vascular cells. PPARs, which belong to the nuclear receptor family of ligand-activated transcription factors, were originally described as gene regulators of various metabolic pathways. Although the PPARalpha, gamma, and beta/delta subtypes are approximately 60% to 80% homologous in their ligand- and DNA-binding domains, significant differences in ligand and target gene specificities are observed. PPARalpha is activated by polyunsaturated fatty acids and oxidized derivatives and by lipid-modifying drugs of the fibrate family, including fenofibrate or gemfibrozil. PPARalpha controls expression of genes implicated in lipid metabolism. PPARgamma, in contrast, is a key regulator of glucose homeostasis and adipogenesis. Ligands of PPARgamma include naturally occurring FA derivatives, such as hydroxyoctadecadienoic acids (HODEs), prostaglandin derivatives such as 15-deoxyDelta12,14-prostaglandin J2, and glitazones, insulin-sensitizing drugs presently used to treat patients with type 2 diabetes. Ligands for PPARbeta/delta are polyunsaturated fatty acids, prostaglandins, and synthetic compounds, some of which are presently in clinical development. PPARbeta/delta stimulates fatty acid oxidation predominantly acting in muscle. All PPARs are expressed in vascular cells, where they exhibit antiinflammatory and antiatherogenic properties. In addition, studies in various animal models as well as clinical data suggest that PPARalpha and PPARgamma activators can modulate atherogenesis in vivo. At present, no data are available relating to possible effects of PPARbeta/delta agonists on atherogenesis. Given the widespread use of PPARalpha and PPARgamma agonists in patients at high risk for cardiovascular disease, the understanding of their function in the vasculature is

  13. Peroxisome proliferator-activated receptors in vascular biology-molecular mechanisms and clinical implications.

    Science.gov (United States)

    Touyz, Rhian M; Schiffrin, Ernesto L

    2006-07-01

    Peroxisome proliferator-activated receptors (PPAR)alpha, gamma and beta/delta belong to the nuclear receptor family of ligand-activated transcription factors. PPARs heterodimerize with the retinoid X receptor (RXR) and then act as transcription factors to modulate the function of many target genes. PPARalpha, gamma and beta/delta subtypes have significant differences in their ligand and gene specificities. PPARalpha is activated by polyunsaturated fatty acids and by fibrate drugs (fenofibrate and gemfibrozil) and controls expression of genes involved in lipid metabolism. PPARgamma is activated by fatty acid derivatives, such as hydroxyoctadecadienoic acid (HODEs), prostaglandin derivatives, such as 15-deoxy-Delta12,14-prostaglandin J2, and thiazolidinedione (glitazone) drugs, such as pioglitazone and rosiglitazone. PPARgamma is a key regulator of glucose homeostasis and adipogenesis. PPARbeta/delta ligands include polyunsaturated fatty acids, prostaglandins and synthetic compounds and stimulate fatty acid oxidation. All PPARs are expressed in vascular cells where they exert antiatherogenic, anti-inflammatory and vasculoprotective actions. Activators of PPARalpha (fibrates) and PPARgamma (thiazolidinediones or glitazones) antagonize angiotensin II effects in vivo and in vitro and have cardiovascular antioxidant and anti-inflammatory actions. PPAR agonists slightly reduce blood pressure are cardio-protective and correct vascular structure and endothelial dysfunction in experimental models of hypertension. Because of these beneficial effects, activators of PPARs may have therapeutic potential in the prevention of cardiovascular disease beyond their actions on carbohydrate and lipid metabolism. The present chapter focuses on the role of PPARs in vascular biology and discusses the clinical implications of using PPAR agonists in the management of vascular disease.

  14. Prognostic and biological significance of peroxisome proliferator-activated receptor-gamma in luminal breast cancer.

    Science.gov (United States)

    Abduljabbar, Rezvan; Al-Kaabi, Methaq Mueen; Negm, Ola H; Jerjees, Dena; Muftah, Abir A; Mukherjee, Abhik; Lai, Chun F; Buluwela, Laki; Ali, Simak; Tighe, Patrick J; Green, Andrew; Ellis, Ian; Rakha, Emad

    2015-04-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is an adopted orphan receptor that belongs to the nuclear receptor superfamily of transcription factors. PPARγ is regarded as a differentiation factor and it plays an important role in regulating adipogenesis, cell growth, proliferation and tumour progression. In breast cancer (BC), PPARγ agonists were reported to inhibit proliferation and growth invasion and promote phenotypic changes associated with a less malignant and more differentiated status. This study aims to assess the prognostic and biological roles of PPARγ protein expression in a large cohort of BC patients (n = 1100) with emphasis on the luminal oestrogen receptor (ER) positive class. Immunohistochemistry was used to assess the levels of PPARγ expression in BC series prepared as tissue microarrays (TMAs). PPARγ antibody specificity was confirmed using Western blotting. PPARγ nuclear expression was detected in 79 % of the cases and its expression was positively correlated with the hormonal receptors (ER, progesterone receptor and androgen receptor). PPARγ levels were significantly higher in tumours with lobular subtype, smaller size and lower grade, while HER2-positive, ductal or medullary tumours were associated with lower PPARγ levels. Survival analysis showed that PPARγ is associated with better outcome in the whole series as well as in luminal ER-positive class. Cox regression model showed that PPARγ is an independent predictor of outcome. Higher PPARγ was associated with longer survival in patients with ER-positive tumours who did not receive hormone therapy. PPARγ is a good prognostic marker associated with hormone receptors. In patients with luminal BCs, PPARγ is a marker of better prognosis and is associated with longer survival.

  15. Peroxisome Proliferator-Activated Receptor α Activation Induces Hepatic Steatosis, Suggesting an Adverse Effect

    Science.gov (United States)

    Yan, Fang; Wang, Qi; Xu, Chao; Cao, Mingfeng; Zhou, Xiaoming; Wang, Tingting; Yu, Chunxiao; Jing, Fei; Chen, Wenbin; Gao, Ling; Zhao, Jiajun

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic triglyceride accumulation, ranging from steatosis to steatohepatitis and cirrhosis. NAFLD is a risk factor for cardiovascular diseases and is associated with metabolic syndrome. Antihyperlipidemic drugs are recommended as part of the treatment for NAFLD patients. Although fibrates activate peroxisome proliferator-activated receptor α (PPARα), leading to the reduction of serum triglyceride levels, the effects of these drugs on NAFLD remain controversial. Clinical studies have reported that PPARα activation does not improve hepatic steatosis. In the present study, we focused on exploring the effect and mechanism of PPARα activation on hepatic triglyceride accumulation and hepatic steatosis. Male C57BL/6J mice, Pparα-null mice and HepG2 cells were treated with fenofibrate, one of the most commonly used fibrate drugs. Both low and high doses of fenofibrate were administered. Hepatic steatosis was detected through oil red O staining and electron microscopy. Notably, in fenofibrate-treated mice, the serum triglyceride levels were reduced and the hepatic triglyceride content was increased in a dose-dependent manner. Oil red O staining of liver sections demonstrated that fenofibrate-fed mice accumulated abundant neutral lipids. Fenofibrate also increased the intracellular triglyceride content in HepG2 cells. The expression of sterol regulatory element-binding protein 1c (SREBP-1c) and the key genes associated with lipogenesis were increased in fenofibrate-treated mouse livers and HepG2 cells in a dose-dependent manner. However, the effect was strongly impaired in Pparα-null mice treated with fenofibrate. Fenofibrate treatment induced mature SREBP-1c expression via the direct binding of PPARα to the DR1 motif of the SREBP-1c gene. Taken together, these findings indicate the molecular mechanism by which PPARα activation increases liver triglyceride accumulation and suggest an adverse effect of

  16. Peroxisome proliferator-activated receptors in cardiac energy metabolism and cardiovascular disease.

    Science.gov (United States)

    Ajith, Thekkuttuparambil Ananthanarayanan; Jayakumar, Thankamani Gopinathan

    2016-07-01

    Cardiomyocytes mainly depend on energy produced from the oxidation of fatty acids and mitochondrial oxidative phosphorylation. Shortage of energy or excessive fat accumulation can lead to cardiac disorders. High saturated fat intake and a sedentary life style have a major influence in the development of cardiovascular disease (CVD). Peroxisome proliferator-activated receptors (PPARs), one of the nuclear receptor super family members, play critical role in the metabolism of lipids by regulating their oxidation and storage. Furthermore, they are involved in glucose homeostasis as well. PPARs, mainly alpha (α) and beta/delta (β/δ), have a significant effect on the lipid metabolism and anti-inflammation in endothelial cells (ECs), vascular smooth muscle cells, and also in cardiomyocytes. Pro-inflammatory cytokines, mainly tumour necrosis factor-α, released at the site of inflammation in the sub-ECs of coronary arteries can inactivate the PPARs which can eventually lead to decreased energy production in the myocardium. Various synthetic ligands of PPAR-α and β/δ have many favourable effects in modulating the vascular diseases and heart failure. Despite the adverse effects from therapy using PPAR- gamma ligands, several laboratories are now focused on synthesizing partial activators which may combine their beneficial effects with lowering of undesirable side effects. This review discusses the role of isoforms of PPAR in the cardiomyocytes energy balance and CVD. The knowledge will help in the synthesis of ligands for their partial activation in order to render energy balance and protection from CVD. © 2016 John Wiley & Sons Australia, Ltd.

  17. Association analysis of peroxisome proliferator-activated receptors gamma gene polymorphisms with asprin hypersensitivity in asthmatics

    Science.gov (United States)

    Oh, Sun-Hee; Park, Se-Min; Park, Jong-Sook; Jang, An-Soo; Lee, Yong-Mok; Uh, Soo-Taek; Kim, Young Hoon; Choi, In-Seon; Kim, Mi-Kyeong; Park, Byeong Lae

    2009-01-01

    Purpose Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors activated by ligands of the nuclear hormone receptor superfamily. The activation of PPARγ regulates inflammation by downregulating the production of Th2 type cytokines and eosinophil function. In addition, a range of natural substances, including arachidonate pathway metabolites such as 15-hydroxyeicosatetranoic acid (15-HETE), strongly promote PPARG expression. Therefore, genetic variants of the PPARG gene may be associated with the development of aspirin-intolerant asthma (AIA). We investigated the relationship between single nucleotide polymorphism (SNP) of the PPARG gene and AIA. Methods Based on the results of an oral aspirin challenge, asthmatics (n=403) were categorized into two groups: those with a decrease in FEV1 of 15% or greater (AIA) or less than 15% (aspirin-tolerant asthma, ATA). We genotyped two single nucleotide polymorphisms in the PPARG gene from Korean asthmatics and normal controls (n=449): +34C>G (Pro12Ala) and +82466C>T (His449His). Results Logistic regression analysis showed that +82466C>T and haplotype 1 (CC) were associated with the development of aspirin hypersensitivity in asthmatics (P=0.04). The frequency of the rare allele of +82466C>T was significantly higher in AIA patients than in ATA patients in the recessive model [P=0.04, OR=3.97 (1.08-14.53)]. In addition, the frequency of PPARG haplotype 1 was significantly lower in AIA patients than in ATA patients in the dominant model (OR=0.25, P=0.04). Conclusions The +82466C>T polymorphism and haplotype 1 of the PPARG gene may be linked to increased risk for aspirin hypersensitivity in asthma. PMID:20224667

  18. Association of peroxisome proliferator-activated receptor-gamma gene polymorphisms with the development of asthma.

    Science.gov (United States)

    Oh, Sun-Hee; Park, Se-Min; Lee, Yoo Hoon; Cha, Ji Yeon; Lee, Ji-Yeon; Shin, Eun Kyong; Park, Jong-Sook; Park, Byeong-Lae; Shin, Hyoung Doo; Park, Choon-Sik

    2009-07-01

    The peroxisome proliferator-activated receptors (PPAR) are the nuclear hormone receptor superfamily of ligand-activated transcriptional factors. PPAR-gamma (PPARG) activation downregulates production of Th2 type cytokines and eosinophil function. Additionally, treatment with a synthetic PPARG ligand can reduce lung inflammation and IFN-gamma, IL-4, and IL-2 production in experimental allergic asthma. In patients with asthma, PPARG gene expression is known to be associated with the airway inflammatory and remodeling responses. Thus, genetic variants of PPARG may be associated with the development of asthma. We genotyped two single nucleotide polymorphisms on the PPARG gene, +34C>G (Pro12Ala) and +82466C>T (His449His), in Korean subjects (839 subjects with asthma and 449 normal controls). Association analysis using logistic regression analysis showed that +82466C>T and haplotypes 1(CC) and 2(CT) were associated with the development of asthma (p=0.01-0.04). The frequency of PPARG-ht2 was significantly lower in the patients with asthma compared to the normal controls in codominant and dominant models (p=0.01, p(corr)=0.03 and p=0.02, p(corr)=0.03, respectively). Conversely, the frequency of PPARG-ht1 was significantly higher in the patients with asthma compared to the normal controls in the codominant model [p=0.04, OR: 1.27 (1.01-1.6)]. In addition, the rare allele frequency of +82466C>T was significantly lower in patients with asthma in comparison to normal controls in the codominant model (OR: 0.78, p=0.04). Thus, polymorphism of the PPARG gene may be linked to an increased risk of asthma development.

  19. Genetic variants of peroxisome proliferator-activated receptor δ are associated with gastric cancer.

    Science.gov (United States)

    Jeon, Christie; Chang, Shen-Chih; Mu, Lina; Zhao, Jinkou; Rao, Jian-Yu; Lu, Qing-Yi; Zhang, Zuo-Feng

    2013-10-01

    Peroxisome proliferator-activated receptors (PPAR) are implicated in pathogenesis of insulin resistance and cancers of the digestive system. We investigated the associations of single nucleotide polymorphisms (SNPs) of PPAR δ and γ with gastric cancer and explored interactions with risk factors of gastric cancer. We conducted our analysis in a case-control study of 196 gastric cancer patients and 397 controls residing in the Taixing region of Jiangsu, China. Six SNPs in the PPARδ (rs2076167, rs3734254) and PPARγ genes (rs10865710, rs1801282, rs3856806, rs13306747) were genotyped. We employed logistic regression to evaluate the association between each genotype and gastric cancer and tested for gene-environment interaction with Helicobacter pylori (H. pylori) infection, smoking status, and meat and salt intake. We found that the G/G variant rs2076167, in tight linkage disequilibrium with rs3734254 (R (2) = 0.97), was associated with increased risk of gastric cancer in a recessive model (OR 2.20, 95 % CI 1.12, 4.32). The association between G/G variant of rs2016167 and gastric cancer was particularly strong among those with higher salt intake (OR 5.11, 95 % CI 1.11, 23.5), but did not vary by H. pylori infection or smoking status. We found that genetic variants of PPARδ were associated with gastric cancer. If the association is confirmed in larger studies, it may implicate a role for PPARδ activators, such as insulin-sensitizing agents, in prevention of gastric cancer.

  20. Peroxisome proliferator-activated receptor-gamma gene: a key regulator of adipocyte differentiation in chickens.

    Science.gov (United States)

    Wang, Y; Mu, Y; Li, H; Ding, N; Wang, Q; Wang, Y; Wang, S; Wang, N

    2008-02-01

    The peroxisome proliferator-activated receptors (PPAR) are members of the nuclear hormone receptor superfamily. Peroxisome proliferator-activated receptor-gamma is regarded as a "master regulator" of adipocyte differentiation in mammals. The current study was designed to investigate the function and regulatory mechanism of PPARgamma in chicken adipogenesis by RNA interference. Preadipocytes were isolated from the abdominal fat tissue of 12-d-old chickens and cultured. Small-interference PPARgamma RNA (siPPARgamma) was synthesized by in vitro transcription and transfected into chicken preadipocytes by using liposomes. The suppressive effect of siPPARgamma was detected by real-time reverse-transcription PCR and reverse-transcription PCR. The results showed that transient transfection with siPPARgamma significantly inhibited differentiation and enhanced proliferation of chicken preadipocytes (P adipogenesis-associated adipocyte fatty acid-binding protein gene was down-regulated when PPARgamma was silenced. The current work indicates that PPARgamma is a key regulator of chicken preadipocyte differentiation.

  1. Tumor necrosis factor alpha and interleukin 11 secreted by malignant breast epithelial cells inhibit adipocyte differentiation by selectively down-regulating CCAAT/enhancer binding protein alpha and peroxisome proliferator-activated receptor gamma: mechanism of desmoplastic reaction.

    Science.gov (United States)

    Meng, L; Zhou, J; Sasano, H; Suzuki, T; Zeitoun, K M; Bulun, S E

    2001-03-01

    The dense layer of fibroblasts that accumulate around malignant breast epithelial cells (i.e., desmoplastic reaction) arises from the breast adipose tissue and provides structural and biochemical support for breast cancer. We report herein a number of epithelial-stromal interactions responsible for desmoplastic reaction in breast cancer using cultured 3T3-L1 murine fibroblasts and human adipose fibroblasts, which can be activated with a mixture of hormones to differentiate to mature adipocytes. Adipocyte differentiation was inhibited by coculturing fibroblasts with various breast cancer cell lines (T47D, MCF-7, SSC202, SSC78, and SSC30) completely or by breast cancer cell conditioned media in a dose-dependent manner; on the other hand, adipocyte differentiation was not inhibited by coculturing with normal human primary mammary epithelial cell conditioned medium. This tumor effect was eliminated using neutralizing antibodies against tumor necrosis factor (TNF)-alpha or interleukin (IL)-11. TNF-alpha and IL-11 levels were 2.5-3 times higher in T47D conditioned medium compared with control medium, and TNF-alpha transcripts were detectable in T47D but not in 3T3-L1 cells in culture, indicating that the malignant epithelial cell is the major site of cytokine production. This was confirmed in vivo in mastectomy specimens, where immunoreactive TNF-alpha and IL-11 were readily detectable in malignant epithelial cells but not in the majority of the surrounding fibroblasts. Adipocyte differentiation is mediated by the expression of a cascade of adipogenic transcription factors, including CCAAT/enhancer binding protein (C/EBP)beta, C/EBPdelta, peroxisome proliferator-activated receptor (PPAR)gamma and C/EBPalpha. C/EBPalpha and PPARgamma are essential for this process. We demonstrated by Northern analysis that exposure of activated 3T3-L1 cells to T47D cell conditioned medium strikingly decreased the levels of PPARgamma and C/EBPalpha transcripts and increased the levels of C

  2. [Role of the fatty acids in ovarian functions: involvement of peroxisome proliferator-activated receptors (PPAR) and adipokines].

    Science.gov (United States)

    Dupont, J; Froment, P; Ramé, C; Pierre, P; Coyral-Castel, S; Chabrolle, C

    2008-12-01

    The impact of nutrition and energy reserves on the reproductive functions is known for a very long time. However, the metabolic factors involved in the interactions between nutrition and reproduction are still poorly understood. These factors may be hormones or nutrients (glucose, protein and fatty acids). However, it remains to determine whether these factors act directly or indirectly on the reproductive tissues. In this issue, we briefly summarize the impact of fatty acids on the development of ovarian follicles, oocyte and embryo. We then discuss the current hypotheses about the mechanisms of action of these fatty acids on the ovarian functions. We describe more particularly the role of some receptors of fatty acids, Peroxisome Proliferator-Activated Receptors (PPAR) and Liver X Receptors (LXR) and two adipokines, leptin and adiponectin on ovarian cells.

  3. Estrogen receptor alpha binds to peroxisome proliferator-activated receptor response element and negatively interferes with peroxisome proliferator-activated receptor gamma signaling in breast cancer cells.

    Science.gov (United States)

    Bonofiglio, Daniela; Gabriele, Sabrina; Aquila, Saveria; Catalano, Stefania; Gentile, Mariaelena; Middea, Emilia; Giordano, Francesca; Andò, Sebastiano

    2005-09-01

    The molecular mechanisms involved in the repressive effects exerted by estrogen receptors (ER) on peroxisome proliferator-activated receptor (PPAR) gamma-mediated transcriptional activity remain to be elucidated. The aim of the present study was to provide new insight into the crosstalk between ERalpha and PPARgamma pathways in breast cancer cells. Using MCF7 and HeLa cells as model systems, we did transient transfections and electrophoretic mobility shift assay and chromatin immunoprecipitation studies to evaluate the ability of ERalpha to influence PPAR response element-mediated transcription. A possible direct interaction between ERalpha and PPARgamma was ascertained by co-immunoprecipitation assay, whereas their modulatory role in the phosphatidylinositol 3-kinase (PI3K)/AKT pathway was evaluated by determining PI3K activity and AKT phosphorylation. As a biological counterpart, we investigated the growth response to the cognate ligands of both receptors in hormone-dependent MCF7 breast cancer cells. Our data show for the first time that ERalpha binds to PPAR response element and represses its transactivation. Moreover, we have documented the physical and functional interactions of ERalpha and PPARgamma, which also involve the p85 regulatory subunit of PI3K. Interestingly, ERalpha and PPARgamma pathways have an opposite effect on the regulation of the PI3K/AKT transduction cascade, explaining, at least in part, the divergent response exerted by the cognate ligands 17beta-estradiol and BRL49653 on MCF7 cell proliferation. ERalpha physically associates with PPARgamma and functionally interferes with PPARgamma signaling. This crosstalk could be taken into account in setting new pharmacologic strategies for breast cancer disease.

  4. Topical Rosiglitazone Treatment Improves Ulcerative Colitis by Restoring Peroxisome Proliferator-Activated Receptor-gamma Activity

    DEFF Research Database (Denmark)

    Pedersen, G.; Brynskov, Jørn

    2010-01-01

    OBJECTIVES: Impaired epithelial expression of peroxisome proliferator-activated receptor-gamma (PPAR gamma) has been described in animal colitis models and briefly in patients with ulcerative colitis, but the functional significance in humans is not well defined. We examined PPAR gamma expression...... and functional activity in human colonic epithelium and explored the potential of topical treatment with rosiglitazone (a PPAR gamma ligand) in patients with ulcerative colitis. METHODS: Spontaneous and rosiglitazone-mediated PPAR gamma and adipophillin expression (a gene transcriptionally activated by PPAR...... for 14 days. RESULTS: PPAR gamma expression was fourfold reduced in epithelial cells from inflamed compared with uninflamed mucosa and controls. Adipophillin levels were decreased in parallel. Rosiglitazone induced a concentration-dependent increase in adipophillin levels and restored PPAR gamma activity...

  5. Targeting the Peroxisome Proliferator-Activated Receptor-γ to Counter the Inflammatory Milieu in Obesity

    Directory of Open Access Journals (Sweden)

    Cesar Corzo

    2013-12-01

    Full Text Available Adipose tissue, which was once viewed as a simple organ for storage of triglycerides, is now considered an important endocrine organ. Abnormal adipose tissue mass is associated with defects in endocrine and metabolic functions which are the underlying causes of the metabolic syndrome. Many adipokines, hormones secreted by adipose tissue, regulate cells from the immune system. Interestingly, most of these adipokines are proinflammatory mediators, which increase dramatically in the obese state and are believed to be involved in the pathogenesis of insulin resistance. Drugs that target peroxisome proliferator-activated receptor-γ have been shown to possess anti-inflammatory effects in animal models of diabetes. These findings, and the link between inflammation and the metabolic syndrome, will be reviewed here.

  6. Peroxisome proliferator-activated receptors (PPARs) and PPAR agonists: the 'future' in dermatology therapeutics?

    Science.gov (United States)

    Gupta, Mrinal; Mahajan, Vikram K; Mehta, Karaninder S; Chauhan, Pushpinder S; Rawat, Ritu

    2015-11-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors and comprise three different isoforms namely PPARα, PPARγ, and PPARβ/δ with PPARβ/δ being the predominant subtype in human keratinocytes. After binding with specific ligands, PPARs regulate gene expression, cell growth and differentiation, apoptosis, inflammatory responses, and tumorogenesis. PPARs also modulate a wide variety of skin functions including keratinocyte proliferation, epidermal barrier formation, wound healing, melanocyte proliferation, and sebum production. Recent studies have shown the importance of PPARs in the pathogenesis of many dermatological disorders. Clinical trials have suggested possible role of PPAR agonists in the management of various dermatoses ranging from acne vulgaris, psoriasis, hirsutism, and lipodystrophy to cutaneous malignancies including melanoma. This article is intended to be a primer for dermatologists in their understanding of clinical relevance of PPARs and PPAR agonists in dermatology therapeutics.

  7. Green tea catechins prevent obesity through modulation of peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Yan, Jingqi; Zhao, Yan; Zhao, Baolu

    2013-09-01

    Epidemiological evidence and experimental studies suggest that drinking green tea is associated with a lower risk of obesity and related diseases. However, the mechanisms of these effects are not clear. In the present study, we investigated the anti-obesity mechanisms of green tea catechins (GTCs) through modulation of peroxisome proliferator activated-receptor (PPAR) pathways in high-fat diet-induced obesity in rats. GTC supplementation significantly attenuated the increased body and liver weights and the elevated serum and liver triglyceride levels. Meanwhile, GTCs increased the PPARγ levels in subcutaneous white adipose tissue (SWAT) and decreased the PPARγ levels in visceral white adipose tissue (VWAT). In addition, GTC treatment up-regulated the levels of PPARδ in SWAT, VWAT, and brown adipose tissue and increased the expression of genes involved in fatty acid oxidation in brown adipose tissue. Our results suggest that GTCs exert their anti-obesity mechanism in part by modulating PPAR signaling pathways.

  8. Antifibrotic effect by activation of peroxisome proliferator-activated receptor-gamma in corneal fibroblasts.

    Science.gov (United States)

    Pan, Hongwei; Chen, Jiansu; Xu, Jintang; Chen, Miaojiao; Ma, Rong

    2009-11-10

    The transformation of quiescent keratocytes to active phenotypes and the ensuing fibrotic response play important roles in corneal scar formation. This study aims to observe the antifibrotic effect of peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist on corneal fibroblasts cultured in vitro, and to explore the potential application of peroxisome proliferator-activated receptor agonist to the prevention of corneal opacity following wound repair. Rabbit corneal keratocytes were cultured in a medium containing 10% serum to induce their transformation to fibroblasts and myofibroblasts, which are similar to those that repair corneas. After incubation with the PPARgamma agonist pioglitazone at different concentrations, the effect of pioglitazone on the migration, contractility, and viability of corneal fibroblasts was examined. The secretion of matrix metalloproteinase-2 and matrix metalloproteinase-9 was determined by gelatin zymography, and the synthesis of collagen I and fibronectin was investigated by western blotting. Treatment with pioglitazone at concentrations ranging from 1 to 10 mum significantly decreased corneal fibroblast migration, as determined by scrape-wound assay, inhibited corneal fibroblast-induced collagen lattice contraction, and reduced MMP-2 and MMP-9 secretion into the supernatant of cell cultures in a dose-dependent manner. The expression of fibronectin was significantly decreased, while the expression of collagen I was only decreased when treated with 10 mum pioglitazone. Cell viability was not evidently changed compared to the control. This in vitro study demonstrated the anti-fibrotic effect of pioglitazone, suggesting that activation of PPARgamma may be a new approach for the treatment of corneal opacity and scar formation in the corneal wound healing process.

  9. Phytoceramide and sphingoid bases derived from brewer's yeast Saccharomyces pastorianus activate peroxisome proliferator-activated receptors

    Directory of Open Access Journals (Sweden)

    Mitsutake Susumu

    2011-08-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptors (PPARs are ligand-activated transcription factors that regulate lipid and glucose metabolism. PPARα is highly expressed in the liver and controls genes involved in lipid catabolism. We previously reported that synthetic sphingolipid analogs, part of which contains shorter-length fatty acid chains than natural sphingolipids, stimulated the transcriptional activities of PPARs. Sphingosine and dihydrosphingosine (DHS are abundant sphingoid bases, and ceramide and dihydroceramide are major ceramide species in mammals. In contrast, phytosphingosine (PHS and DHS are the main sphingoid bases in fungi. PHS and phytoceramide exist in particular tissues such as the epidermis in mammals, and involvement of ceramide species in PPARβ activation in cultured keratinocytes has been reported. The purpose of the present study is to investigate whether natural sphingolipids with C18 fatty acid and yeast-derived sphingoid bases activate PPARs as PPAR agonists. Method Lipids of brewer's yeast contain PHS- and DHS-based sphingolipids. To obtain the sphingoid bases, lipids were extracted from brewer's yeast and acid-hydrolyzed. The sphingoid base fraction was purified and quantified. To assess the effects of sphingolipids on PPAR activation, luciferase reporter assay was carried out. NIH/3T3 and human hepatoma (HepG2 cells were transfected with expression vectors for PPARs and retinoid × receptors, and PPAR responsive element reporter vector. When indicated, the PPAR/Gal4 chimera system was performed to enhance the credibility of experiments. Sphingolipids were added to the cells and the dual luciferase reporter assay was performed to determine the transcriptional activity of PPARs. Results We observed that phytoceramide increased the transcriptional activities of PPARs significantly, whereas ceramide and dihydroceramide did not change PPAR activities. Phytoceramide also increased transactivation of

  10. Peroxisome proliferator activated receptor-γ in pathogenesis of experimental fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Cai-Yan Zhao; Ling-Ling Jiang; Li Li; Zhuo-Jun Deng; Bao-Li Liang; Jian-Mei Li

    2004-01-01

    AIM: To study the expression of peroxisome proliferator activated receptor-γ (PPARγ) in the liver of rats with fatty liver disease (FLD) and to explore the role of PPARγ in the pathogenesis of FLD to provide the basis for using PPARγligand to treat patients with FLD.METHODS: Forty Wistar rats were divided into 4 groups of ten rats each randomly: normal group (group A), alcohol group (group B), fat-rich diet group (group C), alcohol and fat-rich diet group (group D). The rats were sacrificed at the end of the 16th week from the feeding day. Alanine aminotransferase (ALT), tumor necrosis factor-alfa (TNFα)in serum and malondialdehyde (MDA) in liver homogenate were determined; livers were collected for observing pathologic changes by HE, Sudan Ⅳ, Masson stain under microscope. The morphologic results were analyzed by picture quantitative analysis technique. The changes of ultrastructure were also examined under electron microscope.The expression of PPARγ in liver was detected by immunohistochemistry and RT-PCR. The correlations between the expression of PPARγ and biochemical indexes, and liver histology were analyzed.RESULTS: The steatosis, inflammation, necrosis and fibrosis were present in livers of different experimental groups,especially in livers of alcohol and fat-rich diet group. The content of immunodetectable PPARγ was decreasedremarkably in the livers of model rats (group B-D); the level in alcohol and fat-rich diet group (3.43±1.48) was significantly lower than that in normal group (18.34±3.73), alcohol group (8.82±2.52) and fat-rich diet group (11.73±2.51) (all P<0.01).The level of PPARγ mRNA was also lower in the livers of model rats (group B-D) than in'livers of controls. The expression of PPARγ in rat liver correlated negatively with the degree of its inflammation, necrosis and fibrosis, as well as the level of serum TNFα and the content of MDA in liver homogenates, but not with steatosis or serum ALT.CONCLUSION: Decreased expression

  11. Peroxisome proliferator-activated receptor-gamma agonist rosiglitazone attenuates postincisional pain by regulating macrophage polarization

    Energy Technology Data Exchange (ETDEWEB)

    Hasegawa-Moriyama, Maiko, E-mail: hase-mai@m3.kufm.kagoshima-u.ac.jp [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan); Ohnou, Tetsuya; Godai, Kohei; Kurimoto, Tae; Nakama, Mayo; Kanmura, Yuichi [Department of Anesthesiology and Critical Care Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520 (Japan)

    2012-09-14

    Highlights: Black-Right-Pointing-Pointer Rosiglitazone attenuated postincisional pain. Black-Right-Pointing-Pointer Rosiglitazone alters macrophage polarization to F4/80{sup +}CD206{sup +} M2 macrophages at the incisional sites. Black-Right-Pointing-Pointer Transplantation of rosiglitazone-treated macrophages produced analgesic effects. -- Abstract: Acute inflammation triggered by macrophage infiltration to injured tissue promotes wound repair and may induce pain hypersensitivity. Peroxisome proliferator-activated receptor {gamma} (PPAR){gamma} signaling is known to regulate heterogeneity of macrophages, which are often referred to as classically activated (M1) and alternatively activated (M2) macrophages. M1 macrophages have considerable antimicrobial activity and produce a wide variety of proinflammatory cytokines. In contrast, M2 macrophages are involved in anti-inflammatory and homeostatic functions linked to wound healing and tissue repair. Although it has been suggested that PPAR{gamma} agonists attenuate pain hypersensitivity, the molecular mechanism of macrophage-mediated effects of PPAR{gamma} signaling on pain development has not been explored. In this study, we investigated the link between the phenotype switching of macrophage polarization induced by PPAR{gamma} signaling and the development of acute pain hypersensitivity. Local administration of rosiglitazone significantly ameliorated hypersensitivity to heat and mechanical stimuli, and paw swelling. Consistent with the down-regulation of nuclear factor {kappa}B (NF{kappa}B) phosphorylation by rosiglitazone at the incisional sites, the number of F4/80{sup +}iNOS{sup +} M1 macrophages was decreased whereas numbers of F4/80{sup +}CD206{sup +} M2 macrophages were increased in rosiglitazone-treated incisional sites 24 h after the procedure. In addition, gene induction of anti-inflammatory M2-macrophage-associated markers such as arginase1, FIZZ1 and interleukin (IL)-10 were significantly increased, whereas

  12. Effects of peroxisome proliferator-activated receptor-β/δ on sepsis induced acute lung injury

    Institute of Scientific and Technical Information of China (English)

    Wang Cairui; Zhou Guopeng; Zeng Zeng

    2014-01-01

    Background Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the first steps in the development of multiple organ failure induced by sepsis.A systemic excessive inflammatory reaction is currently the accepted mechanism of the pathogenesis of sepsis.Several studies have suggested a protective role of the peroxisome proliferator activated receptor-β/δ (PPAR-β/δ) in related inflammatory diseases.But the role of PPARβ/δ in ALI remains uncertain.The aim of this study was to investigate the role and possible mechanism of PPARβ/δ in ALI induced by sepsis.Methods Cecal ligation and puncture (CLP) was used as a sepsis model.Rats were randomly divided into four groups,the control group (CON,n=6),sham-operation group (SHAM,n=12),cecal ligation and puncture group (CLP,n=30),GW501516 group (CLP+GW,n=25),which underwent CLP and were subcutaneously injected with the PPAR-β/δ agonist GW501516 (0.05 mg/100 g body weight).Survival was monitored to 24 hours after operation.Blood pressure,serum creatinine,blood urea nitrogen,aspartate aminotrasferase and alanine aminotrasferase were measured after CLP.Concentrations of tumor necrosis factor α (TNF-α) and interleukin (IL)-1β in serum were detected by enzyme linked immunosorbent assay (ELISA) kits.Lung tissue samples were stained with H&E and scored according to the degree of inflammation.Bacterial colonies were counted in the peritoneal fluid.Alveolar macrophages were cultured and incubated with GW501516 (0.15 μmol/L) and PPARβ/δ adenovirus and then treated with Lipopolysaccharide (2 μg/ml) for 2 hours.The TNF-α,IL-1β and IL-6 RNA in lung and alveolar macrophages were determined by real-time PCR.Phosphorylation of signal transducer and activator of transcription 3 (STAT3) in lung and alveolar macrophages was detected by Western blotting.Results GW501516 significantly increased the survival of septic rats,decreased histological damage of the lungs,reduced inflammatory cytokines in serum and

  13. Phytoceramide and sphingoid bases derived from brewer's yeast Saccharomyces pastorianus activate peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Murakami, Itsuo; Wakasa, Yukari; Yamashita, Shinji; Kurihara, Toshio; Zama, Kota; Kobayashi, Naoyuki; Mizutani, Yukiko; Mitsutake, Susumu; Shigyo, Tatsuro; Igarashi, Yasuyuki

    2011-08-24

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate lipid and glucose metabolism. PPARα is highly expressed in the liver and controls genes involved in lipid catabolism. We previously reported that synthetic sphingolipid analogs, part of which contains shorter-length fatty acid chains than natural sphingolipids, stimulated the transcriptional activities of PPARs. Sphingosine and dihydrosphingosine (DHS) are abundant sphingoid bases, and ceramide and dihydroceramide are major ceramide species in mammals. In contrast, phytosphingosine (PHS) and DHS are the main sphingoid bases in fungi. PHS and phytoceramide exist in particular tissues such as the epidermis in mammals, and involvement of ceramide species in PPARβ activation in cultured keratinocytes has been reported. The purpose of the present study is to investigate whether natural sphingolipids with C18 fatty acid and yeast-derived sphingoid bases activate PPARs as PPAR agonists. Lipids of brewer's yeast contain PHS- and DHS-based sphingolipids. To obtain the sphingoid bases, lipids were extracted from brewer's yeast and acid-hydrolyzed. The sphingoid base fraction was purified and quantified. To assess the effects of sphingolipids on PPAR activation, luciferase reporter assay was carried out. NIH/3T3 and human hepatoma (HepG2) cells were transfected with expression vectors for PPARs and retinoid × receptors, and PPAR responsive element reporter vector. When indicated, the PPAR/Gal4 chimera system was performed to enhance the credibility of experiments. Sphingolipids were added to the cells and the dual luciferase reporter assay was performed to determine the transcriptional activity of PPARs. We observed that phytoceramide increased the transcriptional activities of PPARs significantly, whereas ceramide and dihydroceramide did not change PPAR activities. Phytoceramide also increased transactivation of PPAR/Gal4 chimera receptors. Yeast-derived sphingoid

  14. Peroxisome proliferator-activated receptor Pro12Ala polymorphism and the risks of gestational diabetes mellitus

    Science.gov (United States)

    Wang, Lihong; Xu, Wenting; Wang, Xu

    2016-01-01

    Abstract Background: Peroxisome proliferator-activated receptors-λ (PPAR-λ) is a member of nuclear receptor superfamily and acts as a ligand-dependent transcription factor often found in the adrenal gland, the spleen, and adipose tissue. The Pro12Ala polymorphism of PPAR-λ has been associated with the risks of gestational diabetes mellitus (GDM); however, association studies have provided conflicting results. The aim of this Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant meta-analysis is to reach a more up-to-date and accurate estimation of the relationship between Pro12Ala genetic polymorphisms and the risks of GDM. Methods: Eligible studies were retrieved by searching PubMed, EMBASE, Web of Science, Ovid, WanFang, and Chinese National Knowledge Databases and selected according to a pre-defined inclusion criterion. The risk of bias was assessed using the Newcastle-Ottawa quality assessment scale. The per-allele odds ratio (OR) of risk allele proline (Pro) was compared between cases and controls in each study to describe the association between the Pro allele and an individual's risk of GDM. The ORs were pooled using both the random-effects model (the DerSimonian and Laird method) and the fixed effects model (the Mantel-Haenszel method) and the 95% confidence interval (95% CI) was calculated using Woolf method. Results: The final meta-analysis included a total of 11 articles of 12 data sets consisting of 7054 controls and 2980 GDM cases. Our results demonstrate that the Pro allele is not associated with GDM [OR: across multiple populations, 95% CI: 0.98–1.24; P(Z) = 0.01; P(Q) = 0.003]. In the stratified analysis by ethnicity, significantly increased risks were found for the Chinese (OR = 2.36; 95% CI: 1.47–3.78) and Korean (OR = 1.39; 95% CI: 1.00–1.93) populations. Conclusion: These data suggest the potential role of Pro allele in the pathogenesis of GDM in Asian populations. Although the funnel plot

  15. Peroxisome Proliferator-Activated Receptor (PPAR) in Regenerative Medicine: Molecular Mechanism for PPAR in Stem Cells' Adipocyte Differentiation.

    Science.gov (United States)

    Xie, Qiang; Tian, Taoran; Chen, Zhaozhao; Deng, Shuwen; Sun, Ke; Xie, Jing; Cai, Xiaoxiao

    2016-01-01

    Regenerative medicine plays an indispensable role in modern medicine and many trials and researches have therefore been developed to fit our medical needs. Tissue engineering has proven that adipose tissue can widely be used and brings advantages to regenerative medicine. Moreover, a trait of adipose stem cells being isolated and grown in vitro is a cornerstone to various applications. Since the adipose tissue has been widely used in regenerative medicine, numerous studies have been conducted to seek methods for gaining more adipocytes. To investigate molecular mechanism for adipocyte differentiation, peroxisome proliferator-activated receptor (PPAR) has been widely studied to find out its functional mechanism, as a key factor for adipocyte differentiation. However, the precise molecular mechanism is still unknown. This review thus summarizes recent progress on the study of molecular mechanism and role of PPAR in adipocyte differentiation.

  16. Potential effects of curcumin on peroxisome proliferator-activated receptor-γ in vitro and in vivo.

    Science.gov (United States)

    Mazidi, Mohsen; Karimi, Ehsan; Meydani, Mohsen; Ghayour-Mobarhan, Majid; Ferns, Gordon A

    2016-03-26

    Natural peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biological properties that appear to operate through diverse mechanisms. Some of these potentially beneficial effects of Cur are due to activation of the nuclear transcription factor PPAR-γ. It is reported (using in vitro and in vivo models) that Cur plays a potential role against several diseases. In this review article, we present the current literature on the effects of Cur on the modulation of inflammatory processes that are mediated through PPAR-γ.

  17. Activation of Penile Proadipogenic Peroxisome Proliferator-Activated Receptor with an Estrogen: Interaction with Estrogen Receptor Alpha during Postnatal Development

    Directory of Open Access Journals (Sweden)

    Mahmoud M. Mansour

    2008-01-01

    Full Text Available Exposure to the estrogen receptor alpha (ER ligand diethylstilbesterol (DES between neonatal days 2 to 12 induces penile adipogenesis and adult infertility in rats. The objective of this study was to investigate the in vivo interaction between DES-activated ER and the proadipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPAR. Transcripts for PPARs , , and and 1a splice variant were detected in Sprague-Dawley normal rat penis with PPAR predominating. In addition, PPAR1b and PPAR2 were newly induced by DES. The PPAR transcripts were significantly upregulated with DES and reduced by antiestrogen ICI 182, 780. At the cellular level, PPAR protein was detected in urethral transitional epithelium and stromal, endothelial, neuronal, and smooth muscular cells. Treatment with DES activated ER and induced adipocyte differentiation in corpus cavernosum penis. Those adipocytes exhibited strong nuclear PPAR expression. These results suggest a biological overlap between PPAR and ER and highlight a mechanism for endocrine disruption.

  18. The effect of bioactive compounds in tea on lipid metabolism and obesity through regulation of peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Lee, Sung-Joon; Jia, Yaoyao

    2015-02-01

    The hypolipidemic and antiobesogenic effects of tea intake have been associated with bioactive compounds that regulate peroxisome proliferator-activated receptors (PPARs). This review describes the recent research on two of these compounds, (-)-epigallocatechin gallate (EGCG) and linalool. Catechins (specifically EGCG) are key bioactive compounds found in tea, and a recent study has shown that linalool may also be an active tea compound. These compounds act on lipid metabolism by regulating PPAR subtypes. EGCG inhibits the key adipogenic transcription factor PPARγ while activating PPARα, whereas linalool is a PPARα agonist activating hepatic fatty acid uptake and subsequent oxidation to reduce plasma triglyceride levels. The collective activities of EGCG and linalool in tea may exert hypolipidemic and antiobesogenic effects by regulating PPARs. The research summarized in this review expands our understanding of the biological and physiological mechanisms of the bioactive compounds found in tea.

  19. Peroxisome proliferator-activated receptors: role of isoform gamma in the antineoplastic effect of iodine in mammary cancer.

    Science.gov (United States)

    Nunez-Anita, R E; Cajero-Juarez, M; Aceves, C

    2011-09-01

    Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors. Three subtypes--PPAR alpha, PPAR beta, and PPAR gamma--have been identified and are differentially expressed in tissues. Originally, they were described as molecular regulators of lipid metabolism; recently, it has been shown that they are also involved in regulating the cell cycle and apoptosis in both normal and tumoral cells. In fact, some synthetic PPAR ligands are used to treat dyslipidemia, metabolic diseases, and type 2 diabetes. Here, we review the role of PPAR gamma (PPARγ) in tumor initiation and progression, emphasizing the relationship between this isoform and the cellular and molecular mechanisms involved in the antineoplastic effect of iodine on mammary cancer.

  20. Potential effects of curcumin on peroxisome proliferator-activated receptor-gamma in vitro and in vivo

    Science.gov (United States)

    Natural peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists are found in food and may be important for health through their anti-inflammatory properties. Curcumin (Cur) is a bright yellow spice, derived from the rhizome of Curcuma longa Linn. It has been shown to have many biologi...

  1. The effect of quercetin and kaempferol aglycones and glucuronides on peroxisome proliferator-activated receptor-gamma (PPAR-¿)

    NARCIS (Netherlands)

    Beekmann, K.; Rubió, L.; Haan, de L.H.J.; Actis Goretta, L.; Burg, van der B.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2015-01-01

    The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-¿). Flavonoids are extensively metabolized during and after uptake and there is little known on the biol

  2. Peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala polymorphism and risk for pediatric obesity

    NARCIS (Netherlands)

    Dedoussis, George V; Vidra, Nikoleta; Butler, Johannah; Papoutsakis, Constantina; Yannakoulia, Mary; Hirschhorn, Joel N; Lyon, Helen N; Vidra, Nikoletta

    2009-01-01

    BACKGROUND: Variation in the peroxisome-proliferator-activated receptor gamma (PPARgamma) gene has been reported to alter the risk for adiposity in adults. METHODS: We investigated the gender related association between the Pro12Ala variant (rs1801282) in obesity and insulin resistance traits in 794

  3. Stable reporter cell lines for peroxisome proliferator-activated receptor y (PPARy)-mediated modulation of gene expression

    NARCIS (Netherlands)

    Gijsbers, L.; Man, H.Y.; Kloet, S.K.; Haan, de L.H.J.; Keijer, J.; Rietjens, I.; Burg, van der B.J.; Aarts, J.M.M.J.G.

    2011-01-01

    Activation of peroxisome proliferator-activated receptor ¿ (PPAR¿) by ligands is associated with beneficial health effects, including anti-inflammatory and insulin-sensitizing effects. The aim of the current study was to develop luciferase reporter gene assays to enable fast and low-cost measurement

  4. The effect of quercetin and kaempferol aglycones and glucuronides on peroxisome proliferator-activated receptor-gamma (PPAR-¿)

    NARCIS (Netherlands)

    Beekmann, K.; Rubió, L.; Haan, de L.H.J.; Actis Goretta, L.; Burg, van der B.; Bladeren, van P.J.; Rietjens, I.M.C.M.

    2015-01-01

    The consumption of dietary flavonoids has been associated with a variety of health benefits, including effects mediated by the activation of peroxisome proliferator-activated receptor-gamma (PPAR-¿). Flavonoids are extensively metabolized during and after uptake and there is little known on the

  5. Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells

    DEFF Research Database (Denmark)

    Desch, Michael; Schreiber, Andrea; Schweda, Frank;

    2010-01-01

    We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse re...

  6. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR) γ activators and pan-PPAR partial agonists

    NARCIS (Netherlands)

    Liberato, Marcelo Vizoná; Nascimento, Alessandro S; Ayers, Steven D; Lin, Jean Z; Cvoro, Aleksandra; Silveira, Rodrigo L; Martínez, Leandro; Souza, Paulo C T; Saidemberg, Daniel; Deng, Tuo; Amato, Angela Angelica; Togashi, Marie; Hsueh, Willa A; Phillips, Kevin; Palma, Mário Sérgio; Neves, Francisco A R; Skaf, Munir S; Webb, Paul; Polikarpov, Igor

    2012-01-01

    Thiazolidinediones (TZDs) act through peroxisome proliferator activated receptor (PPAR) γ to increase insulin sensitivity in type 2 diabetes (T2DM), but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of

  7. Peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala polymorphism and risk for pediatric obesity

    NARCIS (Netherlands)

    Dedoussis, George V; Vidra, Nikoleta; Butler, Johannah; Papoutsakis, Constantina; Yannakoulia, Mary; Hirschhorn, Joel N; Lyon, Helen N; Vidra, Nikoletta

    BACKGROUND: Variation in the peroxisome-proliferator-activated receptor gamma (PPARgamma) gene has been reported to alter the risk for adiposity in adults. METHODS: We investigated the gender related association between the Pro12Ala variant (rs1801282) in obesity and insulin resistance traits in 794

  8. Expression of Peroxisome Proliferator-Activated Receptor γ (PPARγ) in Human Transitional Bladder Cancer and its Role in Inducing Cell Death1

    OpenAIRE

    1999-01-01

    The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor γ (PPARγ), in human bladder cancers. In situ hybridization shows that PPARγ mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARγ was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor α (RXRα), a 9-cis-retinoic acid stimul...

  9. Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population

    OpenAIRE

    Hassan Rooki; Monir-Sadat Haerian; Pedram Azimzadeh; Mahmoud Ebrahimi; Reza Mirhafez; Gordon Ferns; Majid Ghayour-Mobarhan; Mohammad-Reza Zali

    2013-01-01

    Background: Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single n...

  10. Telmisartan improves cardiac fibrosis in diabetes through peroxisome proliferator activated receptor δ (PPARδ): from bedside to bench.

    Science.gov (United States)

    Chang, Wei-Ting; Cheng, Juei-Tang; Chen, Zhih-Cherng

    2016-08-12

    PPARδ instead of the AMPK pathway. PPARδ peroxisome proliferator-activated receptor δ, STAT3 signal transducer and activator of transcription 3, CTGF connective tissue growth factor, MMP9 matrix metallopeptidase 9.

  11. Role of peroxisome proliferator-activated receptors alpha and gamma in gastric ulcer: An overview of experimental evidences

    Institute of Scientific and Technical Information of China (English)

    Lekha; Saha

    2015-01-01

    Peroxisome proliferator-activated receptors(PPARs) are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. Three subtypes, PPARα, PPARβ/δ, and PPARγ, have been identifiedso far. PPARα is expressed in the liver, kidney, small intestine, heart, and muscle, where it activates the fatty acid catabolism and control lipoprotein assembly in response to long-chain unsaturated fatty acids, eicosanoids, and hypolipidemic drugs(e.g., fenofibrate). PPARβ/δ is more broadly expressed and is implicated in fatty acid oxidation, keratinocyte differentiation, wound healing, and macrophage response to very low density lipoprotein metabolism. This isoform has been implicated in transcriptional-repression functions and has been shown to repress the activity of PPARα or PPARγ target genes. PPARγ1 and γ2 are generated from a single-gene peroxisome proliferator-activated receptors gamma by differential promoter usage and alternative splicing. PPARγ1 is expressed in colon, immune system(e.g., monocytes and macrophages), and other tissues where it participates in the modulation of inflammation, cell proliferation, and differentiation. PPARs regulate gene expression through distinct mechanisms: Liganddependent transactivation, ligand-independent repression, and ligand-dependent transrepression. Studies in animals have demonstrated the gastric antisecretory activity of PPARα agonists like ciprofibrate, bezafibrate and clofibrate. Study by Pathak et al also demonstrated the effect of PPARα agonist, bezafibrate, on gastric secretion and gastric cytoprotection in various gastric ulcer models in rats. The majority of the experimental studies is on pioglitazone and rosiglitazone, which are PPARγ activators. In all the studies, both the PPARγ activators showed protection against the gastric ulcer and also accelerate the ulcer healing in gastric ulcer model in rats. Therefore, PPARα and PPARγ may be a target for gastric ulcer therapy

  12. Ligands of Peroxisome Proliferator-activated Receptor Inhibit Homocysteineinduced DNA Methylation of Inducible Nitric Oxide Synthase Gene

    Institute of Scientific and Technical Information of China (English)

    Yideng JIANG; Jianzhong ZHANG; Jiantuan XIONG; Jun CAO; Guizhong LI; Shuren WANG

    2007-01-01

    Homocysteine (Hcy) is a risk factor for atherosclerosis. It is generally accepted that inducible nitric oxide synthase (iNOS) is a key enzyme in the regulation of vascular disease. The aim of the present study is to investigate the effects of peroxisome proliferator-activated receptor ligands on iNOS in the presence of Hcy in human monocytes. Foam cells, induced by oxidize low density lipoprotein (ox-LDL) and phorbol myristate acetate (PMA) in the presence of different concentrations of Hcy, clofibrate and pioglitazone in human monocytes for 4 d, were examined by oil red O staining. The activity of iNOS was detected by real-time quantitative reverse transcription-polymerase chain reaction and Western blot analysis. The capability of DNA methylation was measured by assaying endogenous C5 DNA methyltransferase (C5MTase)activity, and the iNOS promoter methylation level was determined by quantitative MethyLight assays. The results indicated that Hcy increased the activity of C5MTase and the level of iNOS gene DNA methylation,resulting in a decrease of iNOS expression. Clofibrate and pioglitazone could antagonize the Hcy effect on iNOS expression through DNA methylation, resulting in attenuation of iNOS transcription. These findings suggested that Hcy decreased the expression of iNOS by elevating iNOS DNA methylation levels, which can repress the transcription of some genes. Peroxisome proliferator-activated receptor α/γ ligands can down-regulate iNOS DNA methylation, and could be useful for preventing Hcy-induced atherosclerosis by repressing iNOS expression.

  13. Suppression of pancreatic carcinoma growth by activating peroxisome proliferator-activated receptor γ involves angiogenesis inhibition

    Institute of Scientific and Technical Information of China (English)

    Yu-Wei Dong; Xing-Peng Wang; Kai Wu

    2009-01-01

    AIM: To study the possible actions and mechanisms of peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated transcription factor, in pancreatic carcinogenesis,especially in angiogenesis.METHODS: Expressions of PPARγ and retinoid acid receptor (RXRα) were examined by reverse-transcription polymerase chain reaction (RT-PCR) with immunocytochemical staining. Pancreatic carcinoma cells, PANC-1,were treated either with 9-cis-RA, a ligand of RXRα,or with 15-deoxy-Δ12,14 prostaglandin J2(15d-PGJ2), a ligand of PPARγ, or both. Antiproliferative effect was evaluated by cell viability using methyltetrazolium (MTT) assay. A pancreatic carcinoma xenograft tumor model of nude mice was established by inoculating PANC-1 cells subcutaneously. Rosiglitazone, a specific ligand of PPARγ, was administered via water drinking in experimental group of nude mice. After 75 d, all mice were sacrificed. Expression of proliferating cell nuclear antigen (PCNA) in tumor tissue was examined with immunohistochemical staining. Expression of vascular endothelial growth factor (VEGF) mRNA in PANC-1 cells, which were treated with 15d-PGJ2 or 9-cis-RA at variousconcentrations or different duration, was detected by semi-quantitative RT-PCR. Effects of Rosiglitazone on changes of microvascular density (MVD) and VEGF expression were investigated in xenograft tumor tissue. Neovasculature was detected with immunohistochemistry staining labeled with anti-Ⅳ collagen antibody, and indicated by MVD.RESULTS: RT-PCR and immunocytochemical staining showed that PPARγ and RXRα were expressed in PANC-1 cells at both transcription level and translation level. MTT assay demonstrated that 15d-PGJ2, 9-cis-RA and their combination inhibited the growth of PANC-1 cells in a dose-dependent manner. 9-cis-RA had a combined inhibiting action with 15d-PGJ2 on the growth of pancreatic carcinoma. In vivo studies revealed that Rosiglitazone significantly suppressed the growth of pancreatic carcinoma

  14. Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-alpha (PPARalpha).

    Science.gov (United States)

    Tien, Eric S; Hannon, Daniel B; Thompson, Jerry T; Vanden Heuvel, John P

    2006-01-01

    The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-alpha (PPARalpha) was examined. PPAR-binding protein (PBP), PPARgamma coactivator-1alpha (PGC-1alpha), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPARalpha activity in the presence of Wy-14,643. The effects on PPARalpha activity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1alpha, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1alpha. The interaction of PPARalpha with an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPARalpha occurs predominantly via the carboxyl-terminus and mutating (456)LHPLL to (456)LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPARalpha is ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely.

  15. Examination of Ligand-Dependent Coactivator Recruitment by Peroxisome Proliferator-Activated Receptor-α (PPARα)

    Science.gov (United States)

    Tien, Eric S.; Hannon, Daniel B.; Thompson, Jerry T.; Vanden Heuvel, John P.

    2006-01-01

    The ligand-dependent recruitment of coactivators to peroxisome proliferator-activated receptor-α (PPARα) was examined. PPAR-binding protein (PBP), PPARγ coactivator-1α (PGC-1α), steroid receptor coactivator-1 (SRC-1), and CBP/p300-interacting transactivator with ED-rich tail 2 (CITED2) affected PPARα activity in the presence of Wy-14,643. The effects on PPARα activity in light of increased or decreased expression of these coactivators were qualitatively different depending on the ligand examined. Diminished expression of PGC-1α, SRC-1, or PBP by RNAi plasmids affected natural or synthetic agonist activity whereas only Wy-14,643 was affected by decreased PGC-1α. The interaction of PPARα with an LXXLL-containing peptide library showed ligand-specific patterns, indicative of differences in conformational change. The association of coactivators to PPARα occurs predominantly via the carboxyl-terminus and mutating 456LHPLL to 456LHPAA resulted in a dominant-negative construct. This research confirms that coactivator recruitment to PPARα is ligand-dependent and that selective receptor modulators (SRMs) of this important protein are likely. PMID:17259669

  16. Downregulation of peroxisome proliferator-activated receptors (PPARs in nasal polyposis

    Directory of Open Access Journals (Sweden)

    Adner Mikael

    2005-11-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptor (PPAR α, βδ and γ are nuclear receptors activated by fatty acid metabolites. An anti-inflammatory role for these receptors in airway inflammation has been suggested. Methods Nasal biopsies were obtained from 10 healthy volunteers and 10 patients with symptomatic allergic rhinitis. Nasal polyps were obtained from 22 patients, before and after 4 weeks of local steroid treatment (fluticasone. Real-time RT-PCR was used for mRNA quantification and immunohistochemistry for protein localization and quantification. Results mRNA expression of PPARα, PPARβδ, PPARγ was found in all specimens. No differences in the expression of PPARs were obtained in nasal biopsies from patients with allergic rhinitis and healthy volunteers. Nasal polyps exhibited lower levels of PPARα and PPARγ than normal nasal mucosa and these levels were, for PPARγ, further reduced following steroid treatment. PPARγ immunoreactivity was detected in the epithelium, but also found in smooth muscle of blood vessels, glandular acini and inflammatory cells. Quantitative evaluation of the epithelial immunostaining revealed no differences between nasal biopsies from patients with allergic rhinitis and healthy volunteers. In polyps, the PPARγ immunoreactivity was lower than in nasal mucosa and further decreased after steroid treatment. Conclusion The down-regulation of PPARγ, in nasal polyposis but not in turbinates during symptomatic seasonal rhinitis, suggests that PPARγ might be of importance in long standing inflammations.

  17. Peroxisome Proliferator-Activated Receptor Agonists Modulate Neuropathic Pain: a Link to Chemokines?

    Directory of Open Access Journals (Sweden)

    Caroline eFreitag

    2014-08-01

    Full Text Available Chronic pain presents a widespread and intractable medical problem. While numerous pharmaceuticals are used to treat chronic pain, drugs that are safe for extended use and highly effective at treating the most severe pain do not yet exist. Chronic pain resulting from nervous system injury (neuropathic pain is common in conditions ranging from multiple sclerosis to HIV-1 infection to type II diabetes. Inflammation caused by neuropathy is believed to contribute to the generation and maintenance of neuropathic pain. Chemokines are key inflammatory mediators, several of which (MCP-1, RANTES, MIP-1α, fractalkine, SDF-1 among others have been linked to chronic, neuropathic pain in both human conditions and animal models. The important roles chemokines play in inflammation and pain make them an attractive therapeutic target. Peroxisome proliferator-activated receptors are a family of nuclear receptors known for their roles in metabolism. Recent research has revealed that PPARs also play a role in inflammatory gene repression. PPAR agonists have wide-ranging effects including inhibition of chemokine expression and pain behavior reduction in animal models. Experimental evidence suggests a connection between PPAR agonists' pain ameliorating effects and suppression of inflammatory gene expression, including chemokines. In early clinical research, one PPARα agonist, palmitoylethanolamide, shows promise in relieving chronic pain. If this link can be better established, PPAR agonists may represent a new drug therapy for neuropathic pain.

  18. Modulation Effect of Peroxisome Proliferator-Activated Receptor Agonists on Lipid Droplet Proteins in Liver.

    Science.gov (United States)

    Zhu, Yun-Xia; Zhang, Ming-Liang; Zhong, Yuan; Wang, Chen; Jia, Wei-Ping

    2016-01-01

    Peroxisome proliferator-activated receptor (PPAR) agonists are used for treating hyperglycemia and type 2 diabetes. However, the mechanism of action of these agonists is still under investigation. The lipid droplet-associated proteins FSP27/CIDEC and LSDP5, regulated directly by PPARγ and PPARα, are associated with hepatic steatosis and insulin sensitivity. Here, we evaluated the expression levels of FSP27/CIDEC and LSDP5 and the regulation of these proteins by consumption of a high-fat diet (HFD) or administration of PPAR agonists. Mice with diet-induced obesity were treated with the PPARγ or PPARα agonist, pioglitazone or fenofibrate, respectively. Liver tissues from db/db diabetic mice and human were also collected. Interestingly, FSP27/CIEDC was expressed in mouse and human livers and was upregulated in obese C57BL/6J mice. Fenofibrate treatment decreased hepatic triglyceride (TG) content and FSP27/CIDEC protein expression in mice fed an HFD diet. In mice, LSDP5 was not detected, even in the context of insulin resistance or treatment with PPAR agonists. However, LSDP5 was highly expressed in humans, with elevated expression observed in the fatty liver. We concluded that fenofibrate greatly decreased hepatic TG content and FSP27/CIDEC protein expression in mice fed an HFD, suggesting a potential regulatory role for fenofibrate in the amelioration of hepatic steatosis.

  19. Peroxisome Proliferator-Activated Receptor γ (PPARγ) and Ligand Choreography: Newcomers Take the Stage.

    Science.gov (United States)

    Garcia-Vallvé, Santiago; Guasch, Laura; Tomas-Hernández, Sarah; del Bas, Josep Maria; Ollendorff, Vincent; Arola, Lluís; Pujadas, Gerard; Mulero, Miquel

    2015-07-23

    Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARγ agonists, consisting of PPARγ Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARγ ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARγ ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARγ-mediated antidiabetic drugs.

  20. Mitofusin 2 decreases intracellular lipids in macrophages by regulating peroxisome proliferator-activated receptor-γ

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Chun; Ge, Beihai [Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030 (China); He, Chao [Department of Cardiology, China Three Gorges University, Yichang 433000 (China); Zhang, Yi; Liu, Xiaowen [Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030 (China); Liu, Kejian [Department of Cardiology, The First Affiliated Hospital of Medical College, Shihezi University (China); Qian, Cuiping; Zhang, Yu; Peng, Wenzhong [Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030 (China); Guo, Xiaomei, E-mail: xmguo@tjh.tjmu.edu.cn [Department of Cardiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Avenue, Wuhan 430030 (China)

    2014-07-18

    Highlights: • Mfn2 decreases cellular lipid accumulation by activating cholesterol transporters. • PPARγ is involved in the Mfn2-mediated increase of cholesterol transporter expressions. • Inactivation of ERK1/2 and p38 is involved in Mfn2-induced PPARγ expression. - Abstract: Mitofusin 2 (Mfn2) inhibits atherosclerotic plaque formation, but the underlying mechanism remains elusive. This study aims to reveal how Mfn2 functions in the atherosclerosis. Mfn2 expression was found to be significantly reduced in arterial atherosclerotic lesions of both mice and human compared with healthy counterparts. Here, we observed that Mfn2 increased cellular cholesterol transporter expression in macrophages by upregulating peroxisome proliferator-activated receptor-γ, an effect achieved at least partially by inhibiting extracellular signal-regulated kinase1/2 (ERK1/2) and p38 mitogen-activated protein kinases (MAPKs) pathway. These findings provide insights into potential mechanisms of Mfn2-mediated alterations in cholesterol transporter expression, which may have significant implications for the treatment of atherosclerotic heart disease.

  1. Peroxisome Proliferator-Activated Receptor Gamma in Obesity and Colorectal Cancer: the Role of Epigenetics.

    Science.gov (United States)

    Motawi, T K; Shaker, O G; Ismail, M F; Sayed, N H

    2017-09-06

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor that is deregulated in obesity. PPARγ exerts diverse antineoplastic effects. Attempting to determine the clinical relevance of the epigenetic mechanisms controlling the expression PPARγ and susceptibility to colorectal cancer (CRC) in obese subjects, this study investigated the role of some microRNAs and DNA methylation on the deregulation of PPARγ. Seventy CRC patients (34 obese and 36 lean), 22 obese and 24 lean healthy controls were included. MicroRNA levels were measured in serum. PPARγ promoter methylation was evaluated in peripheral blood mononuclear cells (PBMC). PPARγ level was evaluated by measuring mRNA level in PBMC and protein level in serum. The tested microRNAs (miR-27b, 130b and 138) were significantly upregulated in obese and CRC patients. Obese and CRC patients had significantly low levels of PPARγ. A significant negative correlation was found between PPARγ levels and the studied microRNAs. There was a significant PPARγ promoter hypermethylation in CRC patients that correlated to low PPARγ levels. Our results suggest that upregulation of microRNAs 27b, 130b and 138 is associated with susceptibility to CRC in obese subjects through PPARγ downregulation. Hypermethylation of PPARγ gene promoter is associated with CRC through suppression of PPARγ regardless of BMI.

  2. Identification of novel peroxisome proliferator-activated receptor-gamma (PPARγ) agonists using molecular modeling method

    Science.gov (United States)

    Gee, Veronica M. W.; Wong, Fiona S. L.; Ramachandran, Lalitha; Sethi, Gautam; Kumar, Alan Prem; Yap, Chun Wei

    2014-11-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) plays a critical role in lipid and glucose homeostasis. It is the target of many drug discovery studies, because of its role in various disease states including diabetes and cancer. Thiazolidinediones, a synthetic class of agents that work by activation of PPARγ, have been used extensively as insulin-sensitizers for the management of type 2 diabetes. In this study, a combination of QSAR and docking methods were utilised to perform virtual screening of more than 25 million compounds in the ZINC library. The QSAR model was developed using 1,517 compounds and it identified 42,378 potential PPARγ agonists from the ZINC library, and 10,000 of these were selected for docking with PPARγ based on their diversity. Several steps were used to refine the docking results, and finally 30 potentially highly active ligands were identified. Four compounds were subsequently tested for their in vitro activity, and one compound was found to have a K i values of <5 μM.

  3. Peroxisome proliferator-activated receptor gamma inhibits liver cancer proliferation and metastasis in vitro

    Directory of Open Access Journals (Sweden)

    SHEN Bo

    2013-09-01

    Full Text Available ObjectiveTo investigate the inhibitory effect of peroxisome proliferator-activated receptor gamma (PPARγ on the development, progression, invasion, and metastasis of liver cancer cells. MethodsHepatocellular carcinoma (HCC MHCC97L cells were randomly assigned to be transfected with Ad-PPARγ or Ad-LacZ (control. The cells were also exposed to PPARγ agonist rosiglitazone. Cell proliferation, apoptosis, migration, and invasive ability were evaluated using MTS assay, flow cytometry, wound healing test, and transwell invasion assay. Multiple comparisons of means between groups were conducted using one-way analysis of variance with Bonferroni correction; the means of two groups were compared using the t test. ResultsAd-PPARγ transfection resulted in higher expression of PPARγ protein in HCC cells compared with control cells, which suppressed cell proliferation (P<0.01, induced cell apoptosis (P<0.01, and suppressed cell migration and invasion. Moreover, the invasiveness of HCC cells transfected with Ad-PPARγ was reduced by 20%~60%. Rosiglitazone enhanced the inhibitory effect of Ad-PPARγ on the growth and migration of HCC cells. ConclusionPPARγ exerts an inhibitory effect on the proliferative, invasive, and metastatic potential of HCC cells in vitro. This study sheds new light on the search for potential markers and gene therapies for liver cancer.

  4. Peroxisome proliferator-activated receptor γ ligands suppress liver carcinogenesis induced by diethylnitrosamine in rats

    Institute of Scientific and Technical Information of China (English)

    Yan-Tong Guo; Xi-Sheng Leng; Tao Li; Jing-Ming Zhao; Xi-Hou Lin

    2004-01-01

    AIM: Peroxisome proliferator-activated receptor γ (PPARγ)is known to regulate growth arrest and terminal differentiation of adipocytes and is used clinically as a new class of antidiabetic drugs. Recently, several studies have reported that treatment of cancer cells with PPARγ ligands could induce cell differentiation and apoptosis, suggesting a potential application as chemopreventive agents against carcinogenesis. In the present study, 3 different kinds of PPARγ ligands were subjected to the experiments to confirm their suppressive effects on liver carcinogenesis.METHODS: Three PPARγ ligands, pioglitazone (Pio) (200 ppm),rosiglitazone (Rosi) (200 ppm), and troglitazone (Tro)(1 000 ppm) were investigated on the induction of the placental form of rat glutathione S-transferase (rGST P)positive foci, a precancerous lesion of the liver, and liver cancer formation using a diethylnitrosamine-induced liver cancer model in Wistar rats, and dose dependency of a PPARγ ligand was also examined.RESULTS: PPARγ ligands reduced the formation of rGST P-positive foci by diethylnitrosamine and induction of liver cancers was also markedly suppressed by a continuous feeding of Pio at 200 ppm.CONCLUSION: PPARγ ligands are potential chemopreventive agents for liver carcinogenesis.

  5. Peroxisome Proliferator-Activated Receptor γ-Dependent Regulation of Lipolytic Nodes and Metabolic Flexibility

    Science.gov (United States)

    Carobbio, Stefania; Velagapudi, Vidya R.; Barbarroja, Nuria; Moreno-Navarrete, Jose Maria; Tinahones, Francisco Jose; Fernandez-Real, Jose Manuel; Orešič, Matej

    2012-01-01

    Optimal lipid storage and mobilization are essential for efficient adipose tissue. Nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) regulates adipocyte differentiation and lipid deposition, but its role in lipolysis and dysregulation in obesity is not well defined. This investigation aimed to understand the molecular impact of dysfunctional PPARγ on the lipolytic axis and to explore whether these defects are also confirmed in common forms of human obesity. For this purpose, we used the P465L PPARγ mouse as a model of dysfunctional PPARγ that recapitulates the human pparγ mutation (P467L). We demonstrated that defective PPARγ impairs catecholamine-induced lipolysis. This abnormal lipolytic response is exacerbated by a state of positive energy balance in leptin-deficient ob/ob mice. We identified the protein kinase A (PKA) network as a PPARγ-dependent regulatory node of the lipolytic response. Specifically, defective PPARγ is associated with decreased basal expression of prkaca (PKAcatα) and d-akap1, the lipase genes Pnplaz (ATGL) and Lipe (HSL), and lipid droplet protein genes fsp27 and adrp in vivo and in vitro. Our data indicate that PPARγ is required for activation of the lipolytic regulatory network, dysregulation of which is an important feature of obesity-induced insulin resistance in humans. PMID:22310664

  6. Role of Peroxisome Proliferator-Activated Receptor Gamma in Glucose-induced Insulin Secretion

    Institute of Scientific and Technical Information of China (English)

    Ze-Kuan XU; Neng-Guin CHEN; Chang-Yan MA; Zhuo-Xian MENG; Yu-Jie SUN; Xiao HAN

    2006-01-01

    Peroxisome proliferator-activated receptor (PPAR) isoforms (α and γ) are known to be expressed in pancreatic islets as well as in insulin-producing cell lines. Ligands of PPAR have been shown to enhance glucose-induced insulin secretion in rat pancreatic islets. However, their effect on insulin secretion is still unclear. To understand the molecular mechanism by which PPARγ exerts its effect on glucoseinduced insulin secretion, we examined the endogenous activity of PPAR isoforms, and studied the PPARγfunction and its target gene expression in INS-1 cells. We found that: (1) endogenous PPARγ was activated in a ligand-dependent manner in INS-1 cells; (2) overexpression of PPARγ in the absence of PPARγ ligands enhanced glucose-induced insulin secretion, which indicates that the increased glucose-induced insulin secretion is a PPARγ-mediated event; (3) the addition of both PPARγ and retinoid X receptor (RXR) ligands showed a synergistic effect on the augmentation of reporter activity, suggesting that the hetero-dimerization of PPARγand RXR is required for the regulation of the target genes; (4) PPARs upregulated both the glucose transporter 2 (GLUT2) and Cbl-associated protein (CAP) genes in INS-1 cells. Our findings suggest an important mechanistic pathway in which PPARγ enhances glucose-induced insulin secretion by activating the expression of GLUT2 and CAP genes in a ligand-dependent manner.

  7. Interactions between Human Liver Fatty Acid Binding Protein and Peroxisome Proliferator Activated Receptor Selective Drugs

    Directory of Open Access Journals (Sweden)

    Tony Velkov

    2013-01-01

    Full Text Available Fatty acid binding proteins (FABPs act as intracellular shuttles for fatty acids as well as lipophilic xenobiotics to the nucleus, where these ligands are released to a group of nuclear receptors called the peroxisome proliferator activated receptors (PPARs. PPAR mediated gene activation is ultimately involved in maintenance of cellular homeostasis through the transcriptional regulation of metabolic enzymes and transporters that target the activating ligand. Here we show that liver- (L- FABP displays a high binding affinity for PPAR subtype selective drugs. NMR chemical shift perturbation mapping and proteolytic protection experiments show that the binding of the PPAR subtype selective drugs produces conformational changes that stabilize the portal region of L-FABP. NMR chemical shift perturbation studies also revealed that L-FABP can form a complex with the PPAR ligand binding domain (LBD of PPARα. This protein-protein interaction may represent a mechanism for facilitating the activation of PPAR transcriptional activity via the direct channeling of ligands between the binding pocket of L-FABP and the PPARαLBD. The role of L-FABP in the delivery of ligands directly to PPARα via this channeling mechanism has important implications for regulatory pathways that mediate xenobiotic responses and host protection in tissues such as the small intestine and the liver where L-FABP is highly expressed.

  8. KR-62980: a novel peroxisome proliferator-activated receptor gamma agonist with weak adipogenic effects.

    Science.gov (United States)

    Kim, Kwang Rok; Lee, Jeong Hyung; Kim, Seung Jun; Rhee, Sang Dal; Jung, Won Hoon; Yang, Sung-Don; Kim, Sung Soo; Ahn, Jin Hee; Cheon, Hyae Gyeong

    2006-08-14

    The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is the target for the anti-diabetic drugs including thiazolidinediones. We report here the identification and characterization of a novel PPARgamma agonist KR-62980. KR-62980 acted as a selective PPARgamma agonist in transactivation assay with an EC50 of 15 nM. In fully differentiated 3T3-L1 adipocytes, KR-62980 induced [3H]-deoxyglucose uptake in a concentration-dependent manner in the presence of insulin. KR-62980 was weakly adipogenic with little induction of aP2 mRNA, and was able to antagonize the adipogenic effects of rosiglitazone in C3H10T1/2 cells. In vivo pharmacokinetic profile of KR-62980 revealed that the compound exhibited good oral bioavailability of 65% with a terminal elimination half-life of 2.5 h in the rat. Treatment of high fat diet-induced C57BL/6J mice with KR-62980 for 14 days reduced plasma glucose levels with little side effects with regard to weight gain, cardiac hypertrophy and hepatotoxicity. These results suggest that KR-62980 acts as a selective PPARgamma modulator with anti-hyperglycemic activity, and that the mechanism of actions of KR-62980 appears to be different from that of rosiglitazone with improved side effect profiles.

  9. Role of peroxisome proliferator-activated receptors genepolymorphisms in type 2 diabetes and metabolic syndrome

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    Metabolic syndrome (MetS) and type 2 diabetesmellitus (T2DM) are the serious public healthproblems worldwide. Moreover, it is estimated thatMetS patients have about five-fold greater risk of theT2DM development compared with people without thesyndrome. Peroxisome proliferator-activated receptorsare a subgroup of the nuclear hormone receptorsuperfamily of ligand-activated transcription factorswhich play an important role in the pathogenesis ofMetS and T2DM. All three members of the peroxisomeproliferator-activated receptor (PPAR) nuclear receptorsubfamily, PPARα, PPARβ/δ and PPARγ are criticalin regulating insulin sensitivity, adipogenesis, lipidmetabolism, and blood pressure. Recently, more andmore studies indicated that the gene polymorphism ofPPARs, such as Leu162Val and Val227Ala of PPARα, +294T〉 C of PPARβ/δ, Pro12Ala and C1431T of PPARγ, aresignificantly associated with the onset and progressingof MetS and T2DM in different population worldwide.Furthermore, a large body of evidence demonstratedthat the glucose metabolism and lipid metabolism wereinfluenced by gene-gene interaction among PPARsgenes. However, given the complexity pathogenesis ofmetabolic disease, it is unlikely that genetic variation ofa single locus would provide an adequate explanationof inter-individual differences which results in diverseclinical syndromes. Thus, gene-gene interactions andgene-environment interactions associated with T2DMand MetS need future comprehensive studies.

  10. CHARMM Force Field Parameterization of Peroxisome Proliferator-Activated Receptor γ Ligands

    Science.gov (United States)

    Mottin, Melina; Souza, Paulo C. T.; Ricci, Clarisse G.; Skaf, Munir S.

    2016-01-01

    The peroxisome proliferator-activated receptor γ (PPARγ) ligands are important therapeutic drugs for the treatment of type 2 diabetes, obesity and cardiovascular diseases. In particular, partial agonists and non-agonists are interesting targets to reduce glucose levels, presenting few side effects in comparison to full agonists. In this work, we present a set of CHARMM-based parameters of a molecular mechanics force field for two PPARγ ligands, GQ16 and SR1664. GQ16 belongs to the thiazolidinedione class of drugs and it is a PPARγ partial agonist that has been shown to promote the “browning” of white adipose tissue. SR1664 is the precursor of the PPARγ non-agonist class of ligands that activates PPARγ in a non-classical manner. Here, we use quantum chemical calculations consistent with the CHARMM protocol to obtain bonded and non-bonded parameters, including partial atomic charges and effective torsion potentials for both molecules. The newly parameterized models were evaluated by examining the behavior of GQ16 and SR1664 free in water and bound to the ligand binding pocket of PPARγ using molecular dynamics simulations. The potential parameters derived here are readily transferable to a variety of pharmaceutical compounds and similar PPARγ ligands. PMID:28025495

  11. [Association between peroxisome proliferator-activated receptors gene polymorphism and essential hypertension].

    Science.gov (United States)

    Lin, Yao; Gu, Shu-jun; Wu, Ming; Chen, Qiu; Zhou, Zheng-yuan; Yu, Hao; Zhang, Li-jun; Luo, Wen-shu; Guo, Zhi-rong

    2012-06-01

    To investigate the association between ten single nucleotide polymorphism (SNP) in the peroxisome proliferator-activated receptor (PPAR) α/δ/γ and essential hypertension (EH). Participants were recruited within the framework of a cohort populations survey from the PMMJS (Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province) which was conducted in the urban community of Jiangsu province from 1999 to 2007. Eight hundred and twenty subjects (551 non-hypertensive subjects, 269 hypertensive subjects) were randomly selected but were not related to each other. Ten SNP (rs135539, rs1800206, rs4253778 of PPARα; rs2016520, rs9794 of PPARδ; rs10865710, rs1805192, rs4684847, rs709158 and rs3856806 of PPARγ) were selected from the HapMap database. χ(2) test was used to determine whether the whole population was in H-W genetic equilibrium. SHEsis software was used to examine the relations of SNP and linkage equilibrium. Logistic regression model was used to examine the association between ten SNP in the PPAR and EH. Difference on the distribution of four SNP genotypes including rs1800206, rs9794, rs10865710 and rs4684847 between high blood pressure and non-high blood pressure group, high systolic blood pressure (SBP) and normal SBP group, high diastolic blood pressure (DBP) and normal DBP group was significant (P PPARδ and rs4684847, rs10865710 of PPARγ influenced high blood pressure, high SBP and high DBP to different degrees.

  12. Peroxisome proliferator-activated receptors (PPARs) as therapeutic target in neurodegenerative disorders.

    Science.gov (United States)

    Agarwal, Swati; Yadav, Anuradha; Chaturvedi, Rajnish Kumar

    2017-02-19

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors and they serve to be a promising therapeutic target for several neurodegenerative disorders, which includes Parkinson disease, Alzheimer's disease, Huntington disease and Amyotrophic Lateral Sclerosis. PPARs play an important role in the downregulation of mitochondrial dysfunction, proteasomal dysfunction, oxidative stress, and neuroinflammation, which are the major causes of the pathogenesis of neurodegenerative disorders. In this review, we discuss about the role of PPARs as therapeutic targets in neurodegenerative disorders. Several experimental approaches suggest potential application of PPAR agonist as well as antagonist in the treatment of neurodegenerative disorders. Several epidemiological studies found that the regular usage of PPAR activating non-steroidal anti-inflammatory drugs is effective in decreasing the progression of neurodegenerative diseases including PD and AD. We also reviewed the neuroprotective effects of PPAR agonists and associated mechanism of action in several neurodegenerative disorders both in vitro as well as in vivo animal models. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. Peroxisome proliferator-activated receptors in the regulation of female reproductive functions.

    Science.gov (United States)

    Bogacka, Iwona; Kurzynska, Aleksandra; Bogacki, Marek; Chojnowska, Katarzyna

    2015-01-01

    Peroxisome proliferator-activated receptors (PPARs) belong to a ligand-dependent nuclear receptor family. In the past decade, numerous studies have revealed the presence and significance of PPARs in the reproductive system. PPARs are expressed at different levels of hypothalamic-pituitary-gonadal (HPG) axis. They are also present in the uterus as well as in the placenta and embryonic tissues of different species. PPARs significance has been reported during the estrous/menstrual cycle and pregnancy with the gamma isoform studied most frequently. Several studies indicate that PPARs regulate proliferation of ovarian cells, tissue remodeling and steroidogenesis. In the endometrium, PPARs are engaged in the regulation of prostaglandins, steroids and cytokines synthesis. The role of PPARs in the trophoblast differentiation, maturation and invasion as well as in the embryo development has also been demonstrated. In this review, we summarize current findings concerning the role of PPARs in the regulation of reproductive functions at different levels of the HPG axis during various physiological statuses of females. In addition, the role of PPARs in the modulation of uterine functions as well as the placenta and embryo development has also been discussed.

  14. Docking and molecular dynamics simulations of peroxisome proliferator activated receptors interacting with pan agonist sodelglitazar.

    Science.gov (United States)

    Liu, Xu-Yuan; Wang, Run-Ling; Xu, Wei-Ren; Tang, Li-Da; Wang, Shu-Qing; Chou, Kuo-Chen

    2011-10-01

    PPAR (peroxisome proliferator-activated receptor) pan agonists play a critical role in treating metabolic diseases, especially the Type-2 diabetes mellitus (T2DM). GlaxoSmithKline's sodelglitazar (GW677954) is one of the potent PPAR pan agonists, which is currently being investigated in Phase II clinical trials for the treatment of T2DM and its complications. The present study was aimed at investigation into the effect of sodelglitazar at the binding pockets of PPARs. The Schrodinger Suite program (2009) was used for the molecular docking, while the GROMACS program used for the molecular dynamics (MD) simulations. The results thus obtained showed that sodelglitazar being docked well in the active site of PPARs. It was revealed by the MD simulations that the structures of the receptors remained quite stable during the simulations and that the important AF-2 helix showed less flexibility after binding with sodelglitazar. Also, it was observed that sodelglitazar could periodically form hydrogen bonds with the AF-2 helix of PPARs to stabilize the AF-2 helix in an active conformation. Our findings have confirmed that GlaxoSmithKline's sodelglitazar can activate the PPARs, which is quite consistent with the previous biological studies.

  15. Pharmacophore modeling improves virtual screening for novel peroxisome proliferator-activated receptor-gamma ligands

    Science.gov (United States)

    Lewis, Stephanie N.; Garcia, Zulma; Hontecillas, Raquel; Bassaganya-Riera, Josep; Bevan, David R.

    2015-05-01

    Peroxisome proliferator-activated receptor-gamma (PPARγ) is a nuclear hormone receptor involved in regulating various metabolic and immune processes. The PPAR family of receptors possesses a large binding cavity that imparts promiscuity of ligand binding not common to other nuclear receptors. This feature increases the challenge of using computational methods to identify PPAR ligands that will dock favorably into a structural model. Utilizing both ligand- and structure-based pharmacophore methods, we sought to improve agonist prediction by grouping ligands according to pharmacophore features, and pairing models derived from these features with receptor structures for docking. For 22 of the 33 receptor structures evaluated we observed an increase in true positive rate (TPR) when screening was restricted to compounds sharing molecular features found in rosiglitazone. A combination of structure models used for docking resulted in a higher TPR (40 %) when compared to docking with a single structure model (PPARγ ligands using multiple structure models, ligand-based pharmacophore data, evaluation of protein-ligand interactions, and comparison of docking datasets. The unique combination of methods presented here holds potential for more efficient screening of compounds with unknown affinity for PPARγ that could serve as candidates for therapeutic development.

  16. Male and female NOD mice differentially express peroxisome proliferator-activated receptors and pathogenic cytokines.

    Science.gov (United States)

    Yaacob, Nik Soriani; Goh, Kenny Soen Keong; Norazmi, Mohd Nor

    2012-01-01

    The peroxisome proliferator-activated receptors (PPARs) have been implicated in regulating the immune response. We determined the relative changes in the transcriptional expression of PPAR isoforms (α, γ1 and γ2) and cytokines involved in the pathogenesis of type 1 diabetes (T1D) in the immune cells of 5 weeks, 10 weeks and diabetic male non-obese diabetic (NOD) mice compared to those of female NOD mice from our previous studies, "normalized" against their respective non-obese diabetic resistant (NOR) mice controls. Overall PPARα was significantly more elevated in the macrophages of female NOD mice of all age groups whereas PPARγ, particularly the PPARγ2 isoform was more depressed in the macrophages and CD4(+) lymphocytes of female NOD mice compared to their male counterparts. The pro-inflammatory cytokines, IL-1 and TNFα, as well as the Th1 cytokines, IL-2 and IFNγ were more elevated in female NOD mice whereas the Th2 cytokine, IL-4, was more depressed in these mice compared to their male counterparts. These findings suggest that the preponderance of T1D in female NOD mice may be influenced by the more pronounced changes in the expression of PPAR isoforms and pathogenic cytokines compared to those in male NOD mice. Copyright © 2010 Elsevier GmbH. All rights reserved.

  17. The roles of peroxisome proliferator-activated receptors in the metabolic syndrome.

    Science.gov (United States)

    Mansour, Mahmoud

    2014-01-01

    The epidemic of obesity and its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X, is one of the most challenging health problems facing industrialized countries. The nuclear receptors, peroxisome proliferator-activated receptors (PPARs alpha (α), beta (β) also known as delta (δ), and gamma (γ)), have well-documented roles in lipid and glucose metabolism. Pharmacologically, PPARα is activated by fibrate hypolipidemic drugs, whereas PPARγ is activated by insulin sensitizers thiazolidinediones (TZDs). No marketed drug is yet available for PPARβ(δ). The identification of fibrates and TZDs as respective ligands for PPARα and PPARγ was a groundbreaking finding that sparked notable pharmaceutical interest in PPARs as potential drug targets for treatment of the metabolic syndrome. Limiting side effects associated with clinical use of TZDs have emerged in recent years. New and novel PPAR drugs with broad safety margins and therapeutic potentials for the metabolic syndrome are in development. These include partial, dual, or pan PPAR agonists; PPAR antagonists; and selective PPAR modulators. The objective of this chapter is to highlight the therapeutic benefits of targeting more than one PPAR subtype in the treatment of the metabolic syndrome. The pros and cons observed during clinical use of TZDs and the strategies and progress made in the production of new generations of safe and effective PPAR ligands are discussed. © 2014 Elsevier Inc. All rights reserved.

  18. Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ) in vitro.

    Science.gov (United States)

    Dionisi, Mauro; Alexander, Stephen P H; Bennett, Andrew J

    2012-05-14

    Oleamide (ODA) is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs) as potential targets for ODA action. Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro.

  19. Association of Pro12Ala polymorphism in peroxisome proliferator activated receptor gamma with proliferative diabetic retinopathy

    Science.gov (United States)

    Tariq, Khadija; Malik, Saira Bano; Ali, Syeda Hafiza Benish; Maqsood, Sundas Ejaz; Azam, Aisha; Muslim, Irfan; Khan, Muhammad Shakil; Azam, Maleeha; Waheed, Nadia Khalida

    2013-01-01

    Purpose The association of non-synonymous substitution polymorphism rs1801282 (c.34C>G, p.Pro12Ala) in exon 4 of the peroxisome proliferator activated receptor gamma gene with diabetic retinopathy (DR) has been reported inconsistently. Therefore, the purpose of the present study was to understand the population-specific role of the Pro12Ala polymorphism in DR susceptibility in Pakistani subjects. Methods A total of 180 subjects with DR, 193 subjects with type 2 diabetes mellitus (T2DM) with no diabetic retinopathy, and 200 healthy normoglycemic non-retinopathic Pakistani individuals were genotyped for the rs1801282 (c.34C>G) polymorphism using polymerase chain reaction-restriction fragment length polymorphism. Results We found the individuals with T2DM carrying 12Ala were at a reduced risk of developing DR (odds ratio [OR]=0.53; 95% confidence interval [CI]=0.33–0.87). Upon stratified analysis regarding disease severity, we observed this protective effect was confined to proliferative DR (OR=0.4; 95% CI=0.2–0.8) with non-significant effects on the susceptibility of non-proliferative DR (OR=0.67; 95% CI=0.37–1.19). Conclusions We report a protective role of the 12Ala polymorphism against proliferative DR in individuals with T2DM in Pakistan. PMID:23559865

  20. Cyclin D1 repression of peroxisome proliferator-activated receptor gamma expression and transactivation.

    Science.gov (United States)

    Wang, Chenguang; Pattabiraman, Nagarajan; Zhou, Jian Nian; Fu, Maofu; Sakamaki, Toshiyuki; Albanese, Chris; Li, Zhiping; Wu, Kongming; Hulit, James; Neumeister, Peter; Novikoff, Phyllis M; Brownlee, Michael; Scherer, Philipp E; Jones, Joan G; Whitney, Kathleen D; Donehower, Lawrence A; Harris, Emily L; Rohan, Thomas; Johns, David C; Pestell, Richard G

    2003-09-01

    The cyclin D1 gene is overexpressed in human breast cancers and is required for oncogene-induced tumorigenesis. Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor selectively activated by ligands of the thiazolidinedione class. PPAR gamma induces hepatic steatosis, and liganded PPAR gamma promotes adipocyte differentiation. Herein, cyclin D1 inhibited ligand-induced PPAR gamma function, transactivation, expression, and promoter activity. PPAR gamma transactivation induced by the ligand BRL49653 was inhibited by cyclin D1 through a pRB- and cdk-independent mechanism, requiring a region predicted to form an helix-loop-helix (HLH) structure. The cyclin D1 HLH region was also required for repression of the PPAR gamma ligand-binding domain linked to a heterologous DNA binding domain. Adipocyte differentiation by PPAR gamma-specific ligands (BRL49653, troglitazone) was enhanced in cyclin D1(-/-) fibroblasts and reversed by retroviral expression of cyclin D1. Homozygous deletion of the cyclin D1 gene, enhanced expression by PPAR gamma ligands of PPAR gamma and PPAR gamma-responsive genes, and cyclin D1(-/-) mice exhibit hepatic steatosis. Finally, reduction of cyclin D1 abundance in vivo using ponasterone-inducible cyclin D1 antisense transgenic mice, increased expression of PPAR gamma in vivo. The inhibition of PPAR gamma function by cyclin D1 is a new mechanism of signal transduction cross talk between PPAR gamma ligands and mitogenic signals that induce cyclin D1.

  1. Peroxisome proliferator-activated receptor-gamma ligands for the treatment of breast cancer.

    Science.gov (United States)

    Fenner, Martin H; Elstner, Elena

    2005-06-01

    Pioglitazone and rosiglitazone are thiazolidinediones used for the treatment of Type 2 diabetes mellitus. They modulate glucose and fat metabolism, mainly by binding to the nuclear hormone receptor peroxisome proliferator-activated receptor (PPAR)-gamma. PPAR-gamma signalling is involved in a number of other disease conditions including cancer. In breast cancer cells, PPAR-gamma ligands inhibit proliferation and induce apoptosis both in vitro and in vivo. PPAR-gamma ligands also inhibit tumour angiogenesis and invasion. The only published clinical trial using a PPAR-gamma ligand in patients with metastatic breast cancer failed to show any clinical benefits. The mechanism of action of the thiazolidinediones in breast cancer cells is not fully understood but involves interactions with other nuclear hormone receptors, transcriptional co-activators and repressors as well as PPAR-gamma-independent effects. A better understanding of these mechanisms will be needed before PPAR-gamma ligands may be useful in the treatment of breast cancer patients.

  2. Expression of peroxisome proliferator-activated receptor (PPAR) in human prostate cancer.

    Science.gov (United States)

    Segawa, Yoshihiro; Yoshimura, Rikio; Hase, Taro; Nakatani, Tatsuya; Wada, Seiji; Kawahito, Yutaka; Kishimoto, Taketoshi; Sano, Hajime

    2002-05-01

    Recent studies have demonstrated that peroxisome proliferator activator-receptors (PPAR)-gamma is expressed in some cancer cells such as breast, lung, and gastric cancer, and its ligand induces growth arrest of these cancer cells through apoptosis. However, the expression and localization of PPARs in prostate have not been examined. In this study, PPARs expression was investigated in human prostate cancer (PC), prostatic intraepithelial neoplasia (PIN), benign prostatic hyperplasia (BPH), and normal prostate (NP) tissues. Tumor specimens were obtained from 156 patients with PC, 15 with PIN, 20 with BPH, and 12 patients with NP tissues. The expressions were investigated by RT-PCR and immunohistochemical methods. Immunoreactive PPAR-alpha and -beta were significantly apparent in PC tissues. Marked expressions of PPAR-alpha and -beta were also detected in PIN, BPH, and NP groups. However, very weak or no expression of immunoreactive PPAR-gamma was found in BPH and NP cases. In contrast, we found significant expression of immunoreactive PPAR-gamma in cancer cells in PC group and in PIN group. Our results demonstrated that PPAR-gamma is induced in PC, and suggest that PPAR-gamma ligands may mediate its own potent antiproliferative effect against PC cells through differentiation. Copyright 2002 Wiley-Liss, Inc.

  3. Human mannose-binding lectin 2 is directly regulated by peroxisome proliferator-activated receptors via a peroxisome proliferator responsive element.

    Science.gov (United States)

    Tachibana, Keisuke; Takeuchi, Kentaro; Inada, Hirohiko; Sugimoto, Ken; Ishimoto, Kenji; Yamashita, Masanori; Maegawa, Takashi; Yamasaki, Daisuke; Osada, Shigehiro; Tanaka, Toshiya; Rakugi, Hiromi; Hamakubo, Takao; Sakai, Juro; Kodama, Tatsuhiko; Doi, Takefumi

    2013-09-01

    Human mannose-binding lectin (MBL) is encoded by the MBL2 gene and is a key player in innate immunity. However, the mechanism of the transcriptional regulation of MBL2 is largely unknown. The peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play an important role in a number of biological responses, including lipid homeostasis, immune function and adipogenesis. In this study, we showed that PPARα and PPARγ up-regulate the expression of human MBL2. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that PPARs regulate the expression of human MBL2 via the peroxisome proliferator responsive element (PPRE). On the other hand, MBL2 mRNA expression was not affected by the PPARα ligand both in vivo in rat liver and in vitro in rat H4IIE hepatoma cells. Thus, there is a species difference in regulation of MBL2 gene expression by PPARs between humans and rodents. We also show that the species differences in response to PPAR could be due in part to sequence-specific differences in the PPRE in the promoter region of MBL2. These results indicate that human, but not rat, MBL2 expression is regulated by PPARs via a PPRE.

  4. Macrophage peroxisome proliferator-activated receptor γ deficiency delays skin wound healing through impairing apoptotic cell clearance in mice

    OpenAIRE

    Chen, H.; Shi, R.; Luo, B.; Yang, X.; Qiu, L; Xiong, J.; Jiang, M; Y. Liu; Zhang, Z; Wu, Y

    2015-01-01

    Skin wound macrophages are key regulators of skin repair and their dysfunction causes chronic, non-healing skin wounds. Peroxisome proliferator-activated receptor gamma (PPARγ) regulates pleiotropic functions of macrophages, but its contribution in skin wound healing is poorly defined. We observed that macrophage PPARγ expression was upregulated during skin wound healing. Furthermore, macrophage PPARγ deficiency (PPARγ-knock out (KO)) mice exhibited impaired skin wound healing with reduced co...

  5. Carbonic anhydrase III regulates peroxisome proliferator-activated receptor-{gamma}2

    Energy Technology Data Exchange (ETDEWEB)

    Mitterberger, Maria C. [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria); Kim, Geumsoo [Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012 (United States); Rostek, Ursula [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria); Levine, Rodney L. [Laboratory of Biochemistry, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-8012 (United States); Zwerschke, Werner, E-mail: werner.zwerschke@oeaw.ac.at [Cell Metabolism and Differentiation Research Group, Institute for Biomedical Aging Research of the Austrian Academy of Sciences, 6020 Innsbruck (Austria)

    2012-05-01

    Carbonic anhydrase III (CAIII) is an isoenzyme of the CA family. Because of its low specific anhydrase activity, physiological functions in addition to hydrating CO{sub 2} have been proposed. CAIII expression is highly induced in adipogenesis and CAIII is the most abundant protein in adipose tissues. The function of CAIII in both preadipocytes and adipocytes is however unknown. In the present study we demonstrate that adipogenesis is greatly increased in mouse embryonic fibroblasts (MEFs) from CAIII knockout (KO) mice, as demonstrated by a greater than 10-fold increase in the induction of fatty acid-binding protein-4 (FABP4) and increased triglyceride formation in CAIII{sup -/-} MEFs compared with CAIII{sup +/+} cells. To address the underlying mechanism, we investigated the expression of the two adipogenic key regulators, peroxisome proliferator-activated receptor-{gamma}2 (PPAR{gamma}2) and CCAAT/enhancer binding protein-{alpha}. We found a considerable (approximately 1000-fold) increase in the PPAR{gamma}2 expression in the CAIII{sup -/-} MEFs. Furthermore, RNAi-mediated knockdown of endogenous CAIII in NIH 3T3-L1 preadipocytes resulted in a significant increase in the induction of PPAR{gamma}2 and FABP4. When both CAIII and PPAR{gamma}2 were knocked down, FABP4 was not induced. We conclude that down-regulation of CAIII in preadipocytes enhances adipogenesis and that CAIII is a regulator of adipogenic differentiation which acts at the level of PPAR{gamma}2 gene expression. -- Highlights: Black-Right-Pointing-Pointer We discover a novel function of Carbonic anhydrase III (CAIII). Black-Right-Pointing-Pointer We show that CAIII is a regulator of adipogenesis. Black-Right-Pointing-Pointer We demonstrate that CAIII acts at the level of PPAR{gamma}2 gene expression. Black-Right-Pointing-Pointer Our data contribute to a better understanding of the role of CAIII in fat tissue.

  6. Peroxisome proliferator-activated receptor-gamma suppresses cyclooxygenase-2 expression in human prostate cells.

    Science.gov (United States)

    Sabichi, Anita L; Subbarayan, Vemparala; Llansa, Norma; Lippman, Scott M; Menter, David G

    2004-11-01

    Recent studies have found that cyclooxygenase-2 (COX-2) protein expression was low and inducible with cytokines in prostate cancer cells (in the absence of serum) and that, in contrast, COX-2 expression was high in normal prostate epithelial cells (EC). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) was expressed at high levels in the prostate cancer cell line PC-3 but not in ECs. In contrast to previous findings by others, PPAR-gamma ligands did not induce PPAR-gamma expression in EC or PC-3. The present study examined the relationship between PPAR-gamma and COX-2 expression patterns in EC and PC-3 in the presence and absence of serum and/or the PPAR-gamma agonist 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)). We also evaluated the effects that the forced expression of PPAR-gamma1 and PPAR-gamma2 had on COX-2 in ECs. We found that expression of PPAR-gamma and COX-2 protein was inversely correlated in ECs and PC-3. Low COX-2 expression in PC-3 was up-regulated by serum, and 15d-PGJ(2) blocked serum-induced COX-2 expression and activity in a dose-dependent manner. 15d-PGJ(2) had no effect on COX-2 expression in ECs or PPAR-gamma expression in either cell type. However, forced expression of PPAR-gamma1 or PPAR-gamma2 in ECs suppressed the high level of endogenous COX-2. This effect was not isoform specific and was augmented by 15d-PGJ(2). The present study showed that PPAR-gamma activation can be an important regulator of COX-2 in prostate cells and may be an important target for prostate cancer chemoprevention.

  7. Inhibitory effects of peroxisome proliferator-activated receptor γ agonists on collagen IV production in podocytes.

    Science.gov (United States)

    Li, Yanjiao; Shen, Yachen; Li, Min; Su, Dongming; Xu, Weifeng; Liang, Xiubin; Li, Rongshan

    2015-07-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists have beneficial effects on the kidney diseases through preventing microalbuminuria and glomerulosclerosis. However, the mechanisms underlying these effects remain to be fully understood. In this study, we investigate the effects of PPAR-γ agonist, rosiglitazone (Rosi) and pioglitazone (Pio), on collagen IV production in mouse podocytes. The endogenous expression of PPAR-γ was found in the primary podocytes and can be upregulated by Rosi and Pio, respectively, detected by RT-PCR and Western blot. PPAR-γ agonist markedly blunted the increasing of collagen IV expression and extraction in podocytes induced by TGF-β. In contrast, adding PPAR-γ antagonist, GW9662, to podocytes largely prevented the inhibition of collagen IV expression from Pio treatment. Our data also showed that phosphorylation of Smad2/3 enhanced by TGF-β in a time-dependent manner was significantly attenuated by adding Pio. The promoter region of collagen IV gene contains one putative consensus sequence of Smad-binding element (SBE) by promoter analysis, Rosi and Pio significantly ameliorated TGF-β-induced SBE4-luciferase activity. In conclusion, PPAR-γ activation by its agonist, Rosi or Pio, in vitro directly inhibits collagen IV expression and synthesis in primary mouse podocytes. The suppression of collagen IV production was related to the inhibition of TGF-β-driven phosphorylation of Smad2/3 and decreased response activity of SBEs of collagen IV in PPAR-γ agonist-treated mouse podocytes. This represents a novel mechanistic support regarding PPAR-γ agonists as podocyte protective agents.

  8. Catalposide is a natural agonistic ligand of peroxisome proliferator-activated receptor-{alpha}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Ji Hae; Jun, Hee-jin; Hoang, Minh-Hien; Jia, Yaoyao [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Han, Xiang Hua [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Hak-Ju [Division of Green Business Management, Department of Forest Resources Utilization, Korean Forest Research Institute, Seoul 130-712 (Korea, Republic of); Hwang, Bang Yeon, E-mail: byhwang@chungbuk.ac.kr [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (Korea, Republic of); Lee, Sung-Joon, E-mail: junelee@korea.ac.kr [Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Department of Biotechnology, Graduate School of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

    2012-06-15

    Highlights: Black-Right-Pointing-Pointer Catalposide is a novel ligand for PPAR{alpha}. Black-Right-Pointing-Pointer Cell stimulated with catalposide improved fatty acid uptake, regulated target genes in fatty acid {beta}-oxidation and synthesis. Black-Right-Pointing-Pointer Catalposdie reduces hepatic triacylglycerides. Black-Right-Pointing-Pointer Theses demonstrate catalposide could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: Peroxisome proliferator-activated receptor-alpha (PPAR{alpha}) is a nuclear receptor that regulates the expression of genes related to cellular lipid uptake and oxidation. Thus, PPAR{alpha} agonists may be important in the treatment of hypertriglyceridemia and hepatic steatosis. In this study, we demonstrated that catalposide is a novel natural PPAR{alpha} agonist, identified from reporter gene assay-based activity screening with approximately 900 natural plant and seaweed extracts. Results of time-resolved fluorescence resonance energy transfer analyses suggested that the compound interacted directly with the ligand-binding domain of PPAR{alpha}. Cultured hepatocytes stimulated with catalposide exhibited significantly reduced cellular triglyceride concentrations, by 21%, while cellular uptake of fatty acids was increased, by 70% (P < 0.05). Quantitative PCR analysis revealed that the increase in cellular fatty acid uptake was due to upregulation of fatty acid transporter protein-4 (+19% vs. the control) in cells stimulated with catalposide. Additionally, expression of genes related to fatty acid oxidation and high-density lipoprotein metabolism were upregulated, while that of genes related to fatty acid synthesis were suppressed. In conclusion, catalposide is hypolipidemic by activation of PPAR{alpha} via a ligand-mediated mechanism that modulates the expression of in lipid metabolism genes in hepatocytes.

  9. Oleamide activates peroxisome proliferator-activated receptor gamma (PPARγ in vitro

    Directory of Open Access Journals (Sweden)

    Dionisi Mauro

    2012-05-01

    Full Text Available Abstract Background Oleamide (ODA is a fatty acid primary amide first identified in the cerebrospinal fluid of sleep-deprived cats, which exerts effects on vascular and neuronal tissues, with a variety of molecular targets including cannabinoid receptors and gap junctions. It has recently been reported to exert a hypolipidemic effect in hamsters. Here, we have investigated the nuclear receptor family of peroxisome proliferator-activated receptors (PPARs as potential targets for ODA action. Results Activation of PPARα, PPARβ and PPARγ was assessed using recombinant expression in Chinese hamster ovary cells with a luciferase reporter gene assay. Direct binding of ODA to the ligand binding domain of each of the three PPARs was monitored in a cell-free fluorescent ligand competition assay. A well-established assay of PPARγ activity, the differentiation of 3T3-L1 murine fibroblasts into adipocytes, was assessed using an Oil Red O uptake-based assay. ODA, at 10 and 50 μM, was able to transactivate PPARα, PPARβ and PPARγ receptors. ODA bound to the ligand binding domain of all three PPARs, although complete displacement of fluorescent ligand was only evident for PPARγ, at which an IC50 value of 38 μM was estimated. In 3T3-L1 cells, ODA, at 10 and 20 μM, induced adipogenesis. Conclusions We have, therefore, identified a novel site of action of ODA through PPAR nuclear receptors and shown how ODA should be considered as a weak PPARγ ligand in vitro.

  10. Peroxisome proliferator-activated receptor alpha controls hepatic heme biosynthesis through ALAS1.

    Science.gov (United States)

    Degenhardt, Tatjana; Väisänen, Sami; Rakhshandehroo, Maryam; Kersten, Sander; Carlberg, Carsten

    2009-05-01

    Heme is an essential prosthetic group of proteins involved in oxygen transport, energy metabolism and nitric oxide production. ALAS1 (5-aminolevulinate synthase) is the rate-limiting enzyme in heme synthesis in the liver and is highly regulated to adapt to the metabolic demand of the hepatocyte. In the present study, we describe human hepatic ALAS1 as a new direct target for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha). In primary human hepatocytes and in HepG2 cells, PPARalpha agonists induced an increase in ALAS1 mRNA levels, which was abolished by PPARalpha silencing. These effects are mediated by two functional PPAR binding sites at positions -9 and -2.3 kb relative to the ALAS1 transcription start site. PPARalpha ligand treatment also up-regulated the mRNA levels of the genes ALAD (5-aminolevulinate dehydratase), UROS (uroporphyrinogen III synthase), UROD (uroporphyrinogen decarboxylase), CPOX (coproporphyrinogen oxidase) and PPOX (protoporphyrinogen oxidase) encoding for enzymes controlling further steps in heme biosynthesis. In HepG2 cells treated with PPARalpha agonists and in mouse liver upon fasting, the association of PPARalpha, its partner retinoid X receptor, PPARgamma co-activator 1alpha and activated RNA polymerase II with the transcription start site region of all six genes was increased, leading to higher levels of the metabolite heme. In conclusion, these data strongly support a role of PPARalpha in the regulation of human ALAS1 and of five additional genes of the pathway, consequently leading to increased heme synthesis.

  11. Monitoring Solution Structures of Peroxisome Proliferator-Activated Receptor β/δ upon Ligand Binding

    Science.gov (United States)

    Schwarz, Rico; Tänzler, Dirk; Ihling, Christian H.; Sinz, Andrea

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) have been intensively studied as drug targets to treat type 2 diabetes, lipid disorders, and metabolic syndrome. This study is part of our ongoing efforts to map conformational changes in PPARs in solution by a combination of chemical cross-linking and mass spectrometry (MS). To our best knowledge, we performed the first studies addressing solution structures of full-length PPAR-β/δ. We monitored the conformations of the ligand-binding domain (LBD) as well as full-length PPAR-β/δ upon binding of two agonists. (Photo-) cross-linking relied on (i) a variety of externally introduced amine- and carboxyl-reactive linkers and (ii) the incorporation of the photo-reactive amino acid p-benzoylphenylalanine (Bpa) into PPAR-β/δ by genetic engineering. The distances derived from cross-linking experiments allowed us to monitor conformational changes in PPAR-β/δ upon ligand binding. The cross-linking/MS approach proved highly advantageous to study nuclear receptors, such as PPARs, and revealed the interplay between DBD (DNA-binding domain) and LDB in PPAR-β/δ. Our results indicate the stabilization of a specific conformation through ligand binding in PPAR-β/δ LBD as well as full-length PPAR-β/δ. Moreover, our results suggest a close distance between the N- and C-terminal regions of full-length PPAR-β/δ in the presence of GW1516. Chemical cross-linking/MS allowed us gaining detailed insights into conformational changes that are induced in PPARs when activating ligands are present. Thus, cross-linking/MS should be added to the arsenal of structural methods available for studying nuclear receptors. PMID:26992147

  12. Sexually dimorphic adaptation of cardiac function: roles of epoxyeicosatrienoic acid and peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Qin, Jun; Le, Yicong; Froogh, Ghezal; Kandhi, Sharath; Jiang, Houli; Luo, Meng; Sun, Dong; Huang, An

    2016-06-01

    Epoxyeicosatrienoic acids (EETs) are cardioprotective mediators metabolized by soluble epoxide hydrolase (sEH) to form corresponding diols (DHETs). As a sex-susceptible target, sEH is involved in the sexually dimorphic regulation of cardiovascular function. Thus, we hypothesized that the female sex favors EET-mediated potentiation of cardiac function via downregulation of sEH expression, followed by upregulation of peroxisome proliferator-activated receptors (PPARs). Hearts were isolated from male (M) and female (F) wild-type (WT) and sEH-KO mice, and perfused with constant flow at different preloads. Basal coronary flow required to maintain the perfusion pressure at 100 mmHg was significantly greater in females than males, and sEH-KO than WT mice. All hearts displayed a dose-dependent decrease in coronary resistance and increase in cardiac contractility, represented as developed tension in response to increases in preload. These responses were also significantly greater in females than males, and sEH-KO than WT 14,15-EEZE abolished the sex-induced (F vs. M) and transgenic model-dependent (KO vs. WT) differences in the cardiac contractility, confirming an EET-driven response. Compared with M-WT controls, F-WT hearts expressed downregulation of sEH, associated with increased EETs and reduced DHETs, a pattern comparable to that observed in sEH-KO hearts. Coincidentally, F-WT and sEH-KO hearts exhibited increased PPARα expression, but comparable expression of eNOS, PPARβ, and EET synthases. In conclusion, female-specific downregulation of sEH initiates an EET-dependent adaptation of cardiac function, characterized by increased coronary flow via reduction in vascular resistance, and promotion of cardiac contractility, a response that could be further intensified by PPARα. © 2016 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society.

  13. Peroxisome proliferator-activated receptors and Alzheimer's disease: hitting the blood-brain barrier.

    Science.gov (United States)

    Zolezzi, Juan M; Inestrosa, Nibaldo C

    2013-12-01

    The blood-brain barrier (BBB) is often affected in several neurodegenerative disorders, such as Alzheimer's disease (AD). Integrity and proper functionality of the neurovascular unit are recognized to be critical for maintenance of the BBB. Research has traditionally focused on structural integrity more than functionality, and BBB alteration has usually been explained more as a consequence than a cause. However, ongoing evidence suggests that at the early stages, the BBB of a diseased brain often shows distinct expression patterns of specific carriers such as members of the ATP-binding cassette (ABC) transport protein family, which alter BBB traffic. In AD, amyloid-β (Aβ) deposits are a pathological hallmark and, as recently highlighted by Cramer et al. (2012), Aβ clearance is quite fundamental and is a less studied approach. Current knowledge suggests that BBB traffic plays a more important role than previously believed and that pharmacological modulation of the BBB may offer new therapeutic alternatives for AD. Recent investigations carried out in our laboratory indicate that peroxisome proliferator-activated receptor (PPAR) agonists are able to prevent Aβ-induced neurotoxicity in hippocampal neurons and cognitive impairment in a double transgenic mouse model of AD. However, even when enough literature about PPAR agonists and neurodegenerative disorders is available, the problem of how they exert their functions and help to prevent and rescue Aβ-induced neurotoxicity is poorly understood. In this review, along with highlighting the main features of the BBB and its role in AD, we will discuss information regarding the modulation of BBB components, including the possible role of PPAR agonists as BBB traffic modulators.

  14. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications--a review.

    Science.gov (United States)

    Grygiel-Górniak, Bogna

    2014-02-14

    Peroxisome proliferator-activated receptors are expressed in many tissues, including adipocytes, hepatocytes, muscles and endothelial cells; however, the affinity depends on the isoform of PPAR, and different distribution and expression profiles, which ultimately lead to different clinical outcomes. Because they play an important role in lipid and glucose homeostasis, they are called lipid and insulin sensors. Their actions are limited to specific tissue types and thus, reveal a characteristic influence on target cells. PPARα mainly influences fatty acid metabolism and its activation lowers lipid levels, while PPARγ is mostly involved in the regulation of the adipogenesis, energy balance, and lipid biosynthesis. PPARβ/δ participates in fatty acid oxidation, mostly in skeletal and cardiac muscles, but it also regulates blood glucose and cholesterol levels. Many natural and synthetic ligands influence the expression of these receptors. Synthetic ligands are widely used in the treatment of dyslipidemia (e.g. fibrates--PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones--PPARγ agonists). New generation drugs--PPARα/γ dual agonists--reveal hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action while the overexpression of PPARβ/δ prevents the development of obesity and reduces lipid accumulation in cardiac cells, even during a high-fat diet. Precise data on the expression and function of natural PPAR agonists on glucose and lipid metabolism are still missing, mostly because the same ligand influences several receptors and a number of reports have provided conflicting results. To date, we know that PPARs have the capability to accommodate and bind a variety of natural and synthetic lipophilic acids, such as essential fatty acids, eicosanoids, phytanic acid and palmitoylethanolamide. A current understanding of the effects of PPARs, their molecular mechanisms and the role of these receptors in nutrition and therapeutic

  15. Cannabinoids go nuclear: evidence for activation of peroxisome proliferator-activated receptors

    Science.gov (United States)

    O'Sullivan, S E

    2007-01-01

    Cannabinoids act at two classical cannabinoid receptors (CB1 and CB2), a 7TM orphan receptor and the transmitter-gated channel transient receptor potential vanilloid type-1 receptor. Recent evidence also points to cannabinoids acting at members of the nuclear receptor family, peroxisome proliferator-activated receptors (PPARs, with three subtypes α, β (δ) and γ), which regulate cell differentiation and lipid metabolism. Much evidence now suggests that endocannabinoids are natural activators of PPARα. Oleoylethanolamide regulates feeding and body weight, stimulates fat utilization and has neuroprotective effects mediated through activation of PPARα. Similarly, palmitoylethanolamide regulates feeding and lipid metabolism and has anti-inflammatory properties mediated by PPARα. Other endocannabinoids that activate PPARα include anandamide, virodhamine and noladin. Some (but not all) endocannabinoids also activate PPARγ; anandamide and 2-arachidonoylglycerol have anti-inflammatory properties mediated by PPARγ. Similarly, ajulemic acid, a structural analogue of a metabolite of Δ9-tetrahydrocannabinol (THC), causes anti-inflammatory effects in vivo through PPARγ. THC also activates PPARγ, leading to a time-dependent vasorelaxation in isolated arteries. Other cannabinoids which activate PPARγ include N-arachidonoyl-dopamine, HU210, WIN55212-2 and CP55940. In contrast, little research has been carried out on the effects of cannabinoids at PPARδ. In this newly emerging area, a number of research questions remain unanswered; for example, why do cannabinoids activate some isoforms and not others? How much of the chronic effects of cannabinoids are through activation of nuclear receptors? And importantly, do cannabinoids confer the same neuro- and cardioprotective benefits as other PPARα and PPARγ agonists? This review will summarize the published literature implicating cannabinoid-mediated PPAR effects and discuss the implications thereof. PMID:17704824

  16. Peroxisome proliferator-activated receptors and their ligands: nutritional and clinical implications – a review

    Science.gov (United States)

    2014-01-01

    Peroxisome proliferator-activated receptors are expressed in many tissues, including adipocytes, hepatocytes, muscles and endothelial cells; however, the affinity depends on the isoform of PPAR, and different distribution and expression profiles, which ultimately lead to different clinical outcomes. Because they play an important role in lipid and glucose homeostasis, they are called lipid and insulin sensors. Their actions are limited to specific tissue types and thus, reveal a characteristic influence on target cells. PPARα mainly influences fatty acid metabolism and its activation lowers lipid levels, while PPARγ is mostly involved in the regulation of the adipogenesis, energy balance, and lipid biosynthesis. PPARβ/δ participates in fatty acid oxidation, mostly in skeletal and cardiac muscles, but it also regulates blood glucose and cholesterol levels. Many natural and synthetic ligands influence the expression of these receptors. Synthetic ligands are widely used in the treatment of dyslipidemia (e.g. fibrates - PPARα activators) or in diabetes mellitus (e.g. thiazolidinediones - PPARγ agonists). New generation drugs - PPARα/γ dual agonists - reveal hypolipemic, hypotensive, antiatherogenic, anti-inflammatory and anticoagulant action while the overexpression of PPARβ/δ prevents the development of obesity and reduces lipid accumulation in cardiac cells, even during a high-fat diet. Precise data on the expression and function of natural PPAR agonists on glucose and lipid metabolism are still missing, mostly because the same ligand influences several receptors and a number of reports have provided conflicting results. To date, we know that PPARs have the capability to accommodate and bind a variety of natural and synthetic lipophilic acids, such as essential fatty acids, eicosanoids, phytanic acid and palmitoylethanolamide. A current understanding of the effects of PPARs, their molecular mechanisms and the role of these receptors in nutrition and

  17. Genetic polymorphisms in peroxisome proliferator-activated receptor delta associated with obesity.

    Science.gov (United States)

    Shin, Hyoung Doo; Park, Byung Lae; Kim, Lyoung Hyo; Jung, Hye Seung; Cho, Young Min; Moon, Min Kyong; Park, Young Joo; Lee, Hong Kyu; Park, Kyong Soo

    2004-03-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors regulating the expression of genes involved in lipid and glucose metabolism. Three different PPARs, PPAR-alpha, -gamma, and -delta, have been characterized, and they are distinguished from each other by tissue distribution and cell activation. All PPARs are, to different extents, activated by fatty acids and derivatives. Recently, it has been shown that PPAR-delta serves as a widespread regulator of fat burning, suggesting that it might be a potential target in the treatment of obesity and type 2 diabetes. In an effort to identify polymorphic markers in potential candidate genes for type 2 diabetes, we have sequenced PPAR-delta, including -1,500 bp of the 5' flanking region. Nine polymorphisms were identified in PPAR-delta: four in the intron, one in the 5' untranslated region (UTR), and four in the 3' UTR. Among identified polymorphisms, five common sites, including c.-13454G>T, c.-87T>C, c.2022+12G>A, c.2629T>C, and c.2806C>G, were genotyped in subjects with type 2 diabetes and normal control subjects (n = 702). The genetic associations with the risk of type 2 diabetes and metabolic phenotype were analyzed. No significant associations with the risk of type 2 diabetes were detected. However, several positive associations of PPAR-delta polymorphisms with fasting plasma glucose and BMI were detected in nondiabetic control subjects. The genetic information about PPAR-delta from this study would be useful for further genetic study of obesity, diabetes, and other metabolic diseases.

  18. Enhanced expression of peroxisome proliferator-activated receptor gamma in epithelial ovarian carcinoma.

    Science.gov (United States)

    Zhang, G Y; Ahmed, N; Riley, C; Oliva, K; Barker, G; Quinn, M A; Rice, G E

    2005-01-17

    The peroxisome proliferator-activated receptors (PPARs) belong to a subclass of nuclear hormone receptor that executes important cellular transcriptional functions. Previous studies have demonstrated the expression of PPARgamma in several tumours including colon, breast, bladder, prostate, lung and stomach. This study demonstrates the relative expression of PPARgamma in normal ovaries and different pathological grades of ovarian tumours of serous, mucinous, endometrioid, clear cell and mixed subtypes. A total of 56 ovarian specimens including 10 normal, eight benign, 10 borderline, seven grade 1, nine grade 2 and 12 grade 3 were analysed using immunohistochemistry. Immunoreactive PPARgamma was not expressed in normal ovaries. Out of eight benign and 10 borderline tumours, only one tumour in each group showed weak cytoplasmic PPARgamma expression. In contrast, 26 out of 28 carcinomas studied were positive for PPARgamma expression with staining confined to cytoplasmic and nuclear regions. An altered staining pattern of PPARgamma was observed in high-grade ovarian tumours with PPARgamma being mostly localized in the nuclei with little cytoplasmic immunoreactivity. On the other hand, predominant cytoplasmic staining was observed in lower-grade tumours. Significantly increased PPARgamma immunoreactivity was observed in malignant ovarian tumours (grade 1, 2 and 3) compared to benign and borderline tumours (chi2 = 48.80, P < 0.001). Western blot analyses showed significant elevation in the expression of immunoreactive PPARgamma in grade 3 ovarian tumours compared with that of normal ovaries and benign ovarian tumours (P < 0.01). These findings suggest an involvement of PPARgamma in the onset and development of ovarian carcinoma and provide an insight into the regulation of this molecule in the progression of the disease.

  19. The story so far: post-translational regulation of peroxisome proliferator-activated receptors by ubiquitination and SUMOylation.

    Science.gov (United States)

    Wadosky, Kristine M; Willis, Monte S

    2012-02-01

    Many studies have implicated the peroxisome proliferator-activated receptor (PPAR) family of nuclear receptor transcription factors in regulating cardiac substrate metabolism and ATP generation. Recently, evidence from a variety of cell culture and organ systems has implicated ubiquitin and small ubiquitin-like modifier (SUMO) conjugation as post-translational modifications that regulate the activity of PPAR transcription factors and their coreceptors/coactivators. Here we introduce the ubiquitin and SUMO conjugation systems and extensively review how they have been shown to regulate all three PPAR isoforms (PPARα, PPARβ/δ, and PPARγ) in addition to the retinoid X receptor and PPARγ coactivator-1α subunits of the larger PPAR transcription factor complex. We then present how the specific ubiquitin (E3) ligases have been implicated and review emerging evidence that post-translational modifications of PPARs with ubiquitin and/or SUMO may play a role in cardiac disease. Because PPAR activity is perturbed in a variety of forms of heart disease and specific proteins regulate this process (E3 ligases), this may be a fruitful area of investigation with respect to finding new therapeutic targets.

  20. Nuclear receptors of the peroxisome proliferator-activated receptor (PPAR) family in gestational diabetes: from animal models to clinical trials.

    Science.gov (United States)

    Arck, Petra; Toth, Bettina; Pestka, Aurelia; Jeschke, Udo

    2010-08-01

    Gestational diabetes mellitus (GDM) is defined as impaired glucose tolerance and affects 2%-8% of all pregnancies. Among other complications, GDM can lead to the development of type 2 diabetes mellitus (DM 2) in both mother and child. Peroxisome proliferator-activated receptors (PPARs) are major regulators of glucose and lipid metabolism. Furthermore, PPARs are mediators of inflammation and angiogenesis and are involved in the maternal adaptational dynamics during pregnancy to serve the requirements of the growing fetus. PPARs were originally named for their ability to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. The expression of three PPAR isoforms, alpha, beta/delta, and gamma, have been described. Each of them is encoded by different genes; however, they share 60%-80% homology in their ligand-binding and DNA-binding domains. PPARs are involved in trophoblast differentiation, invasion, metabolism, and parturition and are expressed in invasive extravillous trophoblast and villous trophoblast cells. Nuclear receptors, to which PPARs belong, are promising targets for disease-specific treatment strategies because they act as transcription factors controlling cellular processes at the level of gene expression and may produce selective alterations in downstream gene expression. To date, PPAR agonists are therapeutically used in patients with DM 2 and in patients with reproductive disorders such as polycystic ovary syndrome. Because of safety concerns and limited data, PPAR agonists are not yet included in GDM-related treatment strategies. Our objective herein is to review newly emerging generations of selective PPAR modulators and panagonists, which may have potent therapeutic implications in the context of GDM.

  1. Glycogen content regulates peroxisome proliferator activated receptor-∂ (PPAR-∂) activity in rat skeletal muscle.

    Science.gov (United States)

    Philp, Andrew; MacKenzie, Matthew G; Belew, Micah Y; Towler, Mhairi C; Corstorphine, Alan; Papalamprou, Angela; Hardie, D Grahame; Baar, Keith

    2013-01-01

    Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR) coactivator-1α (PGC-1α) and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4): control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]). Gastrocnemius (GTN) muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP) assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E) finished with higher AMPK-α2 activity (147%, pexercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-∂ and initiates AMPK translocation in skeletal muscle in response to exercise.

  2. Evidence for the presence of both peroxisome proliferator-activated receptors alpha and beta in the rat spinal cord.

    Science.gov (United States)

    Benani, A; Krémarik-Bouillaud, P; Bianchi, A; Netter, P; Minn, A; Dauça, M

    2003-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptor superfamily. Different subtypes of PPARs (alpha, beta, and gamma) have been described. Their distinct physiological functions depend on their differential ligand activation profiles but also on their specific tissue expression. Previous studies have described their presence in the central nervous system. However, their expression in the adult rat spinal cord in normal physiological conditions has never been investigated. We demonstrated by using reverse-transcription-polymerase chain reaction, and Western blotting, the mRNA and protein expression of PPARalpha and PPARbeta, but not PPARgamma in cervical, thoracic, and lumbar segments of the spinal cord. Using immunohistochemistry, we also showed for the first time the specific cellular distribution of these transcription factors in the different segments of the spinal cord. In the gray matter, the distribution of PPARalpha was homogenous whereas PPARbeta was specifically localized in motoneurons and in medial part of laminae IV, V, VI, VII, VIII, and X. These latter areas are known as nociceptive afferent pathways to supra-spinal structures such as the medulla reticular nucleus and the thalamus. In the white matter, PPARalpha was localized exclusively in astrocytes while PPARbeta was present in oligodendrocytes. The possible functions of PPARalpha and PPARbeta expressed in both white and gray matters of the spinal cord will be discussed but need further studies.

  3. Novel Histone Deacetylase Inhibitor Modulates Cardiac Peroxisome Proliferator-Activated Receptors and Inflammatory Cytokines in Heart Failure.

    Science.gov (United States)

    Lkhagva, Baigalmaa; Lin, Yung-Kuo; Kao, Yu-Hsun; Chazo, Tze-Fan; Chung, Cheng-Chih; Chen, Shih-Ann; Chen, Yi-Jen

    2015-01-01

    Heart failure (HF) affects cardiac metabolism and inflammation. Histone deacetylases (HDACs) play a critical role in cardiac pathophysiology. This study investigated whether HDAC inhibition can regulate HF by modifying cardiac inflammation and peroxisome proliferator-activated receptor (PPAR) isoforms. Echocardiography, electrocardiography, ELISA and Western blot were performed in rats with isoproterenol-induced HF, with and without orally administered MPT0E014 (a novel HDAC inhibitor, 50 mg/kg for 7 consecutive days). The left ventricles (LVs) of HF rats expressed significantly higher levels of HDAC1, HDAC2, HDAC3, HDAC4 and HDAC6 than the healthy LVs did. HF rats treated with MPT0E014 exhibited improved cardiac fraction shortening with reducing chamber size. The MPT0E014-treated HF LVs exhibited a smaller increase in the expression of interleukin (IL)-6, p22, SMAD2/3, extracellular signal-regulated kinase 1/2, PPAR isoforms and circulatory tumor growth factor-β1 than the untreated HF LVs did. Moreover, MPT0E014-treated HF LVs expressed less fibroblast growth factor receptor than untreated HF LVs did. HDAC inhibition can improve cardiac function and attenuate the effects of HF on cardiac metabolism and inflammation, which might contribute to the beneficial effects of HDAC inhibition in HF. © 2015 S. Karger AG, Basel.

  4. Variation in the peroxisome proliferator-activated receptor delta gene in relation to common metabolic traits in 7,495 middle-aged white people

    DEFF Research Database (Denmark)

    Grarup, N; Albrechtsen, A; Ek, J

    2007-01-01

    Studies in animals reveal that peroxisome proliferator-activated receptor delta (PPARdelta) regulates glucose metabolism and insulin sensitivity in both the liver and skeletal muscles. Moreover, PPARdelta augments physical endurance and increases oxidative metabolism, thereby averting obesity. Th...

  5. Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα) in a Mouse Liver Gene Expression Compendium

    Science.gov (United States)

    The nuclear receptor family member peroxisome proliferator-activated receptor α (PPARα) is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARα in rodents inc...

  6. Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-{gamma} ligand, rosiglitazone

    Energy Technology Data Exchange (ETDEWEB)

    Wakui, Yuta; Inoue, Jun [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan); Ueno, Yoshiyuki, E-mail: yueno@mail.tains.tohoku.ac.jp [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan); Fukushima, Koji; Kondo, Yasuteru; Kakazu, Eiji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru [Division of Gastroenterology, Tohoku University Graduate School of Medicine, 1-1 Seiryo, Aobaku, Sendai 980-8574 (Japan)

    2010-05-28

    Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-{alpha}, the control of HBV infection still remains a clinical challenge. Peroxisome proliferator-activated receptor (PPAR) is a ligand-activated transcription factor, that plays a role in glucose and lipid metabolism, immune reactions, and inflammation. In this study, the suppressive effect of PPAR ligands on HBV replication was examined in vitro using a PPAR{alpha} ligand, bezafibrate, and a PPAR{gamma} ligand, rosiglitazone. The effects were examined in HepG2 cells transfected with a plasmid containing 1.3-fold HBV genome. Whereas bezafibrate showed no effect against HBV replication, rosiglitazone reduced the amount of HBV DNA, hepatitis B surface antigen, and hepatitis B e antigen in the culture supernatant. Southern blot analysis showed that the replicative intermediates of HBV in the cells were also inhibited. It was confirmed that GW9662, an antagonist of PPAR{gamma}, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-{alpha}-2b. In conclusion, this study showed that rosiglitazone inhibited the replication of HBV in vitro, and suggested that the combination therapy of rosiglitazone and nucleot(s)ide analogues or interferon could be a therapeutic option for chronic HBV infection.

  7. Expression profiling of peroxisome proliferator-activated receptor-delta (PPAR-delta) in mouse tissues using tissue microarray.

    Science.gov (United States)

    Higashiyama, Hiroyuki; Billin, Andrew N; Okamoto, Yuji; Kinoshita, Mine; Asano, Satoshi

    2007-05-01

    Peroxisome proliferator-activated receptor-delta (PPAR-delta) is known as a transcription factor involved in the regulation of fatty acid oxidation and mitochondrial biogenesis in several tissues, such as skeletal muscle, liver and adipose tissues. In this study, to elucidate systemic physiological functions of PPAR-delta, we examined the tissue distribution and localization of PPAR-delta in adult mouse tissues using tissue microarray (TMA)-based immunohistochemistry. PPAR-delta positive signals were observed on variety of tissues/cells in multiple systems including cardiovascular, urinary, respiratory, digestive, endocrine, nervous, hematopoietic, immune, musculoskeletal, sensory and reproductive organ systems. In these organs, PPAR-delta immunoreactivity was generally localized on the nucleus, although cytoplasmic localization was observed on several cell types including neurons in the nervous system and cells of the islet of Langerhans. These expression profiling data implicate various physiological roles of PPAR-delta in multiple organ systems. TMA-based immunohistochemistry enables to profile comprehensive protein localization and distribution in a high-throughput manner.

  8. Peroxisome Proliferator-Activated Receptorα Agonists Differentially Regulate Inhibitor of DNA Binding Expression in Rodents and Human Cells

    Directory of Open Access Journals (Sweden)

    María del Carmen González

    2012-01-01

    Full Text Available Inhibitor of DNA binding (Id2 is a helix-loop-helix (HLH transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY. WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2. MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V, the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.

  9. Peroxisome proliferators-activated alpha agonist treatment ameliorates hepatic damage in rats with obstructive jaundice: an experimental study

    Directory of Open Access Journals (Sweden)

    Alper Murat

    2007-11-01

    Full Text Available Abstract Background Peroxisome proliferators-activated receptor alpha (PPARα activation modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of short-term administration of fenofibrate, a PPARα agonist, on proinflammatory cytokines, apoptosis, and hepatocellular damage in cholestasis. Methods Forty male Wistar rats were randomly divided into four groups: I = sham operated, II = bile duct ligation (BDL, III = BDL + vehicle (gum Arabic, IV = BDL + fenofibrate (100 mg/kg/day. All rats were sacrificed on 7th day after obtaining blood samples and liver tissue. Total bilirubin, aminotransferase (AST, alanine aminotransferase (ALT and alkaline phosphatase (ALP, gamma-glutamyl transferase, (GGT, tumor necrosis factor alpha (TNF-α, interleukin 1 beta (IL-1 β, and total bile acid (TBA in serum, and liver damage scores; portal inflammation, necrosis, bile duct number, in liver tissue were evaluated. Apoptosis in liver was also assessed by immunohistochemical staining. Results Fenofibrate administration significantly reduced serum total bilirubin, AST, ALT, ALP, and GGT, TNF-α, IL-1 β levels, and TBA (P P P P Conclusion Short-term administration of fenofibrate to the BDL rats exerts beneficial effects on hepatocellular damage and apoptosis.

  10. Macrophage peroxisome proliferator-activated receptor γ deficiency delays skin wound healing through impairing apoptotic cell clearance in mice.

    Science.gov (United States)

    Chen, H; Shi, R; Luo, B; Yang, X; Qiu, L; Xiong, J; Jiang, M; Liu, Y; Zhang, Z; Wu, Y

    2015-01-15

    Skin wound macrophages are key regulators of skin repair and their dysfunction causes chronic, non-healing skin wounds. Peroxisome proliferator-activated receptor gamma (PPARγ) regulates pleiotropic functions of macrophages, but its contribution in skin wound healing is poorly defined. We observed that macrophage PPARγ expression was upregulated during skin wound healing. Furthermore, macrophage PPARγ deficiency (PPARγ-knock out (KO)) mice exhibited impaired skin wound healing with reduced collagen deposition, angiogenesis and granulation formation. The tumor necrosis factor alpha (TNF-α) expression in wounds of PPARγ-KO mice was significantly increased and local restoration of TNF-α reversed the healing deficit in PPARγ-KO mice. Wound macrophages produced higher levels of TNF-α in PPARγ-KO mice compared with control. In vitro, the higher production of TNF-α by PPARγ-KO macrophages was associated with impaired apoptotic cell clearance. Correspondingly, increased apoptotic cell accumulation was found in skin wound of PPARγ-KO mice. Mechanically, peritoneal and skin wound macrophages expressed lower levels of various phagocytosis-related molecules. In addition, PPARγ agonist accelerated wound healing and reduced local TNF-α expression and wound apoptotic cells accumulation in wild type but not PPARγ-KO mice. Therefore, PPARγ has a pivotal role in controlling wound macrophage clearance of apoptotic cells to ensure efficient skin wound healing, suggesting a potential new therapeutic target for skin wound healing.

  11. Differential effects of triclosan on the activation of mouse and human peroxisome proliferator-activated receptor alpha.

    Science.gov (United States)

    Wu, Yuanfeng; Wu, Qiangen; Beland, Frederick A; Ge, Peter; Manjanatha, Mugimane G; Fang, Jia-Long

    2014-11-18

    Triclosan is an anti-bacterial agent used in many personal care products, household items, medical devices, and clinical settings. Liver tumors occur in mice exposed to triclosan, a response attributed to peroxisome proliferator-activated receptor alpha (PPARα) activation; however, the effects of triclosan on mouse and human PPARα have not been fully evaluated. We compared the effects of triclosan on mouse and human PPARα using PPARα reporter assays and on downstream events of PPARα activation using mouse hepatoma Hepa1c1c7 cells and human hepatoma HepG2 cells. PPARα transcriptional activity was increased by triclosan in a mouse PPARα reporter assay and decreased in a human PPARα reporter assay. Concentrations of triclosan inhibiting 50% cell growth were similar in both human and mouse hepatoma cells. Western blotting analysis showed that triclosan increased acyl-coenzyme A oxidase (ACOX1), a PPARα target, in Hepa1c1c7 cells but decreased the level in HepG2 cells. Treatment of Hepa1c1c7 cells with triclosan enhanced DNA synthesis and suppressed transforming growth factor beta-mediated apoptosis. This did not occur in HepG2 cells. These data demonstrate that triclosan had similar cytotoxicity in Hepa1c1c7 and HepG2 cells, but differential effects on the activation of PPARα, the expression of ACOX1, and downstream events including DNA synthesis and apoptosis.

  12. Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma.

    Science.gov (United States)

    Nagatomo, Akifumi; Nishida, Norihisa; Matsuura, Yoichi; Shibata, Nobuhito

    2013-06-01

    Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARγ) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARγ expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT.

  13. Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

    Directory of Open Access Journals (Sweden)

    Paola Dongiovanni

    2013-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH, a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs, represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation.

  14. Telmisartan protects against microvascular dysfunction during myocardial ischemia/reperfusion injury by activation of peroxisome proliferator-activated receptor gamma

    Science.gov (United States)

    2013-01-01

    Background We investigated the potential of telmisartan to improve microvascular dysfunction induced by myocardial ischemia/reperfusion (I/R) injury by activating the peroxisome proliferator-activated receptor gamma (PPARG) pathway. Methods Forty-eight male rabbits were randomly allocated into sham-operated, I/R, GW9662, telmisartan, telmisartan–GW9662, or candesartan groups. Rabbits were anesthetized, and the left anterior descending coronary artery (LAD) was ligated for 60 minutes. Following reperfusion for 6 hours, angiotensin II content of the heart was determined using radioimmunoassay. Myocardial neutrophil accumulation and microvessel cross-sectional area were examined histologically. Myocardial capillaries were examined with transmission electron microscopy. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the myocardium were measured using enzyme-linked immunosorbent assay. Western blot was utilized for investigating the expression of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and PPARG. Results Angiotensin II concentration was significantly increased in all treatment groups compared with the sham-operated group (P telmisartan, telmisartan-GW9662, and candesartan groups compared with the I/R group (P telmisartan group compared with the telmisartan–GW9662 and candesartan groups. Telmisartan significantly increased PPARG protein expression compared with all other groups (P telmisartan improved microvascular dysfunction during myocardial I/R injury via the PPARG pathway. PMID:23738781

  15. Peroxisome proliferator-activated receptor γ agonist reduces the severity of post-ERCP pancreatitis in rats

    Institute of Scientific and Technical Information of China (English)

    Emma Folch-Puy; Susana Granell; Juan L Iovanna; Marc Barthet; Daniel Closa

    2006-01-01

    AIM:To determine the effects of prophylactic peroxisome proliferator-activated receptor (PPARγ) agonist administration in an experimental model of postendoscopic retrograde cholangiopancreatography (postERCP) acute pancreatitis.METHODS: Post-ERCP pancreatitis was induced in male Wistar rats by infusion of contrast medium into the pancreatic duct. In additional group, rosiglitazone, a PPARγ agonist, was administered 1 h before infusion of contrast medium. Plasma and pancreas samples were obtained 6 h after the infusion.RESULTS: Infusion of contrast medium into the pancreatic duct resulted in an inflammatory process characterized by increased lipase levels in plasma, and edema and myeloperoxidase activity (MPO) in pancreas.This result correlated with the activation of nuclear factor κB (NFκB) and the inducible NO synthase (iNOS)expression in pancreatic cells. Rosiglitazone reduced the increase in lipase and the level of edema and the increase in myeloperoxidase as well as the activation of NFκB and iNOS expression.CONCLUSION: A single oral dose of rosiglitazone, given 1 h before post-ERCP pancreatitis induction is effective in reducing the severity of the subsequent inflammatory process. The protective effect of rosiglitazone was associated with NFκB inhibition and the blockage of leukocyte infiltration in pancreas.

  16. Conjugated linoleic acid (CLA) promotes endurance capacity via peroxisome proliferator-activated receptor δ-mediated mechanism in mice.

    Science.gov (United States)

    Kim, Yoo; Kim, Daeyoung; Park, Yeonhwa

    2016-12-01

    Previously, it was reported that conjugated linoleic acid (CLA) with exercise training potentially improved endurance capacity via the peroxisome proliferator-activated receptor δ (PPARδ)-mediated mechanism in mice. This study determined the role of exercise and/or CLA in endurance capacity and PPARδ-associated regulators. Male 129Sv/J mice were fed either control (soybean oil) or CLA (0.5%) containing diets for 4 weeks and were further divided into sedentary or training regimes. CLA supplementation significantly reduced body weight and fat mass independent of exercise during the experimental period. Endurance capacity was significantly improved by CLA supplementation, while no effect of exercise was observed. Similarly, CLA treatment significantly increased expressions of sirtuin 1 and PPARγ coactivator-1α, up-stream regulators of PPARδ, in both sedentary and trained animals. With respect to downstream markers of PPARδ, CLA up-regulated the key biomarker needed to stimulate mitochondrial biogenesis, nuclear respiratory factor 1. Moreover, CLA supplementation significantly induced overall genes associated with muscle fibers, such as type I (slow-twitch) and type II (fast twitch). Taken together, it suggests that CLA improves endurance capacity independent of mild-intensity exercise via PPARδ-mediated mechanism.

  17. Medium chain fatty acids are selective peroxisome proliferator activated receptor (PPAR γ activators and pan-PPAR partial agonists.

    Directory of Open Access Journals (Sweden)

    Marcelo Vizoná Liberato

    Full Text Available Thiazolidinediones (TZDs act through peroxisome proliferator activated receptor (PPAR γ to increase insulin sensitivity in type 2 diabetes (T2DM, but deleterious effects of these ligands mean that selective modulators with improved clinical profiles are needed. We obtained a crystal structure of PPARγ ligand binding domain (LBD and found that the ligand binding pocket (LBP is occupied by bacterial medium chain fatty acids (MCFAs. We verified that MCFAs (C8-C10 bind the PPARγ LBD in vitro and showed that they are low-potency partial agonists that display assay-specific actions relative to TZDs; they act as very weak partial agonists in transfections with PPARγ LBD, stronger partial agonists with full length PPARγ and exhibit full blockade of PPARγ phosphorylation by cyclin-dependent kinase 5 (cdk5, linked to reversal of adipose tissue insulin resistance. MCFAs that bind PPARγ also antagonize TZD-dependent adipogenesis in vitro. X-ray structure B-factor analysis and molecular dynamics (MD simulations suggest that MCFAs weakly stabilize C-terminal activation helix (H 12 relative to TZDs and this effect is highly dependent on chain length. By contrast, MCFAs preferentially stabilize the H2-H3/β-sheet region and the helix (H 11-H12 loop relative to TZDs and we propose that MCFA assay-specific actions are linked to their unique binding mode and suggest that it may be possible to identify selective PPARγ modulators with useful clinical profiles among natural products.

  18. Activation of peroxisome proliferator-activated receptor α induces lysosomal biogenesis in brain cells: implications for lysosomal storage disorders.

    Science.gov (United States)

    Ghosh, Arunava; Jana, Malabendu; Modi, Khushbu; Gonzalez, Frank J; Sims, Katherine B; Berry-Kravis, Elizabeth; Pahan, Kalipada

    2015-04-17

    Lysosomes are ubiquitous membrane-enclosed organelles filled with an acidic interior and are central to the autophagic, endocytic, or phagocytic pathway. In contrast to its classical function as the waste management machinery, lysosomes are now considered to be an integral part of various cellular signaling processes. The diverse functionality of this single organelle requires a very complex and coordinated regulation of its activity with transcription factor EB (TFEB), a master regulator of lysosomal biogenesis, at its core. However, mechanisms by which TFEB is regulated are poorly understood. This study demonstrates that gemfibrozil, an agonist of peroxisome proliferator-activated receptor (PPAR) α, alone and in conjunction with all-trans-retinoic acid is capable of enhancing TFEB in brain cells. We also observed that PPARα, but not PPARβ and PPARγ, is involved in gemfibrozil-mediated up-regulation of TFEB. Reporter assay and chromatin immunoprecipitation studies confirmed the recruitment of retinoid X receptor α, PPARα, and PGC1α on the PPAR-binding site on the Tfeb promoter as well. Subsequently, the drug-mediated induction of TFEB caused an increase in lysosomal protein and the lysosomal abundance in cell. Collectively, this study reinforces the link between lysosomal biogenesis and lipid metabolism with TFEB at the crossroads. Furthermore, gemfibrozil may be of therapeutic value in the treatment of lysosomal storage disorders in which autophagy-lysosome pathway plays an important role.

  19. Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation.

    Science.gov (United States)

    Fukuda, Kazuki; Matsumura, Takeshi; Senokuchi, Takafumi; Ishii, Norio; Kinoshita, Hiroyuki; Yamada, Sarie; Murakami, Saiko; Nakao, Saya; Motoshima, Hiroyuki; Kondo, Tatsuya; Kukidome, Daisuke; Kawasaki, Shuji; Kawada, Teruo; Nishikawa, Takeshi; Araki, Eiichi

    2015-01-30

    The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe(-/-) mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe(-/-) mice. In conclusion, statins mediate anti-atherogenic effects through PPARγ activation in SMCs. These effects of statins on SMCs may be beneficial for the prevention of atherosclerosis.

  20. Decreased peroxisome proliferator-activated receptor γ level and signalling in sebaceous glands of patients with acne vulgaris.

    Science.gov (United States)

    Dozsa, A; Mihaly, J; Dezso, B; Csizmadia, E; Keresztessy, T; Marko, L; Rühl, R; Remenyik, E; Nagy, L

    2016-07-01

    Little is known about the altered lipid metabolism-related transcriptional events occuring in sebaceous glands of patients with acne vulgaris. Peroxisome proliferator-activated receptor (PPAR)γ, a lipid-activated transcription factor, is implicated in differentiation and lipid metabolism of sebocytes. We have observed that PPARγ and its target genes, ADRP (adipose differentiation related protein) and PGAR (PPARγ angioprotein related protein) are expressed at lower levels in sebocytes from patients with acne than in those from healthy controls (HCs) Furthermore, endogenous PPARγ activator lipids such as arachidonic acid-derived keto-metabolites (e.g. 5KETE, 12KETE) are increased in acne-involved and nonacne-involved skin of patients with acne, compared with skin from healthy individuals. Our findings highlight the possible anti-inflammatory role of endogenous ligand-activated PPARγ signaling in human sebocyte biology, and suggest that modulating PPARγ- expression and thereby signaling might be a promising strategy for the clinical management of acne vulgaris.

  1. Peroxisome proliferator-activated receptorα agonists differentially regulate inhibitor of DNA binding expression in rodents and human cells.

    Science.gov (United States)

    González, María Del Carmen; Corton, J Christopher; Acero, Nuria; Muñoz-Mingarro, Dolores; Quirós, Yolanda; Alvarez-Millán, Juan José; Herrera, Emilio; Bocos, Carlos

    2012-01-01

    Inhibitor of DNA binding (Id2) is a helix-loop-helix (HLH) transcription factor that participates in cell differentiation and proliferation. Id2 has been linked to the development of cardiovascular diseases since thiazolidinediones, antidiabetic agents and peroxisome proliferator-activated receptor (PPAR) gamma agonists, have been reported to diminish Id2 expression in human cells. We hypothesized that PPARα activators may also alter Id2 expression. Fenofibrate diminished hepatic Id2 expression in both late pregnant and unmated rats. In 24 hour fasted rats, Id2 expression was decreased under conditions known to activate PPARα. In order to determine whether the fibrate effects were mediated by PPARα, wild-type mice and PPARα-null mice were treated with Wy-14,643 (WY). WY reduced Id2 expression in wild-type mice without an effect in PPARα-null mice. In contrast, fenofibrate induced Id2 expression after 24 hours of treatment in human hepatocarcinoma cells (HepG2). MK-886, a PPARα antagonist, did not block fenofibrate-induced activation of Id2 expression, suggesting a PPARα-independent effect was involved. These findings confirm that Id2 is a gene responsive to PPARα agonists. Like other genes (apolipoprotein A-I, apolipoprotein A-V), the opposite directional transcriptional effect in rodents and a human cell line further emphasizes that PPARα agonists have different effects in rodents and humans.

  2. The Pro115Gln Missense Mutation of Peroxisome Proliferator Activated Receptor γ (PPARγ Gene in Diabetes in the Pakistani Population

    Directory of Open Access Journals (Sweden)

    Sumbal

    2016-05-01

    Full Text Available Background Diabetes is an alarmingly increasing public health concern. According to a World Health Organization (WHO report, diabetes is highly prevalent in almost all regions of Pakistan, with an overall prevalence of 22.04% in urban and 17.15% in rural areas. In addition to lifestyle factors, genetics plays an important part in the progression to diabetes, of which peroxisome proliferator activated receptors (PPARs, a super-family of transcriptional regulators, are considered to be very critical. Objectives The aim of the current study was to investigate the prevalence of a missense mutation Pro115Gln in the PPARγ; gene in Pakistan and search for its effects on certain serum biochemical parameters. Materials and Methods A total of 1015 subjects (490 diabetics and 525 healthy controls were genotyped by PCR-RFLP and serum profiling was performed. Results We could not detect the mutation in the study subjects, but the anthropometric and biochemical parameters were significantly different between the cases and controls. Conclusions In conclusion, as this mutation is present in a highly conserved region and any change in this region would adversely affect the protein structure and function, so the prevalence of this mutation is very low.

  3. Synthetic and natural Peroxisome Proliferator-Activated Receptor (PPAR) agonists as candidates for the therapy of the metabolic syndrome.

    Science.gov (United States)

    Tan, Chek Kun; Zhuang, Yan; Wahli, Walter

    2017-03-01

    Peroxisome proliferator-activated receptors (PPARs) are the molecular targets of hypolipidemic and insulin-sensitizing drugs and implicated in a multitude of processes that fine-tune the functions of all organs in vertebrates. As transcription factors they sense endogenous and exogenous lipid signaling molecules and convert these signals into intricate gene responses that impact health and disease. The PPARs act as modulators of cellular, organ, and systemic processes, such as lipid and carbohydrate metabolism, making them valuable for understanding body homeostasis influenced by nutrition and exercise. Areas covered: This review concentrates on synthetic and natural PPAR ligands and how they have helped reveal many aspects of the transcriptional control of complex processes important in health. Expert opinion: The three PPARs have complementary roles in the fine-tuning of most fundamental body functions, especially energy metabolism. Understanding their inter-relatedness using ligands that simultaneously modulate the activity of more than one of these receptors is a major goal. This approach may provide essential knowledge for the development of dual or pan-PPAR agonists or antagonists as potential new health-promoting agents and for nutritional approaches to prevent metabolic diseases.

  4. Peroxisome proliferator-activated receptors (PPARs) and ovarian function – implications for regulating steroidogenesis, differentiation, and tissue remodeling

    Science.gov (United States)

    Komar, Carolyn M

    2005-01-01

    The peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors involved in varied and diverse processes such as steroidogenesis, angiogenesis, tissue remodeling, cell cycle, apoptosis, and lipid metabolism. These processes are critical for normal ovarian function, and all three PPAR family members – alpha, delta, and gamma, are expressed in the ovary. Most notably, the expression of PPARgamma is limited primarily to granulosa cells in developing follicles, and is regulated by luteinizing hormone (LH). Although much has been learned about the PPARs since their initial discovery, very little is known regarding their function in ovarian tissue. This review highlights what is known about the roles of PPARs in ovarian cells, and discusses potential mechanisms by which PPARs could influence ovarian function. Because PPARs are activated by drugs currently in clinical use (fibrates and thiazolidinediones), it is important to understand their role in the ovary, and how manipulation of their activity may impact ovarian physiology as well as ovarian pathology. PMID:16131403

  5. Beneficial health effects of Chios Gum Mastic and peroxisome proliferator-activated receptors: indications of common mechanisms.

    Science.gov (United States)

    Georgiadis, Ioannis; Karatzas, Theodore; Korou, Laskarina-Maria; Katsilambros, Nikolaos; Perrea, Despina

    2015-01-01

    For thousands of years, Chios Gum Mastic (CGM), the resin produced by the trunk of Pistachia lentiscus var Chia, has been used for culinary and medicinal purposes and several therapeutic properties have been attributed to it. CGM has been used in traditional medicine of various nations in the eastern Mediterranean area. This survey was carried out to identify biological mechanisms that could explain traditional usage and recent pharmacological findings. We reviewed the related scientific literature available from the NCBI PUBMED database on CGM studies and on natural products showing peroxisome proliferator-activated receptor (PPAR) agonist effects. We investigated whether CGM qualifies as a PPAR modulator. A large number of studies demonstrate that CGM has antioxidant, anti-inflammatory, hypolipidemic, and anticancer properties. Recently, the first evidence of CGM antidiabetic effect became known. CGM chemical composition has been extensively analyzed and the presence of several compounds, especially triterpenoids is well documented. Some of them, oleanonic acid, oleanolic acid, and gallic acid are considered to act as PPAR modulators. PPARs are nuclear receptors functioning as transcription factors and thereby controlling cellular functions at the level of gene expression. PPARs are involved in the pathways of significant diseases, such as metabolic syndrome, diabetes mellitus, dyslipidemia, inflammation, atheromatosis, and neoplasias, constituting a key target for pharmacological interventions. This article proposes that the synergistic action of some constituents of CGM on PPARs and more precisely on both PPARs isotypes-α and -γ, may be one of the major biological mechanisms via which CGM exerts its multiple effects.

  6. Cross-talk between heme oxygenase and peroxisome proliferator-activated receptors in the regulation of physiological functions.

    Science.gov (United States)

    Ndisang, Joseph Fomusi

    2014-06-01

    Peroxisome-proliferator-activated-receptors (PPARs) are transcription factors belonging to the superfamily of nuclear receptors. The isoforms of PPAR include PPAR alpha, PPAR gamma and PPAR delta (also known as PPAR beta). Generally, PPARs potentiate insulin sensitivity, improve glucose/lipid metabolism, suppress inflammation/oxidative stress, attenuate excessive immune responses, regulate cell-growth and differentiation. Interestingly, agonists of PPAR gamma and PPAR alpha have been shown to upregulate the heme-oxygenase (HO)-system. Conversely, the HO-system also enhances PPAR alpha, and potentiates the expression and activity of PPAR gamma. Moreover, the HO-system and related products including bilirubin, biliverdin, carbon monoxide and ferritin have been shown to increase insulin sensitivity, improve glucose/lipid metabolism, suppress inflammation/oxidative stress, abate immune response, and modulate cell-growth/differentiation. Therefore, an intimate, reciprocal, stimulatory and synergistic relationship between PPAR-signaling and the HO-system can be envisaged in the regulation of physiological functions. Thus, both the HO-system and PPARs-signaling participate in fine-tuning similar physiological functions, so novel pharmacological agents capable of optimizing this interaction should be sought. The coordinated regulation of PPAR-signaling and the HO-system may constitute the basis for future drug design.

  7. The subtypes of peroxisome proliferator-activated receptors expressed by human podocytes and their role in decreasing podocyte injury.

    Science.gov (United States)

    Miglio, Gianluca; Rosa, Arianna Carolina; Rattazzi, Lorenza; Grange, Cristina; Collino, Massimo; Camussi, Giovanni; Fantozzi, Roberto

    2011-01-01

    Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, and three subtypes (α, β and γ) have been identified. PPAR activation has been reported to decrease renal injury and markers of glomerular dysfunction in models of renal ischemia/reperfusion (I/R). However, both the I/R effects and the effects of PPAR agonists on podocytes, an integral cellular part of the glomerular filtration barrier, remain to be established. By using oxygen/glucose deprivation-reoxygenation as an in vitro model that mimics in vivo I/R, the effects of PPAR agonists on podocyte death were compared. Human immortalized podocytes were treated with gemfibrozil, GW0742, pioglitazone or rosiglitazone, as a single or repeated challenge. Cell loss, necrotic and apoptotic cell death were measured. Only the repeated treatment with each PPAR agonist significantly prevented cell death, mainly by decreasing apoptosis. In comparison, in a model of serum deprivation-induced apoptosis, both treatments were effective, although the repeated treatment achieved the more pronounced effect. Finally, our results showed that preservation of Bcl-2, Bax and nephrin expression accompanied the anti-apoptotic effects exerted by PPAR agonists in human podocytes. These findings contribute to clarification of the pathophysiological role of renal PPARs and suggest that selective PPARα, PPARβ or PPARγ agonists may exert similar protective effects on podocytes by decreasing apoptotic cell death. © 2010 The Authors. British Journal of Pharmacology © 2010 The British Pharmacological Society.

  8. New Insights into the Role of Peroxisome Proliferator-Activated Receptors in Regulating the Inflammatory Response after Tissue Injury

    Science.gov (United States)

    Neher, Miriam D.; Weckbach, Sebastian; Huber-Lang, Markus S.; Stahel, Philip F.

    2012-01-01

    Major trauma results in a strong inflammatory response in injured tissue. This posttraumatic hyperinflammation has been implied in the adverse events leading to a breakdown of host defense mechanisms and ultimately to delayed organ failure. Ligands to peroxisome proliferator-activated receptors (PPARs) have recently been identified as potent modulators of inflammation in various acute and chronic inflammatory conditions. The main mechanism of action mediated by ligand binding to PPARs is the inhibition of the nuclear transcription factor NF-κB, leading to downregulation of downstream gene transcription, such as for genes encoding proinflammatory cytokines. Pharmacological PPAR agonists exert strong anti-inflammatory properties in various animal models of tissue injury, including central nervous system trauma, ischemia/reperfusion injury, sepsis, and shock. In addition, PPAR agonists have been shown to induce wound healing process after tissue trauma. The present review was designed to provide an up-to-date overview on the current understanding of the role of PPARs in the pathophysiology of the inflammatory response after major trauma. Therapeutic options for using recombinant PPAR agonists as pharmacological agents in the management of posttraumatic inflammation will be discussed. PMID:22481914

  9. Association between the Pro12Ala Polymorphism of the Peroxisome Proliferator-Activated Receptor Gamma Gene and Strength Athlete Status

    Science.gov (United States)

    Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Cieszczyk, Pawel; Zarebska, Aleksandra; Sawczyn, Stanislaw

    2013-01-01

    Background The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG) Pro12Ala polymorphism produces a decreased binding affinity of the PPARγ2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. Methodology The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A χ2 test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni’s correction for multiple testing was applied. Results A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007). Conclusion The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin-dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio. PMID:23799144

  10. Peroxisome Proliferator-Activated Receptor Genetic Polymorphisms and Nonalcoholic Fatty Liver Disease: Any Role in Disease Susceptibility?

    Science.gov (United States)

    Dongiovanni, Paola; Valenti, Luca

    2013-01-01

    Nonalcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extend from simple steatosis, that is, increased hepatic lipid content, to nonalcoholic steatohepatitis (NASH), a condition that may progress to cirrhosis with its associated complications. Nuclear hormone receptors act as intracellular lipid sensors that coordinate genetic networks regulating lipid metabolism and energy utilization. This family of transcription factors, in particular peroxisome proliferator-activated receptors (PPARs), represents attractive drug targets for the management of NAFLD and NASH, as well as related conditions such as type 2 diabetes and the metabolic syndrome. The impact on the regulation of lipid metabolism observed for PPARs has led to the hypothesis that genetic variants within the human PPARs genes may be associated with human disease such as NAFLD, the metabolic syndrome, and/or coronary heart disease. Here we review the available evidence on the association between PPARs genetic polymorphism and the susceptibility to NAFLD and NASH, and we provide a meta-analysis of the available evidence. The impact of PPAR variants on the susceptibility to NASH in specific subgroup of patients, and in particular on the response to therapies, especially those targeting PPARs, represents promising new areas of investigation. PMID:23431284

  11. Association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma gene and strength athlete status.

    Science.gov (United States)

    Maciejewska-Karlowska, Agnieszka; Sawczuk, Marek; Cieszczyk, Pawel; Zarebska, Aleksandra; Sawczyn, Stanislaw

    2013-01-01

    The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG) Pro12Ala polymorphism produces a decreased binding affinity of the PPARγ2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A χ(2) test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni's correction for multiple testing was applied. A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007). The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin-dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio.

  12. Association between the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor gamma gene and strength athlete status.

    Directory of Open Access Journals (Sweden)

    Agnieszka Maciejewska-Karlowska

    Full Text Available BACKGROUND: The 12Ala allele of the Peroxisome Proliferator-Activated Receptor gamma gene (PPARG Pro12Ala polymorphism produces a decreased binding affinity of the PPARγ2 protein, resulting in low activation of the target genes. The 12Ala allele carriers display a significantly improved insulin sensitivity that may result in better glucose utilisation in working skeletal muscles. We hypothesise that the PPARG 12Ala allele could be associated with strength athlete status in Polish athletes. METHODOLOGY: The genotype distribution of PPARG Pro12Ala was examined in 660 Polish athletes. The athletes were stratified into four subgroups: endurance, strength-endurance, sprint-strength and strength. Control samples were prepared from 684 unrelated sedentary volunteers. A χ(2 test was used to compare the PPARG Pro12Ala allele and genotype frequencies between the different groups of athletes and control subjects. Bonferroni's correction for multiple testing was applied. RESULTS: A statistically significant higher frequency of PPARG 12Ala alleles was observed in the subgroup of strength athletes performing short-term and very intense exertion characterised by predominant anaerobic energy production (13.2% vs. 7.5% in controls; P = 0.0007. CONCLUSION: The PPARG 12Ala allele may be a relevant genetic factor favouring strength abilities in professional athletes, especially in terms of insulin-dependent metabolism, a shift of the energy balance towards glucose utilisation and the development of a favourable weight-to-strength ratio.

  13. Activation of peroxisome proliferator-activated receptor-{alpha} enhances fatty acid oxidation in human adipocytes

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joo-Young; Hashizaki, Hikari; Goto, Tsuyoshi; Sakamoto, Tomoya; Takahashi, Nobuyuki [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan); Kawada, Teruo, E-mail: fat@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji, Kyoto 611-0011 (Japan)

    2011-04-22

    Highlights: {yields} PPAR{alpha} activation increased mRNA expression levels of adipocyte differentiation marker genes and GPDH activity in human adipocytes. {yields} PPAR{alpha} activation also increased insulin-dependent glucose uptake in human adipocytes. {yields} PPAR{alpha} activation did not affect lipid accumulation in human adipocytes. {yields} PPAR{alpha} activation increased fatty acid oxidation through induction of fatty acid oxidation-related genes in human adipocytes. -- Abstract: Peroxisome proliferator-activated receptor-{alpha} (PPAR{alpha}) is a key regulator for maintaining whole-body energy balance. However, the physiological functions of PPAR{alpha} in adipocytes have been unclarified. We examined the functions of PPAR{alpha} using human multipotent adipose tissue-derived stem cells as a human adipocyte model. Activation of PPAR{alpha} by GW7647, a potent PPAR{alpha} agonist, increased the mRNA expression levels of adipocyte differentiation marker genes such as PPAR{gamma}, adipocyte-specific fatty acid-binding protein, and lipoprotein lipase and increased both GPDH activity and insulin-dependent glucose uptake level. The findings indicate that PPAR{alpha} activation stimulates adipocyte differentiation. However, lipid accumulation was not changed, which is usually observed when PPAR{gamma} is activated. On the other hand, PPAR{alpha} activation by GW7647 treatment induced the mRNA expression of fatty acid oxidation-related genes such as CPT-1B and AOX in a PPAR{alpha}-dependent manner. Moreover, PPAR{alpha} activation increased the production of CO{sub 2} and acid soluble metabolites, which are products of fatty acid oxidation, and increased oxygen consumption rate in human adipocytes. The data indicate that activation of PPAR{alpha} stimulates both adipocyte differentiation and fatty acid oxidation in human adipocytes, suggesting that PPAR{alpha} agonists could improve insulin resistance without lipid accumulation in adipocytes. The expected

  14. Dual and pan-peroxisome proliferator-activated receptors (PPAR co-agonism: the bezafibrate lessons

    Directory of Open Access Journals (Sweden)

    Tenenbaum Alexander

    2005-09-01

    Full Text Available Abstract There are three peroxisome proliferator-activated receptors (PPARs subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar. The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients

  15. Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons

    Science.gov (United States)

    Tenenbaum, Alexander; Motro, Michael; Fisman, Enrique Z

    2005-01-01

    There are three peroxisome proliferator-activated receptors (PPARs) subtypes which are commonly designated PPAR alpha, PPAR gamma and PPAR beta/delta. PPAR alpha activation increases high density lipoprotein (HDL) cholesterol synthesis, stimulates "reverse" cholesterol transport and reduces triglycerides. PPAR gamma activation results in insulin sensitization and antidiabetic action. Until recently, the biological role of PPAR beta/delta remained unclear. However, treatment of obese animals by specific PPAR delta agonists results in normalization of metabolic parameters and reduction of adiposity. Combined treatments with PPAR gamma and alpha agonists may potentially improve insulin resistance and alleviate atherogenic dyslipidemia, whereas PPAR delta properties may prevent the development of overweight which typically accompanies "pure" PPAR gamma ligands. The new generation of dual-action PPARs – the glitazars, which target PPAR-gamma and PPAR-alpha (like muraglitazar and tesaglitazar) are on deck in late-stage clinical trials and may be effective in reducing cardiovascular risk, but their long-term clinical effects are still unknown. A number of glitazars have presented problems at a late stage of clinical trials because of serious side-effects (including ragaglitazar and farglitazar). The old and well known lipid-lowering fibric acid derivative bezafibrate is the first clinically tested pan – (alpha, beta/delta, gamma) PPAR activator. It is the only pan-PPAR activator with more than a quarter of a century of therapeutic experience with a good safety profile. Therefore, bezafibrate could be considered (indeed, as a "post hoc" understanding) as an "archetype" of a clinically tested pan-PPAR ligand. Bezafibrate leads to considerable raising of HDL cholesterol and reduces triglycerides, improves insulin sensitivity and reduces blood glucose level, significantly lowering the incidence of cardiovascular events and new diabetes in patients with features of

  16. Transcription of human resistin gene involves an interaction of Sp1 with peroxisome proliferator-activating receptor gamma (PPARgamma.

    Directory of Open Access Journals (Sweden)

    Anil K Singh

    Full Text Available BACKGROUND: Resistin is a cysteine rich protein, mainly expressed and secreted by circulating human mononuclear cells. While several factors responsible for transcription of mouse resistin gene have been identified, not much is known about the factors responsible for the differential expression of human resistin. METHODOLOGY/PRINCIPAL FINDING: We show that the minimal promoter of human resistin lies within approximately 80 bp sequence upstream of the transcriptional start site (-240 whereas binding sites for cRel, CCAAT enhancer binding protein alpha (C/EBP-alpha, activating transcription factor 2 (ATF-2 and activator protein 1 (AP-1 transcription factors, important for induced expression, are present within sequences up to -619. Specificity Protein 1(Sp1 binding site (-276 to -295 is also present and an interaction of Sp1 with peroxisome proliferator activating receptor gamma (PPARgamma is necessary for constitutive expression in U937 cells. Indeed co-immunoprecipitation assay demonstrated a direct physical interaction of Sp1 with PPARgamma in whole cell extracts of U937 cells. Phorbol myristate acetate (PMA upregulated the expression of resistin mRNA in U937 cells by increasing the recruitment of Sp1, ATF-2 and PPARgamma on the resistin gene promoter. Furthermore, PMA stimulation of U937 cells resulted in the disruption of Sp1 and PPARgamma interaction. Chromatin immunoprecipitation (ChIP assay confirmed the recruitment of transcription factors phospho ATF-2, Sp1, Sp3, PPARgamma, chromatin modifier histone deacetylase 1 (HDAC1 and the acetylated form of histone H3 but not cRel, C/EBP-alpha and phospho c-Jun during resistin gene transcription. CONCLUSION: Our findings suggest a complex interplay of Sp1 and PPARgamma along with other transcription factors that drives the expression of resistin in human monocytic U937 cells.

  17. Peroxisome Proliferator-Activated Receptor-alpha Is a Functional Target of p63 in Adult Human Keratinocytes

    DEFF Research Database (Denmark)

    Pozzi, Silvia; Boergesen, Michael; Sinha, Satrajit;

    2009-01-01

    healing process, is a target of p63 in human keratinocytes. Silencing of p63 by RNA interference and transient transfections showed that p63 represses PPARalpha through a functional region of promoter B. Chromatin immunoprecipitation analyses indicate that p63 is bound to this region, in the absence......p63 is a master switch in the complex network of signaling pathways controlling the establishment and maintenance of stratified epithelia. We provide evidence that peroxisome proliferator-activated receptor-alpha (PPARalpha), a ligand-activated nuclear receptor that participates in the skin wound...

  18. Peroxisome proliferator-activated receptor-γ 34C>G polymorphism and colorectal cancer risk: A meta-analysis

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM: To investigate the association between peroxisome proliferator-activated receptor-γ (PPAR-γ ) gene polymorphism 34 C>G and colorectal cancer (CRC),a meta-analysis review was performed in this report.METHODS: A systematic literature search and selection of eligible relevant studies were carried out.Nine independent studies with a total number of 4533 cases and 6483 controls were included in the meta-analysis on the association between polymorphism 34 C>G and CRC.RESULTS: There was no evidence for the as...

  19. Activating Peroxisome Proliferator-Activated Receptors (PPARs): a New Sight for Chrysophanol to Treat Paraquat-Induced Lung Injury.

    Science.gov (United States)

    Li, Ang; Liu, Yuguang; Zhai, Lu; Wang, Liying; Lin, Zhe; Wang, Shumin

    2016-04-01

    The aim of this study is to evaluate the protective effects of chrysophanol (CH) against paraquat (PQ)-induced pulmonary injury. Fifty BALB/C mice were randomized into five groups: (1) control, (2) PQ, (3) PQ + dexamethasone (Dex, 2 mg/kg), (4) PQ + CH (10 mg/kg), and (5) PQ + CH (20 mg/kg). A single dose of PQ (50 mg/kg, i.p.) was intraperitoneally given to induce acute lung injury. Then mice were treated with CH (10 and 20 mg/kg/day, orally) for 7 days. At the end of the experiment, animals were euthanized and then bronchoalveolar lavage fluid (BALF) and lung tissues were collected for histological observation, biochemical analysis, and Western blot analysis. Malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), interleukin-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α) levels in BALF were determined. The levels of SOD and MDA in the lung were also detected. The peroxisome proliferator-activated receptor (PPAR)-γ and nuclear factor-kappaB (NF-κB) pathway proteins in the lung were determined by Western blot. Histological examination indicated that CH attenuated lung inflammation caused by PQ. Biochemical results showed that CH treatment significantly reduced the levels of MDA, MPO, and inflammatory cytokines and increased the level of SOD, compared to those in the PQ group. Meanwhile, Western Blot results revealed that CH increased PPAR-γ expression and inhibited NF-κB pathway activation after PQ challenge. These findings suggested the potential therapeutic effects of CH which is derived from a natural product on PQ-induced pulmonary injury.

  20. [Pathophysiological relevance of peroxisome proliferators activated receptors (PPAR) to joint diseases - the pro and con of agonists].

    Science.gov (United States)

    Jouzeau, Jean-Yves; Moulin, David; Koufany, Meriem; Sebillaud, Sylvie; Bianchi, Arnaud; Netter, Patrick

    2008-01-01

    Peroxisome proliferators activated receptors (PPAR) are ligand-inducible nuclear transacting factors comprising three subtypes, PPARalpha, PPARbeta/delta and PPARgamma, which play a key role in lipids and glucose homeostasis. All PPAR subtypes have been identified in joint or inflammatory cells and their activation resulted in a transcriptional repression of pro-inflammatory cytokines (IL-1, TNFalpha), early inflammatory genes (NOS(2), COX-2, mPGES-1) or matrix metalloproteases (MMP-1, MMP-13), at least for the gamma subtype. PPAR full agonists were also shown to stimulate IL-1 receptor antagonist (IL-1Ra) production by cytokine-stimulated articular cells in a subtype-dependent manner. These anti-inflammatory and anti-catabolic properties were confirmed in animal models of joint diseases where PPAR agonists reduced synovial inflammation while preventing cartilage destruction or inflammatory bone loss, although many effects required much higher doses than needed to restore insulin sensitivity or to lower circulating lipid levels. However, these promising effects of PPAR full agonists were hampered by their ability to reduce the growth factor-dependent synthesis of extracellular matrix components or to induce chondrocyte apoptosis, by the possible contribution of immunosuppressive properties to their anti-arthritic effects, by the increased adipocyte differentiation secondary to prolonged stimulation of PPARgamma, and by a variable contribution of PPAR subtypes depending on the system. Clinical data are scarce in rheumatoid arthritis (RA) patients whereas thousands of patients worldwilde, treated with PPAR agonists for type 2 diabetes or dyslipidemia, are paradoxically prone to suffer from osteoarthritis (OA). Whereas high dosage of full agonists may expose RA patients to cardiovascular adverse effects, the proof of concept that PPAR agonists have therapeutical relevance to OA may benefit from an epidemiological follow-up of joint lesions in diabetic or

  1. Altered hyperlipidemia, hepatic steatosis, and hepatic peroxisome proliferator-activated receptors in rats with intake of tart cherry.

    Science.gov (United States)

    Seymour, E Mitchell; Singer, Andrew A M; Kirakosyan, Ara; Urcuyo-Llanes, Daniel E; Kaufman, Peter B; Bolling, Steven F

    2008-06-01

    Elevated plasma lipids, glucose, insulin, and fatty liver are among components of metabolic syndrome, a phenotypic pattern that typically precedes the development of Type 2 diabetes. Animal studies show that intake of anthocyanins reduces hyperlipidemia, obesity, and atherosclerosis and that anthocyanin-rich extracts may exert these effects in association with altered activity of tissue peroxisome proliferator-activated receptors (PPARs). However, studies are lacking to test this correlation using physiologically relevant, whole food sources of anthocyanins. Tart cherries are a rich source of anthocyanins, and whole cherry fruit intake may also affect hyperlipidemia and/or affect tissue PPARs. This hypothesis was tested in the Dahl Salt-Sensitive rat having insulin resistance and hyperlipidemia. For 90 days, Dahl rats were pair-fed AIN-76a-based diets supplemented with either 1% (wt:wt) freeze-dried whole tart cherry or with 0.85% additional carbohydrate to match macronutrient and calorie provision. After 90 days, the cherry-enriched diet was associated with reduced fasting blood glucose, hyperlipidemia, hyperinsulinemia, and reduced fatty liver. The cherry diet was also associated with significantly enhanced hepatic PPAR-alpha mRNA, enhanced hepatic PPAR-alpha target acyl-coenzyme A oxidase mRNA and activity, and increased plasma antioxidant capacity. In conclusion, physiologically relevant tart cherry consumption reduced several phenotypic risk factors that are associated with risk for metabolic syndrome and Type 2 diabetes. Tart cherries may represent a whole food research model of the health effects of anthocyanin-rich foods and may possess nutraceutical value against risk factors for metabolic syndrome and its clinical sequelae.

  2. Fasting-induced increases in aquaporin 7 and adipose triglyceride lipase mRNA expression in adipose tissue are attenuated by peroxisome proliferator-activated receptor alpha deficiency.

    Science.gov (United States)

    Walker, C G; Holness, M J; Gibbons, G F; Sugden, M C

    2007-07-01

    To investigate the impact of peroxisome proliferator-activated receptor alpha deficiency on gene expression of adipose triglyceride lipase and the glycerol transporter aquaglyceroporin 7 in white adipose tissue in the fed and fasted states in relation to glycerol release by isolated adipocytes. Studies using wild-type and peroxisome proliferator-activated receptor alpha null mice. Hormone and metabolite concentrations, real-time polymerase chain reaction (PCR), basal and stimulated adipocyte lipolysis, estimated by glycerol release. Peroxisome proliferator-activated receptor alpha deficiency blocked the increase in aquaglyceroporin 7 transcript level and attenuated the increase in adipose triglyceride lipase transcript level in white adipose tissue elicited by fasting. Fasting glycerol levels were lower in peroxisome proliferator-activated receptor alpha null than wild-type mice, despite increased mobilization of adipocyte fat reserves in vivo as indicated by reduced adipose tissue masses (three distinct depots) and a significantly lower epididymal adipocyte diameter. Basal net glycerol release was unchanged but beta-adrenergic-stimulated net glycerol release was higher with isolated adipocytes from fasted peroxisome proliferator-activated receptor alpha null mice compared with those of fasted wild-type mice. Peroxisome proliferator-activated receptor alpha deficiency prevents effects of fasting to increase adipocyte aquaglyceroporin 7 gene expression, and influences the regulation of inter-tissue glycerol flux after fasting via lowered adipocyte aquaglyceroporin 7 expression. Lowered gene expression of adipose triglyceride lipase and aquaglyceroporin 7 in peroxisome proliferator-activated receptor alpha null mice is not limiting for adipose triglyceride breakdown in vivo during fasting.

  3. PPARγ的翻译后修饰%Posttranslational Modifications of Peroxisome Proliferator-activated Receptor γ

    Institute of Scientific and Technical Information of China (English)

    陈勇军; 刘智勇; 沈萍萍

    2012-01-01

    过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor gamma,PPARγ)是一种配体依赖性核转录因子,它具有调控细胞分化、脂肪代谢、糖代谢及炎症等多种生物学功能.机体对PPARγ转录活性的调控方式是多种多样的,包括蛋白表达水平、配体以及转录辅助因子等不同层次上的调控.近年来众多证据揭示,蛋白翻译后修饰(posttranslational modifications,PTMs)是机体调节PPARγ转录活性的另一重要方式.目前,已报道的PPARγ翻译后修饰包括磷酸化、泛素化、SUMO化和亚硝基化等,它们能够改变蛋白构象、调控蛋白相互作用、改变受体与配体间的亲和力,从而调控PPARγ下游基因的转录.重要的是,PPARγ的翻译后修饰与一些疾病如糖尿病、动脉粥样硬化、肿瘤等密切相关.本文将主要围绕PPARγ的各种翻译后修饰及其在疾病的发生、发展和治疗中的意义作一综述.%Peroxisome proliferator-activated receptor γ(PPARγ) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors. PPARγ regulates various biological processes such as cell differentiation, lipid metabolism, glucose metabolism and inflammation. It is acknowledged that the transcriptional activity of PPARγ may be fine-tuned by several mechanisms in vivo. For example, the expression level of PPARγ, the availability of its ligand and the association between PPARγ and corepressor/coactivator have been demonstrated to be able to regulate PPARγ activation. In addition, mounting evidence has defined posttranslational modifications (PTMs) as a novel essential factor tightly modulating PPARγ activation recently. Several PTMs of PPARγ including phosphorylation, ubiquitination, sumoylation and S-nitrosylation, might regulate its target genes by tuning protein conformation, protein-protein interactions and the affinity between the receptor and ligand. Importantly, there are some

  4. Peroxisome proliferator-activated receptor-gamma as a potential therapeutic target in the treatment of preeclampsia.

    LENUS (Irish Health Repository)

    McCarthy, Fergus P

    2012-01-31

    Preeclampsia is a multisystemic disorder of pregnancy characterized by hypertension, proteinuria, and maternal endothelial dysfunction. It is a major cause of maternal and perinatal morbidity and mortality and is thought to be attributable, in part, to inadequate trophoblast invasion. Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor expressed in trophoblasts, and the vasculature of which activation has been shown to improve endothelium-dependent vasodilatation in hypertensive conditions. We investigated the effects of the administration of a PPAR-gamma agonist using the reduced uterine perfusion pressure (RUPP) rat model of preeclampsia. The selective PPAR-gamma agonist, rosiglitazone, was administered to pregnant rats that had undergone RUPP surgery. To investigate whether any observed beneficial effects of PPAR-gamma activation were mediated by the antioxidant enzyme, heme oxygenase 1, rosiglitazone was administered in combination with the heme oxygenase 1 inhibitor tin-protoporphyrin IX. RUPP rats were characterized by hypertension, endothelial dysfunction, and elevated microalbumin:creatinine ratios. Rosiglitazone administration ameliorated hypertension, improved vascular function, and reduced the elevated microalbumin:creatinine ratio in RUPP rats. With the exception of microalbumin:creatinine ratio, these beneficial effects were abrogated in the presence of the heme oxygenase 1 inhibitor. Administration of a PPAR-gamma agonist prevented the development of several of the pathophysiological characteristics associated with the RUPP model of preeclampsia, via a heme oxygenase 1-dependent pathway. The findings from this study provide further insight into the underlying etiology of preeclampsia and a potential therapeutic target for the treatment of preeclampsia.

  5. Peroxisome proliferator-activated receptor-gamma abrogates Smad-dependent collagen stimulation by targeting the p300 transcriptional coactivator.

    Science.gov (United States)

    Ghosh, Asish K; Bhattacharyya, Swati; Wei, Jun; Kim, Suyeon; Barak, Yaacov; Mori, Yasuji; Varga, John

    2009-09-01

    Ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) abrogate the stimulation of collagen gene transcription induced by transforming growth factor-beta (TGF-beta). Here, we delineate the mechanisms underlying this important novel physiological function for PPAR-gamma in connective tissue homeostasis. First, we demonstrated that antagonistic regulation of TGF-beta activity by PPAR-gamma ligands involves cellular PPAR-gamma, since 15-deoxy-Delta12,14-prostaglandin J(2) (15d-PGJ(2)) failed to block TGF-beta-induced responses in either primary cultures of PPAR-gamma-null murine embryonic fibroblasts, or in normal human skin fibroblasts with RNAi-mediated knockdown of PPAR-gamma. Next, we examined the molecular basis underlying the abrogation of TGF-beta signaling by PPAR-gamma in normal human fibroblasts in culture. The results demonstrated that Smad-dependent transcriptional responses were blocked by PPAR-gamma without preventing Smad2/3 activation. In contrast, the interaction between activated Smad2/3 and the transcriptional coactivator and histone acetyltransferase p300 induced by TGF-beta, and the accumulation of p300 on consensus Smad-binding DNA sequences and histone H4 hyperacetylation at the COL1A2 locus, were all prevented by PPAR-gamma. Wild-type p300, but not a mutant form of p300 lacking functional histone acetyltransferase, was able to restore TGF-beta-induced stimulation of COL1A2 in the presence of PPAR-gamma ligands. Collectively, these results indicate that PPAR-gamma blocked Smad-mediated transcriptional responses by preventing p300 recruitment and histone H4 hyperacetylation, resulting in the inhibition of TGF-beta-induced collagen gene expression. Pharmacological activation of PPAR-gamma thus may represent a novel therapeutic approach to target p300-dependent TGF-beta profibrotic responses such as stimulation of collagen gene expression.

  6. Metabolic Profiling of Chicken Embryos Exposed to Perfluorooctanoic Acid (PFOA and Agonists to Peroxisome Proliferator-Activated Receptors.

    Directory of Open Access Journals (Sweden)

    Anna Mattsson

    Full Text Available Untargeted metabolic profiling of body fluids in experimental animals and humans exposed to chemicals may reveal early signs of toxicity and indicate toxicity pathways. Avian embryos develop separately from their mothers, which gives unique possibilities to study effects of chemicals during embryo development with minimal confounding factors from the mother. In this study we explored blood plasma and allantoic fluid from chicken embryos as matrices for revealing metabolic changes caused by exposure to chemicals during embryonic development. Embryos were exposed via egg injection on day 7 to the environmental pollutant perfluorooctanoic acid (PFOA, and effects on the metabolic profile on day 12 were compared with those caused by GW7647 and rosiglitazone, which are selective agonists to peroxisome-proliferator activated receptor α (PPARα and PPARγ, respectively. Analysis of the metabolite concentrations from allantoic fluid by Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA showed clear separation between the embryos exposed to GW7647, rosiglitazone, and vehicle control, respectively. In blood plasma only GW7647 caused a significant effect on the metabolic profile. PFOA induced embryo mortality and increased relative liver weight at the highest dose. Sublethal doses of PFOA did not significantly affect the metabolic profile in either matrix, although single metabolites appeared to be altered. Neonatal mortality by PFOA in the mouse has been suggested to be mediated via activation of PPARα. However, we found no similarity in the metabolite profile of chicken embryos exposed to PFOA with those of embryos exposed to PPAR agonists. This indicates that PFOA does not activate PPAR pathways in our model at concentrations in eggs and embryos well above those found in wild birds. The present study suggests that allantoic fluid and plasma from chicken embryos are useful and complementary matrices for exploring effects on the metabolic

  7. Activation of intestinal peroxisome proliferator-activated receptor-α increases high-density lipoprotein production

    Science.gov (United States)

    Colin, Sophie; Briand, Olivier; Touche, Véronique; Wouters, Kristiaan; Baron, Morgane; Pattou, François; Hanf, Rémy; Tailleux, Anne; Chinetti, Giulia; Staels, Bart; Lestavel, Sophie

    2013-01-01

    Aims Peroxisome Proliferator-Activated Receptor (PPAR) α is a transcription factor controlling lipid metabolism in liver, heart, muscle and macrophages. PPARα-activation increases plasma HDL-cholesterol and exerts hypotriglyceridemic actions via the liver. However, the intestine expresses PPARα, produces HDL and chylomicrons and is exposed to diet-derived PPARα ligands. Therefore, we examined the effects of PPARα-activation on intestinal lipid and lipoprotein metabolism. Methods and Results The impact of PPARα-activation was evaluated in term of HDL-related gene expression in mice, ex-vivo in human jejunal biopsies and in Caco-2/TC7 cells. ApoAI/HDL secretion, cholesterol esterification and trafficking were also studied in-vitro. In parallel to improving plasma lipid profiles and increasing liver and intestinal expression of fatty-acid-oxidation genes, treatment with the dual PPARα/δ-ligand GFT505 resulted in a more pronounced increase of plasma HDL compared to fenofibrate in mice. GFT505, but not fenofibrate, increased the expression of HDL-production genes such as apolipoprotein-AI and ATP-Binding-Cassette-A1 transporter in murine intestines. A similar increase was observed upon PPARα-activation of human biopsies and Caco-2/TC7 cells. Additionally, HDL secretion by Caco-2/TC7 cells increased. Moreover, PPARα-activation decreased the cholesterol-esterification capacity of Caco-2/TC7 cells, modified cholesterol trafficking and reduced apolipoprotein-B secretion. Conclusions PPARα-activation reduces cholesterol esterification, suppresses chylomicron- and increases HDL-secretion by enterocytes. These results identify the intestine as a target organ of PPARα-ligands with entero-hepatic tropism to reduce atherogenic dyslipidemia. PMID:22843443

  8. Statins meditate anti-atherosclerotic action in smooth muscle cells by peroxisome proliferator-activated receptor-γ activation

    Energy Technology Data Exchange (ETDEWEB)

    Fukuda, Kazuki [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Matsumura, Takeshi, E-mail: takeshim@gpo.kumamoto-u.ac.jp [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Senokuchi, Takafumi; Ishii, Norio; Kinoshita, Hiroyuki; Yamada, Sarie; Murakami, Saiko [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Nakao, Saya [Department of Environmental & Symbiotic Sciences, Prefectural University of Kumamoto, Kumamoto (Japan); Motoshima, Hiroyuki; Kondo, Tatsuya; Kukidome, Daisuke; Kawasaki, Shuji [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan); Kawada, Teruo [Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto (Japan); Nishikawa, Takeshi; Araki, Eiichi [Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto (Japan)

    2015-01-30

    Highlights: • Statins induce PPARγ activation in vascular smooth muscle cells. • Statin-induced PPARγ activation is mediated by COX-2 expression. • Statins suppress cell migration and proliferation in vascular smooth muscle cells. • Statins inhibit LPS-induced inflammatory responses by PPARγ activation. • Fluvastatin suppress the progression of atherosclerosis and induces PPARγ activation in the aorta of apoE-deficient mice. - Abstract: The peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of lipid and glucose metabolism, and its activation is reported to suppress the progression of atherosclerosis. We have reported that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) activate PPARγ in macrophages. However, it is not yet known whether statins activate PPARγ in other vascular cells. In the present study, we investigated whether statins activate PPARγ in smooth muscle cells (SMCs) and endothelial cells (ECs) and thus mediate anti-atherosclerotic effects. Human aortic SMCs (HASMCs) and human umbilical vein ECs (HUVECs) were used in this study. Fluvastatin and pitavastatin activated PPARγ in HASMCs, but not in HUVECs. Statins induced cyclooxygenase-2 (COX-2) expression in HASMCs, but not in HUVECs. Moreover, treatment with COX-2-siRNA abrogated statin-mediated PPARγ activation in HASMCs. Statins suppressed migration and proliferation of HASMCs, and inhibited lipopolysaccharide-induced expression of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α) in HASMCs. These effects of statins were abrogated by treatment with PPARγ-siRNA. Treatment with statins suppressed atherosclerotic lesion formation in Apoe{sup −/−} mice. In addition, transcriptional activity of PPARγ and CD36 expression were increased, and the expression of MCP-1 and TNF-α was decreased, in the aorta of statin-treated Apoe{sup −/−} mice. In conclusion, statins mediate anti-atherogenic effects

  9. The peroxisome proliferator-activated receptor γ (PPARγ) controls natural protective mechanisms against lipid peroxidation in amyotrophic lateral sclerosis.

    Science.gov (United States)

    Benedusi, Valeria; Martorana, Francesca; Brambilla, Liliana; Maggi, Adriana; Rossi, Daniela

    2012-10-19

    Recent evidence highlights the peroxisome proliferator-activated receptors (PPARs) as critical neuroprotective factors in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To gain new mechanistic insights into the role of these receptors in the context of ALS, here we investigated how PPAR transcriptional activity varies in hSOD1(G93A) ALS transgenic mice. We demonstrate that PPARγ-driven transcription selectively increases in the spinal cord of symptomatic hSOD1(G93A) mice. This phenomenon correlates with the up-regulation of target genes, such as lipoprotein lipase and glutathione S-transferase α-2, which are implicated in scavenging lipid peroxidation by-products. Such events are associated with enhanced PPARγ immunoreactivity within motor neuronal nuclei. This observation, and the fact that PPARγ displays increased responsiveness in cultured hSOD1(G93A) motor neurons, points to a role for this receptor in neutralizing deleterious lipoperoxidation derivatives within the motor cells. Consistently, in both motor neuron-like cultures and animal models, we report that PPARγ is activated by lipid peroxidation end products, such as 4-hydroxynonenal, whose levels are elevated in the cerebrospinal fluid and spinal cord from ALS patients. We propose that the accumulation of critical concentrations of lipid peroxidation adducts during ALS progression leads to the activation of PPARγ in motor neurons. This in turn triggers self-protective mechanisms that involve the up-regulation of lipid detoxification enzymes, such as lipoprotein lipase and glutathione S-transferase α-2. Our findings indicate that anticipating natural protective reactions by pharmacologically modulating PPARγ transcriptional activity may attenuate neurodegeneration by limiting the damage induced by lipid peroxidation derivatives.

  10. Peroxisome proliferator-activated receptor gamma B cell-specific deficient mice have an impaired antibody response1

    Science.gov (United States)

    Ramon, Sesquile; Bancos, Simona; Thatcher, Thomas H.; Murant, Thomas I.; Moshkani, Safiehkhatoon; Sahler, Julie M.; Bottaro, Andrea; Sime, Patricia J.; Phipps, Richard P.

    2012-01-01

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand activated transcription factor, has important anti-inflammatory and anti-proliferative functions and it has been associated with diseases including diabetes, scarring and atherosclerosis among others. PPARγ is expressed in most bone marrow derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote antibody production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. Here, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development as well as the levels of circulating antigen-specific antibodies during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of antigen-specific antibodies and low numbers of antigen-experienced antibody-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within neither primary nor secondary lymphoid organs during development. This is the first report to show under physiological conditions that PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and antibody production. PMID:23041568

  11. Peroxisome proliferator-activated receptor γ B cell-specific-deficient mice have an impaired antibody response.

    Science.gov (United States)

    Ramon, Sesquile; Bancos, Simona; Thatcher, Thomas H; Murant, Thomas I; Moshkani, Safiehkhatoon; Sahler, Julie M; Bottaro, Andrea; Sime, Patricia J; Phipps, Richard P

    2012-11-15

    Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. PPARγ, a ligand-activated transcription factor, has important anti-inflammatory and antiproliferative functions, and it has been associated with diseases including diabetes, scarring, and atherosclerosis, among others. PPARγ is expressed in most bone marrow-derived cells and influences their function. PPARγ ligands can stimulate human B cell differentiation and promote Ab production. A knowledge gap is that the role of PPARγ in B cells under physiological conditions is not known. We developed a new B cell-specific PPARγ (B-PPARγ) knockout mouse and explored the role of PPARγ during both the primary and secondary immune response. In this article, we show that PPARγ deficiency in B cells decreases germinal center B cells and plasma cell development, as well as the levels of circulating Ag-specific Abs during a primary challenge. Inability to generate germinal center B cells and plasma cells is correlated to decreased MHC class II expression and decreased Bcl-6 and Blimp-1 levels. Furthermore, B-PPARγ-deficient mice have an impaired memory response, characterized by low titers of Ag-specific Abs and low numbers of Ag-experienced, Ab-secreting cells. However, B-PPARγ-deficient mice have no differences in B cell population distribution within primary or secondary lymphoid organs during development. This is the first report, to our knowledge, to show that, under physiological conditions, PPARγ expression in B cells is required for an efficient B cell-mediated immune response as it regulates B cell differentiation and Ab production.

  12. Increased renin production in mice with deletion of peroxisome proliferator-activated receptor-gamma in juxtaglomerular cells.

    Science.gov (United States)

    Desch, Michael; Schreiber, Andrea; Schweda, Frank; Madsen, Kirsten; Friis, Ulla G; Weatherford, Eric T; Sigmund, Curt D; Sequeira Lopez, Maria Luisa; Gomez, R Ariel; Todorov, Vladimir T

    2010-03-01

    We recently found that endogenous (free fatty acids) and pharmacological (thiazolidinediones) agonists of nuclear receptor Peroxisome proliferator-activated receptor (PPAR)gamma stimulate renin transcription. In addition, the renin gene was identified as a direct target of PPARgamma. The mouse renin gene is regulated by PPARgamma through a distal enhancer direct repeat closely related to consensus PPAR response element (PPRE). In vitro studies demonstrated that PPARgamma knockdown stimulated PPRE-driven transcription. These data predicted that deficiency of PPARgamma would upregulate mouse renin expression. Consistent with these observations knockdown of PPARgamma increased the transcription of a reporter gene driven by the mouse renin PPRE-like motif in vitro. To study the impact of PPARgamma on renin production in vivo, we used a cre/lox system to generate double-transgenic mice with disrupted PPARgamma locus in renin-producing juxtaglomerular (JG) cells of the kidney (RC-PPARgamma(fl/fl) mice). We provide evidence that PPARgamma expression was effectively reduced in JG cells of RC-PPARgamma(fl/fl) mice. Fluorescent immunohistochemistry showed stronger renin signal in RC-PPARgamma(fl/fl) than in littermate control RC-PPARgamma(wt/wt) mice. Renin mRNA levels and plasma renin concentration in RC-PPARgamma(fl/fl) mice were almost 2-fold higher than in littermate controls. Arterial blood pressure and pressure control of renal vascular resistance, which play decisive roles in the regulation of renin production were indistinguishable between RC-PPARgamma(wt/wt) and RC-PPARgamma(fl/fl) mice. These data demonstrate that the JG-specific PPARgamma deficiency results in increased mouse renin expression in vivo thus corroborating earlier in vitro results. PPARgamma appears to be a relevant transcription factor for the control of renin gene in JG cells.

  13. Curcumin inhibits trinitrobenzene sulphonic acid-induced colitis in rats by activation of peroxisome proliferator-activated receptor gamma.

    Science.gov (United States)

    Zhang, Ming; Deng, Changsheng; Zheng, Jiaju; Xia, Jian; Sheng, Dan

    2006-08-01

    Curcumin is a widely used spice with anti-inflammatory and anti-cancer properties. It has been reported that curcumin held therapeutic effects on experimental colitis by inhibition of nuclear factor kappa B (NF-kappaB). The peroxisome proliferator-activated receptor gamma (PPARgamma) is a nuclear receptor with anti-tumor and anti-inflammatory effects and its activation may inhibit the nuclear translocation of NF-kappaB. Several studies have shown that PPARgamma ligands had an important therapeutic effect in colitis. However there is no report about the alteration of PPARgamma in trinitrobenzene sulphonic acid (TNBS)-induced colitis treated with curcumin. In this study, we administered curcumin (30 mg/kg/day) by intraperitoneal injection immediately after colitis was induced and the injection lasted for two weeks. have evaluated the effects of curcumin on the colitis induced by trinitrobenzene sulphonic acid (TNBS). Curcumin (30 mg/kg d) was administered by intraperitoneal just after colitis was induced and lasted for two weeks. Therapeutic effects of dexamethasone (Dex, 2 mg/kg d) alone and the combined effects of curcumin+Dex were also examined. We found that curcumin improved long-term survival rate of disease-bearing rats, promoted rat body weight recovery, and decreased macroscopic scores of the colitis. The expression levels of PPARgamma, 15-deoxy-D12,14-prostaglandin J(2) (15d-PGJ(2)) and prostaglandin E(2) (PGE(2)) were all increased, but the expression level of cyclooxygenase-2 (COX-2) was decreased in rats after administration of curcumin. Treatment with Dex improved PPARgamma expression and inhibited the expression of COX-2, 15d-PGJ(2) and PGE(2). Combined effects of curcumin+Dex were similar to that of Dex. In summary, curcumin showed therapeutic effects on TNBS-induced colitis and the mechanisms by which curcumin exerts its effects may involve activation of PPARgamma and its ligands.

  14. Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8.

    Science.gov (United States)

    Thomas, Maria; Winter, Stefan; Klumpp, Britta; Turpeinen, Miia; Klein, Kathrin; Schwab, Matthias; Zanger, Ulrich M

    2015-01-01

    The cytochrome P450, CYP2C8, metabolizes more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However, predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα), a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613) previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N = 150). Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ∼60 and ∼50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150 and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions -2762/-2775 bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/β-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/β-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype.

  15. Peroxisome proliferator-activated receptor alpha, PPARα, directly regulates transcription of cytochrome P450 CYP2C8

    Directory of Open Access Journals (Sweden)

    Maria eThomas

    2015-11-01

    Full Text Available The cytochrome P450, CYP2C8, metabolises more than 60 clinically used drugs as well as endogenous substances including retinoic acid and arachidonic acid. However predictive factors for interindividual variability in the efficacy and toxicity of CYP2C8 drug substrates are essentially lacking. Recently we demonstrated that peroxisome proliferator-activated receptor alpha (PPARα, a nuclear receptor primarily involved in control of lipid and energy homeostasis directly regulates the transcription of CYP3A4. Here we investigated the potential regulation of CYP2C8 by PPARα. Two linked intronic SNPs in PPARα (rs4253728, rs4823613 previously associated with hepatic CYP3A4 status showed significant association with CYP2C8 protein level in human liver samples (N=150. Furthermore, siRNA-mediated knock-down of PPARα in HepaRG human hepatocyte cells resulted in up to ~60% and ~50% downregulation of CYP2C8 mRNA and activity, while treatment with the PPARα agonist WY14,643 lead to an induction by >150% and >100%, respectively. Using chromatin immunoprecipitation scanning assay we identified a specific upstream gene region that is occupied in vivo by PPARα. Electromobility shift assay demonstrated direct binding of PPARα to a DR-1 motif located at positions -2762/-2775bp upstream of the CYP2C8 transcription start site. We further validated the functional activity of this element using luciferase reporter gene assays in HuH7 cells. Moreover, based on our previous studies we demonstrated that WNT/β-catenin acts as a functional inhibitor of PPARα-mediated inducibility of CYP2C8 expression. In conclusion, our data suggest direct involvement of PPARα in both constitutive and inducible regulation of CYP2C8 expression in human liver, which is further modulated by WNT/ β-catenin pathway. PPARA gene polymorphism could have a modest influence on CYP2C8 phenotype.

  16. Regulation of Liver Energy Balance by the Nuclear Receptors Farnesoid X Receptor and Peroxisome Proliferator Activated Receptor α.

    Science.gov (United States)

    Kim, Kang Ho; Moore, David D

    2017-01-01

    The liver undergoes major changes in substrate utilization and metabolic output over the daily feeding and fasting cycle. These changes occur acutely in response to hormones such as insulin and glucagon, with rapid changes in signaling pathways mediated by protein phosphorylation and other post-translational modifications. They are also reflected in chronic alterations in gene expression in response to nutrient-sensitive transcription factors. Among these, the nuclear receptors farnesoid X receptor (FXR) and peroxisome proliferator activated receptor α (PPARα) provide an intriguing, coordinated response to maintain energy balance in the liver. FXR is activated in the fed state by bile acids returning to the liver, while PPARα is activated in the fasted state in response to the free fatty acids produced by adipocyte lipolysis or possibly other signals. Key Messages: Previous studies indicate that FXR and PPARα have opposing effects on each other's primary targets in key metabolic pathways including gluconeogenesis. Our more recent work shows that these 2 nuclear receptors coordinately regulate autophagy: FXR suppresses this pathway of nutrient and energy recovery, while PPARα activates it. Another recent study indicates that FXR activates the complement and coagulation pathway, while earlier studies identify this as a negative target of PPARα. Since secretion is a very energy- and nutrient-intensive process for hepatocytes, it is possible that FXR licenses it in the nutrient-rich fed state, while PPARα represses it to spare resources in the fasted state. Energy balance is a potential connection linking FXR and PPARα regulation of autophagy and secretion, 2 seemingly unrelated aspects of hepatocyte function. FXR and PPARα act coordinately to promote energy balance and homeostasis in the liver by regulating autophagy and potentially protein secretion. It is quite likely that their impact extends to additional pathways relevant to hepatic energy balance, and

  17. Peroxisome proliferator-activated receptors alpha and gamma2 polymorphisms in nonalcoholic fatty liver disease: a study in Brazilian patients.

    Science.gov (United States)

    Domenici, Fernanda Aparecida; Brochado, Maria José Franco; Martinelli, Ana de Lourdes Candolo; Zucoloto, Sergio; da Cunha, Selma Freire de Carvalho; Vannucchi, Helio

    2013-10-25

    Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of hepatic steatosis in the absence of excess alcohol consumption. The pathogenesis of fatty liver disease and steatohepatitis (NASH) is not fully elucidated, but the common association with visceral obesity, hyperlipidemia, hypertension and type 2 diabetes mellitus (T2DM) suggests that it is the hepatic manifestation of metabolic syndrome. Peroxisome proliferator-activated receptor PPARα and PPARγ are members of a family of nuclear receptors involved in the metabolism of lipids and carbohydrates, adipogenesis and sensitivity to insulin. The objective of this study was to analyze the polymorphisms Leu162Val of PPARα and Pro12Ala of PPARγ as genetic risk factors for the development and progression of NAFLD. One hundred and three NAFLD patients (89 NASH, 14 pure steatosis) and 103 healthy volunteers were included. Single nucleotide polymorphisms (SNPs) Leu162Val and Pro12Ala were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). NASH patients presented higher BMI, AST and prevalence of T2DM than patients with pure steatosis. A higher prevalence of 12Ala allele was observed in the NASH Subgroup when compared to Control Group. When we grouped NASH and Steatosis Subgroups (NAFLD), we found lower serum glucose and more advanced fibrosis in the Leu162Val SNP. On the other hand, there was no statistical difference in clinical, laboratorial and histological parameters according to the Pro12Ala SNP. We documented a lower prevalence of 12Ala allele of gene PPARγ in the NASH Subgroup when compared to Control Group. In NAFLD patients, there were no associations among the occurrence of Pro12Ala SNP with clinical, laboratorial and histological parameters. We also documented more advanced fibrosis in the Leu162Val SNP. The obtained data suggest that Pro12Ala SNP may result in protection against liver injury and that Leu162Val SNP may be involved in the

  18. Cardiac metabolism, inflammation, and peroxisome proliferator-activated receptors modulated by 1,25-dihydroxyvitamin D3 in diabetic rats.

    Science.gov (United States)

    Lee, Ting-I; Kao, Yu-Hsun; Chen, Yao-Chang; Tsai, Wen-Chin; Chung, Cheng-Chih; Chen, Yi-Jen

    2014-09-01

    High free fatty acid with reduced glucose utilization in diabetes mellitus (DM) impairs cardiac function. Peroxisome proliferator-activated receptors (PPARs) modulate myocardial lipid and glucose homeostasis. The active 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) regulates oxidative stress and inflammation, which may play a key role in the modulation of PPARs. The aim of this study was to investigate whether 1,25(OH)2D3 can modulate the cardiac PPARs and fatty acid metabolism. Electrocardiogram, echocardiogram, and Western blot analysis were used to evaluate cardiac fatty acid metabolism, inflammation, and PPAR isoform expression in Wistar-Kyoto (WKY) rats, DM rats, and DM rats treated with 1,25(OH)2D3. Compared to healthy rats, DM and 1,25(OH)2D3-treated DM rats had lower body weight. DM rats had larger left ventricular end-diastolic diameter, and longer QT interval than healthy or 1,25(OH)2D3-treated DM rats. Moreover, compared to healthy or 1,25(OH)2D3-treated DM rats, DM rats had fewer cardiac PPAR-α and PPAR-δ protein expressions, but had increased cardiac PPAR-γ protein levels, tumor necrosis factor-α, interleukin-6, 5' adenosine monophosphate-activated protein kinaseα2, phosphorylated acetyl CoA carboxylase, carnitine palmitoyltransferase 1, PPAR-γ coactivator 1-α, cluster of differentiation 36, and diacylglycerol acyltransferase 2 protein expressions. 1,25(OH)2D3 significantly changed the cardiac function and fatty acid regulations in DM hearts, which may be caused by its regulations on cardiac PPARs and proinflammatory cytokines. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  19. Polymorphisms of peroxisome proliferator-activated receptors and survival of lung cancer and upper aero-digestive tract cancers.

    Science.gov (United States)

    Yang, Ying; Burke, Rita V; Jeon, Christie Y; Chang, Shen-Chih; Chang, Po-Yin; Morgenstern, Hal; Tashkin, Donald P; Mao, Jenny; Cozen, Wendy; Mack, Thomas M; Rao, Jianyu; Zhang, Zuo-Feng

    2014-09-01

    Peroxisome proliferator-activated receptors (PPARs) are transcriptional factors involved in several biological processes such as inflammation, cancer growth, progression and apoptosis that are important in lung and upper aero-digestive tract (UADT) cancer outcomes. Nonetheless, there are no published studies of the relationship between PPARs gene polymorphisms and survival of patients with lung cancer or UADT cancers. 1212 cancer patients (611 lung, 303 oral, 100 pharyngeal, 90 laryngeal, and 108 esophageal) were followed for a median duration of 11 years. We genotyped three potentially functional single nucleotide polymorphisms (SNPs) using Taqman - rs3734254 of the gene PPARD and rs10865710 and rs1801282 of the gene PPARG - and investigated their associations with lung and UADT cancer survival using Cox regression. A semi-Bayesian shrinkage approach was used to reduce the potential for false positive findings when examining multiple associations. The variant homozygote CC (vs. TT) of PPARD rs3734254 was inversely associated with mortality of both lung cancer (adjusted hazard ratio [aHR]=0.63, 95% confidence interval [CI]=0.42, 0.96) and UADT cancers (aHR=0.51, 95% CI=0.27, 0.99). Use of the semi-Bayesian shrinkage approach yielded a posterior aHR for lung cancer of 0.66 (95% posterior limits=0.44, 0.98) and a posterior aHR for UADT cancers of 0.58 (95% posterior limits=0.33, 1.03). Our findings suggest that lung-cancer patients with the CC variant of PPARD rs3734254 may have a survival advantage over lung-cancer patients with other gene variants. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  20. Promising link between selenium and peroxisome proliferator activated receptor gamma in the treatment protocols of obesity as well as depression.

    Science.gov (United States)

    Donma, M M; Donma, O

    2016-04-01

    Considerable interest has been given to the significance of peroxisome proliferator activated receptors (PPARs) in macronutrient metabolism, however, there is not sufficient data concerning the interactions between PPARs and micronutrients. Investigations performed on PPARγ and one of the essential micronutrients selenium (Se) have shown that both parameters may lead to alterations in obesity-related or mood disorders. Therefore, it is plausible to consider PPARγ and Se together as a powerful combination during the treatment of two associated diseases; obesity and depression. PPARγ has been shown to be involved in the antidepressant-like activity. It is also an important parameter to be considered in obesity as the master regulator of adipogenesis. The mechanism of action of PPARγ is initiated by ligand binding which induces a conformational change in the receptor. Se is capable of alleviating inflammatory signaling pathways. Obesity is associated with chronic low-grade inflammation. Depression is also defined as an inflammatory disorder. Inflammatory mediators such as tumor necrosis factor-alpha (TNFα) participate in the progression of depression. They are also obesity-associated parameters. Due to TNFα induced depressive-like behaviors and the positive association between this proinflammatory cytokine and obesity, TNFα-activated signaling pathways and those inhibiting them have recently gained importance as potential targets and therapeutic tools, respectively. More studies are necessary to develop compounds with therapeutic nature against depressive disorders and obesity. PPARγ is an important signaling pathway that occurs at the crossroads of depression and obesity. Se, aside from its anti-inflammatory, anticarcinogenic and antioxidative nature, affects also the way of PPARγ action. Se supplementation or fortification as well as the development of the partial agonists of PPARγ in which lipophilic Se compounds are used as ligand followed by

  1. Regulation of retinoic acid receptor beta expression by peroxisome proliferator-activated receptor gamma ligands in cancer cells.

    Science.gov (United States)

    James, Sharon Y; Lin, Feng; Kolluri, Siva Kumar; Dawson, Marcia I; Zhang, Xiao-kun

    2003-07-01

    The peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor family member that can form a heterodimeric complex with retinoid X receptor (RXR) and initiate transcription of target genes. In this study, we have examined the effects of the PPAR gamma ligand ciglitazone and the RXR ligand SR11237 on growth and induction of retinoic acid receptor (RAR) beta expression in breast and lung cancer cells. Our results demonstrated that ciglitazone and SR11237 cooperatively inhibited the growth of ZR-75-1 and T-47D breast cancer and Calu-6 lung cancer cells. Gel shift analysis indicated that PPAR gamma, in the presence of RXR, formed a strong complex with a retinoic acid response element (beta retinoic acid response element) in the RAR beta promoter. In reporter gene assays, RXR ligands and ciglitazone, but not the PPAR gamma ligand 15d-PGJ(2), cooperatively promoted the transcriptional activity of the beta retinoic acid response element. Ciglitazone, but not 15d-PGJ(2), strongly induced RAR beta expression in human breast and lung cancer cell lines when used together with SR11237. The induction of RAR beta expression by the ciglitazone and SR11237 combination was diminished by a PPAR gamma-selective antagonist, bisphenol A diglycidyl ether. All-trans-retinoic acid or the combination of ciglitazone and SR11237 was able to induce RAR beta in all-trans-retinoic acid-resistant MDA-MB-231 breast cancer cells only when the orphan receptor chick ovalbumin upstream promoter transcription factor was expressed, or in the presence of the histone deacetylase inhibitor trichostatin A. These studies indicate the existence of a novel RAR beta-mediated signaling pathway of PPAR gamma action, which may provide a molecular basis for developing novel therapies involving RXR and PPAR gamma ligands in potentiating antitumor responses.

  2. Fenofibrate, a peroxisome proliferator-activated receptor α ligand, prevents abnormal liver function induced by a fasting–refeeding process

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Joon No; Dutta, Raghbendra Kumar; Kim, Seul-Gi; Lim, Jae-Young; Kim, Se-Jin; Choe, Seong-Kyu [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Yoo, Kyeong-Won [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Immune-network Pioneer Research Center, Department of Biochemistry, College of Medicine, Dong-A University, Busan (Korea, Republic of); Song, Seung Ryel [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Do-Sim [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Department of Laboratory of Medicine, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); So, Hong-Seob [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of); Park, Raekil, E-mail: rkpark@wku.ac.kr [Center for Metabolic Function Regulation, and Department of Microbiology, School of Medicine, Wonkwang University, Iksan (Korea, Republic of)

    2013-12-06

    Highlights: •A fasting–refeeding high fat diet (HDF) model mimics irregular eating habit. •A fasting–refeeding HFD induces liver ballooning injury. •A fasting–refeeding HDF process elicits hepatic triglyceride accumulation. •Fenofibrate, PPARα ligand, prevents liver damage induced by refeeding HFD. -- Abstract: Fenofibrate, a peroxisome proliferator-activated receptor α (PPARα) agonist, is an anti-hyperlipidemic agent that has been widely used in the treatment of dyslipidemia. In this study, we examined the effect of fenofibrate on liver damage caused by refeeding a high-fat diet (HFD) in mice after 24 h fasting. Here, we showed that refeeding HFD after fasting causes liver damage in mice determined by liver morphology and liver cell death. A detailed analysis revealed that hepatic lipid droplet formation is enhanced and triglyceride levels in liver are increased by refeeding HFD after starvation for 24 h. Also, NF-κB is activated and consequently induces the expression of TNF-α, IL1-β, COX-2, and NOS2. However, treating with fenofibrate attenuates the liver damage and triglyceride accumulation caused by the fasting–refeeding HFD process. Fenofibrate reduces the expression of NF-κB target genes but induces genes for peroxisomal fatty acid oxidation, peroxisome biogenesis and mitochondrial fatty acid oxidation. These results strongly suggest that the treatment of fenofibrate ameliorates the liver damage induced by fasting–refeeding HFD, possibly through the activation of fatty acid oxidation.

  3. Telmisartan ameliorates lipopolysaccharide-induced innate immune response through peroxisome proliferator-activated receptor-γ activation in human monocytes

    Science.gov (United States)

    Pang, Tao; Benicky, Julius; Wang, Juan; Orecna, Martina; Sanchez-Lemus, Enrique; Saavedra, Juan M.

    2011-01-01

    Objective Angiotensin II type 1 receptor (AT1) blockers (ARBs) reduce the bacterial endotoxin lipopolysaccharide (LPS)-induced innate immune response in human circulating monocytes expressing few AT1. To clarify the mechanisms of anti-inflammatory effects of ARBs with different peroxisome proliferator-activated receptor-γ (PPARγ)-activating potencies, we focused our study on telmisartan, an ARB with the highest PPARγ-stimulating activity. Methods Human circulating monocytes and monocytic THP-1 (human acute monocytic leukemia cell line) cells were exposed to 50 ng/ml LPS with or without pre-incubation with telmisartan. AT1 mRNA and protein expressions were determined by real-time PCR and membrane receptor binding assay, respectively. The expression of pro-inflammatory factors was determined by real-time PCR, western blot analysis and ELISA. PPARγ activation was measured by electrophoretic mobility shift assay and its role was determined by pharmacological inhibition and PPARγ gene silencing. Results In human monocytes, telmisartan significantly attenuated the LPS-induced expression of pro-inflammatory factors, the release of pro-inflammatory cytokines and prostaglandin E2, nuclear factor-κB activation and reactive oxygen species formation. In THP-1 cells, telmisartan significantly reduced LPS-induced tumor necrosis factor-α, inhibitor of κB-α, monocyte chemotactic protein-1 (MCP-1) and lectin-like oxidized low-density lipoprotein receptor-1 gene expression and MCP-1-directed migration. Telmisartan also stimulated the expression of the PPARγ target genes cluster of differentiation 36 and ATP-binding cassette subfamily G member 1 in monocytes. The anti-inflammatory effects of telmisartan were prevented by both PPARγ antagonism and PPARγ gene silencing. Anti-inflammatory effects of ARBs correlated with their PPARγ agonist potency. Conclusion Our observations demonstrate that in human monocytes, ARBs inhibit the LPS-induced pro-inflammatory response to a

  4. T33, a novel peroxisome proliferator-activated receptor agonist, exerts neuroprotective action via its anti-inflammatory activities

    Institute of Scientific and Technical Information of China (English)

    Ying WANG; Yu-she YANG; Xi-can TANG; Hai-yan ZHANG

    2011-01-01

    To examine the neuroprotective effects of T33,a peroxisome proliferator-activated receptor gamma/alpha (PPARY/α) agonist,in acute ischemic models in vitro and in vivo.Methods:Primary astrocytes subjected to oxygen-glucose deprivation/reperfusion (O/R) and BV-2 cells subjected to hypoxia were used as a model simulating the ischemic core and penumbra,respectively.The mRNA levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were measured using qPCR.The levels of TNF-α secreted by BV-2 cells were measured using ELISA.Protein levels of cyclooxygenase-2 (COX-2),p65,phosphorylated I-κBα/I-κBα,phosphorylated I-κB kinase (plKK),phosphorylated eukaryote initiation factor 2α (p-elF-2α)/elF-2α and p-p38/p38 were detected using Western blot.PPARY activity was measured using EMSA.The neuroprotection in vivo was examined in rat middle cerebral artery occlusion (MCAO) model with neurological scoring and TTC staining.Results:Addition of T33 (0.5 μmol/L) increased the level of I-κBα protein in primary astrocytes subjected to O/R,which was due to promoting protein synthesis without affecting degradation.In primary astrocytes subjected to O/R,addition of T33 amplified I-κBα gene transcription and mRNA translation,thus suppressing the nuclear factor-kappa B (NF-κB) pathway and reducing inflammatory mediators (TNF-α,IL-1β,and COX-2).In BV-2 cells subjected to hypoxia,T33 (0.5 μmol/L) reduced TNF-α,COX-2,and p-P38 production,which was antagonized by pre-administration of the specific PPARy antagonist GW9662 (30 μmol/L).T33 (2 mg/kg,ip) attenuated MCAO-induced inflammatory responses and brain infarction,which was antagonized by pre-administered GW9662 (4 mg/kg,ip).Conclusion:T33 exerted anti-inflammatory effects in the ischemic core and penumbra via PPARY activation,which contributed to its neuroprotective action.

  5. A new ligand for the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), GW7845, inhibits rat mammary carcinogenesis.

    Science.gov (United States)

    Suh, N; Wang, Y; Williams, C R; Risingsong, R; Gilmer, T; Willson, T M; Sporn, M B

    1999-11-15

    We have tested a new ligand for peroxisome proliferator-activated receptor-gamma, GW7845, as an inhibitor of experimental mammary carcinogenesis, using the classic rat model with nitrosomethylurea as carcinogen. Rats were first treated with a single dose of nitrosomethylurea (50 mg/kg body weight, i.p.). Starting 1 week later, they were fed GW7845, at either 60 or 30 mg/kg of diet, for 2 months. This agent significantly reduced tumor incidence, tumor number, and tumor weight at both doses. This is the first report of the use of a ligand for peroxisome proliferator-activated receptor-gamma to prevent experimental breast cancer.

  6. Peroxisome Proliferator-Activated Receptor-γ in Amyotrophic Lateral Sclerosis and Huntington's Disease

    Directory of Open Access Journals (Sweden)

    Mahmoud Kiaei

    2008-04-01

    Full Text Available Amyotrophic lateral sclerosis (ALS is a debilitating and one of the most common adult-onset neurodegenerative diseases with the prevalence of about 5 per 100 000 individuals. It results in the progressive loss of upper and lower motor neurons and leads to gradual muscle weakening ultimately causing paralysis and death. ALS has an obscure cause and currently no effective treatment exists. In this review, a potentially important pathway is described that can be activated by peroxisome proliferator-activated receptor-γ (PPAR-γ agonists and has the ability to block the neuropathological damage caused by inflammation in ALS and possibly in other neudegenerative diseases like Huntington's disease (HD. Neuroinflammation is a common pathological feature in neurodegenerative diseases. Therefore, PPAR-γ agonists are thought to be neuroprotective in ALS and HD. We and others have tested the neuroprotective effect of pioglitazone (Actos, a PPAR-γ agonist, in G93A SOD1 transgenic mouse model of ALS and found significant increase in survival of G93A SOD1 mice. These findings suggest that PPAR-γ may be an important regulator of neuroinflammation and possibly a new target for the development of therapeutic strategies for ALS. The involvement of PPAR-γ in HD is currently under investigation, one study finds that the treatment with rosiglitazone had no protection in R6/2 transgenic mouse model of HD. PPAR-γ coactivator-1α (PGC-1α is a transcriptional coactivator that works together with combination of other transcription factors like PPAR-γ in the regulation of mitochondrial biogenesis. Therefore, PPAR-γ is a possible target for ALS and HD as it functions as transcription factor that interacts with PGC-1α. In this review, the role of PPAR-γ in ALS and HD is discussed based on the current literature and hypotheses.

  7. Glycogen content regulates peroxisome proliferator activated receptor-∂ (PPAR-∂ activity in rat skeletal muscle.

    Directory of Open Access Journals (Sweden)

    Andrew Philp

    Full Text Available Performing exercise in a glycogen depleted state increases skeletal muscle lipid utilization and the transcription of genes regulating mitochondrial β-oxidation. Potential candidates for glycogen-mediated metabolic adaptation are the peroxisome proliferator activated receptor (PPAR coactivator-1α (PGC-1α and the transcription factor/nuclear receptor PPAR-∂. It was therefore the aim of the present study to examine whether acute exercise with or without glycogen manipulation affects PGC-1α and PPAR-∂ function in rodent skeletal muscle. Twenty female Wistar rats were randomly assigned to 5 experimental groups (n = 4: control [CON]; normal glycogen control [NG-C]; normal glycogen exercise [NG-E]; low glycogen control [LG-C]; and low glycogen exercise [LG-E]. Gastrocnemius (GTN muscles were collected immediately following exercise and analyzed for glycogen content, PPAR-∂ activity via chromatin immunoprecipitation (ChIP assays, AMPK α1/α2 kinase activity, and the localization of AMPK and PGC-1α. Exercise reduced muscle glycogen by 47 and 75% relative to CON in the NG-E and LG-E groups, respectively. Exercise that started with low glycogen (LG-E finished with higher AMPK-α2 activity (147%, p<0.05, nuclear AMPK-α2 and PGC-1α, but no difference in AMPK-α1 activity compared to CON. In addition, PPAR-∂ binding to the CPT1 promoter was significantly increased only in the LG-E group. Finally, cell reporter studies in contracting C2C12 myotubes indicated that PPAR-∂ activity following contraction is sensitive to glucose availability, providing mechanistic insight into the association between PPAR-∂ and glycogen content/substrate availability. The present study is the first to examine PPAR-∂ activity in skeletal muscle in response to an acute bout of endurance exercise. Our data would suggest that a factor associated with muscle contraction and/or glycogen depletion activates PPAR-∂ and initiates AMPK translocation in skeletal

  8. Peroxisome Proliferator-Activated Receptor Gamma and Regulations by the Ubiquitin-Proteasome System in Pancreatic Cancer

    Directory of Open Access Journals (Sweden)

    Athina Stravodimou

    2012-01-01

    Full Text Available Pancreatic cancer is one of the most lethal forms of human cancer. Although progress in oncology has improved outcomes in many forms of cancer, little progress has been made in pancreatic carcinoma and the prognosis of this malignancy remains grim. Several molecular abnormalities often present in pancreatic cancer have been defined and include mutations in K-ras, p53, p16, and DPC4 genes. Nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARγ has a role in many carcinomas and has been found to be overexpressed in pancreatic cancer. It plays generally a tumor suppressor role antagonizing proteins promoting carcinogenesis such as NF-κB and TGFβ. Regulation of pathways involved in pancreatic carcinogenesis is effectuated by the Ubiquitin Proteasome System (UPS. This paper will examine PPARγ in pancreatic cancer, the regulation of this nuclear receptor by the UPS, and their relationship to other pathways important in pancreatic carcinogenesis.

  9. Peroxisome proliferator-activated receptor subtype- and cell-type-specific activation of genomic target genes upon adenoviral transgene delivery

    DEFF Research Database (Denmark)

    Nielsen, Ronni; Grøntved, Lars; Stunnenberg, Hendrik G

    2006-01-01

    Investigations of the molecular events involved in activation of genomic target genes by peroxisome proliferator-activated receptors (PPARs) have been hampered by the inability to establish a clean on/off state of the receptor in living cells. Here we show that the combination of adenoviral...... delivery and chromatin immunoprecipitation (ChIP) is ideal for dissecting these mechanisms. Adenoviral delivery of PPARs leads to a rapid and synchronous expression of the PPAR subtypes, establishment of transcriptional active complexes at genomic loci, and immediate activation of even silent target genes....... We demonstrate that PPARgamma2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPARgamma2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (alpha, gamma, and beta...

  10. Telmisartan prevents weight gain and obesity through activation of peroxisome proliferator-activated receptor-delta-dependent pathways

    DEFF Research Database (Denmark)

    He, Hongbo; Yang, Dachun; Ma, Liqun

    2010-01-01

    Telmisartan shows antihypertensive and several pleiotropic effects that interact with metabolic pathways. In the present study we tested the hypothesis that telmisartan prevents adipogenesis in vitro and weight gain in vivo through activation of peroxisome proliferator-activated receptor (PPAR......)-delta-dependent pathways in several tissues. In vitro, telmisartan significantly upregulated PPAR-delta expression in 3T3-L1 preadipocytes in a time- and dose-dependent manner. Other than enhancing PPAR-delta expression by 68.2+/-17.3% and PPAR-delta activity by 102.0+/-9.0%, telmisartan also upregulated PPAR......-gamma expression, whereas neither candesartan nor losartan affected PPAR-delta expression. In vivo, long-term administration of telmisartan significantly reduced visceral fat and prevented high-fat diet-induced obesity in wild-type mice and hypertensive rats but not in PPAR-delta knockout mice. Administration...

  11. Pioglitazone Suppresses CXCR7 Expression To Inhibit Human Macrophage Chemotaxis through Peroxisome Proliferator-Activated Receptor γ.

    Science.gov (United States)

    Zhao, Duo; Zhu, Zhicheng; Li, Dan; Xu, Rihao; Wang, Tiance; Liu, Kexiang

    2015-11-17

    Cardiovascular disease is the leading cause of morbidity and mortality in patients with type 2 diabetes mellitus (T2DM). Pioglitazone, the widely used thiazolidinedione, is shown to be efficient in the prevention of cardiovascular complications of T2DM. In this study, we report that pioglitazone inhibits CXCR7 expression and thus blocks chemotaxis in differentiated macrophage without perturbing cell viability or macrophage differentiation. In addition, pioglitazone-mediated CXCR7 suppression and chemotaxis inhibition occur via activating peroxisome proliferator-activated receptor γ (PPARγ) but not PPARα in differentiated macrophage. More importantly, pioglitazone therapy-induced PPARγ activation suppresses CXCR7 expression in human carotid atherosclerotic lesions. Collectively, our data demonstrate that pioglitazone suppresses CXCR7 expression to inhibit human macrophage chemotaxis through PPARγ.

  12. Synthesis, in vitro evaluation, and molecular modeling investigation of benzenesulfonimide peroxisome proliferator-activated receptors α antagonists.

    Science.gov (United States)

    Ammazzalorso, Alessandra; Carrieri, Antonio; Verginelli, Fabio; Bruno, Isabella; Carbonara, Giuseppe; D'Angelo, Alessandra; De Filippis, Barbara; Fantacuzzi, Marialuigia; Florio, Rosalba; Fracchiolla, Giuseppe; Giampietro, Letizia; Giancristofaro, Antonella; Maccallini, Cristina; Cama, Alessandro; Amoroso, Rosa

    2016-05-23

    Recent evidences suggest a moderate activation of Peroxisome Proliferator-Activated Receptors (PPARs) could be favorable in metabolic diseases, reducing side effects given from full agonists. PPAR partial agonists and antagonists represent, to date, interesting tools to better elucidate biological processes modulated by these receptors. In this work are reported new benzenesulfonimide compounds able to block PPARα, synthesized and tested by transactivation assays and gene expression analysis. Some of these compounds showed a dose-dependent antagonistic behavior on PPARα, submicromolar potency, different profiles of selectivity versus PPARγ, and a repressive effect on CPT1A expression. Dockings and molecular dynamics on properly selected benzenesulfonimide derivatives furnished fresh insights into the molecular determinant most likely responsible for PPARα antagonism. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  13. Peroxisome proliferator activated receptor-gamma (PPAR-gamma) mediates the action of gamma linolenic acid in breast cancer cells.

    Science.gov (United States)

    Jiang, W G; Redfern, A; Bryce, R P; Mansel, R E

    2000-02-01

    Gamma linolenic acid (GLA) is a polyunsaturated fatty acid, which induces cytotoxicity and regulates cell adhesion in cancer cells. The molecular mechanism of these actions is not clear. We have shown that GLA acts via peroxisome proliferator activated receptors (PPARs), by stimulating their phosphorylation and translocation to the nucleus. Removing PPAR gamma with antisense oligos abolished the effect of GLA on the expression of adhesion molecules and tumour suppressor genes, whereas removal of PPAR alpha had no effect. Tissues from patients with breast cancer showed a reduction of expression of both PPARs in cancer tissues, as compared with normal. Thus, PPAR gamma serves as the receptor for GLA in the regulation of gene expression in breast cancer cells.

  14. Peroxisome proliferator-activated receptor: effects on nutritional homeostasis, obesity and diabetes mellitus Receptores activados por los proliferadores de peroxisomas: implicaciones sobre la homeostasis nutricional, en la obesidad y en la diabetes mellitus

    OpenAIRE

    M. Viana Abranches; F. C. Esteves de Oliveira; Bressan, J. (J.)

    2011-01-01

    The obesity and the metabolic disorders associated characterize the metabolic syndrome, which has increased at an alarming rate around the world. It is known that environmental and genetic factors are involved in the genesis of obesity. Peroxisome Proliferator-Activated Receptors (PPARs) stand out among these factors. They compose the nuclear receptor superfamily and there are in three isoforms (PPARα,PPARβ/δ and PPARγ), which play an important role in the regulation of...

  15. MCP-1 (Monocyte Chemotactic Protein-1)-induced Protein, a Recently Identified Zinc Finger Protein, Induces Adipogenesis in 3T3-L1 Pre-adipocytes without Peroxisome Proliferator-activated Receptor γ*

    OpenAIRE

    Younce, Craig W; Azfer, Asim; Kolattukudy, Pappachan E.

    2009-01-01

    Adipogenesis is a key differentiation process relevant to obesity and associated diseases such as type 2 diabetes. This process involves temporally regulated genes controlled by a set of transcription factors, CCAAT/enhancer-binding proteins (C/EBP) β, C/EBPδ, and C/EBPα and peroxisome proliferator-activated receptor γ (PPARγ). Currently, PPARγ is universally accepted as the master regulator that is necessary and sufficient to induce adipogenesis as no known factor can induce adipogenesis wit...

  16. Rational screening of peroxisome proliferator-activated receptor-γ agonists from natural products: potential therapeutics for heart failure.

    Science.gov (United States)

    Chen, Rui; Wan, Jing; Song, Jing; Qian, Yan; Liu, Yong; Gu, Shuiming

    2017-12-01

    Peroxisome proliferator-activated receptor-γ (PPARγ) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Activation of PPARγ pathway has been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis in heart failure. Thus, the protein has been raised as an attractive target for heart failure therapy. This work attempted to discover new and potent PPARγ agonists from natural products using a synthetic strategy of computer virtual screening and transactivation reporter assay. A large library of structurally diverse, drug-like natural products was compiled, from which those with unsatisfactory pharmacokinetic profile and/or structurally redundant compounds were excluded. The binding mode of remaining candidates to PPARγ ligand-binding domain (LBD) was computationally modelled using molecular docking and their relative binding potency was ranked by an empirical scoring scheme. Consequently, eight commercially available hits with top scores were selected and their biological activity was determined using a cell-based reporter-gene assay. Four natural product compounds, namely ZINC13408172, ZINC4292805, ZINC44179 and ZINC901461, were identified to have high or moderate agonistic potency against human PPARγ with EC50 values of 0.084, 2.1, 0.35 and 5.6 μM, respectively, which are comparable to or even better than that of the approved PPARγ full agonists pioglitazone (EC50 = 0.16 μM) and rosiglitazone (EC50 = 0.034 μM). Hydrophobic interactions and van der Waals contacts are the primary chemical forces to stabilize the complex architecture of PPARγ LBD domain with these agonist ligands, while few hydrogen bonds, salt bridges and/or π-π stacking at the complex interfaces confer selectivity and specificity for the domain-agonist recognition. The integrated in vitro-in silico screening strategy can be successfully applied to rational discovery of

  17. Inflammatory reaction versus endogenous peroxisome proliferator-activated receptors expression,re-exploring secondary organ complications of spontaneously hypertensive rats

    Institute of Scientific and Technical Information of China (English)

    SUN Li; KE Yan; ZHU Chun-yun; TANG Ning; TIAN Deng-ke; GAO Yue-hong; ZHENG Jian-pu; BIAN Ka

    2008-01-01

    Background The chronic pathological changes in vascular walls of hypertension may exert destructive effects on multiple organ systems.Accumulating evidence indicates that inflammatory reactions are involved in the pathological changes of hypertension.Three peroxisome proliferator-activated receptors (PPARs) have been identified:PPARα,PPARβ/δ,and PPARγ,all of which have multiple biological effects,especially the inhibition of inflammation.The aim of this study was to evaluate PPAR isoforms expression profile in important organs of spontaneously hypertensive rats (SHR) and to understand the modulation of endogenous PPAR isoforms under inflammatory condition.Methods Tissues (kidney,liver,heart,and brain) were dissected from SHR and age-matched control Wistar-Kyoto rats (WKY) to investigate the abundance of PPAR isoforms and PPAR-responsive genes (acyl-CoA oxidase and CD36).The expression of CCAAT/enhancer-binding protein δ (C/EBPδ),which can trans-activate PPARγ expression,was also observed.The inflammatory response was analyzed by the expression of inflammatory mediators inducible nitric oxide synthase (iNOS),intercellular adhesion molecule-1 (ICAM-1),vascular cell adhesion molecule-1 (VCAM-1),E-selectin,interleukin-1 beta (IL-1β),and tumor necrosis factor alpha (TNFα),and formation of carbonyl and nitrated proteins.Results The expressions of 3 PPAR isoforms and PPAR-responsive genes were markedly upregulated in SHR compared with those of WKY.Specifically,the expression of PPARa protein in the kidney,liver,heart and brain increased by 130.76 %,91.48%,306.24%,and 90.70%;PPARβ/δ upregulated by 109.34%,161.98%,137.04%,and 131.66%;PPARγ increased by 393.76%,193.17%,559.29%,and 591.18%.In consistent with the changes in PPARγ,the expression of C/EBPδ was also dramatically elevated in SHR.Inflammatory mediators expressions were significantly increased in the most organs of SHR than WKY.As a consequence,increased formation of carbonyl and nitrated proteins were

  18. Identification, organ expression and ligand-dependent expression levels of peroxisome proliferator activated receptors in grass carp (Ctenopharyngodon idella).

    Science.gov (United States)

    He, Shan; Liang, Xu-Fang; Qu, Chun-Mei; Huang, Wei; Shen, Dan; Zhang, Wen-Bing; Mai, Kang-Sen

    2012-03-01

    The peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors belonging to the nuclear receptor family, and can regulate various genes involved in lipid metabolism. The aim of the present study was to investigate the tissue distribution patterns of PPARs and their ligand specificities in grass carp. We cloned three PPAR isotypes of the species and evaluated their organ distribution patterns using real-time PCR. Through analyzing the deduced amino acid sequences identities between the products cloned in grass carp and those described in other species, we concluded that the same type of PPAR amino acid sequences in different species were with high homology, and different subtypes of PPAR in the same species were with low homology. The mRNA constitutive expression level of PPARα predominated in the liver, but was weak in other tested tissues. PPARβ was present in all tested organs, and particularly abundant in heart, liver and muscle. PPARγ was only detected in the liver, and to a lesser extent in brain, muscle and visceral adipose tissue. Grass carp were intraperitoneally injected with 50 mg kg(-1) body mass (bw) dose of clofibrate, 42 mg kg(-1) bw dose of 2-bromo palmitate and 1 mg kg(-1) bw dose of 15-deoxy-Δ(12,14) prostaglandin J2 (15d-PGJ2), respectively, and the relative changes of the mRNA abundance of PPARs in liver were analyzed by real-time PCR. Clofibrate was able to increase the expressions of both PPARα and β, but was not able to for PPARγ. 2-bromo palmitate could affect the expressions of both PPARβ and γ, but was not able to for PPARα. 15d-PGJ2 was able to induce PPARβ expression, but PPARα and γ were not enhanced. Consequently, these results indicate that clofibrate, 2-bromo palmitate and 15d-PGJ2 could be applied as the activators of grass carp PPARs. Copyright © 2011 Elsevier Inc. All rights reserved.

  19. Peroxisome proliferator-activated receptor gamma modulation and lipogenic response in adipocytes of small-for-gestational age offspring

    Directory of Open Access Journals (Sweden)

    Yee Jennifer K

    2012-06-01

    Full Text Available Abstract Background Small-for-gestational age (SGA at birth increases risk of development of adult obesity and insulin resistance. A model of SGA rat offspring has been shown to exhibit increased adipose tissue expression of a key adipogenic transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ, and increased fatty acid de novo synthesis during the nursing period, prior to onset of obesity. PPARγ agonists have been studied for potential use in the prevention of insulin resistance. Moreover, SGA adipocytes exhibit age-dependent differences in lipogenesis as mediated by PPARγ. The effects of PPARγ modulators on lipogenic gene expression and de novo lipogenesis on the age-dependent changes in SGA adipocytes are not known. The objectives of this study were: 1 to determine the adipogenic and lipogenic potential in SGA adipocytes at postnatal day 1 (p1 and day 21 (p21, 2 to determine how the PPARγ activator- and repressor-ligands affect the lipogenic potential, and 3 to determine the fatty acid metabolic response to PPARγ activator-ligand treatment. Methods Primary adipocyte cultures from p1 and p21 SGA and Control male offspring were established from a known maternal food-restriction model of SGA. Cell proliferation and Oil Red O (ORO staining were quantified. Adipocytes were treated with increasing doses of rosiglitazone or bisphenol-A diglycidyl ether (BADGE. PPARγ and SREBP1 protein expression were determined. De novo lipogenesis with rosiglitazone treatment at p21 was studied using 50% U13C-glucose and gas chromatography/mass spectrometry. Results At p1 and p21, SGA demonstrated increased cell proliferation and increased ORO staining. At p21, SGA demonstrated increased lipogenic gene expression and increased glucose-mediated fatty acid de novo synthesis compared with Controls. In response to rosiglitazone, SGA adipocytes further increased glucose utilization for fatty acid synthesis. SGA lipogenic gene expression

  20. Peroxisome proliferator-activated receptor γ enhances adiponectin secretion via up-regulating DsbA-L expression.

    Science.gov (United States)

    Jin, Dan; Sun, Jun; Huang, Jing; Yu, Xiaoling; Yu, An; He, Yiduo; Li, Qiang; Yang, Zaiqing

    2015-08-15

    Disulfide-bond A oxidoreductase like-protein (DsbA-L) was identified as a molecular chaperone facilitating the assembly and secretion of adiponectin, an adipokine with multiple beneficial effects. In obesity the level of DsbA-L is reduced with a concomitant decrease of the circulating adiponectin level, especially of the high molecular weight form (HMW). Both rodent and human studies have shown that the nuclear receptor peroxisome proliferator-activated receptor (PPAR)-γ agonists increase adiponectin levels in serum by activating PPARγ, which up-regulates critical endoplasmic reticulum (ER) chaperones thus facilitating protein folding. As shown in the present study, overexpression of PPARγ in human embryonic kidney (HEK) 293 cells elicited the cellular release of HMW adiponectin. PPARγ enhanced expression of DsbA-L by binding directly to peroxisome proliferator response element (PPRE) site within the DsbA-L promoter. Conversely, in differentiated 3T3-L1 cells, PPARγ knockdown resulted in decreased expression of Adiponectin, DsbA-L and ERp44. DsbA-L expression increased after PPARγ agonist treatment and decreased upon treatment with PPARγ antagonist in 3T3-L1 adipocytes. DsbA-L deficiency in differentiated 3T3-L1 cells impaired the secretion of adiponectin. We therefore propose that DsbA-L plays an important role in facilitating HMW adiponectin formation and release from cells under the regulation of PPARγ. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  1. Nifedipine inhibits advanced glycation end products (AGEs) and their receptor (RAGE) interaction-mediated proximal tubular cell injury via peroxisome proliferator-activated receptor-gamma activation

    Energy Technology Data Exchange (ETDEWEB)

    Matsui, Takanori [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Yamagishi, Sho-ichi, E-mail: shoichi@med.kurume-u.ac.jp [Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume (Japan); Takeuchi, Masayoshi [Department of Pathophysiological Science, Faculty of Pharmaceutical Science, Hokuriku University, Kanazawa (Japan); Ueda, Seiji; Fukami, Kei; Okuda, Seiya [Department of Medicine, Kurume University School of Medicine, Kurume (Japan)

    2010-07-23

    Research highlights: {yields} Nifedipine inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma}. {yields} GW9662 treatment alone increased RAGE mRNA levels in tubular cells. {yields} Nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-{beta} gene expression in tubular cells, all of which were blocked by GW9662. -- Abstract: There is a growing body of evidence that advanced glycation end products (AGEs) and their receptor (RAGE) interaction evokes oxidative stress generation and subsequently elicits inflammatory and fibrogenic reactions, thereby contributing to the development and progression of diabetic nephropathy. We have previously found that nifedipine, a calcium-channel blocker (CCB), inhibits the AGE-induced mesangial cell damage in vitro. However, effects of nifedipine on proximal tubular cell injury remain unknown. We examined here whether and how nifedipine blocked the AGE-induced tubular cell damage. Nifedipine, but not amlodipine, a control CCB, inhibited the AGE-induced up-regulation of RAGE mRNA levels in tubular cells, which was prevented by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}). GW9662 treatment alone was found to increase RAGE mRNA levels in tubular cells. Further, nifedipine inhibited the AGE-induced reactive oxygen species generation, NF-{kappa}B activation and increases in intercellular adhesion molecule-1 and transforming growth factor-beta gene expression in tubular cells, all of which were blocked by GW9662. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-oxidative and anti-inflammatory agent against AGEs in tubular cells by suppressing RAGE expression

  2. Analysis of the heat shock response in mouse liver reveals dependence on the Nuclear Receptor Peroxisome Proliferator-Activated Receptor alpha (PPARalpha)

    NARCIS (Netherlands)

    Vallanat, B.; Anderson, S.P.; Brown-Borg, H.M.; Ren, H.; Kersten, A.H.; Jonnalagadda, S.; Srinivasan, S.; Corton, J.C.

    2010-01-01

    Background - The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARa) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by heat shock (HS) through

  3. Opposing effects of fatty acids and acyl-CoA esters on conformation and cofactor recruitment of peroxisome proliferator-activated receptors

    DEFF Research Database (Denmark)

    JØrgensen, Claus; Krogsdam, Anne-M; Kratchmarova, Irina;

    2002-01-01

    The peroxisome proliferator-activated receptors (PPARs) bind and are activated by a variety of fatty acids and derivatives thereof. Agonist binding enhances PPAR-mediated transactivation via release of corepressors and recruitment of coactivator complexes. Recently, we and others have reported...

  4. Lipid-binding proteins modulate ligand-dependent trans-activation by peroxisome proliferator-activated receptors and localize to the nucleus as well as the cytoplasm

    DEFF Research Database (Denmark)

    Helledie, T; Antonius, M; Sorensen, R V;

    2000-01-01

    Peroxisome proliferator-activated receptors (PPARs) are activated by a variety of fatty acids, eicosanoids, and hypolipidemic and insulin-sensitizing drugs. Many of these compounds bind avidly to members of a family of small lipid-binding proteins, the fatty acid-binding proteins (FABPs). Fatty...

  5. Peroxisome proliferator-activated receptor (PPAR) alpha and PPAR beta/delta, but not PPAR gamma, modulate the expression of genes involved in cardiac lipid metabolism

    NARCIS (Netherlands)

    Gilde, AJ; van der Lee, KAJM; Willemsen, PHM; Chinetti, G; van der Leij, FR; van der Vusse, GJ; Staels, B; van Bilsen, M

    2003-01-01

    Long-chain fatty acids ( FA) coordinately induce the expression of a panel of genes involved in cellular FA metabolism in cardiac muscle cells, thereby promoting their own metabolism. These effects are likely to be mediated by peroxisome proliferator-activated receptors (PPARs). Whereas the

  6. Noradrenaline represses PPAR (peroxisome-proliferator-activated receptor) gamma2 gene expression in brown adipocytes: intracellular signalling and effects on PPARgamma2 and PPARgamma1 protein levels

    DEFF Research Database (Denmark)

    Lindgren, Eva M; Nielsen, Ronni; Petrovic, Natasa

    2004-01-01

    PPAR (peroxisome-proliferator-activated receptor) gamma is expressed in brown and white adipose tissues and is involved in the control of differentiation and proliferation. Noradrenaline stimulates brown pre-adipocyte proliferation and brown adipocyte differentiation. The aim of the present study...

  7. Peroxisome Proliferator-Activated Receptor-alpha-Null Mice Have Increased White Adipose Tissue Glucose Utilization, GLUT4, and Fat Mass: Role in Liver and Brain

    NARCIS (Netherlands)

    Knauf, C.; Rieusset, J.; Foretz, M.; Cani, P.D.; Uldry, M.; Hosokawa, M.; Martinez, E.; Bringart, M.; Waget, A.; Kersten, A.H.; Desvergne, B.; Gremlich, S.; Wahli, W.; Seydoux, J.; Delzenne, N.M.; Thorens, B.; Burcelin, R.

    2006-01-01

    Activation of the peroxisome proliferator-activated receptor (PPAR)-¿ increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPAR¿ knockout mice with wild type and confirmed that

  8. Peroxisome Proliferator-Activated Receptor-alpha-Null Mice Have Increased White Adipose Tissue Glucose Utilization, GLUT4, and Fat Mass: Role in Liver and Brain

    NARCIS (Netherlands)

    Knauf, C.; Rieusset, J.; Foretz, M.; Cani, P.D.; Uldry, M.; Hosokawa, M.; Martinez, E.; Bringart, M.; Waget, A.; Kersten, A.H.; Desvergne, B.; Gremlich, S.; Wahli, W.; Seydoux, J.; Delzenne, N.M.; Thorens, B.; Burcelin, R.

    2006-01-01

    Activation of the peroxisome proliferator-activated receptor (PPAR)-¿ increases lipid catabolism and lowers the concentration of circulating lipid, but its role in the control of glucose metabolism is not as clearly established. Here we compared PPAR¿ knockout mice with wild type and confirmed that

  9. Peroxisome Proliferator-activated Receptor gamma Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)

    NARCIS (Netherlands)

    Jeninga, E.H.; Bugge, A.; Nielsen, R.; Kersten, A.H.; Hamers, N.; Dani, C.; Wabitsch, M.; Berger, R.; Stunnenberg, H.G.; Mandrup, S.; Kalkhoven, E.

    2009-01-01

    The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPAR gamma targ

  10. A common building block for the syntheses of amorfrutin and cajaninstilbene acid libraries toward efficient binding with peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Aidhen, Indrapal S; Mukkamala, Ramesh; Weidner, Christopher; Sauer, Sascha

    2015-01-16

    A common building block for the synthesis of amorfrutin and cajaninstilbene acid derivatives has been developed. The library of synthesized compounds has enabled identification of new nontoxic ligands of peroxisome proliferator-activated receptors (PPAR) and potential inhibitors of the transcriptional corepressor protein NCoR. The biological data holds promise in identification of new potential leads for the antidiabetic drug discovery process.

  11. The Hinge-Helix 1 Region of Peroxisome Proliferator-Activated Receptor γ1 (PPARγ1) Mediates Interaction with Extracellular Signal-Regulated Kinase 5 and PPARγ1 Transcriptional Activation: Involvement in Flow-Induced PPARγ Activation in Endothelial Cells

    OpenAIRE

    Akaike, Masashi; Che, Wenyi; Marmarosh, Nicole-Lerner; Ohta, Shinsuke; Osawa, Masaki; Ding,Bo; Berk, Bradford C.; Yan, Chen; Abe, Jun-ichi

    2004-01-01

    Peroxisome proliferator-activated receptors (PPAR) are ligand-activated transcription factors that form a subfamily of the nuclear receptor gene family. Since both flow and PPARγ have atheroprotective effects and extracellular signal-regulated kinase 5 (ERK5) kinase activity is significantly increased by flow, we investigated whether ERK5 kinase regulates PPARγ activity. We found that activation of ERK5 induced PPARγ1 activation in endothelial cells (ECs). However, we could not detect PPARγ p...

  12. A complex between 6-iodolactone and the peroxisome proliferator-activated receptor type gamma may mediate the antineoplastic effect of iodine in mammary cancer.

    Science.gov (United States)

    Nuñez-Anita, R E; Arroyo-Helguera, O; Cajero-Juárez, M; López-Bojorquez, L; Aceves, C

    2009-06-01

    Recently we and other groups have shown that molecular iodine (I(2)) exhibits potent antiproliferative and apoptotic effects in mammary cancer models. In the human breast cancer cell line MCF-7, I(2) treatment generates iodine-containing lipids similar to 6-iodo-5-hydroxy-eicosatrienoic acid and the 6-iodolactone (6-IL) derivative of arachidonic acid (AA), and it significantly decreases cellular proliferation and induces caspase-dependent apoptosis. Several studies have shown that AA is a natural ligand of the peroxisome proliferator-activated receptors (PPARs), which are nuclear transcription factors thought to participate in regulating cancer cell proliferation. Our results show that in MCF-7 cells: (1) 6-IL binds specifically and with high affinity to PPAR proteins (EMSA assays), (2) 6-IL activates both transfected (by transactivation assays) and endogenous (by lipid accumulation) peroxisome proliferator response elements, and (3) 6-IL supplementation increases PPAR gamma and decreases PPAR alpha expression. These results implicate PPARs in a molecular mechanism by which I(2), through formation of 6-IL, inhibits the growth of human breast cancer cells.

  13. Peroxisome proliferator-activated receptor alpha induction of uncoupling protein 2 protects against acetaminophen-induced liver toxicity.

    Science.gov (United States)

    Patterson, Andrew D; Shah, Yatrik M; Matsubara, Tsutomu; Krausz, Kristopher W; Gonzalez, Frank J

    2012-07-01

    Acetaminophen (APAP) overdose causes acute liver failure in humans and rodents due in part to the destruction of mitochondria as a result of increased oxidative stress followed by hepatocellular necrosis. Activation of the peroxisome proliferator-activated receptor alpha (PPARα), a member of the nuclear receptor superfamily that controls the expression of genes encoding peroxisomal and mitochondrial fatty acid β-oxidation enzymes, with the experimental ligand Wy-14,643 or the clinically used fibrate drug fenofibrate, fully protects mice from APAP-induced hepatotoxicity. PPARα-humanized mice were also protected, whereas Ppara-null mice were not, thus indicating that the protection extends to human PPARα and is PPARα-dependent. This protection is due in part to induction of the PPARα target gene encoding mitochondrial uncoupling protein 2 (UCP2). Forced overexpression of UCP2 protected wildtype mice against APAP-induced hepatotoxicity in the absence of PPARα activation. Ucp2-null mice, however, were sensitive to APAP-induced hepatotoxicity despite activation of PPARα with Wy-14,643. Protection against hepatotoxicity by UCP2-induction through activation of PPARα is associated with decreased APAP-induced c-jun and c-fos expression, decreased phosphorylation of JNK and c-jun, lower mitochondrial H(2)O(2) levels, increased mitochondrial glutathione in liver, and decreased levels of circulating fatty acyl-carnitines. These studies indicate that the PPARα target gene UCP2 protects against elevated reactive oxygen species generated during drug-induced hepatotoxicity and suggest that induction of UCP2 may also be a general mechanism for protection of mitochondria during fatty acid β-oxidation.

  14. Peroxisome proliferator-activated receptor-g is essential in the pathogenesis of gastric carcinoma

    Institute of Scientific and Technical Information of China (English)

    Xiu-Mei Ma; Hong Yu; Na Huai

    2009-01-01

    AIM: To investigate whether peroxisome proliferatoractivated receptor γ(PPAR-γ) is expressed in human gastric carcinoma and whether PPAR-γ is a potential target for gastric carcinoma therapy. METHODS: PPAR-γ protein in gastric carcinoma was examined by immunohistochemistry. In the gastric carcinoma cell line MGC803, PPAR-γ, survivin, Skp2 and p27 protein and mRNA were examined by Western blotting and real-time reverse transcription-polymerase chain reaction, respectively; proliferation was examined by MTT; apoptosis was examined by chromatin staining with Hoechst 33342 and fluorescence activated cell sorting (FACS). and cell cycle was examined by FACS; the knockdown of PPAR-g was done by RNA interference.RESULTS: A high level of expression of PPAR-γ was observed in human gastric carcinoma and in a human gastric carcinoma cell line MGC803. The PPAR-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) inhibited growth, and induced apoptosis and G1/G0 cell cycle arrest in MGC803 cells in a concentration-dependent and time-dependent manner. The effect of 15d-PGJ2 on MGC803 cells was not reversed by the selective and irreversible antagonist GW9662 for PPAR-γ. Furthermore,survivin and Skp2 expression were decreased, whereas p27 expression was enhanced following 15d-PGJ2 treatment in a dose-dependent manner in MGC803 cells.Interestingly, we also found that small interfering RNA for PPAR-γ inhibited growth and induced apoptosis in MGC803 cells. The inhibition of PPAR-γ function may be a potentially important and novel modality for treatment and prevention of gastric carcinoma.CONCLUSION: A PPAR-γ agonist inhibited growth of human gastric carcinoma MGC803 cells by inducing apoptosis and G1/G0 cell cycle arrest with the involvement of survivin, Skp2 and p27 and not via PPAR-γ.

  15. Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activates promyogenic signaling pathways, thereby promoting myoblast differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Sang-Jin; Go, Ga-Yeon; Yoo, Miran; Kim, Yong Kee [Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul 140-742 (Korea, Republic of); Seo, Dong-Wan [College of Pharmacy, Dankook University, Cheonan 330-714 (Korea, Republic of); Kang, Jong-Sun [Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746 (Korea, Republic of); Bae, Gyu-Un, E-mail: gbae@sookmyung.ac.kr [Research Center for Cell Fate Control, College of Pharmacy, Sookmyung Women' s University, Seoul 140-742 (Korea, Republic of)

    2016-01-29

    Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) regulates postnatal myogenesis by alleviating myostatin activity, but the molecular mechanisms by which it regulates myogenesis are not fully understood. In this study, we investigate molecular mechanisms of PPARβ/δ in myoblast differentiation. C2C12 myoblasts treated with a PPARβ/δ agonist, GW0742 exhibit enhanced myotube formation and muscle-specific gene expression. GW0742 treatment dramatically activates promyogenic kinases, p38MAPK and Akt, in a dose-dependent manner. GW0742-stimulated myoblast differentiation is mediated by p38MAPK and Akt, since it failed to restore myoblast differentiation repressed by inhibition of p38MAPK and Akt. In addition, GW0742 treatment enhances MyoD-reporter activities. Consistently, overexpression of PPARβ/δ enhances myoblast differentiation accompanied by elevated activation of p38MAPK and Akt. Collectively, these results suggest that PPARβ/δ enhances myoblast differentiation through activation of promyogenic signaling pathways. - Highlights: • A PPARβ/δ agonist, GW0742 promotes myoblast differentiation. • GW0742 activates both p38MAPK and Akt activation in myogenic differentiation. • GW0742 enhances MyoD activity for myogenic differentiation. • Overexpression of PPARβ/δ enhances myoblast differentiation via activating promyogenic signaling pathways. • This is the first finding for agonistic mechanism of PPARβ/δ in myogenesis.

  16. Genomewide effects of peroxisome proliferator-activated receptor gamma in macrophages and dendritic cells--revealing complexity through systems biology.

    Science.gov (United States)

    Cuaranta-Monroy, Ixchelt; Kiss, Mate; Simandi, Zoltan; Nagy, Laszlo

    2015-09-01

    Systems biology approaches have become indispensable tools in biomedical and basic research. These data integrating bioinformatic methods gained prominence after high-throughput technologies became available to investigate complex cellular processes, such as transcriptional regulation and protein-protein interactions, on a scale that had not been studied before. Immunology is one of the medical fields that systems biology impacted profoundly due to the plasticity of cell types involved and the accessibility of a wide range of experimental models. In this review, we summarize the most important recent genomewide studies exploring the function of peroxisome proliferator-activated receptor γ in macrophages and dendritic cells. PPARγ ChIP-seq experiments were performed in adipocytes derived from embryonic stem cells to complement the existing data sets and to provide comparators to macrophage data. Finally, lists of regulated genes generated from such experiments were analysed with bioinformatics and system biology approaches. We show that genomewide studies utilizing high-throughput data acquisition methods made it possible to gain deeper insights into the role of PPARγ in these immune cell types. We also demonstrate that analysis and visualization of data using network-based approaches can be used to identify novel genes and functions regulated by the receptor. The example of PPARγ in macrophages and dendritic cells highlights the crucial importance of systems biology approaches in establishing novel cellular functions for long-known signaling pathways. © 2015 Stichting European Society for Clinical Investigation Journal Foundation.

  17. Local release of pioglitazone (a peroxisome proliferator-activated receptor γ agonist) accelerates proliferation and remodeling phases of wound healing.

    Science.gov (United States)

    Sakai, Shigeki; Sato, Keisuke; Tabata, Yasuhiko; Kishi, Kazuo

    2016-01-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily known for its anti-inflammatory and macrophage differentiation effects, as well as its ability to promote fat cell differentiation and reduce insulin resistance. Pioglitazone (Pio) is a PPARγ agonist used clinically as an anti-diabetic agent for improving insulin sensitivity in patients with diabetes. The objective of this study was to develop a drug delivery system (DDS) for the local release of Pio to promote wound healing. Pio of low aqueous solubility was water-solubilized by micelles formed from gelatin grafted with L-lactic acid oligomers, and incorporated into a biodegradable gelatin hydrogel. An 8-mm punch biopsy tool was used to prepare two skin wounds on either side of the midline of 8-week-old mice. Wounds were treated by the hydrogels with (Pio-hydrogel group) or without (control group) Pio, and the wound area were observed 1, 4, 7, and 14 days after treatment. In addition, a protein assay and immunohistological stain were performed to determine the effects of the Pio-hydrogel on inflammation and macrophage differentiation. The Pio-hydrogels promote wound healing. Moreover, Western blotting analysis demonstrated that treatment with Pio-hydrogels resulted in decreased levels of the cytokines MIP-2 and TGF-β, and increased levels of glucose-regulating adiponectin. It is concluded that Pio-incorporated hydrogels promote the proliferation and remodeling phases of wound healing, and may prove to be effective as wound dressings.

  18. Activation of Peroxisome Proliferator-Activated Receptor Alpha Improves Aged and UV-Irradiated Skin by Catalase Induction

    Science.gov (United States)

    Shin, Mi Hee; Lee, Se-Rah; Kim, Min-Kyoung; Shin, Chang-Yup

    2016-01-01

    Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear hormone receptor involved in the transcriptional regulation of lipid metabolism, fatty acid oxidation, and glucose homeostasis. Its activation stimulates antioxidant enzymes such as catalase, whose expression is decreased in aged human skin. Here we investigated the expression of PPARα in aged and ultraviolet (UV)-irradiated skin, and whether PPARα activation can modulate expressions of matrix metalloproteinase (MMP)-1 and procollagen through catalase regulation. We found that PPARα mRNA level was significantly decreased in intrinsically aged and photoaged human skin as well as in UV-irradiated skin. A PPARα activator, Wy14643, inhibited UV-induced increase of MMP-1 and decrease of procollagen expression and caused marked increase in catalase expression. Furthermore, production of reactive oxygen species (ROS) was suppressed by Wy14643 in UV-irradiated and aged dermal fibroblasts, suggesting that the PPARα activation-induced upregulation of catalase leads to scavenging of ROS produced due to UV irradiation or aging. PPARα knockdown decreased catalase expression and abolished the beneficial effects of Wy14643. Topical application of Wy14643 on hairless mice restored catalase activity and prevented MMP-13 and inflammatory responses in skin. Our findings indicate that PPARα activation triggers catalase expression and ROS scavenging, thereby protecting skin from UV-induced damage and intrinsic aging. PMID:27611371

  19. Peroxisome proliferator-activated receptor γ decouples fatty acid uptake from lipid inhibition of insulin signaling in skeletal muscle.

    Science.gov (United States)

    Hu, Shanming; Yao, Jianrong; Howe, Alexander A; Menke, Brandon M; Sivitz, William I; Spector, Arthur A; Norris, Andrew W

    2012-06-01

    Peroxisome proliferator-activated receptor γ (PPARγ) is expressed at low levels in skeletal muscle, where it protects against adiposity and insulin resistance via unclear mechanisms. To test the hypothesis that PPARγ directly modulates skeletal muscle metabolism, we created two models that isolate direct PPARγ actions on skeletal myocytes. PPARγ was overexpressed in murine myotubes by adenotransfection and in mouse skeletal muscle by plasmid electroporation. In cultured myotubes, PPARγ action increased fatty acid uptake and incorporation into myocellular lipids, dependent upon a 154 ± 20-fold up-regulation of CD36 expression. PPARγ overexpression more than doubled insulin-stimulated thymoma viral proto-oncogene (AKT) phosphorylation during low lipid availability. Furthermore, in myotubes exposed to palmitate levels that inhibit insulin signaling, PPARγ overexpression increased insulin-stimulated AKT phosphorylation and glycogen synthesis over 3-fold despite simultaneously increasing myocellular palmitate uptake. The insulin signaling enhancement was associated with an increase in activating phosphorylation of phosphoinositide-dependent protein kinase 1 and a normalized expression of palmitate-induced genes that antagonize AKT phosphorylation. In vivo, PPARγ overexpression more than doubled insulin-dependent AKT phosphorylation in lipid-treated mice but did not augment insulin-stimulated glucose uptake. We conclude that direct PPARγ action promotes myocellular storage of energy by increasing fatty acid uptake and esterification while simultaneously enhancing insulin signaling and glycogen formation. However, direct PPARγ action in skeletal muscle is not sufficient to account for the hypoglycemic actions of PPARγ agonists during lipotoxicity.

  20. Structural and Biochemical Basis for the Binding Selectivity of Peroxisome Proliferator-activated Receptor [gamma] to PGC-1[alpha

    Energy Technology Data Exchange (ETDEWEB)

    Li, Yong; Kovach, Amanda; Suino-Powell, Kelly; Martynowski, Dariusz; Xu, H. Eric (Pitt); (Van Andel)

    2008-07-23

    The functional interaction between the peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) and its coactivator PGC-1{alpha} is crucial for the normal physiology of PPAR{gamma} and its pharmacological response to antidiabetic treatment with rosiglitazone. Here we report the crystal structure of the PPAR{gamma} ligand-binding domain bound to rosiglitazone and to a large PGC-1{alpha} fragment that contains two LXXLL-related motifs. The structure reveals critical contacts mediated through the first LXXLL motif of PGC-1{alpha} and the PPAR{gamma} coactivator binding site. Through a combination of biochemical and structural studies, we demonstrate that the first LXXLL motif is the most potent among all nuclear receptor coactivator motifs tested, and only this motif of the two LXXLL-related motifs in PGC-1{alpha} is capable of binding to PPAR{gamma}. Our studies reveal that the strong interaction of PGC-1{alpha} and PPAR{gamma} is mediated through both hydrophobic and specific polar interactions. Mutations within the context of the full-length PGC-1{alpha} indicate that the first PGC-1{alpha} motif is necessary and sufficient for PGC-1{alpha} to coactivate PPAR{gamma} in the presence or absence of rosiglitazone. These results provide a molecular basis for specific recruitment and functional interplay between PPAR{gamma} and PGC-1{alpha} in glucose homeostasis and adipocyte differentiation.

  1. Peroxisome Proliferator-activated Receptor-γ Coactivator 1-α (PGC1α) Protects against Experimental Murine Colitis*

    Science.gov (United States)

    Cunningham, Kellie E.; Vincent, Garret; Sodhi, Chhinder P.; Novak, Elizabeth A.; Ranganathan, Sarangarajan; Egan, Charlotte E.; Stolz, Donna Beer; Rogers, Matthew B.; Firek, Brian; Morowitz, Michael J.; Gittes, George K.; Zuckerbraun, Brian S.; Hackam, David J.; Mollen, Kevin P.

    2016-01-01

    Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α) is the primary regulator of mitochondrial biogenesis and was recently found to be highly expressed within the intestinal epithelium. PGC1α is decreased in the intestinal epithelium of patients with inflammatory bowel disease, but its role in pathogenesis is uncertain. We now hypothesize that PGC1α protects against the development of colitis and helps to maintain the integrity of the intestinal barrier. We selectively deleted PGC1α from the intestinal epithelium of mice by breeding a PGC1αloxP/loxP mouse with a villin-cre mouse. Their progeny (PGC1αΔIEC mice) were subjected to 2% dextran sodium sulfate (DSS) colitis for 7 days. The SIRT1 agonist SRT1720 was used to enhance PGC1α activation in wild-type mice during DSS exposure. Mice lacking PGC1α within the intestinal epithelium were more susceptible to DSS colitis than their wild-type littermates. Pharmacologic activation of PGC1α successfully ameliorated disease and restored mitochondrial integrity. These findings suggest that a depletion of PGC1α in the intestinal epithelium contributes to inflammatory changes through a failure of mitochondrial structure and function as well as a breakdown of the intestinal barrier, which leads to increased bacterial translocation. PGC1α induction helps to maintain mitochondrial integrity, enhance intestinal barrier function, and decrease inflammation. PMID:26969166

  2. Effect of polymorphism in the peroxisome proliferator-activated receptor gamma gene on litter size of pigs.

    Science.gov (United States)

    Wang, Guiying; Kong, Lujun; Hu, Peng; Fu, Jinlian; Wang, Aiguo

    2011-03-01

    The association of polymorphisms in peroxisome proliferator-activated receptor γ (PPARγ) gene with litter size was studied in Large White and Landrace pig. Three SNP loci (P1, P2 and P7) on PPARγ(2) gene were determined by PCR-SSCP and the results showed that there were A → G mutations at 220 and 324 bp in 5'-regulator region and at 147 bp in exon 6, respectively. Allele frequencies were analysed in two breeds. Information on 2341 litter records from 564 sows was used to analyse the trait total number born (TNB) and number born alive (NBA). In Large White, TNB and NBA of genotype BB for P2 locus were the lowest, and the TNB and NBA of third and following parities and all parities were 0.74 and 0.51 piglets per litter less (P NBA of the first parity of genotype BB for P1 locus were 2.0 piglets per litter higher than AA (P NBA of genotype BB were 0.66 and 0.97 piglets per litter (P NBA of the second parity of genotype AA were obviously higher than those of AB (P NBA of each parity of genotype AA were both about 2 piglets per litter more than those of BB (P < 0.05). The results indicated that PPARγ gene was significantly associated with litter size in pigs.

  3. Porcine peroxisome proliferator-activated receptor delta mediates the lipolytic effects of dietary fish oil to reduce body fat deposition.

    Science.gov (United States)

    Yu, Y H; Wang, P H; Cheng, W T K; Mersmann, H J; Wu, S C; Ding, S T

    2010-06-01

    Peroxisome proliferator-activated receptor delta promotes fatty acid catabolism and energy expenditure in skeletal muscle and adipose tissues. A ligand for PPARdelta is required to activate PPARdelta function. Polyunsaturated fatty acids are potential ligands for PPARdelta activation. The current experiment was designed to determine the potential for PUFA, particularly from dietary fish oil, to activate porcine PPARdelta in vivo. Transgenic mice were generated to overexpress porcine PPARdelta in the adipose tissue. Mice were fed a high-saturated fat (13% beef tallow), or high-unsaturated fat (13% fish oil) diet, or a diet containing 4 mg/kg of a PPARdelta ligand (L165041) for 4 mo. Compared with beef tallow feeding, fish oil feeding reduced fat mass and decreased (P lipase and adipocyte fatty acid-binding protein) was decreased in transgenic mice fed fish oil or the PPARdelta ligand. In the same mice, expression of the lipolytic gene, hormone-sensitive lipase was increased (P Fish oil feeding also stimulated expression of genes participating in fatty acid oxidation in the liver of transgenic mice compared with wild-type mice. Overall, these results indicate that PUFA may serve as natural and effective regulators of lipid catabolism in vivo and many of these effects may be generated from activation of PPARdelta.

  4. Peroxisome proliferator-activated receptor gamma (PPARγ) in brown trout: Interference of estrogenic and androgenic inputs in primary hepatocytes.

    Science.gov (United States)

    Lopes, Célia; Madureira, Tânia Vieira; Ferreira, Nádia; Pinheiro, Ivone; Castro, L Filipe C; Rocha, Eduardo

    2016-09-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is a pivotal regulator of lipid and glucose metabolism in vertebrates. Here, we isolated and characterized for the first time the PPARγ gene from brown trout (Salmo trutta f. fario). Hormones have been reported to interfere with the regulatory function of PPARγ in various organisms, albeit with little focus on fish. Thus, primary hepatocytes isolated from juveniles of brown trout were exposed to 1, 10 and 50μM of ethinylestradiol (EE2) or testosterone (T). A significant (3 fold) decrease was obtained in response to 50μM of EE2 and to 10 and 50μM of T (13 and 14 folds), while a 3 fold increase was observed at 1μM of EE2. Therefore, trout PPARγ seems a target for natural/synthetic compounds with estrogenic or androgenic properties and so, we advocate considering PPARγ as another alert sensor gene when assessing the effects of sex-steroid endocrine disruptors.

  5. Ligands for peroxisome proliferator-activated receptor gamma inhibit growth of pancreatic cancers both in vitro and in vivo.

    Science.gov (United States)

    Itami, A; Watanabe, G; Shimada, Y; Hashimoto, Y; Kawamura, J; Kato, M; Hosotani, R; Imamura, M

    2001-11-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed largely in adipose tissues and plays an important role in adipocyte differentiation. Several studies have recently shown that ligands of PPARgamma could lead to growth inhibition in some malignancies. In our study, we focused on pancreatic cancers, because the prognosis of advanced pancreatic cancer has not significantly improved due to its resistance to various chemotherapeutic regimens, so that a novel strategy should be required. We show here that PPARgamma is expressed in 5 pancreatic cancer cell lines detected in both mRNA and protein level as well as in human primary and metastatic pancreatic carcinomas examined by immunohistochemical studies. A specific ligand of PPARgamma, troglitazone, led to G1 accumulation with the increase in p27(Kip1), but not p21(Waf1/Cip1) and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPARgamma in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in part, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPARgamma. Our results suggest that ligands of PPARgamma may be a novel therapeutic agent for the treatment of pancreatic carcinomas.

  6. Assessment of chitosan-affected metabolic response by peroxisome proliferator-activated receptor bioluminescent imaging-guided transcriptomic analysis.

    Directory of Open Access Journals (Sweden)

    Chia-Hung Kao

    Full Text Available Chitosan has been widely used in food industry as a weight-loss aid and a cholesterol-lowering agent. Previous studies have shown that chitosan affects metabolic responses and contributes to anti-diabetic, hypocholesteremic, and blood glucose-lowering effects; however, the in vivo targeting sites and mechanisms of chitosan remain to be clarified. In this study, we constructed transgenic mice, which carried the luciferase genes driven by peroxisome proliferator-activated receptor (PPAR, a key regulator of fatty acid and glucose metabolism. Bioluminescent imaging of PPAR transgenic mice was applied to report the organs that chitosan acted on, and gene expression profiles of chitosan-targeted organs were further analyzed to elucidate the mechanisms of chitosan. Bioluminescent imaging showed that constitutive PPAR activities were detected in brain and gastrointestinal tract. Administration of chitosan significantly activated the PPAR activities in brain and stomach. Microarray analysis of brain and stomach showed that several pathways involved in lipid and glucose metabolism were regulated by chitosan. Moreover, the expression levels of metabolism-associated genes like apolipoprotein B (apoB and ghrelin genes were down-regulated by chitosan. In conclusion, these findings suggested the feasibility of PPAR bioluminescent imaging-guided transcriptomic analysis on the evaluation of chitosan-affected metabolic responses in vivo. Moreover, we newly identified that downregulated expression of apoB and ghrelin genes were novel mechanisms for chitosan-affected metabolic responses in vivo.

  7. Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating peroxisome proliferator-activated receptor γ

    Institute of Scientific and Technical Information of China (English)

    Yan-Qin Zhang; Xiao-Qing Tang; Li Sun; Lin Dong; Yong Qin; Hua-Qing Liu; Hong Xia; Jian-Guo Cao

    2007-01-01

    AIM: To examine whether and how rosiglitazone enhances apoptosis induced by fluorouracil in human colon cancer (HT-29) cells.METHODS: Human colon cancer HT-29 cells were cultured in vitro and treated with fluorouracil and/or rosiglitazone. Proliferation and growth of HT-29 cells were evaluated by MTT assay and trypan blue exclusion methods, respectively. The apoptosis of HT-29 cells was determined by acridine orange/ethidium bromide staining and flow cytometry using PI fluorescence staining. The expressions of peroxisome proliferator-activated receptor y (PPARy), Bcl-2 and Bax in HT-29 cells were analyzed by Western blot.RESULTS: Although rosiglitazone at the concentration below 30 umol/L for 72 h exerted almost no inhibitory effect on proliferation and growth of HT-29 cells, it could significantly enhance fluorouracil-induced HT-29 cell proliferation and growth inhibition. Furthermore, 10 umol/L rosilitazone did not induce apoptosis of HT-29 cells but dramatically enhanced fluorouracil-induced apoptosis of HT-29 cells. However, rosiglitazone did not improve apoptosis induced by fluorouracil in HT-29 cells pretreated with GW9662, a PPARy antagonist. Meanwhile, the expression of Bax and PPARy was up-regulated, while the expression of Bcl-2 was down regulated in HT-29 cells treated with rosiglitazone in a time-dependent manner. However, the effect of rosiglitazone on Bcl-2 and Bax was blocked or diminished in the presence of GW9662.CONCLUSION: Rosiglitazone enhances fluorouracil-induced apoptosis of HT-29 cells by activating PPARγ.

  8. Activation of peroxisome proliferator-activated receptor α in human endothelial cells increases plasminogen activator inhibitor type-1 expression

    Institute of Scientific and Technical Information of China (English)

    叶平; 胡晓晖; 刘永学; 赵亚力

    2003-01-01

    Objective To investigate the effect of peroxisome proliferator-activated receptors (PPARs) activators on plasminogen activator inhibitor 1 (PAI-1) expression in human umbilical vein endothelial cells and elucidate a possible mechanism.Methods Human umbilical vein endothelial cells (HUVECs) were obtained from normal fetus, and cultured conventionally. Then the HUVEC were exposed to fatty acids and prostaglandin J2 in varying concentrations with fresh media. RT-PCR and ELISA were used to determine the expression of PPAR and PAI-1 in HUVECs. Transient co-transfection of PAI-1 promoter and PPARα gene or PPARγ gene to ECV304 was performed.Results PPARα, PPARδ and PPARγ mRNA in HUVECs were detected by RT-PCR. Treatment of HUVECs with PPARα and PPARγ activators-linolenic acid, linoleic acid, oleic acid and prostaglandin J2, but not with stearic acid could augment PAI-I mRNA expression and protein secretion in a concentration-dependent manner. Proportional induction of PAI-1 promoter activity was observed through increasing amounts of PPARα DNA in HUVECs through a transient gene transfection assay, although the mRNA expression of the 3 subtypes of PPAR with their activators were not changed compared with controls.Conclusions HUVECs express PPARs. PPARs activators may increase PAI-1 expression in endothelial cells (EC). Although PPARs expression was not enhanced after being stimulated by their activators in EC, the functionally active PPARα is probably involved in regulating PAI-1 expression in EC.

  9. Adiponectin expression is induced by vitamin E via a peroxisome proliferator-activated receptor gamma-dependent mechanism.

    Science.gov (United States)

    Landrier, Jean-François; Gouranton, Erwan; El Yazidi, Claire; Malezet, Christiane; Balaguer, Patrick; Borel, Patrick; Amiot, Marie-Josèphe

    2009-12-01

    Adiponectin is a well-known adipokine secreted by adipocytes that presents insulin-sensitizing properties. The regulation of expression of this adipokine by micronutrients is largely unknown. We demonstrate here that adiponectin expression is induced in adipocytes after exposure to tocopherols via the peroxisome proliferator-activated receptor gamma (PPARgamma) pathway. Vitamin E force feeding resulted in an induction of adiponectin in mice at both mRNA and protein levels. Adiponectin mRNA and protein secretion were also increased by vitamin E (alpha- and gamma-tocopherol) in 3T3-L1 cells, together with PPARgamma mRNA, independent of an antioxidant effect. In transient transfections, both alpha- and gamma-vitamers induced the luciferase gene reporter under the control of a human adiponectin promoter via a PPAR-responsive element. The induction of adiponectin by tocopherols seems to be PPARgamma dependent, because it was blocked by the specific antagonist GW9662. Finally, we showed that intracellular concentrations of a PPARgamma endogenous ligand, 15-deoxy-Delta12,14-prostaglandin J2, increased after treatment with tocopherols in 3T3-L1 cells. In summary, vitamin E up-regulates adiponectin expression via a mechanism that implicates PPARgamma together with its endogenous ligand 15-deoxy-Delta12,14-prostaglandin J2. The induction of adiponectin via an original molecular mechanism could be considered as the basis for the beneficial effect of vitamin E on insulin sensitivity.

  10. Prenatal polycyclic aromatic hydrocarbon, adiposity, peroxisome proliferator-activated receptor (PPAR γ methylation in offspring, grand-offspring mice.

    Directory of Open Access Journals (Sweden)

    Zhonghai Yan

    Full Text Available RATIONALE: Greater levels of prenatal exposure to polycyclic aromatic hydrocarbon (PAH have been associated with childhood obesity in epidemiological studies. However, the underlying mechanisms are unclear. OBJECTIVES: We hypothesized that prenatal PAH over-exposure during gestation would lead to weight gain and increased fat mass in offspring and grand-offspring mice. Further, we hypothesized that altered adipose gene expression and DNA methylation in genes important to adipocyte differentiation would be affected. MATERIALS AND METHODS: Pregnant dams were exposed to a nebulized PAH mixture versus negative control aerosol 5 days a week, for 3 weeks. Body weight was recorded from postnatal day (PND 21 through PND60. Body composition, adipose cell size, gene expression of peroxisome proliferator-activated receptor (PPAR γ, CCAAT/enhancer-binding proteins (C/EBP α, cyclooxygenase (Cox-2, fatty acid synthase (FAS and adiponectin, and DNA methylation of PPAR γ, were assayed in both the offspring and grand-offspring adipose tissue. FINDINGS: Offspring of dams exposed to greater PAH during gestation had increased weight, fat mass, as well as higher gene expression of PPAR γ, C/EBP α, Cox2, FAS and adiponectin and lower DNA methylation of PPAR γ. Similar differences in phenotype and DNA methylation extended through the grand-offspring mice. CONCLUSIONS: Greater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

  11. Peroxisome Proliferator-Activated Receptor γ Expression Is Inversely Associated with Macroscopic Vascular Invasion in Human Hepatocellular Carcinoma

    Directory of Open Access Journals (Sweden)

    Hui-Tzu Hsu

    2016-07-01

    Full Text Available Peroxisome proliferator-activated receptor γ (PPARγ is a ligand-activated nuclear receptor that regulates cellular lipid and glucose metabolism and also plays an inhibitory role in various cancers. However, the role of PPARγ in hepatocellular carcinoma (HCC remains controversial. This study aimed to investigate the prognostic value of PPARγ in HCC and its role in inhibiting tumor progression, namely, HCC cell growth, migration, and angiogenesis. Immunohistochemical PPARγ staining was examined in 83 HCC specimens to investigate the clinicopathological correlations between PPARγ expression and various parameters. The functional role of PPARγ was determined via PPARγ overexpression and knockdown in HCC cells. Patients with low HCC tissue PPARγ expression were significantly younger (p = 0.006, and exhibited more tumor numbers (p = 0.038, more macroscopic vascular invasion (MVI (p = 0.008, and more advanced TNM (size of primary tumor, number of regional lymph nodes, and distant metastasis stages at diagnosis (p = 0.013 than patients with high HCC tissue PPARγ expression. PPARγ knockdown increased HCC cell growth, migration, and angiogenesis, while PPARγ overexpression reduced HCC cell growth, migration, and angiogenesis. These results suggest that low PPARγ expression is an independent predictor of more MVI in HCC patients. PPARγ contributes to the suppression of HCC cell growth, migration, and angiogenesis. Therefore, PPARγ may be a therapeutic target in HCC patients.

  12. A lard-rich high-fat diet increases hepatic peroxisome proliferator-activated receptors in endotoxemic rats.

    Science.gov (United States)

    Kai, Motoki; Miyoshi, Makoto; Fujiwara, Mayu; Nishiyama, Yuya; Inoue, Taketo; Maeshige, Noriaki; Hamada, Yasuhiro; Usami, Makoto

    2017-05-15

    Diets high in saturated fatty acids activate chronic inflammation. We previously reported that, in even acute inflammation caused by lipopolysaccharide (LPS), liver injury was exacerbated in rats fed a lard-rich diet. Peroxisome proliferator-activated receptors (PPARs) are related to inflammation and are also key regulators of lipid metabolism. In this study, we examined effects of high-fat diet on liver injury and hepatic lipid metabolism during endotoxemia, measuring hepatic PPARs and other markers. Male Wistar rats were fed a high-fat diet (HFD, 60 kcal% fat) or control diet (CD, 10 kcal% fat) for 4 or 12 wk, injected with LPS and sacrificed at 0, 1.5, or 6 h. Analyses included plasma aspartate transaminase (AST) and alanine transaminase (ALT) levels, messenger RNA (mRNA) and protein levels of hepatic PPARα and PPARγ, and mRNA levels of enzymes related to fatty acid oxidation and synthesis. Endotoxemic rats on HFD for 12 wk, but not 4 wk, had higher mRNA and protein levels for hepatic PPARs, than did those on CD (P PPARα and PPARγ expression in endotoxemic rats. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. PPAR modulators and PPAR pan agonists for metabolic diseases: the next generation of drugs targeting peroxisome proliferator-activated receptors?

    Science.gov (United States)

    Feldman, P L; Lambert, M H; Henke, B R

    2008-01-01

    The Peroxisome Proliferator-Activated Receptors-PPAR alpha, PPAR gamma, and PPAR delta--are members of the nuclear receptor gene family that have emerged as therapeutic targets for the development of drugs to treat human metabolic diseases. The discovery of high affinity, subtype-selective agonists for each of the three PPAR subtypes has allowed elucidation of the pharmacology of these receptors and development of first-generation therapeutic agents for the treatment of diabetes and dyslipidemia. However, despite proven therapeutic benefits of selective PPAR agonists, safety concerns and dose-limiting side effects have been observed, and a number of late-stage development failures have been reported. Scientists have continued to explore ligand-based activation of PPARs in hopes of developing safer and more effective drugs. This review highlights recent efforts on two newer approaches, the simultaneous activation of all three PPAR receptors with a single ligand (PPAR pan agonists) and the selective modulation of a single PPAR receptor in a cell or tissue specific manner (selective PPAR modulator or SPPARM) in order to induce a subset of target genes and affect a restricted number of metabolic pathways.

  14. Ligand binding reduces SUMOylation of the peroxisome proliferator-activated receptor γ (PPARγ activation function 1 (AF1 domain.

    Directory of Open Access Journals (Sweden)

    Rolf Diezko

    Full Text Available Peroxisome proliferator-activated receptor gamma (PPARγ is a ligand-activated nuclear receptor regulating adipogenesis, glucose homeostasis and inflammatory responses. The activity of PPARγ is controlled by post-translational modifications including SUMOylation and phosphorylation that affects its biological and molecular functions. Several important aspects of PPARγ SUMOylation including SUMO isoform-specificity and the impact of ligand binding on SUMOylation remain unresolved or contradictory. Here, we present a comprehensive study of PPARγ1 SUMOylation. We show that PPARγ1 can be modified by SUMO1 and SUMO2. Mutational analyses revealed that SUMOylation occurs exclusively within the N-terminal activation function 1 (AF1 domain predominantly at lysines 33 and 77. Ligand binding to the C-terminal ligand-binding domain (LBD of PPARγ1 reduces SUMOylation of lysine 33 but not of lysine 77. SUMOylation of lysine 33 and lysine 77 represses basal and ligand-induced activation by PPARγ1. We further show that lysine 365 within the LBD is not a target for SUMOylation as suggested in a previous report, but it is essential for full LBD activity. Our results suggest that PPARγ ligands negatively affect SUMOylation by interdomain communication between the C-terminal LBD and the N-terminal AF1 domain. The ability of the LBD to regulate the AF1 domain may have important implications for the evaluation and mechanism of action of therapeutic ligands that bind PPARγ.

  15. Peroxisome Proliferator-activated Receptors as Potential Targets for Carcinogenic Activity of Polychlorinated Biphenyls: A Computational Perspective.

    Science.gov (United States)

    Sheikh, Ishfaq Ahmad; Khweek, Arwa Abu; Beg, Mohd Amin

    2016-11-01

    Polychlorinated biphenyls (PCBs) are ubiquitous environment-contaminating synthetic chemicals that have been associated with increased risk of hepatic cancer, melanoma, non-Hodgkin lymphoma and cancer of many other body organs. Structural binding analyses of PCB 77 and PCB 118 with peroxisome proliferator-activated receptors (PPARα, PPARβ/δ and PPARγ) was performed to predict the association of PCBs with potential disruption of PPAR signaling pathways. The crystal structures of human PPARα, PPARβ/δ and PPARγ were obtained from the Protein Data Bank. Structures of PCB 77 and PCB 118 were obtained from PubChem database. Docking was performed using glide (Schrodinger) induced fit docking (IFD) module. The PCB 77 and PCB 118 interacted with PPARα, PPARβ/δ and PPARγ showing an overlapping of 40-58% interacting amino acid residues with synthetic co-complex agonists of the three PPARs. The binding affinity was higher for PCB 118 than for PCB 77 during docking interactions with each of the three PPARs. The consistent commonality of interacting residues for PCB 77 and PCB 118 with co-complex synthetic agonists of the PPARs together with good binding affinity suggested that the PPAR signaling pathway is a potential target for toxicologic activity of PCBs. Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  16. [Selective regulation of peroxisome proliferator-activated receptors on fatty acid binding protein-4 in human syncytiotrophoblast cells].

    Science.gov (United States)

    Li, Yuan; Gu, Hang

    2012-10-01

    To observe the selective regulation of peroxisome proliferator-activated receptors (PPAR) on fatty acid binding protein-4 (FABP4) in human syncytiotrophoblasts. Cultivate normal human syncytiotrophoblast cells, and put in the specific antagonists and agonists of PPAR each subtypes receptors, then observe the different expression of FABP4 mRNA and protein. Pretreated the human syncytiotrophoblast cells with the agonists (GW7647, GW0742) and antagonists (GW6471, GSK0660) of PPARα and PPARβ receptors, the expression of the FABP4 was not significantly change (P > 0.05). However pretreated with PPAR γ agonists (rosiglitazone, 1×10(-9), 1×10(-8), 1×10(-7) and 1×10(-6) mol/L), the expression of FABP4 mRNA and protein could be dose dependent-promoted significantly (mRNA: 1.27 ± 0.12, 1.45 ± 0.14, 1.57 ± 0.14, 1.72 ± 0.12, protein:1.10 ± 0.08, 1.37 ± 0.09, 1.60 ± 0.13, 1.79 ± 0.14; P PPARγ regulated the expression of FABP4 mRNA and protein selectively. And the regulation will not be influenced by the other two PPAR subtypes.

  17. Fragmented Lactic Acid Bacterial Cells Activate Peroxisome Proliferator-Activated Receptors and Ameliorate Dyslipidemia in Obese Mice.

    Science.gov (United States)

    Nakamura, Futoshi; Ishida, Yu; Sawada, Daisuke; Ashida, Nobuhisa; Sugawara, Tomonori; Sakai, Manami; Goto, Tsuyoshi; Kawada, Teruo; Fujiwara, Shigeru

    2016-03-30

    Recent studies suggest that peroxisome proliferator-activated receptor (PPAR) activation ameliorates metabolic disorders, including dyslipidemia. To identify an effective PPAR agonist, we screened the in vitro PPARα/γ activation ability of organic solvent extracts from food-oriented bacterial strains belonging to 5 genera and 32 species, including lactic acid bacteria, and of these, Lactobacillus amylovorus CP1563 demonstrated the highest PPARα/γ agonist activity. We also found that physical fragmentation of the strain could substitute organic solvent extraction for the expression of CP1563 activity in vitro. For functional food manufacturing, we selected the fragmented CP1563 and conducted subsequent animal experiments. In an obese mouse model, we found that treatment with fragmented CP1563 for 12 weeks decreased the levels of low-density lipoprotein (LDL)-cholesterol and triglyceride in plasma, significantly decreased the atherosclerosis index, and increased the plasma high-density lipoprotein (HDL)-cholesterol level. Thus, we conclude that fragmented CP1563 may be a candidate for the prevention and treatment of dyslipidemia.

  18. Gender specific association of genetic variation in peroxisome proliferator-activated receptor (PPAR)gamma-2 with longevity.

    Science.gov (United States)

    Barbieri, Michelangela; Bonafè, Massimiliano; Rizzo, Maria Rosaria; Ragno, Emilia; Olivieri, Fabiola; Marchegiani, Francesca; Franceschi, Claudio; Paolisso, Giuseppe

    2004-07-01

    Long-lived subjects have been shown to have peculiar anthropometric features (i.e. lower body mass index (BMI)) and metabolic parameters (i.e. improved insulin sensitivity). Life style and a genetic background potentially protective against the age-related metabolic derangement might contribute to such a particular phenotype. Peroxisome proliferator-activated receptor (PPAR)gamma-2 is an important regulator of adipose tissue metabolism, insulin sensitivity and inflammatory response. Thus, the potential role of genetic variability at Pro/Ala loci of PPARG gene on longevity was studied in 222 long-lived subjects and 250 aged subjects. We found a different Pro/Ala genotype frequency distribution between long-lived and aged men subjects, long-lived men having an increased frequency of Pro/Ala genotype (20 vs 8.5%); no differences was found when allele and genotype distribution of Pro/Ala gene polymorphism were analyzed in the two age group of women. Interestingly, subjects with Pro/Ala polymorphism had significantly lower BMI than Ala/Ala and Pro/Pro polymorphism. In conclusion, our study demonstrated that paraoxonase Pro/Ala gene polyporphism is associated with human longevity. Such an effect is probably due to the effect of Pro/Ala polymorphism on body composition and appears to be gender specific.

  19. Zebrafish as a Model to Study the Role of Peroxisome Proliferating-Activated Receptors in Adipogenesis and Obesity.

    Science.gov (United States)

    Den Broeder, Marjo J; Kopylova, Victoria A; Kamminga, Leonie M; Legler, Juliette

    2015-01-01

    The Peroxisome Proliferator-Activated Receptors (PPARs) PPARA and PPARD are regulators of lipid metabolism with important roles in energy release through lipid breakdown, while PPARG plays a key role in lipid storage and adipogenesis. The aim of this review is to describe the role of PPARs in lipid metabolism, adipogenesis, and obesity and evaluate the zebrafish as an emerging vertebrate model to study the function of PPARs. Zebrafish are an appropriate model to study human diseases, including obesity and related metabolic diseases, as pathways important for adipogenesis and lipid metabolism which are conserved between mammals and fish. This review synthesizes knowledge on the role of PPARs in zebrafish and focuses on the putative function of PPARs in zebrafish adipogenesis. Using in silico analysis, we confirm the presence of five PPARs (pparaa, pparab, pparda, ppardb, and pparg) in the zebrafish genome with 67-74% identity to human and mouse PPARs. During development, pparda/b paralogs and pparg show mRNA expression around the swim bladder and pancreas, the region where adipocytes first develop, whereas pparg is detectable in adipocytes at 15 days post fertilization (dpf). This review indicates that the zebrafish is a promising model to investigate the specific functions of PPARs in adipogenesis and obesity.

  20. Small heterodimer partner-interacting leucine zipper protein inhibits adipogenesis by regulating peroxisome proliferator-activated receptor γ activity.

    Science.gov (United States)

    Jang, Hoon; Kim, Hyoung-Joo; Kim, Dong-Hwan; Park, Jae-Kyung; Sun, Wu-Sheng; Hwang, Seongsoo; Oh, Keon-Bong; Jang, Won-Gu; Lee, Jeong-Woong

    2015-07-01

    Adipocytes play a critical role in energy balance. Growth of fat tissue is achieved via an increase in adipocyte mass and the formation of newly differentiated adipocytes from precursor cells. Understanding the cellular and molecular mechanisms of adipocyte differentiation is crucial for the study of obesity- and fat-related diseases. The present study was designed to study whether small heterodimer partner-interacting leucine zipper protein (SMILE), a novel co-repressor, could regulate differentiation of adipocyte in 3T3-L1 cells. Treatment of endoplasmic stress inducers, thapsigargin and tunicamycin, inhibited adipocyte differentiation, stimulated Smile mRNA expression, and repressed the expression of adiponectin (Adipoq) in 3T3-L1 pre-adipocyte. Overexpression of SMILE in 3T3-L1 cells decreased the expression of the mRNA encoding Adipoq, a major marker of adipocytes, significantly. Furthermore, knockdown of SMILE recovered the thapsigargin-mediated repression of Adipoq transcription. Co-immunoprecipitation experiments revealed that SMILE interacted physically with PPARγ in 3T3-L1 cells. In addition, chromatin immunoprecipitation experiments revealed that SMILE suppressed the binding affinity of PPARγ for the Adipoq promoter. We demonstrate that SMILE controls adipocyte differentiation by regulating the transactivity of peroxisome proliferator-activated receptor γ (PPARγ). These findings demonstrate that SMILE represses adipocyte differentiation by regulating PPARγ transactivity; hence, SMILE is a potential regulator of PPARγ-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.

  1. Identification and mechanism of 10-carbon fatty acid as modulating ligand of peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Malapaka, Raghu R V; Khoo, Sokkean; Zhang, Jifeng; Choi, Jang H; Zhou, X Edward; Xu, Yong; Gong, Yinhan; Li, Jun; Yong, Eu-Leong; Chalmers, Michael J; Chang, Lin; Resau, James H; Griffin, Patrick R; Chen, Y Eugene; Xu, H Eric

    2012-01-02

    Peroxisome proliferator-activated receptors (PPARα, -β/δ, and -γ) are a subfamily of nuclear receptors that plays key roles in glucose and lipid metabolism. PPARγ is the molecular target of the thiazolidinedione class of antidiabetic drugs that has many side effects. PPARγ is also activated by long chain unsaturated or oxidized/nitrated fatty acids, but its relationship with the medium chain fatty acids remains unclear even though the medium chain triglyceride oils have been used to control weight gain and glycemic index. Here, we show that decanoic acid (DA), a 10-carbon fatty acid and a major component of medium chain triglyceride oils, is a direct ligand of PPARγ. DA binds and partially activates PPARγ without leading to adipogenesis. Crystal structure reveals that DA occupies a novel binding site and only partially stabilizes the AF-2 helix. DA also binds weakly to PPARα and PPARβ/δ. Treatments with DA and its triglyceride form improve glucose sensitivity and lipid profiles without weight gain in diabetic mice. Together, these results suggest that DA is a modulating ligand for PPARs, and the structure can aid in designing better and safer PPARγ-based drugs.

  2. Pro12Ala polymorphism of the peroxisome proliferator-activated receptor γ2 in patients with fatty liver diseases

    Science.gov (United States)

    Rey, Johannes W; Noetel, Andrea; Hardt, Aline; Canbay, Ali; Alakus, Hakan; zur Hausen, Axel; Dienes, Hans Peter; Drebber, Uta; Odenthal, Margarete

    2010-01-01

    AIM: To test the occurrence of the Pro12Ala mutation of the peroxisome proliferator-activated receptor-γ (PPARγ)2-gene in patients with non-alcoholic fatty liver disease (NAFLD) or alcoholic fatty liver disease (AFLD). METHODS: DNA from a total of 622 specimens including 259 blood samples of healthy blood donors and 363 histologically categorized liver biopsies of patients with NAFLD (n = 263) and AFLD (n = 100) were analyzed by Real-time polymerase chain reaction using allele-specific probes. RESULTS: In the NAFLD and the AFLD collective, 3% of the patients showed homozygous occurrence of the Ala12 PPARγ2-allele, differing from only 1.5% cases in the healthy population. In NAFLD patients, a high incidence of the Ala12 mutant was not associated with the progression of fatty liver disease. However, we observed a significantly higher risk (odds ratio = 2.50, CI: 1.05-5.90, P = 0.028) in AFLD patients carrying the mutated Ala12 allele to develop inflammatory alterations. The linkage of the malfunctioning Ala12-positive PPARγ2 isoform to an increased risk in patients with AFLD to develop severe steatohepatitis and fibrosis indicates a more prominent anti-inflammatory impact of PPARγ2 in progression of AFLD than of NAFLD. CONCLUSION: In AFLD patients, the Pro12Ala single nuclear polymorphism should be studied more extensively in order to serve as a novel candidate in biomarker screening for improved prognosis. PMID:21155004

  3. Genotyping of peroxisome proliferator-activated receptor gamma (PPAR-γ) polymorphism (Pro12Ala) in Iranian population.

    Science.gov (United States)

    Namvaran, Fatemeh; Rahimi-Moghaddam, Parvaneh; Azarpira, Negar

    2011-03-01

    The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear hormone receptor. It is predominantly expressed in adipose tissue and as a receptor for thiazolidinediones, it has drawn attentions towards itself as a key molecule to trigger pathways involving in some diseases such as cancers, type 2 diabetes, inflammations and osteoporosis. A proline changed to alanine in codon 12 of PPAR-γ gene (Pro12Ala) has been known to be responsible for decreased risk of type 2 diabetes. The aim of the present study is to investigate the frequency of Pro12Ala polymorphism in PPAR-γ in healthy Iranian population to compare with other populations. Understanding this polymorphism may help us in better diagnosis, prevention, and therapeutic approaches toward a better management of diseases such as type 2 diabetes and osteoporosis. 128 healthy volunteers were enrolled in this study. To determine single nucleotide polymorphisms (SNPs), we did real time polymerase chain reaction (RT-PCR), using TaqMan allelic discrimination assays. Genotype frequencies for PPAR-γ gene Pro12Ala (rs1801282) polymorphism were 0.86 for CC, 0.14 for CG, 0.00 for GG while allelic frequencies were 0.93 and 0.0.07 for C and G, respectively. There are statistical differences between the distribution of the PPAR-γ-2 Pro12Ala polymorphism in other populations and Iranian population.

  4. Association of peroxisome proliferator-activated receptor-gamma 2 Pro12Ala polymorphism with advanced-stage endometriosis.

    Science.gov (United States)

    Hwang, Kyu Ri; Choi, Young Min; Kim, Jong Mee; Lee, Gyoung Hoon; Kim, Jin Ju; Chae, Soo Jin; Moon, Shin Yong

    2010-11-01

    To investigate whether the peroxisome proliferator-activated receptor (PPAR)-γ2 Pro12Ala polymorphism is associated with a risk of advanced-stage endometriosis in a Korean population.   Case-control study in a collective of 446 patients and 427 controls. The Pro12Ala polymorphism of PPAR-γ2 gene was genotyped using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. The distribution of the PPAR-γ2 Pro12Ala polymorphism was different between the advanced-stage endometriosis group and the control group (non-CC rates were 5.2% for patients with advanced endometriosis and 10.1% for the control group, respectively, P = 0.006). The frequency for the Ala-12 allele variant was significantly lower in patients with advanced stage of endometriosis (2.7%) than in the control group (5.3%) (P = 0.006). These findings suggest that the PPAR-γ2 Pro12Ala polymorphism is associated with advanced-stage endometriosis in the Korean population. Unlike results from other studies reported so far, the Ala-12 allele may have protective effects against advanced-stage endometriosis in the Korean population. © 2010 John Wiley & Sons A/S.

  5. The role of peroxisome proliferator-activated receptor γ in immune responses to enteroaggregative Escherichia coli infection.

    Directory of Open Access Journals (Sweden)

    Casandra W Philipson

    Full Text Available BACKGROUND: Enteroaggregative Escherichia coli (EAEC is recognized as an emerging cause of persistent diarrhea and enteric disease worldwide. Mucosal immunity towards EAEC infections is incompletely understood due in part to the lack of appropriate animal models. This study presents a new mouse model and investigates the role of peroxisome proliferator-activated receptor gamma (PPARγ in the modulation of host responses to EAEC in nourished and malnourished mice. METHODS/PRINCIPAL FINDINGS: Wild-type and T cell-specific PPARγ null C57BL/6 mice were fed protein-deficient diets at weaning and challenged with 5×10(9cfu EAEC strain JM221 to measure colonic gene expression and immune responses to EAEC. Antigen-specific responses to E. coli antigens were measured in nourished and malnourished mice following infection and demonstrated the immunosuppressive effects of malnutrition at the cellular level. At the molecular level, both pharmacological blockade and deletion of PPARγ in T cells resulted in upregulation of TGF-β, IL-6, IL-17 and anti-microbial peptides, enhanced Th17 responses, fewer colonic lesions, faster clearance of EAEC, and improved recovery. The beneficial effects of PPARγ blockade on weight loss and EAEC clearance were abrogated by neutralizing IL-17 in vivo. CONCLUSIONS: Our studies provide in vivo evidence supporting the beneficial role of mucosal innate and effector T cell responses on EAEC burden and suggest pharmacological blockade of PPARγ as a novel therapeutic intervention for EAEC infection.

  6. Peroxisome proliferator-activated receptor- gamma expression in human malignant and normal brain, breast and prostate-derived cells.

    Science.gov (United States)

    Nwankwo, J O; Robbins, M E

    2001-01-01

    The constitutive and gamma -linolenic acid (GLA)-induced expression of peroxisome proliferator-activated receptor gamma (PPAR gamma) immunoreactive protein in a panel of human malignant brain (U87MG, T98G); breast (MCF-7, MB MDA-231, MB MDA 435) and prostate (ALVA, DU-145, LNCaP, PC3) cell lines have been compared with those for their normal cell counterparts, the human normal astrocyte (NHA), mammary epithelial (HMEC) and prostate epithelial (PrEC) cells, respectively. Constitutive levels of expression for PPAR gamma protein were significantly higher in the malignant cell lines relative to their normal cells. GLA supplementation did not affect the protein expression in malignant cells but caused 6- and 3-fold increases in normal breast and prostate cells, respectively. Since activation of PPAR gamma protein in some human malignant cell lines has been demonstrated to induce tumour cell death, these findings signal the need to exploit the significantly elevated expression of this protein in the therapy of human cancer. Copyright 2001 Harcourt Publishers Ltd.

  7. Expression of peroxisome proliferator-activated receptor (PPAR)gamma in gastric cancer and inhibitory effects of PPARgamma agonists.

    Science.gov (United States)

    Sato, H; Ishihara, S; Kawashima, K; Moriyama, N; Suetsugu, H; Kazumori, H; Okuyama, T; Rumi, M A; Fukuda, R; Nagasue, N; Kinoshita, Y

    2000-11-01

    Peroxisome proliferator-activated receptor (PPAR) gamma is expressed in human colon cancer, prostate cancer and breast cancer cells, and PPARgamma activation induces growth inhibition in these cells. PPARgamma expression in human gastric cancer cells, however, has not been fully investigated. We report the PPARgamma expression in human gastric cancer, and the effect of PPARgamma ligands on proliferation of gastric carcinoma cell lines. Immunohistochemistry was used to demonstrate the presence of PPARgamma protein in surgically resected specimens from well differentiated, moderately differentiated and poorly differentiated adenocarcinoma. We used reverse transcription-polymerase chain reaction and Northern and Western blot analyses to demonstrate PPARgamma expression in four human gastric cancer cell lines. PPARgamma agonists (troglitazone and 15-deoxy-Delta(12,14)-prostaglandin J2) showed dose-dependent inhibitory effects on the proliferation of the gastric cancer cells, and their effect was augmented by the simultaneous addition of 9- cis retinoic acid, a ligand of RXRalpha. Flow cytometry demonstrated G1 cell cycle arrest and a significant increase of annexin V-positive cells after treatment with troglitazone. These results suggest that induction of apoptosis together with G1 cell cycle arrest may be one of the mechanisms of the antiproliferative effect of PPARgamma activation in human gastric cancer cells. Copyright 2000 Cancer Research Campaign.

  8. Genetic variation in the peroxisome proliferator-activated receptor (PPAR) and peroxisome proliferator-activated receptor gamma co-activator 1 (PGC1) gene families and type 2 diabetes.

    Science.gov (United States)

    Villegas, Raquel; Williams, Scott M; Gao, Yu-Tang; Long, Jirong; Shi, Jiajun; Cai, Hui; Li, Honglan; Chen, Ching-Chu; Tai, E Shyong; Hu, Frank; Cai, Qiuyin; Zheng, Wei; Shu, Xiao-Ou

    2014-01-01

    We used a two-stage study design to evaluate whether variations in the peroxisome proliferator-activated receptors (PPAR) and the PPAR gamma co-activator 1 (PGC1) gene families (PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B) are associated with type 2 diabetes (T2D) risk. Stage I used data from a genome-wide association study (GWAS) from Shanghai, China (1019 T2D cases and 1709 controls) and from a meta-analysis of data from the Asian Genetic Epidemiology Network for T2D (AGEN-T2D). Criteria for selection of single nucleotide polymorphisms (SNPs) for stage II were: (1) P < 0.05 in single marker analysis in Shanghai GWAS and P < 0.05 in the meta-analysis or (2) P < 10(-3) in the meta-analysis alone and (3) minor allele frequency ≥ 0.10. Nine SNPs from the PGC1 family were assessed in stage II (an independent set of middle-aged men and women from Shanghai with 1700 T2D cases and 1647 controls). One SNP in PPARGC1B, rs251464, was replicated in stage II (OR = 0.87; 95% CI: 0.77-0.99). Gene-body mass index (BMI) and gene-exercise interactions and T2D risk were evaluated in a combined dataset (Shanghai GWAS and stage II data: 2719 cases and 3356 controls). One SNP in PPARGC1A, rs12640088, had a significant interaction with BMI. No interactions between the PPARGC1B gene and BMI or exercise were observed. © 2013 John Wiley & Sons Ltd/University College London.

  9. Peroxisome-proliferator-activated receptors gamma and peroxisome-proliferator-activated receptors beta/delta and the regulation of interleukin 1 receptor antagonist expression by pioglitazone in ischaemic brain.

    Science.gov (United States)

    Glatz, Torben; Stöck, Ivonne; Nguyen-Ngoc, Miriam; Gohlke, Peter; Herdegen, Thomas; Culman, Juraj; Zhao, Yi

    2010-07-01

    The imbalance between the production and release of interleukin-1 (IL-1) ligands, IL-1alpha, IL-1beta and IL-1 receptor antagonist (IL-1ra) in ischaemic brain exaggerates inflammatory responses and contributes to neuronal death. Cerebral ischaemia also upregulates the peroxisome-proliferator-activated receptor (PPAR) gamma. We studied in rats the effects of the PPARgamma agonist, pioglitazone, on the regulation of IL-1beta, IL-1ra and IL-1 receptor I (IL-1RI) expression in ischaemic brain after occlusion of the middle cerebral artery for 90 min. Pioglitazone or vehicle was infused intracerebroventricularly over a 5-day period before, during and 24 or 48 h after middle cerebral artery occlusion. The expression of IL-1beta, IL-1ra and IL-1RI in the peri-infarct cortex was investigated by immunohistochemistry, Western blotting and immunofluorescence staining. The mechanisms of the IL-1ra regulation by pioglitazone and the neuroprotection under excitotoxic neuronal injury were studied in primary cortical neurones expressing PPARgamma and PPAR beta/delta. Cerebral ischaemia increased the expression of IL-1beta, IL-1RI and IL-1ra in the ischaemic cortex. Pioglitazone reduced IL-1beta, but upregulated IL-1ra and increased the number of IL-1ra immunoreactive cells. In primary cortical neurones, pioglitazone stimulated the IL-1ra production via activation of the PPARbeta/delta, but prevented excitotoxic neuronal injury and death by a PPARgamma-dependent mechanism. Our data demonstrate that activation of PPARgamma and PPAR beta/delta by proglitazone in neurones triggers diverse neuroprotective mechanisms. The restoration of the equilibrium between I1-1beta and IL-1ra in ischaemic brain tissue limits IL-1beta signalling, reduces inflammatory responses and is an important mechanism by which thiazolidinediones improve the recovery from ischaemic stroke.

  10. Common polymorphisms of the peroxisome proliferator-activated receptor-gamma (Pro12Ala) and peroxisome proliferator-activated receptor-gamma coactivator-1 (Gly482Ser) and the response to pioglitazone in Chinese patients with type 2 diabetes mellitus.

    Science.gov (United States)

    Hsieh, Ming-Chia; Lin, Kun-Der; Tien, Kai-Jen; Tu, Shih-Te; Hsiao, Jeng-Yueh; Chang, Shun-Jen; Lin, Shiu-Ru; Shing, Shih-Jang; Chen, Hung-Chun

    2010-08-01

    We investigated the effects of the common polymorphisms in the peroxisome proliferator-activated receptor-gamma (PPAR-gamma; Pro12Ala) and in PPAR-gamma coactivator-1(PGC-1; Gly482Ser) genes on the response to pioglitazone in Chinese with type 2 diabetes mellitus. A total of 250 patients with type 2 diabetes mellitus were treated with pioglitazone (30 mg/d) for 24 weeks without a change in previous medications. All patients were genotyped for the PPAR-gamma Pro12Ala and PGC-1 Gly482Ser polymorphisms. The Ala12Ala and Pro12Ala genotypes (26.0% vs 13.5%, P = .025) and Ala allele (15.6% vs 7.3%, P = .008) were significantly more frequent in pioglitazone responders than in nonresponders. The distribution of PGC-1 genotypes and alleles was not significantly different between responders and nonresponders. The decrease in fasting glucose (50.4 +/- 52.2 vs 43.3 +/- 51.7 mg/dL, P Pro12Ala and Ala12Ala) than in those without the allele (Pro12Pro). Baseline fasting glucose and triglyceride levels were related to the response of pioglitazone. Only the PPAR-gamma Pro12Ala polymorphism was found to be associated with the response of pioglitazone by multiple logistic regression analysis. The PPAR-gamma Pro12Ala gene polymorphism is associated with the response to pioglitazone in Chinese patients with type 2 diabetes mellitus. These findings may be helpful for targeted treatment of diabetes by identifying patients who are likely to respond to pioglitazone. Copyright 2010 Elsevier Inc. All rights reserved.

  11. Peroxisome Proliferator-activated Receptor - Activation Promotes Infiltration of Alternatively Activated Macrophages into Adipose Tissue

    NARCIS (Netherlands)

    Stienstra, R.; Duval, C.N.C.; Keshtkar Ghiasabadi, S.; Laak, van der J.; Kersten, A.H.; Müller, M.R.

    2008-01-01

    Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators, including tumor necrosis factor alpha and interleukin-6 (IL-6). Recent data suggest that during diet-

  12. Peroxisome proliferator-activated receptor gamma activation promotes infiltration of alternatively activated macrophages into adipose tissue.

    NARCIS (Netherlands)

    Stienstra, R.; Duval, C.; Keshtkar, S.; Laak, J. ter; Kersten, S.; Muller, M.

    2008-01-01

    Obesity is associated with infiltration of macrophages into adipose tissue. Adipose macrophages may contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators, including tumor necrosis factor alpha and interleukin-6 (IL-6). Recent data suggest that during diet-

  13. Polymorphisms of the peroxisome proliferator-activated receptor γ (PPARγ) gene are associated with osteoporosis

    DEFF Research Database (Denmark)

    Harsløf, T; Tofteng, C L; Husted, L B

    2011-01-01

    Stimulation of PPARγ turns mesenchymal stem cells into adipocytes instead of osteoblasts. We investigated the effect of polymorphisms in the PPARγ gene on BMD and fracture risk in two Danish cohorts and found opposing effects of certain SNPs and haplotypes in the two cohorts probably owing...... to environmental factors. INTRODUCTION: Stimulation of PPARγ causes development of mesenchymal stem cells to adipocytes instead of osteoblasts leading to decreased osteoblast number and BMD. The aim of this study was to examine the effect of PPARG polymorphisms on BMD and fracture risk in two Danish cohorts: AROS...

  14. Peroxisome proliferator-activated receptor-γ agonists and diabetes: Current evidence and future perspectives

    Directory of Open Access Journals (Sweden)

    Francesco Chiarelli

    2008-04-01

    Full Text Available Francesco Chiarelli, Daniele Di MarzioDepartment of Pediatrics, University of Chieti, ItalyAbstract: Since their initial availability in 1997, the thiazolidinediones (TZDs have become one of the most commonly prescribed classes of medications for type 2 diabetes. In addition to glucose control, the TZDs have a number of pleiotropic effects on myriad traditional and non-traditional risk factors for diabetes. TZDs may benefit cardiovascular parameters, such as lipids, blood pressure, inflammatory biomarkers, endothelial function and fibrinolytic state. In this review, we summarise the experimental, preclinical and clinical data regarding the effects of the TZDs in conditions for which they are indicated and discuss their potential in the treatment of other conditions.Keywords: PPARγ, thiazolidinediones, rosiglitazone, pioglitazone, troglitazone

  15. Protective Effect of Peroxisome Proliferator-Activated Receptor α Activation against Cardiac Ischemia-Reperfusion Injury Is Related to Upregulation of Uncoupling Protein-3

    OpenAIRE

    2016-01-01

    Activation of peroxisome proliferator-activated receptor α (PPARα) confers cardioprotection, while its mechanism remains elusive. We investigated the protective effect of PPARα activation against cardiac ischemia-reperfusion injury in terms of the expression of uncoupling protein (UCP). Myocardial infarct size and UCP expression were measured in rats treated with WY-14643 20 mg/kg, a PPARα ligand, or vehicle. WY-14643 increased UCP3 expression in vivo. Myocardial infarct size was decreased in...

  16. Citronellol and geraniol, components of rose oil, activate peroxisome proliferator-activated receptor α and γ and suppress cyclooxygenase-2 expression.

    Science.gov (United States)

    Katsukawa, Michiko; Nakata, Rieko; Koeji, Satomi; Hori, Kazuyuki; Takahashi, Saori; Inoue, Hiroyasu

    2011-01-01

    We evaluated the effects of rose oil on the peroxisome proliferator-activated receptor (PPAR) and cyclooxygenase-2 (COX-2). Citronellol and geraniol, the major components of rose oil, activated PPARα and γ, and suppressed LPS-induced COX-2 expression in cell culture assays, although the PPARγ-dependent suppression of COX-2 promoter activity was evident only with citronellol, indicating that citronellol and geraniol were the active components of rose oil.

  17. Adipose-specific peroxisome proliferator-activated receptor γ knockout causes insulin resistance in fat and liver but not in muscle

    OpenAIRE

    He, Weimin; Barak, Yaacov; Hevener, Andrea; Olson, Peter; Liao, Debbie; Le, Jamie; Nelson, Michael; Ong, Estelita; Olefsky, Jerrold M.; Evans, Ronald M

    2003-01-01

    Syndrome X, typified by obesity, insulin resistance (IR), dyslipidemia, and other metabolic abnormalities, is responsive to antidiabetic thiazolidinediones (TZDs). Peroxisome proliferator-activated receptor (PPAR) γ, a target of TZDs, is expressed abundantly in adipocytes, suggesting an important role for this tissue in the etiology and treatment of IR. Targeted deletion of PPARγ in adipose tissue resulted in marked adipocyte hypocellularity and hypertrophy, elevated levels of plasma free fat...

  18. Peroxisome proliferator-activated receptor gamma in the human pituitary gland: expression and splicing pattern in adenomas versus normal pituitary.

    Science.gov (United States)

    Occhi, G; Albiger, N; Berlucchi, S; Gardiman, M; Scanarini, M; Scienza, R; Fassina, A; Mantero, F; Scaroni, C

    2007-07-01

    Pituitary adenomas are slow-growing tumours arising within the pituitary gland. If secreting, they give rise to well-known syndromes such as Cushing's disease or acromegaly; when hormonally inactive, they come to clinical attention often with local mass effects or pituitary deficiency. Peroxisome proliferator-activated receptor gamma (PPARgamma), a nuclear hormone receptor with a key role in fat and glucose metabolism, but also involved in several neoplasia, has recently been detected in pituitary adenomas. In the present study, we evaluated the occurrence and splicing profile of PPARgamma in 43 cases of pituitary adenoma of different subtypes and compared it to 12 normal pituitary glands. By real-time polymerase chain reaction, PPARgamma was expressed as much in adrenocorticotrophic hormone (ACTH)-secreting and ACTH-silent adenomas as in controls, with a moderate underexpression in somatotrophinomas and prolactinomas and overexpression in 54% of nonfunctioning pituitary adenomas (NFPA). There was no apparent qualitative change in the splicing profile of pathological pituitary glands, nor was the presence of specific isoforms with dominant negative effects against PPARgamma detected. Western blotting revealed similar expression levels in the different subgroups of pituitary adenomas and normal glands. Immunohistochemistry confirmed PPARgamma expression in approximately one-half of analysed samples. The intra- and intergroup differences observed in pituitary adenomas may represent new elements in the process of understanding the different clinical responses of Cushing's and Nelson patients to PPARgamma-ligand treatment. Moreover, the higher level of PPARgamma expression detected in the NFPA subgroup may suggest its possible role as a molecular target in these pituitary adenomas, paving the way for investigations on the effectiveness of treatment with thiazolidinediones in such patients.

  19. Effects of a methanolic fraction of soybean seeds on the transcriptional activity of peroxisome proliferator-activated receptors (PPAR

    Directory of Open Access Journals (Sweden)

    V.S. Carrara

    2009-06-01

    Full Text Available Since the anti-inflammatory, antidiabetic and hypolipidemic effects of soy isoflavones may be mediated by activation of peroxisome proliferator-activated receptors (PPAR, the present study investigated whether the methanolic fractions obtained from soybean seeds (E1 and soybean seed coats with hypocotyls (E2 could influence PPARα, PPARγ and PPARβ/δ transcriptional activity. The isoflavones from E1 and E2 were quantified by HPLC analysis. E1 and E2 were rich in isoflavones (daidzin, glycitin, genistin, malonyldaidzin, malonylglycitin, malonylgenistin, daidzein, glycitein, and genistein. Moreover, E1 and E2 showed no evidence of genetically modified material containing the gene CP4 EPSPS. To investigate PPAR transcriptional activity, human promonocytic U-937 cells were treated with E1 and E2 (200, 400, 800, and 1600 µg/mL, positive controls or vehicle. Data are reported as fold-activation of the luciferase reporter driven by the PPAR-responsive element. Dose-response analysis revealed that E1 and E2 induced the transcriptional activity of PPARα (P < 0.001, with activation comparable to that obtained with 0.1 mM bezafibrate (positive control at 1600 µg/mL (4-fold and 800 µg/mL (9-fold, respectively. In addition, dose-response analysis revealed that E1 and E2 activated PPARβ/δ (P < 0.05, and the activation at 800 µg/mL (4- and 9-fold, respectively was comparable to that of 0.1 mM bezafibrate (positive control. However, no effect on PPARγ was observed. Activation of PPARα is consistent with the lipid-lowering activity of soy isoflavones in vivo, but further studies are needed to determine the physiological significance of PPARβ/δ activation.

  20. The peroxisome proliferator-activated receptor-γ agonist pioglitazone protects against cisplatin-induced renal damage in mice.

    Science.gov (United States)

    Jesse, Cristiano R; Bortolatto, Cristiani F; Wilhelm, Ethel A; Roman, Silvane Souza; Prigol, Marina; Nogueira, Cristina W

    2014-01-01

    Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists not only improve metabolic abnormalities of diabetes and consequent diabetic nephropathy, but they also protect against non-diabetic kidney disease in experimental models. Here, we investigated the effect of PPAR-γ agonist pioglitazone against acute renal injury on a cisplatin model in mice. Nephrotoxicity was induced by a single intraperitoneal (i.p.) injection of cisplatin (10 mg kg(-1)). Pioglitazone was administered for six consecutive days in doses of 15 or 30 mg kg(-1)  day(-1), per os (p.o.), starting 3 days before cisplatin injection. Cisplatin treatment to mice induced a marked renal failure, characterized by a significant increase in serum urea and creatinine levels and alterations in renal tissue architecture. Cisplatin exposure induced oxidative stress as indicated by decreased levels of non-enzymatic antioxidant defenses [glutathione (GSH) and ascorbic acid levels] and components of the enzymatic antioxidant defenses [superoxide dismutase (SOD), catalase (CAT) glutathione peroxidase (GPx), glutathione reductase (GR) and and glutathione S-transferase(GST) activities)] in renal tissue. Administration of pioglitazone markedly protected against the increase in urea and creatinine levels and histological alterations in kidney induced by cisplatin treatment. Pioglitazone administration ameliorated GSH and ascorbic acid levels decreased by cisplatin exposure in mice. Pioglitazone protected against the inhibition of CAT, SOD, GPx, GR and GST activities induced by cisplatin in the kidneys of mice. These results indicated that pioglitazone has a protective effect against cisplatin-induced renal damage in mice. The protection is mediated by preventing the decline of antioxidant status. The results have implications in use of PPAR-γ agonists in human application for protecting against drugs-induced nephrotoxicity.

  1. Peroxisome proliferator-activated receptor γ ligands induce cell cycle arrest and apoptosis in human renal carcinoma cell lines

    Institute of Scientific and Technical Information of China (English)

    Feng-guang YANG; Zhi-wen ZHANG; Dian-qi XIN; Chang-jin SHI; Jie-ping WU; Ying-lu GUO; You-fei GUAN

    2005-01-01

    Aim: To study the effect of peroxisome proliferator-actived receptor γ (PPARγ)ligands on cell proliferation and apoptosis in human renal carcinoma cell lines.Methods: The expression of PPARγ was investigated by reverse transcriptase polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry.The effect of thiazolidinedione (TZD) PPARγ ligands on growth of renal cell carcinoma (RCC) cells was measured by MTT assay and flow cytometric analysis. Cell death ELISA, Hoechst 33342 fluorescent staining and DNA ladder assay were used to observe the effects of PPARγ ligands on apoptosis. Regulatory proteins of cell cycle and apoptosis were detected by Western blot analysis. Results:PPARγ was expressed at much higher levels in renal tumors than in the normal kidney (2.16±0.85 vs 0.90±0.73; P<0.01 ). TZD PPARγ ligands inhibited RCC cell growth in a dose-dependent manner with IC50 values of 7.08 μmol/L and 11.32 μmol/L for pioglitazone, and 5.71 μmol/L and 8.38 μmol/L for troglitazone in 786-O and A498 cells, respectively. Cell cycle analysis showed a G0/G1 arrest in human RCC cells following 24-h exposure to TZD. Analysis of cell cycle regulatory proteins revealed that TZD decreased the protein levels of proliferating cell nuclear antigen, pRb, cyclin D1, and Cdk4 but increased the levels of p21 and p27 in a timedependent manner. Furthermore, high doses of TZD induced massive apoptosis in renal cancer cells, with increased Bax expression and decreased Bcl-2 expression.Conclusion: TZD PPARγ ligands showed potent inhibitory effect on proliferation,and could induce apoptosis in RCC cells. These results suggest that ligands for PPARγ have potential antitumor effects on renal carcinoma cells.

  2. Activation of peroxisome proliferator-activated receptor gamma by rosiglitazone increases sirt6 expression and ameliorates hepatic steatosis in rats.

    Directory of Open Access Journals (Sweden)

    Soo Jin Yang

    Full Text Available BACKGROUND: Sirt6 has been implicated in the regulation of hepatic lipid metabolism and the development of hepatic steatosis. The aim of this study was to address the potential role of Sirt6 in the protective effects of rosiglitazone (RGZ on hepatic steatosis. METHODS: To investigate the effect of RGZ on hepatic steatosis, rats were treated with RGZ (4 mg·kg⁻¹·day⁻¹ by stomach gavage for 6 weeks. The involvement of Sirt6 in the RGZ's regulation was evaluated by Sirt6 knockdown in AML12 mouse hepatocytes. RESULTS: RGZ treatment ameliorated hepatic lipid accumulation and increased expression of Sirt6, peroxisome proliferator-activated receptor gamma coactivtor-1-α (Ppargc1a/PGC1-α and Forkhead box O1 (Foxo1 in rat livers. AMP-activated protein kinase (AMPK phosphorylation was also increased by RGZ, accompanied by alterations in phosphorylation of LKB1. Interestingly, in free fatty acid-treated cells, Sirt6 knockdown increased hepatocyte lipid accumulation measured as increased triglyceride contents (p = 0.035, suggesting that Sirt6 may be beneficial in reducing hepatic fat accumulation. In addition, Sirt6 knockdown abolished the effects of RGZ on hepatocyte fat accumulation, mRNA and protein expression of Ppargc1a/PGC1-α and Foxo1, and phosphorylation levels of LKB1 and AMPK, suggesting that Sirt6 is involved in RGZ-mediated metabolic effects. CONCLUSION: Our results demonstrate that RGZ significantly decreased hepatic lipid accumulation, and that this process appeared to be mediated by the activation of the Sirt6-AMPK pathway. We propose Sirt6 as a possible therapeutic target for hepatic steatosis.

  3. Effects of Sulfonylureas on Peroxisome Proliferator-Activated Receptor γ Activity and on Glucose Uptake by Thiazolidinediones

    Directory of Open Access Journals (Sweden)

    Kyeong Won Lee

    2011-08-01

    Full Text Available BackgroundSulfonylurea primarily stimulates insulin secretion by binding to its receptor on the pancreatic β-cells. Recent studies have suggested that sulfonylureas induce insulin sensitivity through peroxisome proliferator-activated receptor γ (PPARγ, one of the nuclear receptors. In this study, we investigated the effects of sulfonylurea on PPARγ transcriptional activity and on the glucose uptake via PPARγ.MethodsTranscription reporter assays using Cos7 cells were performed to determine if specific sulfonylureas stimulate PPARγ transactivation. Glimepiride, gliquidone, and glipizide (1 to 500 µM were used as treatment, and rosiglitazone at 1 and 10 µM was used as a control. The effects of sulfonylurea and rosiglitazone treatments on the transcriptional activity of endogenous PPARγ were observed. In addition, 3T3-L1 adipocytes were treated with rosiglitazone (10 µM, glimepiride (100 µM or both to verify the effect of glimepiride on rosiglitazone-induced glucose uptake.ResultsSulfonylureas, including glimepiride, gliquidone and glipizide, increased PPARγ transcriptional activity, gliquidone being the most potent PPARγ agonist. However, no additive effects were observed in the presence of rosiglitazone. When rosiglitazone was co-treated with glimepiride, PPARγ transcriptional activity and glucose uptake were reduced compared to those after treatment with rosiglitazone alone. This competitive effect of glimepiride was observed only at high concentrations that are not achieved with clinical doses.ConclusionSulfonylureas like glimepiride, gliquidone and glipizide increased the transcriptional activity of PPARγ. Also, glimepiride was able to reduce the effect of rosiglitazone on PPARγ agonistic activity and glucose uptake. However, the competitive effect does not seem to occur at clinically feasible concentrations.

  4. Different skeletal effects of the peroxisome proliferator activated receptor (PPAR)alpha agonist fenofibrate and the PPARgamma agonist pioglitazone.

    Science.gov (United States)

    Syversen, Unni; Stunes, Astrid K; Gustafsson, Björn I; Obrant, Karl J; Nordsletten, Lars; Berge, Rolf; Thommesen, Liv; Reseland, Janne E

    2009-03-30

    All the peroxisome proliferator activated receptors (PPARs) are found to be expressed in bone cells. The PPARgamma agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs) have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARalpha agonist fenofibrate (FENO) and the PPARgamma agonist pioglitazone (PIO) on bone in intact female rats. Rats were given methylcellulose (vehicle), fenofibrate or pioglitazone (35 mg/kg body weight/day) by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied. The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1. We show opposite skeletal effects of PPARalpha and gamma agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARalpha activation.

  5. Different skeletal effects of the peroxisome proliferator activated receptor (PPARα agonist fenofibrate and the PPARγ agonist pioglitazone

    Directory of Open Access Journals (Sweden)

    Nordsletten Lars

    2009-03-01

    Full Text Available Abstract Background All the peroxisome proliferator activated receptors (PPARs are found to be expressed in bone cells. The PPARγ agonist rosiglitazone has been shown to decrease bone mass in mice and thiazolidinediones (TZDs have recently been found to increase bone loss and fracture risk in humans treated for type 2 diabetes mellitus. The aim of the study was to examine the effect of the PPARα agonist fenofibrate (FENO and the PPARγ agonist pioglitazone (PIO on bone in intact female rats. Methods Rats were given methylcellulose (vehicle, fenofibrate or pioglitazone (35 mg/kg body weight/day by gavage for 4 months. BMC, BMD, and body composition were measured by DXA. Histomorphometry and biomechanical testing of excised femurs were performed. Effects of the compounds on bone cells were studied. Results The FENO group had higher femoral BMD and smaller medullary area at the distal femur; while trabecular bone volume was similar to controls. Whole body BMD, BMC, and trabecular bone volume were lower, while medullary area was increased in PIO rats compared to controls. Ultimate bending moment and energy absorption of the femoral shafts were reduced in the PIO group, while similar to controls in the FENO group. Plasma osteocalcin was higher in the FENO group than in the other groups. FENO stimulated proliferation and differentiation of, and OPG release from, the preosteoblast cell line MC3T3-E1. Conclusion We show opposite skeletal effects of PPARα and γ agonists in intact female rats. FENO resulted in significantly higher femoral BMD and lower medullary area, while PIO induced bone loss and impairment of the mechanical strength. This represents a novel effect of PPARα activation.

  6. Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, Lianying [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); College of Life Science, Dezhou University, Dezhou 253023 (China); Ren, Xiao-Min; Wan, Bin [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China); Guo, Liang-Hong, E-mail: LHGuo@rcees.ac.cn [State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, P.O. Box 2871, 18 Shuangqing Road, Beijing 100085 (China)

    2014-09-15

    Perfluorinated compounds (PFCs) have been shown to disrupt lipid metabolism and even induce cancer in rodents through activation of peroxisome proliferator-activated receptors (PPARs). Lines of evidence showed that PPARα was activated by PFCs. However, the information on the binding interactions between PPARγ and PFCs and subsequent alteration of PPARγ activity is still limited and sometimes inconsistent. In the present study, in vitro binding of 16 PFCs to human PPARγ ligand binding domain (hPPARγ-LBD) and their activity on the receptor in cells were investigated. The results showed that the binding affinity was strongly dependent on their carbon number and functional group. For the eleven perfluorinated carboxylic acids (PFCAs), the binding affinity increased with their carbon number from 4 to 11, and then decreased slightly. The binding affinity of the three perfluorinated sulfonic acids (PFSAs) was stronger than their PFCA counterparts. No binding was detected for the two fluorotelomer alcohols (FTOHs). Circular dichroim spectroscopy showed that PFC binding induced distinctive structural change of the receptor. In dual luciferase reporter assays using transiently transfected Hep G2 cells, PFCs acted as hPPARγ agonists, and their potency correlated with their binding affinity with hPPARγ-LBD. Molecular docking showed that PFCs with different chain length bind with the receptor in different geometry, which may contribute to their differences in binding affinity and transcriptional activity. - Highlights: • Binding affinity between PFCs and PPARγ was evaluated for the first time. • The binding strength was dependent on fluorinated carbon chain and functional group. • PFC binding induced distinctive structural change of the receptor. • PFCs could act as hPPARγ agonists in Hep G2 cells.

  7. Telmisartan promotes potential glucose homeostasis in stroke-resistant spontaneously hypertensive rats via peroxisome proliferator-activated receptor γ activation.

    Science.gov (United States)

    Omote, Yoshio; Deguchi, Kentaro; Kurata, Tomoko; Yamashita, Toru; Sato, Kota; Hishikawa, Nozomi; Abe, Koji

    2015-01-01

    An angiotensin 2 type 1 receptor blocker (ARB) telmisartan possesses not only an anti-hypertensive effect but also an anti-metabolic syndrome effect due to peroxisome proliferator-activated receptor γ (PPAR-γ) activation. In the present study, we examined the effects of telmisartan on the angiotensin 2 type 1 receptor (AT1R), PPAR-γ, and insulin receptor (IR) in stroke-resistant spontaneously hypertensive rats (SHR-SR), comparing them with Wistar rats. Three-months-old SHR-SR rats were divided into three treatment groups, i.e., vehicle (SHR/Ve), low-dose telmisartan (0.3 mg/kg/day, SHR/Low), and high-dose telmisartan (3 mg/kg/day, SHR/High). Compared with Wistar rats, SHR/Ve increased the staining of AT1R, PPAR-γ and IR in the cerebral cortical neurons. On the other hand, telmisartan dose-dependently suppressed the excessive expression of AT1R and IR, but enhanced PPAR-γ activation. Low-dose telmisartan showed these effects even without lowering blood pressure (BP), while high-dose telmisartan lowered BP and showed further effects. The present study suggests that even a low dose of telmisartan decreased AT1R and IR, and increased PPAR-γ in the cerebral cortex of SHR-SR without lowering BP, probably by improving glucose homeostasis. The high dose of telmisartan showed further decreases in AT1R and IR, and further PPAR-γ activation while lowering BP, suggesting an additive benefit to lowering BP, namely the improvement of glucose homeostasis.

  8. Truncated peroxisome proliferator-activated receptor-γ coactivator 1α splice variant is severely altered in Huntington's disease.

    Science.gov (United States)

    Johri, Ashu; Starkov, Anatoly A; Chandra, Abhishek; Hennessey, Thomas; Sharma, Abhijeet; Orobello, Sara; Squitieri, Ferdinando; Yang, Lichuan; Beal, M Flint

    2011-01-01

    Reduced peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α) gene expression has been observed in striatal cell lines, transgenic mouse models of Huntington's disease (HD), and brain tissue from HD patients. As this protein is a key transcription regulator of the expression of many mitochondrial proteins, these observations strongly support the role of aberrant mitochondrial function in the pathogenesis of HD. The PGC1α protein undergoes posttranslational modifications that affect its transcriptional activity. The N-truncated splice variant of PGC1α (NT-PGC1α) is produced in tissues, but the role of truncated splice variants of PGC1α in HD and in the regulation of mitochondrial gene expression has not been elucidated. To examine the expression and modulation of expression of NT-PGC1α levels in HD. We found that the NT-PGC1α protein, a splice variant of ∼38 kDa, but not full-length PGC1α is severely and consistently altered in human HD brain, human HD myoblasts, mouse HD models, and HD striatal cells. NT-PGC1α levels were significantly upregulated in HD cells and mouse brown fat by physiologically relevant stimuli that are known to upregulate PGC1α gene expression. This resulted in an increase in mitochondrial gene expression and cytochrome c content. Our data suggest that NT-PGC1α is an important component of the PGC1α transcriptional network, which plays a significant role in the pathogenesis of HD. Copyright © 2011 S. Karger AG, Basel.

  9. Developmental Effects of Perfluorononanoic Acid in the Mouse Are Dependent on Peroxisome Proliferator-Activated Receptor-Alpha

    Directory of Open Access Journals (Sweden)

    Cynthia J. Wolf

    2010-01-01

    Full Text Available Perfluorononanoic acid (PFNA is one of the perfluoroalkyl acids found in the environment and in tissues of humans and wildlife. Prenatal exposure to PFNA negatively impacts survival and development of mice and activates the mouse and human peroxisome proliferator-activated receptor-alpha (PPAR. In the current study, we used PPAR knockout (KO and 129S1/SvlmJ wild-type (WT mice to investigate the role of PPAR in mediating PFNA-induced in vivo effects. Pregnant KO and WT mice were dosed orally with water (vehicle control: 10 ml/kg, 0.83, 1.1, 1.5, or 2 mg/kg PFNA on gestational days (GDs 1–18 (day of sperm plug = GD 0. Maternal weight gain, implantation, litter size, and pup weight at birth were unaffected in either strain. PFNA exposure reduced the number of live pups at birth and survival of offspring to weaning in the 1.1 and 2 mg/kg groups in WT. Eye opening was delayed (mean delay 2.1 days and pup weight at weaning was reduced in WT pups at 2 mg/kg. These developmental endpoints were not affected in the KO. Relative liver weight was increased in a dose-dependent manner in dams and pups of the WT strain at all dose levels but only slightly increased in the highest dose group in the KO strain. In summary, PFNA altered liver weight of dams and pups, pup survival, body weight, and development in the WT, while only inducing a slight increase in relative liver weight of dams and pups at 2 mg/kg in KO mice. These results suggest that PPAR is an essential mediator of PFNA-induced developmental toxicity in the mouse.

  10. Atorvastatin and fenofibrate increase apolipoprotein AV and decrease triglycerides by up-regulating peroxisome proliferator-activated receptor-α

    Science.gov (United States)

    Huang, Xian-sheng; Zhao, Shui-ping; Bai, Lin; Hu, Min; Zhao, Wang; Zhang, Qian

    2009-01-01

    Background and purpose: Combining statin and fibrate in clinical practice provides a greater reduction of triglycerides than either drug given alone, but the mechanism for this effect is poorly understood. Apolipoprotein AV (apoAV) has been implicated in triglyceride metabolism. This study was designed to investigate the effect of the combination of statin and fibrate on apoAV and the underlying mechanism(s). Experimental approach: Hypertriglyceridaemia was induced in rats by giving them 10% fructose in drinking water for 2 weeks. They were then treated with atorvastatin, fenofibrate or the two agents combined for 4 weeks, and plasma triglyceride and apoAV measured. We also tested the effects of these two agents on triglycerides and apoAV in HepG2 cells in culture. Western blot and reverse transcription polymerase chain reaction was used to measure apoAV and peroxisome proliferator-activated receptor-α (PPARα) expression. Key results: The combination of atorvastatin and fenofibrate resulted in a greater decrease in plasma triglycerides and a greater increase in plasma and hepatic apoAV than either agent given alone. Hepatic expression of the PPARα was also more extensively up-regulated in rats treated with the combination. A similar, greater increase in apoAV and a greater decrease in triglycerides were observed following treatment of HepG2 cells pre-exposed to fructose), with the combination. Adding an inhibitor of PPARα (MK886) abolished the effects of atorvastatin on HepG2 cells. Conclusions and implications: A combination of atorvastatin and fenofibrate increased apoAV and decreased triglycerides through up-regulation of PPARα. PMID:19694729

  11. Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Peter C Konturek; Artur Dembinski; Zygmunt Warzecha; Grzegorz Burnat; Piotr Ceranowicz; Eckhart G Hahn; Marcin Dembinski; Romana Tomaszewska; Stanislaw J Konturek

    2005-01-01

    AIM: To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ (PPARγ)ligand, on the development of acute pancreatitis (AP) and on the expression of heat shock protein 70 (HSP70) in the pancreas.METHODS: AP was induced in rats by subcutaneous infusion of cerulein for 5 h. Pancreatic blood flow was measured by laser Doppler flowmetry. Plasma lipase activity, interleukin-1β (IL-1β) and IL-10 were determined.Pancreatic weight and histology were evaluated and pancreatic DNA synthesis and blood flow as well as pancreatic mRNA for IL-1β and HSP70 were assessed in rats treated with pioglitazone alone or in combination with cerulein.RESULTS: Pioglitazone administered (10-100 mg/kg I.g.)30 min before cerulein, attenuated dose-dependently the pancreatic tissue damage in cerulein-induced pancreatitis (CIP) as demonstrated by the improvement of pancreatic histology, reduction in plasma lipase activity,plasma concentration of pro-inflammatory IL-1β and its gene expression in the pancreas and attenuation of the pancreatitis-evoked fall in pancreatic blood flow. CIP increased pancreatic HSP70 mRNA and protein expression in the pancreas and this effect was enhanced by pioglitazone treatment.CONCLUSION: Pioglitazone attenuates CIP and the beneficial effect of this pioglitazone is multifactorial probably due to its anti-inflammatory activities, to the suppression of IL-1β and to the overexpression of HSP70.PPARγ ligands could represent a new therapeutic option in the treatment of AP.

  12. The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis

    Science.gov (United States)

    Marder, Wendy; Khalatbari, Shokoufeh; Myles, James D.; Hench, Rita; Lustig, Susan; Yalavarthi, Srilakshmi; Parameswaran, Aishwarya; Brook, Robert D.; Kaplan, Mariana J.

    2013-01-01

    Background Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD). Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD. We hypothesized that the peroxisome proliferator activated receptor‐γ (PPAR‐γ) pioglitazone could promote potent vasculoprotective and anti‐inflammatory effects in RA. Methods and Results One hundred forty‐three non‐diabetic adult RA patients (76.2% female, age 55.2±12.1 [mean±SD]) on stable RA standard of care treatment were enrolled in a randomized, double‐blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3‐month duration/arm and a 2‐month washout period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified. RA disease activity was assessed with the 28‐Joint Count Disease Activity Score (DAS‐28) C‐reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire. When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo. Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles. The drug was well tolerated. Conclusions Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues. The clinical implications of these findings remain to be established. Clinical Trial Registration URL: ClinicalTrials.gov Unique Identifier: NCT00554853. PMID:24252844

  13. Design novel dual agonists for treating type-2 diabetes by targeting peroxisome proliferator-activated receptors with core hopping approach.

    Directory of Open Access Journals (Sweden)

    Ying Ma

    Full Text Available Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator-activated receptors have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones, the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful "core hopping" and "glide docking" techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR-gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion predictions that the new agonists hold high potential to become drug candidates. Or at the very least, the findings reported here may stimulate new strategy or provide useful insights for discovering more effective dual agonists for treating type-2 diabetes. Since the "core hopping" technique allows for rapidly screening novel cores to help overcome unwanted properties by generating new lead compounds with improved core properties, it has not escaped our notice that the current strategy along with the corresponding computational procedures can also be utilized to find novel and more effective drugs for treating other illnesses.

  14. Age-related decrease in expression of peroxisome proliferator-activated receptor α and its effects on development of dyslipidemia

    Institute of Scientific and Technical Information of China (English)

    YE Ping; WANG Zhao-jun; ZHANG Xiu-jin; ZHAO Ya-li

    2005-01-01

    Background Ageing is associated with increased incidence of dyslipidemia. To investigate potential molecular mechanisms, the effects of age and fibrate administration on peroxisome proliferator-activated receptor α(PPARα) expression in livers of young and old rats were studied.Methods A total of 16 young (2-month-old) and 16 old rats (24-month-old) were randomly assigned to a control group and fenofibrate group (fenofibrate in a total therapeutic dosage of 0.5% in ratio to each treated rat weight in 14 days). RT-PCR was applied to evaluate hepatic mRNA expression of PPARα and its target genes. Western blotting was used to determine PPARα protein level in liver tissue. Results When compared with 2-month-old rats, the liver tissue from 24-month-old rats showed reduced expression of PPARα mRNA (52%, P<0.05) and protein (109%, P<0.01). Consequently, the mRNA levels of PPAR target genes, LPL, ACO, ACS and CPT-1 were markedly lowered by 19%, 8%, 13% and 9% respectively, and apoCIII increased by 24% in livers from 24-month-old rats, compared with values obtained from 2-month-old rats (P<0.05). Fenofibrate therapy significantly lowered plasma triglyceride and total cholesterol levels in old rats, accompanied with improvement in hepatic expression of genes, including LPL, ACO, ACS, CPT-1 and apoCIII, but no change was found in PPARα expression in livers from either 24-month or 2-month-old rats. Conclusions The decrease in the hepatic PPARα expression is probably directly related to the lipid metabolic disturbances observed in old animals. The beneficial effects of fenofibrate administration in old rats suggests that fibrates may be useful for treating lipid disturbances in old people.

  15. Pioglitazone, a specific ligand of peroxisome proliferator-activated receptor-gamma, protects pancreas against acute cerulein-induced pancreatitis

    Science.gov (United States)

    Konturek, Peter C; Dembinski, Artur; Warzecha, Zygmunt; Burnat, Grzegorz; Ceranowicz, Piotr; Hahn, Eckhart G; Dembinski, Marcin; Tomaszewska, Romana; Konturek, Stanislaw J

    2005-01-01

    AIM: To determine the effect of pioglitazone, a specific peroxisome proliferator-activated receptor-γ (PPARγ) ligand, on the development of acute pancreatitis (AP) and on the expression of heat shock protein 70 (HSP70) in the pancreas. METHODS: AP was induced in rats by subcutaneous infusion of cerulein for 5 h. Pancreatic blood flow was measured by laser Doppler flowmetry. Plasma lipase activity, interleukin-1β (IL-1β) and IL-10 were determined. Pancreatic weight and histology were evaluated and pancreatic DNA synthesis and blood flow as well as pancreatic mRNA for IL-1β and HSP70 were assessed in rats treated with pioglitazone alone or in combination with cerulein. RESULTS: Pioglitazone administered (10-100 mg/kg i.g.) 30 min before cerulein, attenuated dose-dependently the pancreatic tissue damage in cerulein-induced pancreatitis (CIP) as demonstrated by the improvement of pancreatic histology, reduction in plasma lipase activity, plasma concentration of pro-inflammatory IL-1β and its gene expression in the pancreas and attenuation of the pancreatitis-evoked fall in pancreatic blood flow. CIP increased pancreatic HSP70 mRNA and protein expression in the pancreas and this effect was enhanced by pioglitazone treatment. CONCLUSION: Pioglitazone attenuates CIP and the beneficial effect of this pioglitazone is multifactorial probably due to its anti-inflammatory activities, to the suppression of IL-1β and to the overexpression of HSP70. PPARγ ligands could represent a new therapeutic option in the treatment of AP. PMID:16419161

  16. Effect of ligand of peroxisome proliferator-activated receptor γ on the biological characters of hepatic stellate cells

    Institute of Scientific and Technical Information of China (English)

    Yan-Tong Guo; Xi-Sheng Leng; Tao Li; Ji-Run Peng; Sheng-Han Song; Liang-Fa Xiong; Zhi-Zhong Qin

    2005-01-01

    AIM: To study the effect of rosiglitazone, which is a ligand of peroxisome proliferator-activated receptor gamma (PPARγ), on the expression of PPARγ in hepatic stellate cells (HSCs) and on the biological characteristics of HSCs.METHODS: The activated HSCs were divided into three groups: control group, 3 μmol/L rosiglitazone group, and 10 μmol/L rosiglitazone group. The expression of PPARγ,α-smooth muscle actin (α-SMA), and type Ⅰ and Ⅲ collagen was detected by RT-PCR, Western blot and immunocytochemical staining, respectively. Cell proliferation was determined with methylthiazolyltetrazolium (MTT) colorimetric assay. Cell apoptosis was demonstrated with flow cytometry.RESULTS: The expression of PPARγ at mRNA and protein level markedly increased in HSCs of 10 μmol/L rosiglitazone group (tvalue was 10.870 and 4.627 respectively, P<0.01in both). The proliferation of HSCs in 10 μmol/L rosiglitazone group decreased significantly (t = 5.542, P<0.01), α-SMA expression level and type Ⅰ collagen synthesis ability were also reduced vs controls (tvalue= 10.256 and 14.627respectively, P<0.01 in both). The apoptotic rate of HSCs significantly increased in 10 μmol/L rosiglitazone group vs control (x2= 16.682, P<0.01).CONCLUSION: By increasing expression of PPARγ in activated HSCs, rosiglitazone, an agonist of PPARγ,decreases α-SMA expression and type Ⅰ collagen synthesis,inhibits cell proliferation, and induces cell apoptosis.

  17. Genomewide Analyses Define Different Modes of Transcriptional Regulation by Peroxisome Proliferator-Activated Receptor-β/δ (PPARβ/δ)

    Science.gov (United States)

    Schönbauer, Anne; Meissner, Wolfgang; Scharfe, Maren; Jarek, Michael; Blöcker, Helmut; Müller-Brüsselbach, Sabine; Müller, Rolf

    2011-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors with essential functions in lipid, glucose and energy homeostasis, cell differentiation, inflammation and metabolic disorders, and represent important drug targets. PPARs heterodimerize with retinoid X receptors (RXRs) and can form transcriptional activator or repressor complexes at specific DNA elements (PPREs). It is believed that the decision between repression and activation is generally governed by a ligand-mediated switch. We have performed genomewide analyses of agonist-treated and PPARβ/δ-depleted human myofibroblasts to test this hypothesis and to identify global principles of PPARβ/δ-mediated gene regulation. Chromatin immunoprecipitation sequencing (ChIP-Seq) of PPARβ/δ, H3K4me3 and RNA polymerase II enrichment sites combined with transcriptional profiling enabled the definition of 112 bona fide PPARβ/δ target genes showing either of three distinct types of transcriptional response: (I) ligand-independent repression by PPARβ/δ; (II) ligand-induced activation and/or derepression by PPARβ/δ; and (III) ligand-independent activation by PPARβ/δ. These data identify PPRE-mediated repression as a major mechanism of transcriptional regulation by PPARβ/δ, but, unexpectedly, also show that only a subset of repressed genes are activated by a ligand-mediated switch. Our results also suggest that the type of transcriptional response by a given target gene is connected to the structure of its associated PPRE(s) and the biological function of its encoded protein. These observations have important implications for understanding the regulatory PPAR network and PPARβ/δ ligand-based drugs. PMID:21283829

  18. The involvement of peroxisome proliferator activated receptors (PPARs) in prostaglandin F2α production by porcine endometrium.

    Science.gov (United States)

    Bogacka, I; Bogacki, M; Kurzyńska, A; Chojnowska, K

    2013-12-01

    In the present study, we investigated the in vitro effects of peroxisome proliferator activated receptor (PPAR) ligands on PGF2α secretion and mRNA expression of prostaglandin F synthase (PGFS) in porcine endometrial explants collected on days 10-12 and 14-16 of the estrous cycle or pregnancy. The explants were incubated for 6h with: PPARα ligands - WY-14643 (agonist) and MK 886 (antagonist); PPARβ ligands - l-165,041 (agonist) and GW 9662 (antagonist); PPARγ ligands - 15d-prostaglandin J2 (PGJ2, agonist), rosiglitazone (agonist) and T0070907 (antagonist). The expression of PGFS mRNA in the endometrium and the concentration of PGF2α in culture media were determined by real time RT-PCR and radioimmunoassay, respectively. During the estrous cycle (days 10-12 and 14-16), the agonists - WY-14643 (PPARα), l-165,041 (PPARβ), PGJ2 and rosiglitazone (PPARγ) - increased PGF2α secretion but did not affect PGFS mRNA abundance. During pregnancy (days 10-12 and 14-16), PPARα and PPARγ ligands did not change PGF2α release, whereas PPARβ agonist augmented PGF2α release on days 14-16 of pregnancy. In addition, WY-14643 and l-165,041 increased PGFS mRNA level in both examined periods of pregnancy. PPARγ agonist (PGJ2) and antagonist (T0070907) enhanced PGFS mRNA abundance in the endometrium on days 10-12 and 14-16 of pregnancy, respectively. The results indicate that PPARs are involved in the production of PGF2α by porcine endometrium, and that the sensitivity of the endometrium to PPAR ligands depends on reproductive status of animals. Copyright © 2013 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish Academy of Sciences in Olsztyn. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  19. Integrated virtual screening for the identification of novel and selective peroxisome proliferator-activated receptor (PPAR) scaffolds.

    Science.gov (United States)

    Nevin, Daniel K; Peters, Martin B; Carta, Giorgio; Fayne, Darren; Lloyd, David G

    2012-06-14

    We describe a fully customizable and integrated target-specific "tiered" virtual screening approach tailored to identifying and characterizing novel peroxisome proliferator activated receptor γ (PPARγ) scaffolds. Built on structure- and ligand-based computational techniques, a consensus protocol was developed for use in the virtual screening of chemical databases, focused toward retrieval of novel bioactive chemical scaffolds for PPARγ. Consequent from application, three novel PPAR scaffolds displaying distinct chemotypes have been identified, namely, 5-(4-(benzyloxy)-3-chlorobenzylidene)dihydro-2-thioxopyrimidine-4,6(1H,5H)-dione (MDG 548), 3-((4-bromophenoxy)methyl)-N-(4-nitro-1H-pyrazol-1-yl)benzamide (MDG 559), and ethyl 2-[3-hydroxy-5-(5-methyl-2-furyl)-2-oxo-4-(2-thienylcarbonyl)-2,5-dihydro-1H-pyrrol-1-yl]-4-methyl-1,3-thiazole-5-carboxylate (MDG 582). Fluorescence polarization(FP) and time resolved fluorescence resonance energy transfer (TR-FRET) show that these compounds display high affinity competitive binding to the PPARγ-LBD (EC(50) of 215 nM to 5.45 μM). Consequent characterization by a TR-FRET activation reporter assay demonstrated agonism of PPARγ by all three compounds (EC(50) of 467-594 nM). Additionally, differential PPAR isotype specificity was demonstrated through assay against PPARα and PPARδ subtypes. This work showcases the ability of target specific "tiered screen" protocols to successfully identify novel scaffolds of individual receptor subtypes with greater efficacy than isolated screening methods.

  20. Preterm and infection-driven preterm labor: the role of peroxisome proliferator-activated receptors and retinoid X receptor.

    Science.gov (United States)

    Holdsworth-Carson, Sarah J; Permezel, Michael; Rice, Greg E; Lappas, Martha

    2009-06-01

    Approximately 8% of births are complicated by preterm delivery. To improve neonatal outcomes, a greater understanding of the mechanisms surrounding preterm parturition is required. Peroxisome proliferator-activated receptors (PPARs) have been implicated in the regulation of labor at term where they exhibit anti-inflammatory properties. Thus, we hypothesize that dysregulation of PPAR expression and activity may be associated with preterm labor and infection-associated preterm labor. The aim of this study was to compare the expression and activity of PPARs and the expression of retinoid X-receptor alpha (RXRA) in gestational tissues from term and preterm deliveries, and from infection-associated preterm deliveries. Quantitative RT-PCR, western blotting and activity ELISA were used to study expression and DNA binding profiles. Compared with term, preterm parturition was associated with an increased expression of PPAR delta (PPARD; mRNA and protein), PPAR gamma (PPARG; protein) and RXRA (protein) in the placenta and PPARD (mRNA and protein) and RXRA (mRNA) in the choriodecidua. There was, however, no change in preterm PPAR DNA binding activity compared with term. Preterm chorioamnionitis (CAM) demonstrated protein degradation in the choriodecidua and was associated with a decline in the mRNA expression of PPAR alpha (PPARA) and RXRA compared with uninfected preterm cases. PPAR DNA binding activity increased in the placenta (PPARD and PPARG) and decreased in the amnion (PPARA and PPARG) in association with preterm CAM. In conclusion, idiopathic preterm deliveries were associated with an increase in PPAR:RXR expression and preterm CAM was associated with a decrease in PPAR:RXR expression and tissue-specific alterations in transcriptional activity. The reasons for such dysregulation remain to be determined; however, the data are consistent with the hypothesis that PPARs may play a role in preterm labor and infection-complicated preterm deliveries.

  1. Chemerin, a novel peroxisome proliferator-activated receptor gamma (PPARgamma) target gene that promotes mesenchymal stem cell adipogenesis.

    Science.gov (United States)

    Muruganandan, Shanmugam; Parlee, Sebastian D; Rourke, Jillian L; Ernst, Matthew C; Goralski, Kerry B; Sinal, Christopher J

    2011-07-08

    Chemerin is an adipocyte-secreted protein that regulates adipogenesis and the metabolic function of mature adipocytes via activation of chemokine-like receptor 1 (CMKLR1). Herein we report the interaction of peroxisome proliferator-activated receptor γ (PPARγ) and chemerin in the context of adipogenesis. Knockdown of chemerin or CMKLR1 expression or antibody neutralization of secreted chemerin protein arrested adipogenic clonal expansion of bone marrow mesenchymal stem cells (BMSCs) by inducing a loss of G(2)/M cyclins (cyclin A2/B2) but not the G(1)/S cyclin D2. Forced expression of PPARγ in BMSCs did not completely rescue this loss of clonal expansion and adipogenesis following chemerin or CMKLR1 knockdown. However, forced expression and/or activation of PPARγ in BMSCs as well as non-adipogenic cell types such as NIH-3T3 embryonic fibroblasts and MCA38 colon carcinoma cells significantly induced chemerin expression and secretion. Sequence analysis revealed a putative PPARγ response element (PPRE) sequence within the chemerin promoter. This PPRE was able to confer PPARγ responsiveness on a heterologous promoter, and mutation of this sequence abolished activation of the chemerin promoter by PPARγ. Chromatin immunoprecipitation confirmed the direct association of PPARγ with this PPRE. Treatment of mice with rosiglitazone elevated chemerin mRNA levels in adipose tissue and bone marrow coincident with an increase in circulating chemerin levels. Together, these findings support a fundamental role for chemerin/CMKLR1 signaling in clonal expansion during adipocyte differentiation as well as a role for PPARγ in regulating chemerin expression.

  2. The peroxisome proliferator-activated receptor N-terminal domain controls isotype-selective gene expression and adipogenesis.

    Science.gov (United States)

    Hummasti, Sarah; Tontonoz, Peter

    2006-06-01

    Peroxisome proliferator-activated receptors (PPARgamma, PPARalpha, and PPARdelta) are important regulators of lipid metabolism. Although they share significant structural similarity, the biological effects associated with each PPAR isotype are distinct. For example, PPARalpha and PPARdelta regulate fatty acid catabolism, whereas PPARgamma controls lipid storage and adipogenesis. The different functions of PPARs in vivo can be explained at least in part by the different tissue distributions of the three receptors. The question of whether the receptors have different intrinsic activities and regulate distinct target genes, however, has not been adequately explored. We have engineered cell lines that express comparable amounts of each receptor. Transcriptional profiling of these cells in the presence of selective agonists reveals partially overlapping but distinct patterns of gene regulation by the three PPARs. Moreover, analysis of chimeric receptors points to the N terminus of each receptor as the key determinant of isotype-selective gene expression. For example, the N terminus of PPARgamma confers the ability to promote adipocyte differentiation when fused to the PPARdelta DNA binding domain and ligand binding domain, whereas the N terminus of PPARdelta leads to the inappropriate expression of fatty acid oxidation genes in differentiated adipocytes when fused to PPARgamma. Finally, we demonstrate that the N terminus of each receptor functions in part to limit receptor activity because deletion of the N terminus leads to nonselective activation of target genes. A more detailed understanding of the mechanisms by which the individual PPARs differentially regulate gene expression should aid in the design of more effective drugs, including tissue- and target gene-selective PPAR modulators.

  3. Peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk.

    Science.gov (United States)

    Wang, Wei; Shao, Yan; Tang, Shenhua; Cheng, Xianyong; Lian, Haifeng; Qin, Chengyong

    2015-01-01

    The association between the peroxisome proliferator-activated receptor-γ (PPARγ) Pro12Ala polymorphism and colorectal cancer (CRC) risk was inconclusive. We conducted a meta-analysis to evaluate the association between PPARγ Pro12Ala polymorphism and CRC risk. We searched Pubmed, EMBASE, and China National Knowledge Infrastructure databases. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. A total of 17 case-control studies with 12635 and 15803 controls were included in this meta-analysis. Overall, PPARγ Pro12Ala polymorphism was associated with CRC risk (OR = 0.84, 95% CI 0.75-0.94, P = 0.003, I(2) = 35%). In the subgroup analysis by ethnicity, a significant association was found among Caucasians (OR = 0.85, 95% CI 0.75-0.96, P = 0.007, I(2) = 38%) but not among Asians (OR = 0.76, 95% CI 0.51-1.12, P = 0.17, I(2) = 28%). In the subgroup analysis by CRC site, a significant association was found among colon cancer (OR = 0.81, 95% CI 0.66-0.98, P = 0.03, I(2) = 16%) but not among rectal cancer (OR = 0.83, 95% CI 0.57-1.21, P = 0.34, I(2) = 63%). The sensitivity analysis did not influence the result by omitting low-quality studies (OR = 0.76, 95% CI 0.63-0.93, P = 0.006, I(2) = 51%). In conclusion, this meta-analysis suggested that PPARγ Pro12Ala polymorphism was significant associated with CRC risk.

  4. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma (PPARgamma) gene in inflammatory bowel disease.

    Science.gov (United States)

    Atug, Ozlen; Tahan, Veysel; Eren, Fatih; Tiftikci, Arzu; Imeryuz, Nese; Hamzaoglu, Hulya Over; Tozun, Nurdan

    2008-12-01

    Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) has recently been implicated as an endogenous regulator of cellular proliferation and inflammation. Impaired expression of PPAR-gamma in colonic epithelial cells in ulcerative colitis (UC) and increased expression in hypertrophic mesenteric adipose tissue in Crohn's disease (CD) have been reported. Furthermore, PPAR-gamma ligands have been shown to inhibit tissue injury associated with immune activation in UC. Any mutation in PPAR-gamma gene may be responsible for the increase in inflammatory mediators and hence the perpetuation of inflammation in inflammatory bowel disease (IBD) patients. One common polymorphism in PPAR-gamma gene is proline to alanine substitution (Pro12Ala) which results from a CCA to GCA missense substitution in codon 12 of exon 2 of the PPAR-gamma gene. In this study, we aimed to explore Pro12Ala polymorphism in PPAR-gamma gene in IBD in Turkish patients. 69 patients with CD, 45 with UC and 100 controls of similar age and sex were studied. Genomic DNA was isolated from peripheral blood leucocytes and mutagenically separated-polymerase chain reaction (PCR) analyses were performed to determine the Pro12Ala polymorphism of the PPAR-gamma gene. We observed no significant differences in the frequency of the Pro12Ala polymorphism in the PPAR-gamma gene among subjects with CD, UC and controls (15.9%, 15.5% and 13%, respectively, p>0.05). These results suggest that Pro12Ala polymorphism in the PPAR-gamma gene relates neither to the risk of the development of inflammatory bowel disease nor to the clinical subtypes of CD in the Turkish population.

  5. The peroxisome proliferator-activated receptor gamma is an inhibitor of ErbBs activity in human breast cancer cells.

    Science.gov (United States)

    Pignatelli, M; Cortés-Canteli, M; Lai, C; Santos, A; Perez-Castillo, A

    2001-11-01

    One of the most interesting recent developments in the nuclear receptor field has been the identification of natural and synthetic agonists of the peroxisome proliferator-activated receptor (PPAR) family, coupled with a growing recognition that the gamma isoform (PPARgamma) affects pathways important in a variety of human diseases. Here we show that the activation of PPARgamma through the 15-deoxy-Delta-12,14-prostaglandin J(2) (PG-J(2)) ligand causes a dramatic inhibition of ErbB-2 and ErbB-3 tyrosine phosphorylation caused by neuregulin 1 (NRG1) and neuregulin 2 (NRG2) in MCF-7 cells. This effect is accompanied by a very efficient blocking of ErbBs effects upon proliferation, differentiation and cell death in these cells. Preincubation of MCF-7 cells with PG-J(2) before addition of NRG1 and NRG2 had a dramatic growth-suppressive effect accompanied by accumulation of cells in the G0/G1 compartment of the cell cycle, and a marked increase in apoptosis. NRG1 and NRG2 induce G1 progression, which was associated with stimulation of the phosphatidylinositol-3 kinase (PI 3-K) pathway, whereas survival was dependent on ERK1/ERK2 activation. Both pathways were inhibited by PG-J(2). Furthermore, PG-J(2) can abolish the NRG1 and NRG2-induced increase in anchorage-independent growth of these cells. PG-J(2) also blocks phosphorylation of other receptor tyrosine kinases, such as IGF-IR, in MCF-7 cells, and suppress proliferation of other breast cancer cell lines. In summary, our data show a specific inhibitory action of PG-J(2) on the activity of the ErbB receptors in breast cancer cells.

  6. Association of Pro12Ala Polymorphism of Peroxisome Proliferator-Activated Receptor gamma 2 (PPARγ2) Gene with Type 2 Diabetes Mellitus in Ethnic Kashmiri Population.

    Science.gov (United States)

    Majid, Misbah; Masood, Akbar; Kadla, Showkat Ahmad; Hameed, Iqra; Ganai, Bashir A

    2017-02-01

    Type 2 diabetes mellitus (T2DM) is characterized by chronic hyperglycemia associated with insulin resistance and relative insulin deficiency. T2DM is believed to be attributable to the combined effect of genetic and environmental factors. Peroxisome proliferator-activated receptor gamma 2 (PPARγ2) is one of the main candidate genes that are implicated in T2DM. A common proline 12 alanine (Pro12Ala) polymorphism in PPARγ2 has been shown to be associated with T2DM. The aim of this work was to investigate the possible role of PPARγ2 gene polymorphism, as a genetic risk factor for T2DM. The study comprised 200 ethnic unrelated subjects (100 T2DM patients and 100 controls). PCR-RFLP technique was used for genotyping analysis. The frequency of the Pro allele was 79 and 91.5 % for controls and cases, respectively (P Pro12Ala polymorphism was in Hardy-Weinberg equilibrium in both patients and controls (χ (2) = 0.13, P > 0.05). We found a significant association of Pro12Ala polymorphism of PPARγ2 gene with T2DM, however the genotypes showed statistically significant association only with few clinical parameters including body mass index, total cholesterol, and low-density lipoprotein (P < 0.05). The study signifies that Pro allele in PPARγ2 may be a genotypic risk factor that confers susceptibility to T2DM in ethnic Kashmiri population.

  7. Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway

    Directory of Open Access Journals (Sweden)

    Lin CH

    2016-11-01

    Full Text Available Ching-Han Lin,1,* Shang-Yu Lee,2,* Chun-Cheng Zhang,3 Ye-Fong Du,1 Hao-Chang Hung,1 Hung-Tsung Wu,4 Horng-Yih Ou1 1Department of Internal Medicine, Division of Endocrinology and Metabolism, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, 2Department of Internal Medicine, Division of Endocrinology and Metabolism, Chi-Mei Medical Center, 3Department of Internal Medicine, Division of Holistic Care, Chi-Mei Medical Center, 4Research Center of Clinical Medicine, National Cheng Kung University Hospital, Tainan, Taiwan *These authors contributed equally to this work Abstract: Fenretinide is a novel anticancer agent reported to exhibit anti-invasive and antimetastatic activities. It has also been shown to improve obesity and diabetes, although the effects of fenretinide on hypertension are still unknown, and the detailed mechanisms remain unclear. In this study, we have shown that treatment with lipopolysaccharide (LPS decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ in RAW264.7 macrophages, and pretreatment with fenretinide reversed the effect of LPS on PPARγ expression. In addition, LPS-induced pro-inflammatory cytokine production, including tumor necrosis factor-α, interleukin 6, and monocyte chemoattractant protein 1 were dose-dependently reversed by fenretinide, and the effects of fenretinide on LPS-induced pro-inflammatory cytokine production were blocked by treatment with PPARγ antagonist. Moreover, fenretinide decreased LPS-induced inducible nitric oxide synthase expression and nitrogen oxide production. These effects were blocked by the pretreatment with PPARγ antagonist in a dose-dependent manner, indicating fenretinide activated PPARγ to exert anti-inflammation activity. In view of the role of inflammation in hypertension and the anti-inflammatory action of fenretinide, we found that administration of fenretinide in spontaneously hypertensive rats

  8. Peroxisome proliferator-activated receptor {alpha} agonism prevents renal damage and the oxidative stress and inflammatory processes affecting the brains of stroke-prone rats.

    Science.gov (United States)

    Gelosa, Paolo; Banfi, Cristina; Gianella, Anita; Brioschi, Maura; Pignieri, Alice; Nobili, Elena; Castiglioni, Laura; Cimino, Mauro; Tremoli, Elena; Sironi, Luigi

    2010-11-01

    A growing body of evidence suggests that chronic kidney disease is a significant risk for cardiovascular events and stroke regardless of traditional risk factors. The aim of this study was to examine the effects of peroxisome proliferator-activated receptor (PPAR) agonists on the tissue damage affecting salt-loaded spontaneously hypertensive stroke-prone rats ( SHRSPs), an animal model that develops a complex pathology characterized by systemic inflammation, hypertension, and proteinuria and leads to end-organ injury (initially renal and subsequently cerebral). Compared with the PPARγ agonist rosiglitazone, the PPARα ligands fenofibrate and clofibrate significantly increased survival (p damage, and glomerular sclerosis, reduced the number of ED-1-positive cells and collagen accumulation, and decreased the renal expression of interleukin-1β, transforming growth factor β, and monocyte chemoattractant protein 1. It also prevented the plasma and urine accumulation of acute-phase and oxidized proteins, suggesting that the protection induced by PPARα agonists was at least partially caused by their anti-inflammatory and antioxidative properties. The results of this study demonstrate that PPAR agonism has beneficial effects on spontaneous brain and renal damage in SHRSPs by inhibiting systemic inflammation and oxidative stress, and they support carrying out future studies aimed at evaluating the effect of PPARα agonists on proteinuria and clinical outcomes in hypertensive patients with renal disease at increased risk of stroke.

  9. Activin receptor-like kinase 7 suppresses lipolysis to accumulate fat in obesity through downregulation of peroxisome proliferator-activated receptor γ and C/EBPα.

    Science.gov (United States)

    Yogosawa, Satomi; Mizutani, Shin; Ogawa, Yoshihiro; Izumi, Tetsuro

    2013-01-01

    We previously identified a quantitative trait locus for adiposity, non-insulin-dependent diabetes 5 (Nidd5), on mouse chromosome 2. In the current study, we identified the actual genetic alteration at Nidd5 as a nonsense mutation of the Acvr1c gene encoding activin receptor-like kinase 7 (ALK7), one of the type I transforming growth factor-β receptors, which results in a COOH-terminal deletion of the kinase domain. We further showed that the ALK7 dysfunction causes increased lipolysis in adipocytes and leads to decreased fat accumulation. Conversely, ALK7 activation inhibits lipolysis by suppressing the expression of adipose lipases. ALK7 and activated Smads repress those lipases by downregulating peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (C/EBP) α. Although PPARγ and C/EBPα act as adipogenic transcription factors during adipocyte differentiation, they are lipolytic in sum in differentiated adipocytes and are downregulated by ALK7 in obesity to accumulate fat. Under the obese state, ALK7 deficiency improves glucose tolerance and insulin sensitivity by preferentially increasing fat combustion in mice. These findings have uncovered a net lipolytic function of PPARγ and C/EBPα in differentiated adipocytes and point to the ALK7-signaling pathway that is activated in obesity as a potential target of medical intervention.

  10. Peroxisome Proliferator-Activated Receptor Gamma Negatively Regulates the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Toward Myofibroblasts in Liver Fibrogenesis

    Directory of Open Access Journals (Sweden)

    Shuangshuang Jia

    2015-11-01

    Full Text Available Background/Aims: Bone marrow-derived mesenchymal stem cells (BMSCs have been confirmed to have capacity to differentiate toward hepatic myofibroblasts, which contribute to fibrogenesis in chronic liver diseases. Peroxisome proliferator-activated receptor gamma (PPARγ, a ligand-activated transcription factor, has gained a great deal of recent attention as it is involved in fibrosis and cell differentiation. However, whether it regulates the differentiation of BMSCs toward myofibroblasts remains to be defined. Methods: Carbon tetrachloride or bile duct ligation was used to induce mouse liver fibrosis. Expressions of PPARγ, α-smooth muscle actin, collagen α1 (I and collagen α1 (III were detected by real-time RT-PCR and Western blot or immunofluorescence assay. Results: PPARγ expression was decreased in mouse fibrotic liver. In addition, PPARγ was declined during the differentiation of BMSCs toward myofibroblasts induced by transforming growth factor β1. Activation of PPARγ stimulated by natural or synthetic ligands suppressed the differentiation of BMSCs. Additionally, knock down of PPARγ by siRNA contributed to BMSC differentiation toward myofibroblasts. Furthermore, PPARγ activation by natural ligand significantly inhibited the differentiation of BMSCs toward myofibroblasts in liver fibrogenesis and alleviated liver fibrosis. Conclusions: PPARγ negatively regulates the differentiation of BMSCs toward myofibroblasts, which highlights a further mechanism implicated in the BMSC differentiation.

  11. Development of a cell-based high-throughput peroxisome proliferator-activated receptors (PPARs) screening model and its application for evaluation of the extracts from Rhizoma Coptis.

    Science.gov (United States)

    Xia, Zhi-Ning; Lin, Ye-Xin; Guo, Li-Xia; Yang, Feng-Qing; Xu, Pan; Zhang, Yong-Lan; Liu, Jian-Hui

    2013-01-01

    To date, peroxisome proliferator-activated receptors (PPARs) are becoming the new therapeutic targets for the treatment of metabolic diseases, such as Type 2 diabetes, obesity, and cardiovascular disease. In this study, a cell-based high-throughput PPARs (PPARα/β/γ) model was developed for the screening of PPARs agonists. The screening conditions were evaluated through analyzing the expression value of luciferase. Finally, 24 h of drug acting time, 5 times of the dilution factor of luciferase zymolyte, and about 2 × 10(4) cells/ well on HeLa cells in 96-well plates were used, respectively. Furthermore, the quality of high-throughput screening (HTS) in stability and reliability was evaluated by the Z'-factor. Additionally, different extracts of Rhizoma Coptis and berberine were tested by the developed method. The results suggested that both the EtOAc extract and berberine were able to activate PPARα/β/γ, and Rhizoma Coptis contains potential natural agonists of PPARs besides berberine. In conclusion, the developed HTS assay is a simple, rapid, stable, and specific method for the screening of PPARs natural agonists.

  12. Peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARβ/δ) gene expression profile on ram spermatozoa and their relation to the sperm motility.

    Science.gov (United States)

    Kadivar, Ali; Heidari Khoei, Heidar; Hassanpour, Hossein; Ghanaei, Hamid; Golestanfar, Arefeh; Mehraban, Hossein; Davoodian, Najmeh; Dehghani Tafti, Roohollah

    2016-01-01

    Peroxisome proliferator-activated receptors (PPARs) are a member of nuclear receptors superfamily, which mainly regulate the expression of target genes involved in lipid and energy metabolism. These receptors are divided to three isotypes: PPARα, PPARγ and PPARβ/δ. Each isotype has a distinct tissue distribution relating to the distinct functions. In this study, the mRNA abundance for PPARα, PPARγ and PPARβ/δ was evaluated and compared with high and low motile ram spermatozoa. Semen samples from 6 adult rams were fractionated on a two layer discontinuous Percoll gradient to high and low motile sperm and quantitative parameters of sperm motility were determined by CASA. Total RNA was extracted and the mRNA abundance for each gene was measured by relative quantification technique with Real time PCR. The levels of three isotypes of PPAR transcripts were significantly higher in high motile semen samples using quantitative RT-PCR. Some of sperm motility indices were also significantly correlated with PPARα and PPARγ relative expression. This study revealed the novel association of PPAR gene isotypes with sperm motility. Data from our study suggested PPARs are one of the possible factors that can be studied in male infertility.

  13. Ginsenoside 20S-protopanaxatriol (PPT) activates peroxisome proliferator-activated receptor gamma (PPARgamma) in 3T3-L1 adipocytes.

    Science.gov (United States)

    Han, Kyu Lee; Jung, Myeong Ho; Sohn, Jong Hee; Hwang, Jae-Kwan

    2006-01-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of the nuclear receptor of ligand-activated transcription factors, regulates the expression of key genes involved in lipid and glucose metabolism or adipocyte differentiation. Ligands for this receptor have emerged as potent insulin sensitizers used in the treatment of Type2 diabetes. Ginseng saponins or ginsenosides are reported to provide anti-diabetic activity as well as to modulate glucose metabolism, although the mechanism remains unclear. In this study, we examined the effect of ginsenosides on activation of PPARgamma and adipogenes in 3T3-L1. Using a GAL-4/PPARgamma transactivation assay, 20(S)-protopanaxatriol (PPT), one of the ginsenoside metabolites, was found to increase PPARgamma-transactivation activity dose-dependently with similar activity as troglitazone, a well-known PPARgamma agonist. PPT enhanced adipogenesis by increasing the expression of PPARgamma target genes such as aP2, LPL and PEPCK. Furthermore, PPT significantly increased expression of glucose transporter 4 (GLUT4). These results indicate that PPT can be developed as a PPARgamma agonist for the improvement of insulin resistance associated with diabetes.

  14. Caffeic Acid Inhibits UVB-induced Inflammation and Photocarcinogenesis Through Activation of Peroxisome Proliferator-activated Receptor-γ in Mouse Skin.

    Science.gov (United States)

    Balupillai, Agilan; Prasad, Rajendra N; Ramasamy, Karthikeyan; Muthusamy, Ganesan; Shanmugham, Mohana; Govindasamy, Kanimozhi; Gunaseelan, Srithar

    2015-11-01

    In this study, the effect of caffeic acid (CA) on both acute and chronic UVB-irradiation-induced inflammation and photocarcinogenesis was investigated in Swiss albino mice. Animals were exposed to 180 mJ cm(-2) of UVB once daily for 10 consecutive days and thrice weekly for 30 weeks for acute and chronic study respectively. UVB exposure for 10 consecutive days showed edema formation, increased lipid peroxidation and decreased antioxidant status with activation of inflammatory molecules such as TNF-α, IL-6, COX-2 and NF-κB. However, CA (15 mg per kg.b.wt.) administration before each UVB exposure decreased lipid peroxidation, inflammatory markers expression and enhanced antioxidant status probably through the activation of peroxisome proliferator-activated receptors (PPARγ) in the mice skin. PPARγ is considered a potential target for photochemoprevention because it inhibits UVB-mediated inflammatory responses. In this study, UVB exposure for 30 weeks caused squamous cell carcinoma and upregulation of iNOS, VEGF and TGF-β and downregulation of p53 and tumor incidence in the mice skin. Both topical (CAT) and intraperitoneal (CAIP) treatment before each UVB exposure downregulates iNOS, VEGF, TGF-β, upregulates p53 and reduces tumors multiplicity in the mice skin. Thus, CA offers protection against UVB-induced photocarcinogenesis probably through activation of anti-inflammatory transcription factor PPARγ in the mice.

  15. Peroxisome Proliferator Activator Receptor (PPAR-γ Ligand, but Not PPAR-α, Ameliorates Cyclophosphamide-Induced Oxidative Stress and Inflammation in Rat Liver

    Directory of Open Access Journals (Sweden)

    Azza A. K. El-Sheikh

    2014-01-01

    Full Text Available Hepatoprotective potential of peroxisome proliferator activator receptor (PPAR-α and -γ agonists, fenofibrate (FEN, and pioglitazone (PIO, respectively, against cyclophosphamide (CP-induced toxicity has been investigated in rat. FEN and PIO (150 and 10 mg/kg/day, resp. were given orally for 4 weeks. In separate groups, CP (150 mg/kg, i.p. was injected as a single dose 5 days before the end of experiment, with or without either PPAR agonist. CP induced hepatotoxicity, as it caused histopathological alterations, with increased serum alanine and aspartate transaminases, total bilirubin, albumin, alkaline phosphatase and lactate dehydrogenase. CP caused hepatic oxidative stress, indicated by decrease in tissue reduced glutathione, with increase in malondialdehyde and nitric oxide levels. CP also caused decrease in hepatic antioxidant enzyme levels, including catalase, superoxide dismutase, glutathione peroxidase, and glutathione S-transferase. Furthermore, CP increased serum and hepatic levels of the inflammatory marker tumor necrosis factor (TNF-α, evaluated using ELISA. Preadministration of PIO, but not FEN, prior to CP challenge improved hepatic function and histology, and significantly reversed oxidative and inflammatory parameters. In conclusion, activation of PPAR-γ, but not PPAR-α, conferred protection against CP-induced hepatotoxicity, via activation of antioxidant and anti-inflammatory mechanisms, and may serve as supplement during CP chemotherapy.

  16. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha increased apoptosis of human endometrial cancer HEC-1A cells

    Directory of Open Access Journals (Sweden)

    Yang H

    2016-08-01

    Full Text Available Hui Yang, Rui Yang, Hao Liu, Zhongqian Ren, Cuicui Wang, Da Li, Xiaoxin Ma Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, People’s Republic of China Background: Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α coactivates multiple transcription factors and regulates several metabolic processes. In this study, we focused on the roles of PGC-1α in the apoptosis of endometrial cancer HEC-1A cells. Materials and methods: PGC-1α expression in the HEC-1A cells was detected with real-time polymerase chain reaction and Western blot. Small interfering RNA directed against PGC-1α was designed and synthesized, and RNA interference technology was used to knock down PGC-1α mRNA and protein expression. Cell apoptosis, cell cycle, and mitochondrial membrane potential were then analyzed using flow cytometry. The expression of apoptotic proteins, Bcl-2 and Bax, was detected with Western blot. Results: The specific downregulation of PGC-1α expression in the HEC-1A cells increased their apoptosis through the mitochondrial apoptotic pathway by reducing the expression of Bcl-2 and increasing the expression of Bax. Conclusion: These results suggest that PGC-1α influences the apoptosis of HEC-1A cells and also provides a molecular basis for further investigation of the apoptotic mechanism in human endometrial cancer. Keywords: endometrial cancer, PGC-1α, apoptosis, Bcl-2, Bax

  17. Two Isomeric C16 Oxo-Fatty Acids from the Diatom Chaetoceros karianus Show Dual Agonist Activity towards Human Peroxisome Proliferator-Activated Receptors (PPARs α/γ

    Directory of Open Access Journals (Sweden)

    Angel Moldes-Anaya

    2017-05-01

    Full Text Available The peroxisome proliferator-activated receptors (PPARs function as ligand-activated transcription factors that convert signals in the form of lipids to physiological responses through the activation of metabolic target genes. Due to their key roles in lipid and carbohydrate metabolism, the PPARs are important drug targets. However, for several of the PPAR drugs currently in use, adverse side effects have been reported. In an effort to identify compounds from marine organisms that may serve as molecular scaffolds for the development of novel and safer PPAR-targeting drugs, we performed a bioassay-guided screening of organic extracts made from organisms supplied by the Norwegian Biobank of Arctic Marine Organisms (Marbank. Among several interesting hits, we identified two poorly described isomeric oxo-fatty acids from the microalgae Chaetoceros karianus for which we provide the first evidence that they might display dual specificity towards human PPARα and PPARγ. Principal component analysis showed that C. karianus stood out from other Chaetoceros species, both with respect to the metabolic profile and the PPAR activity. The isolation of these compounds holds the potential of uncovering a PPAR pharmacophore with tunable activity and specificity.

  18. Genetic variants in the epithelial sodium channel associate with oedema in type 2 diabetic patients receiving the peroxisome proliferator-activated receptor gamma agonist farglitazar.

    Science.gov (United States)

    Spraggs, Colin; McCarthy, Alun; McCarthy, Linda; Hong, Guizhu; Hughes, Arlene; Lin, Xiwu; Sathe, Ganesh; Smart, Devi; Traini, Christopher; Van Horn, Stephanie; Warren, Liling; Mosteller, Michael

    2007-12-01

    Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists are highly effective in the treatment of type 2 diabetes. In some patients, PPARgamma ligands are associated with fluid retention/oedema, for which the mechanism is not fully understood. A pharmacogenetic study was undertaken to investigate effects of variations in 21 candidate genes related to epithelial sodium channel (ENaC) pathways on oedema. This study used DNA samples collected from type 2 diabetes phase III clinical trials of the PPARgamma agonist farglitazar (administered alone or in combination with insulin or glyburide) and investigated oedema reported as an adverse event as phenotype. Initial case-control analysis of oedema identified candidate gene single nucleotide polymorphisms with significant associations. These included three polymorphisms in ENaCbeta subunit (SCNN1B) that showed significant associations (Paccounting for clinical factors influencing oedema supported these observations. One of the SCNN1B polymorphisms, at position -405 of the 5' flanking region (rs34241435), was predicted to modify transcriptional interactions and in a transfected COS cell luciferase reporter gene assay exhibited higher promoter activity. These exploratory studies provide clinical pharmacogenetic and functional genomic evidence to support a pivotal role for ENaC regulation in PPARgamma-induced oedema and provide insight into mechanisms and possible management of this side effect.

  19. Relationship between Single Nucleotide Polymorphisms in the Peroxisome Proliferator-Activated Receptor Gamma Gene and Fatty Acid Composition in Korean Native Cattle

    Directory of Open Access Journals (Sweden)

    Jea-young Lee

    2016-02-01

    Full Text Available The peroxisome proliferator-activated receptor gamma (PPARγ gene plays an important role in the biosynthesis process controlled by a number of fatty acid transcription factors. This study investigates the relationships between 130 single-nucleotide polymorphisms (SNPs in the PPARγ gene and the fatty acid composition of muscle fat in the commercial population of Korean native cattle. We identified 38 SNPs and verified relationships between 3 SNPs (g.1159-71208 A>G, g.42555-29812 G>A, and g.72362 G>T and the fatty acid composition of commercial Korean native cattle (n = 513. Cattle with the AA genotype of g.1159-71208 A>G and the GG genotype of g.42555-29812 G>A and g.72362 G>T had higher levels of monounsaturated fatty acids and carcass traits (p<0.05. The results revealed that the 3 identified SNPs in the PPARγ gene affected fatty acid composition and carcass traits, suggesting that these 3 SNPs may improve the flavor and quality of beef in commercial Korean native cattle.

  20. Peroxisome proliferator-activated receptor (PPAR)β/δ, a possible nexus of PPARα- and PPARγ-dependent molecular pathways in neurodegenerative diseases: Review and novel hypotheses.

    Science.gov (United States)

    Aleshin, Stepan; Strokin, Mikhail; Sergeeva, Marina; Reiser, Georg

    2013-10-01

    Peroxisome proliferator-activated receptors (PPARα, -β/δ and -γ) are lipid-activated transcription factors. Synthetic PPARα and PPARγ ligands have neuroprotective properties. Recently, PPARβ/δ activation emerged as the focus of a novel approach for the treatment of a wide range of neurodegenerative diseases. To fill the gap of knowledge about the role of PPARβ/δ in brain, new hypotheses about PPARβ/δ involvement in neuropathological processes are requested. In this paper, we describe a novel hypothesis, claiming the existence of tight interactions between the three PPAR isotypes, which we designate the "PPAR triad". We propose that PPARβ/δ has a central control of the PPAR triad. The majority of studies analyze the regulation only by one of the PPAR isotypes. A few reports describe the mutual regulation of expression levels of all three PPAR isotypes by PPAR agonists. Analysis of these studies where pairwise interactions of PPARs were described allows us to support the existence of the PPAR triad with central role for PPARβ/δ. In the present review, we propose the hypothesis that in a wide range of brain disorders, PPARβ/δ plays a central role between PPARα and PPARγ. Finally, we prove the advantages of the PPAR triad concept by describing hypotheses of PPARβ/δ involvement in the regulation of myelination, glutamate-induced neurotoxicity, and signaling pathways of reactive oxygen species/NO/Ca(2+). Copyright © 2013 Elsevier Ltd. All rights reserved.

  1. Peroxisome proliferator-activated receptors (PPAR) downregulate the expression of pro-inflammatory molecules in an experimental model of myocardial infarction.

    Science.gov (United States)

    Ibarra-Lara, María de la Luz; Sánchez-Aguilar, María; Soria, Elizabeth; Torres-Narváez, Juan Carlos; Del Valle-Mondragón, Leonardo; Cervantes-Pérez, Luz Graciela; Pérez-Severiano, Francisca; Ramírez-Ortega, Margarita Del Carmen; Pastelín-Hernández, Gustavo; Oidor-Chan, Víctor Hugo; Sánchez-Mendoza, Alicia

    2016-06-01

    Myocardial infarction (MI) has been associated with an inflammatory response and a rise in TNF-α, interleukin (IL)-1β, and IL-6. Peroxisome proliferator-activated receptors (PPARs) promote a decreased expression of inflammatory molecules. We aimed to study whether PPAR stimulation by clofibrate decreases inflammation and reduces infarct size in rats with MI. Male Wistar rats were randomized into 3 groups: control, MI + vehicle, and MI + clofibrate (100 mg/kg). Treatment was administered for 3 consecutive days, previous to 2 h of MI. MI induced an increase in protein expression, mRNA content, and enzymatic activity of inducible nitric oxide synthase (iNOS). Additionally, MI incited an increased expression of matrix metalloproteinase (MMP)-2 and MMP-9, intercellular adhesion molecule (ICAM)-1, and IL-6. MI also elevated the nuclear content of nuclear factor-κB (NF-κB) and decreased IκB, both in myocyte nuclei and cytosol. Clofibrate treatment prevented MI-induced changes in iNOS, MMP-2 and MMP-9, ICAM-1, IL-6, NF-κB, and IκB. Infarct size was smaller in clofibrate-treated rats compared to MI-vehicle animals. In silico analysis exhibited 3 motifs shared by genes from renin-angiotensin system, PPARα, iNOS, MMP-2 and MMP-9, ICAM-1, and VCAM-1, suggesting a cross regulation. In conclusion, PPARα-stimulation prevents overexpression of pro-inflammatory molecules and preserves viability in an experimental model of acute MI.

  2. Response to micronized fenofibrate treatment is associated with the peroxisome-proliferator-activated receptors alpha G/C intron7 polymorphism in subjects with type 2 diabetes.

    Science.gov (United States)

    Foucher, Christelle; Rattier, Stephanie; Flavell, David M; Talmud, Philippa J; Humphries, Steve E; Kastelein, John J P; Ayyobi, Amir; Pimstone, Simon; Frohlich, Jiri; Ansquer, Jean-Claude; Steiner, George

    2004-12-01

    The association between polymorphisms in candidate genes related to lipoprotein metabolism and the reduction in plasma triglyceride (TG) in response to fenofibrate treatment was evaluated in subjects with type 2 diabetes treated with micronized fenofibrate (200 mg/day) for at least 3 years in the Diabetes Atherosclerosis Intervention Study. The cholesteryl ester transfer protein Taq1B, LPL S447X, hepatic lipase -514 C-->T, peroxisome-proliferator-activated receptors alpha (PPARA) L162V and G/C intron 7 polymorphisms and the apolipoprotein E2/E3/E4 alleles were genotyped using PCR and restriction enzyme digestion. Subjects were divided into high TG-responders (with > 30% TG relative reduction after treatment) and low TG-responders. The frequency of the PPARA intron 7 G/G genotype was higher in high TG-responders than in low TG-responders (85% vs. 69%, P genetic polymorphisms examined. In stepwise logistic regression, baseline TG and only the PPARA intron 7 polymorphism among the others were selected in the model as significant predictors of TG-response (odds ratio: 3.10, 95% CI: 1.28-7.52, P = 0.012 for PPARA polymorphism). With age, gender, body mass index, smoking status and HbA1c as additional factors, baseline TG (PPPARA gene intron 7 G/G genotype were associated with TG reduction > 30% after fenofibrate treatment in patients with type 2 diabetes.

  3. Interaction Between Peroxisome Proliferator Activated Receptor δ and Epithelial Membrane Protein 2 Polymorphisms Influences HDL-C Levels in the Chinese Population.

    Science.gov (United States)

    Ke, Tingjing; Dorajoo, Rajkumar; Han, Yi; Khor, Chiea-Chuen; van Dam, Rob M; Yuan, Jian-Min; Koh, Woon-Puay; Liu, Jianjun; Teo, Yik Ying; Goh, Daniel Y T; Tai, E Shyong; Wong, Tien Yin; Cheng, Ching-Yu; Friedlander, Yechiel; Heng, Chew-Kiat

    2016-09-01

    Peroxisome proliferator activated receptors (PPARs) are transcription factors involved in the regulation of key metabolic pathways. Numerous in vivo and in vitro studies have established their important roles in lipid metabolism. A few SNPs in PPAR genes have been reported to be associated with lipid levels. In this study, we aimed to investigate the interactive effects between single nucleotide polymorphisms (SNPs) in three PPAR isoforms α/δ/γ and other genetic variants across the genome on plasma high-density lipoprotein-cholesterol (HDL-C) levels. Study subjects (N = 2003) were genotyped using Illumina HumanOmniZhongHua-8 Beadchip. Fifty-three tag SNPs ± 100 kb of PPAR α, δ, and γ (r(2) PPARδ SNP rs2267668 and epithelial membrane protein 2 (EMP2) downstream SNP rs7191411 (N = 1993, β = 0.74, adjusted P = 0.022). This interaction was successfully replicated in the meta-analysis of two additional Chinese cohorts (N = 3948, P = 0.01). The present study showed a novel SNP × SNP interaction between rs2267668 in PPARδ and rs7191411 in EMP2 that has significant impact on circulating HDL-C levels in the Singaporean Chinese population. © 2016 John Wiley & Sons Ltd/University College London.

  4. HIV-1 Nef protein in the nucleus influences adipogenesis as well as viral transcription through the peroxisome proliferator-activated receptors.

    Science.gov (United States)

    Otake, Kaori; Omoto, Shinya; Yamamoto, Takuya; Okuyama, Harumi; Okada, Hidechika; Okada, Noriko; Kawai, Masahiro; Saksena, Nitin K; Fujii, Yoichi R

    2004-01-23

    Although the HIV-1 Nef protein (27 kDa) localizes primarily in cytoplasm, there is considerable evidence suggesting its occasional localization in the nucleus. Nef is known to play an important role in transcriptional events and viral replication, but the actual target of Nef in the nucleus remains to be identified. To examine the functional roles of Nef in the nucleus and its possible interactions with other unknown factors in the nucleus. High-density microarray analysis was used to screen directly the unique functions of Nef on host gene transcription. The nuclear localization of Nef and its effects on the expression of peroxisome proliferator-activated receptors (PPAR) was examined using PPAR promoter/reporter assay and immunoblotting. A long terminal repeat/reporter assay was used to investigated the effects of Nef and PPAR on viral transcription. Nef in the nucleus suppressed PPAR gamma expression and reduced fatty acid levels in human T and macrophage cell lines. Expression of Nef or PPAR suppressed viral replication; the effect of PPAR gamma or retinoid X receptor-alpha on viral replication were reduced by coexpression of Nef in MT(-)4 T cells. Nef may be involved in both viral replication and the wasting syndrome associated with AIDS.

  5. Distribution and genotype frequency of the C1431T and pro12ala polymorphisms of the peroxisome proliferator activator receptor gamma gene in an Iranian population.

    Science.gov (United States)

    Rooki, Hassan; Haerian, Monir-Sadat; Azimzadeh, Pedram; Ebrahimi, Mahmoud; Mirhafez, Reza; Ferns, Gordon; Ghayour-Mobarhan, Majid; Zali, Mohammad-Reza

    2013-10-01

    Peroxisome proliferator activator receptor gamma (PPARγ) is a nuclear transcription factor regulating multiple genes involved in cell growth, differentiation, carbohydrate and lipid metabolism and energy production. Several genetic variations in the PPARγ gene have been identified to be associated with diabetes, obesity, dyslipidemia, insulin resistance, metabolic syndrome and coronary artery disease. The present study was designed to explore the distribution of two common single nucleotide polymorphisms of the PPARγ gene (C1431T and Pro12Ala) in an Iranian population. Genotype frequencies for these two polymorphisms were compared for 160 healthy Iranian individuals with reports from other populations. The Genotyping was performed using real-time polymerase chain reaction. The genotype distribution of the C1431T PPARγ polymorphism was 0.869 for the CC genotype, 0.119 for the CT genotype and 0.013 for uncommon TT genotype. Allelic frequencies were 0.93 for C and 0.07 for T allele respectively. For the Pro12Ala polymorphism of PPARγ gene, genotypic distributions and allelic frequencies were, 0.813 for CC, 0.181 for CG and 0.06 for GG and 0.903 for C and 0.097 for G respectively. Allelic and genotypic frequencies for both polymorphisms of PPARγ gene were in Hardy-Weinberg equilibrium. Iran is a country with an ethnically diverse population and a comparison of allelic and genotypic frequencies of PPARγ C1431T and Pro12Ala polymorphisms between our population and others showed significant differences.

  6. Interaction of maternal peroxisome proliferator-activated receptor gamma2 Pro12Ala polymorphism with fetal sex affects maternal glycemic control during pregnancy.

    Science.gov (United States)

    Hocher, Berthold; Schlemm, Ludwig; Haumann, Hannah; Poralla, Christine; Chen, You-Peng; Li, Jian; Guthmann, Florian; Bamberg, Christian; Kalache, Karim D; Pfab, Thiemo

    2010-02-01

    It was suggested that fetal sex may substantially affect maternal glycemic control during pregnancy in genetically susceptible mothers. The peroxisome proliferator-activated receptor gamma2 (PPARgamma2) Pro12Ala polymorphism is known to affect glycemic control and may act in a sex-specific manner. This polymorphism is thus an attractive candidate to test this hypothesis using a second independent functionally relevant polymorphism. We analyzed the impact of fetal sex on maternal glycemic control during pregnancy in relation to the maternal PPARgamma2 Pro12Ala polymorphism. Two-thousand fourteen Caucasian women without preexisting diabetes and preexisting hypertension with singleton pregnancies delivering consecutively at the Charité obstetrics department were genotyped. Glycemic control was analyzed by measuring total glycated hemoglobin at birth. Correction for confounding factors and multiple testing was considered in the analysis. The maternal PPARgamma2 Pro12Ala polymorphism without consideration of fetal sex had no effect on blood pressure, new onset of proteinuria and total glycated hemoglobin at delivery. Mothers carrying both G alleles (GG genotype) delivering a girl had a higher (P = 0.015) total glycated hemoglobin (6.81 or - 0.50%) versus mothers carrying the same alleles but delivering boys (5.85 + or - 0.58%). Comparing mothers with the GG genotype delivering girls with mothers with CC or CG genotypes also delivering girls (6.32 + or - 0.72%) revealed a significantly higher maternal total glycated hemoglobin at delivery in the former group (P Pro12Ala polymorphism.

  7. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala: lack of association with weight gain in psychiatric inpatients treated with olanzapine or clozapine.

    Science.gov (United States)

    Staeker, Julia; Leucht, Stefan; Steimer, Werner

    2012-04-01

    Weight gain is a common problem of treatment with atypical antipsychotics. However, the dimension of body weight change differs interindividually, and various genetic factors are considered to be associated with this effect. Peroxisome proliferator-activated receptor gamma (PPARG) Pro12Ala polymorphism and its reported relationship to type 2 diabetes susceptibility and body mass accumulation prompted us to investigate the impact of this single nucleotide polymorphism (SNP) on antipsychotic-induced changes of body weight and body mass index (BMI) in a naturalistic study design. Included were 138 olanzapine- and 32 clozapine-treated psychiatric inpatients whose demographic data, medical anamnesis, and drug treatment were assessed at admission to hospital and 4 weeks thereafter. The PPARG Pro12Ala SNP was determined with a validated real-time PCR assay. In contrast to previous investigations, we did not detect significant variations of weight gain among the different PPARG Pro12Ala genotypes. Our results suggest that the examined polymorphism appears to play a minor or no role in clinical practice concerning antipsychotic drug-induced weight gain.

  8. 过氧化物酶体增殖物激活受体-γ及核因子-κB在特应性皮炎患者皮损中的表达及意义%Expression and role of peroxisome proliferator-activated receptor-γand nuclear factor-κB in the skin lesions of patients with atopic dermatitis

    Institute of Scientific and Technical Information of China (English)

    黎志刚; 吴江; 刘衍彬; 许志萍; 郑学毅; 孙广政

    2013-01-01

      目的观察过氧化物酶体增殖物激活受体-γ(PPAR-γ)及核因子-κB (NF-κB)在特应性皮炎患者皮损中的表达情况,探讨其在特应性皮炎发病中的作用。方法采用免疫组化Western blotting法检测22例特应性皮炎患者皮损及非皮损,以及12名正常皮肤组织中PPAR-γ、NF-κB的表达。结果特应性皮炎患者皮损组PPAR-γ的阳性表达计数为0.738±0.069,低于正常对照组的0.869±0.048和非皮损组的0.802±0.026(P<0.05);特应性皮炎患者皮损组NF-κB的阳性表达计数为0.937±0.039,高于正常对照组的0.735±0.015和非皮损组的0.796±0.068(P<0.05);特应性皮炎患者皮损组PPAR-γ和NF-κB表达呈负相关(P<0.05)。结论特应性皮炎患者皮损组PPAR-γ表达减弱、NF-κB表达增强在发病过程中可能起一定的作用,为特应性皮炎患者的临床治疗提供了新的思路。%  Objective To evaluate the expression of peroxisome proliferator-activated receptor-γ(PPAR-γ) and nuclear factor-κB (NF-κB) in the skin lesions of patients with atopic dermatitis, and to explore their effect on the pathogenesis of atopic dermatitis. Methods Immunohistochemistry and Western blotting was perform on the investigate the PPAR-γand NF-κB expression in lesions specimens and non-lesions specimens from 22 cases of atopic dermatitis and 12 cases of normal skin tissue. Results The positive score of PPAR-γ(0.738±0.069) in the skin lesions of patients with atopic dermatitis was lower than the normal control group (0.869±0.048, P<0.05) and non-lesional group (0.802±0.026, P<0.05). The positive score of NF-κB (0.937±0.039) in the skin lesions of patients with atopic dermatitis was higher than the normal control group ( 0.735±0.015, P<0.05) and non-lesional group(0.796±0.068, P<0.05). There was negative correlation between PPAR-γand NF-κB expression in atopic dermatitis patients with lesions group (P<0.05). Conclusion

  9. Decreased hepatic peroxisome proliferator-activated receptor-γ contributes to increased sensitivity to endotoxin in obstructive jaundice

    Institute of Scientific and Technical Information of China (English)

    Xin Lv; Jian-Gang Song; Hong-Hai Li; Jun-Ping Ao; Ping Zhang; Ye-Sheng Li; Shao-Li Song; Xiang-Rui Wang

    2011-01-01

    AIM:To investigate the role of hepatic peroxisome proliferator-activated receptor -γ (PPAR-γ) in increased susceptibility to endotoxin-induced toxicity in rats with bile duct ligation during endotoxemia. METHODS: Male Sprague-Dawley rats were subjected to bile duct ligation (BDL). Sham-operated animals served as controls. DNA binding were determined by polymerase chain reaction, Western blotting analysis, and electrophoretic mobility shift assay, respectively. BDL and sham-operated rats received a non-lethal dose of intraperitoneal lipopolysaccharide (LPS) injection (3 mg/kg, i.p.). Additionally, the potential beneficial effects of the PPAR-γ agonist rosiglitazone were determined in BDL and sham-operated rats treated with a non-lethal dose of LPS. Survival was assessed in BDL rats treated with a non-lethal dose of LPS and in sham-operated rats treated at a lethal dose of LPS (6 mg/kg, i.p.). RESULTS: PPAR-γ activity in rats undergoing BDL was significantly lower than in the sham-controls. Hepatic PPAR-γ gene expression was downregulated at both the mRNA and protein levels. In a parallel group, serum levels of pro-inflammatory cytokines were nearly undetectable in the sham-operated rats. When challenged with a non-lethal dose of LPS (3 mg/kg), the BDL rats had approximately a 2.4-fold increase in serum IL-6, a 2.7 fold increase in serum TNF-α, 2.2-fold increase in serum IL-1 and 4.2-fold increase in serum ALT. The survival rate was significantly lower as compared with that in sham-operated group. Additionally, rosiglitazone significantly reduced the concentration of TNF-α, IL-1β, IL-6 and ALT in sham-operated rats, but not in BDL rats, in response to LPS (3 mg/kg). Also, the survival was improved by rosiglitazone in sham-operated rats challenged with a lethal dose of LPS, but not in BDL rats, even with a non-lethal dose of LPS (3 mg/kg). CONCLUSION: Obstructive jaundice downregulates hepatic PPAR-γ expression, which in turn may contribute to

  10. Role of peroxisome proliferator-activated receptor a activation in acute myocardial damage induced by isoproterenol in rats

    Institute of Scientific and Technical Information of China (English)

    YUAN Jie; WU Jian; HANG Zhi-gang; ZHONG Xue-kuan; ZHOU Ling-wang; YU Bo

    2008-01-01

    Background Peroxisome proliferator-activated receptor(PPAR)a is one of the subtypes of PPARs.It regulates metabolism of lipid and lipoprotein,as well as glucose homeostasis.In addition,PPARa influences cellular proliferation, inflammation,differentiation and apoptosis,which plays a vital role in cardiovascular diseases.The purpose of this study was to investigate the role and mechanisms of PPARa activation in relation to acute myocardial damage induced by isoproterenol in rats.Methods Thirty male Wister rats were randomly divided into controI group,isoproterenol (Iso)injured group and fenofibrate(FF)treatment group.Acute myocardiaI damage caused by isoproterenol intraperitoneaI injection induced ischemia was established.We determined the levels of creatine kinase(CK)and lactic dehvdroqenase(LDH)in serum as welI as the concentrations of free fatty acids(FFA)in serum and myocardium.The mRNA expressions of PPARa, muscular type carnitine palmitransferase(M-CPT-1)and medium chain lipid acetyl coenzyme A dehydrogenase(MCAD) were analyzed by reverse transcription-polymerase chain reaction(RT-PCR).Results Compared with the control group.the Ievels of serum CK and LDH were significantly increased after FF and ISO treatments.Moreover.the concentrations of FFA in both serum and myocardium were obviously increased in the ISO group and FF group,while the mRNA expressions of PPARa,M-CPT-I and MCAD declined,respectively(P≤0.01).When compared with the lSO group.significant decreases in serum CK and LDH were obsewed in the FF group.The concentrations of FFA both in serum and myocardiaI tissue were markedly decreased in the FF group.while the expressions of PPARo.M-CPT-I and MCAD mRNA were increased(vs Iso,P≤O.01).Conclusions The utilization of FFA was reduced in isoproterenol induced acute myocardial damage.PPARa activation by its activator fenofibrate may play a key role in energy metabolism in acute myocardial damage induced by isoproterenol in rats.

  11. Expression for peroxisome proliferator-activated receptor gamma in pituitary adenomas 38 cases for semi-quantitative immunohistochemical analysis

    Institute of Scientific and Technical Information of China (English)

    Xiaojie Lu; Kailai Chen; Weiyang Ji; Qing Wang; Bing Li; Jiang'an Li; Jiyong Sun

    2008-01-01

    BACKGROUND:It has been reposed that peroxisome proliferator-activated receptor γ(PPAR γ)is highly expressed in lung cancer,colon cancer,and gastric cancer,as well as other tumors.OBJECTIVE:To study expression of PPAR γ in pituitary adenomas and analyze the role of PPAR γ in hormonal typing of pituitary adenomas.DESIGN,TIME AND SETTING:Semi-quantitative immunohistochemistry of pathological specimens.The experiment was conducted at the Department of Neurosurgery,Wuxi Second Hospital Affiliated to Nanjing Medical University between January 2002 and May 2005.MATERIALS:Surgical resection samples of pituitary adenomas from 38 cases(18 male and 20 female)were analyzed.Eight cases were determined to be invasive pituitary adenomas and 30 cases were non-invasive pituitary adenomas.Hormonal classification of the types of pituitary adenomas revealed somatotrophic adenomas in six cases,corticotrophic adenoma in five cases,prolactinomas in 13 cases,multi-hormone secreting adenomas in six cases,and eight cases of adenoma without altered endocrine function.Five autopsy specimens were collected dunng the same period from patients of matching age that died from unrelated diseases and were included as normal anterior pituitary controls.METHODS:Cell counts for positive immunohistochemical signals were recorded from histopathological sections.The percentage of positive cells was reported as a semi-quantitative analysis.MAIN OUTCOME MEASURES:The rate of PPAR γ positive cells in different types of adenoma was based on hormonal levels and invasiveness of pituitary tumor cells.RESULTS:All tumor biopsies were determined to express PPAR γ.T1le rate of PPAR γ-positive cells ranged between 8%-65% in the pituitary adenomas.According to hormonal type,PPAR γ expression did not vary between the groups.In addition.there was no significant difference in PPAR γ expression between the non-invasive and invasive pituitary adenomas.CONCLUSIONS:Human pituitary adenomas express PPAR γ,and this

  12. Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha

    Directory of Open Access Journals (Sweden)

    Li Jin-Lian

    2012-03-01

    Full Text Available Abstract Background Excessive oxidative stress and lipid peroxidation have been demonstrated to play important roles in the production of liver damage. L-carnitine is a natural substance and acts as a carrier for fatty acids across the inner mitochondrial membrane for subsequent beta-oxidation. It is also an antioxidant that reduces metabolic stress in the cells. Recent years L-carnitine has been proposed for treatment of various kinds of disease, including liver injury. This study was conducted to evaluate the protective effect of L-carnitine against hydrogen peroxide (H2O2-induced cytotoxicity in a normal human hepatocyte cell line, HL7702. Methods We analyzed cytotoxicity using MTT assay and lactate dehydrogenase (LDH release. Antioxidant activity and lipid peroxidation were estimated by reactive oxygen species (ROS levels, activities and protein expressions of superoxide dismutase (SOD and catalase (CAT, and malondialdehyde (MDA formation. Expressions of peroxisome proliferator-activated receptor (PPAR-alpha and its target genes were evaluated by RT-PCR or western blotting. The role of PPAR-alpha in L-carnitine-enhanced expression of SOD and CAT was also explored. Statistical analysis was performed by a one-way analysis of variance, and its significance was assessed by Dennett's post-hoc test. Results The results showed that L-carnitine protected HL7702 cells against cytotoxity induced by H2O2. This protection was related to the scavenging of ROS, the promotion of SOD and CAT activity and expression, and the prevention of lipid peroxidation in cultured HL7702 cells. The decreased expressions of PPAR-alpha, carnitine palmitoyl transferase 1 (CPT1 and acyl-CoA oxidase (ACOX induced by H2O2 can be attenuated by L-carnitine. Besides, we also found that the promotion of SOD and CAT protein expression induced by L-carnitine was blocked by PPAR-alpha inhibitor MK886. Conclusions Taken together, our findings suggest that L-carnitine could protect HL

  13. The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.

    Science.gov (United States)

    Yoo, Hong Sik; Cichocki, Joseph A; Kim, Sungkyoon; Venkatratnam, Abhishek; Iwata, Yasuhiro; Kosyk, Oksana; Bodnar, Wanda; Sweet, Stephen; Knap, Anthony; Wade, Terry; Campbell, Jerry; Clewell, Harvey J; Melnyk, Stepan B; Chiu, Weihsueh A; Rusyn, Ivan

    2015-10-01

    Exposure to the ubiquitous environmental contaminant trichloroethylene (TCE) is associated with cancer and non-cancer toxicity in both humans and rodents. Peroxisome proliferator-activated receptor-alpha (PPARα) is thought to be playing a role in liver toxicity in rodents through activation of the receptor by the TCE metabolite trichloroacetic acid (TCA). However, most studies using genetically altered mice have not assessed the potential for PPARα to alter TCE toxicokinetics, which may lead to differences in TCA internal doses and hence confound inferences as to the role of PPARα in TCE toxicity. To address this gap, male and female wild type (129S1/SvImJ), Pparα-null, and humanized PPARα (hPPARα) mice were exposed intragastrically to 400 mg/kg TCE in single-dose (2, 5 and 12 h) and repeat-dose (5 days/week, 4 weeks) studies. Interestingly, following either a single- or repeat-dose exposure to TCE, levels of TCA in liver and kidney were lower in Pparα-null and hPPARα mice as compared with those in wild type mice. Levels of trichloroethanol (TCOH) were similar in all strains. TCE-exposed male mice consistently had higher levels of TCA and TCOH in all tissues compared with females. Additionally, in both single- and repeat-dose studies, a similar degree of induction of PPARα-responsive genes was observed in liver and kidney of hPPARα and wild type mice, despite the difference in hepatic and renal TCA levels. Additional sex- and strain-dependent effects were observed in the liver, including hepatocyte proliferation and oxidative stress, which were not dependent on TCA or TCOH levels. These data demonstrate that PPARα status affects the levels of the putative PPARα agonist TCA following TCE exposure. Therefore, interpretations of studies using Pparα-null and hPPARα mice need to consider the potential contribution of genotype-dependent toxicokinetics to observed differences in toxicity, rather than attributing such differences only to receptor

  14. Identification of glabridin as a bioactive compound in licorice (Glycyrrhiza glabra L.) extract that activates human peroxisome proliferator-activated receptor gamma (PPARγ).

    Science.gov (United States)

    Rebhun, John F; Glynn, Kelly M; Missler, Stephen R

    2015-10-01

    Licorice, the root and stolons of the Glycyrrhiza plant (Fabaceae), has been used for centuries as a food additive (sweetener), in cosmetics, and in traditional medicine. In this research, we provide evidence that licorice extract activates peroxisome proliferator-activated receptor gamma (PPARγ) and, as identified through HPLC fractionation and mass spectroscopy, one of the activating phytochemicals is glabridin. Glabridin was shown to bind to and activate PPARγ. It was also shown to activate PPARγ-regulated gene expression in human hepatoma cells similar to known PPARγ ligands and that the expression was blocked by a PPARγ specific antagonist.

  15. Association of peroxisome proliferator-activated receptor single-nucleotide polymorphisms and gene-gene interactions with the lipoprotein(a)

    Institute of Scientific and Technical Information of China (English)

    解惠坚

    2014-01-01

    Objective To examine the associations of 10 singlenucleotide polymorphisms(SNPs)in peroxisome proliferator-activated receptor(PPARs)gene with lipoprotein(a)level,and to investigate if there is gene-gene interaction among the SNPs on lipoprotein(a)level.Methods Totally 644 subjects(234 men and 410 women)were enrolled from Prevention of Multiple Metabolic Disorders and Metabolic Syndrome Study Cohort,which was an urban community survey study conducted in Jiangsu province.Ten SNPs in PPARα(rs135539,rs4253778,

  16. Discovery of New Drugs That Target Peroxisomal Proliferator-Activated Receptor Gamma (PPAR-Gamma) for the Treatment of Breast Tumors

    Science.gov (United States)

    2001-09-01

    Aug 01) 4. TITLE AND SUBTITLE 5. FUNDING NUMBERS Discovery of New Drugs that Target Peroxisomal DAMD17-00-1-0686 Proliferator-Activated Receptor...of breast tumor cells and can be used to develop new drugs to treat breast cancer. The specific aims of this proposal are: 1. Evaluate in vitro...Ft. Detrick, MD 21702-5012. AUTHORITY USAMRMC ltr, 28 Aug 2002 THIS PAGE IS UNCLASSIFIED AD Award Number: DAMD17-00-1-0686 TITLE: Discovery of New

  17. A Novel Splicing Variant of Peroxisome Proliferator-Activated Receptor-γ (Pparγ1sv) Cooperatively Regulates Adipocyte Differentiation with Pparγ2

    OpenAIRE

    Yasuhiro Takenaka; Ikuo Inoue; Takanari Nakano; Yuichi Shinoda; Masaaki Ikeda; Takuya Awata; Shigehiro Katayama

    2013-01-01

    Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate expression of a number of genes associated with the cellular differentiation and development. Here, we show the abundant and ubiquitous expression of a newly identified splicing variant of mouse Pparγ (Pparγ1sv) that encodes PPARγ1 protein, and its importance in adipogenesis. The novel splicing variant has a unique 5'-UTR sequence, relative to those of Pparγ1 and Pparγ2 mRNAs, indicating the presence of a ...

  18. β-Arrestin-1 Protein Represses Adipogenesis and Inflammatory Responses through Its Interaction with Peroxisome Proliferator-activated Receptor-γ (PPARγ)*

    OpenAIRE

    Zhuang, Le-nan; Hu, Wen-Xiang; Xin, Shun-Mei; Zhao,Jian; Pei, Gang

    2011-01-01

    One of the master regulators of adipogenesis and macrophage function is peroxisome proliferator-activated receptor-γ (PPARγ). Here, we report that a deficiency of β-arrestin-1 expression affects PPARγ-mediated expression of lipid metabolic genes and inflammatory genes. Further mechanistic studies revealed that β-arrestin-1 interacts with PPARγ. β-Arrestin-1 suppressed the formation of a complex between PPARγ and 9-cis-retinoic acid receptor-α through its direct interaction with PPARγ. The int...

  19. Curcumin protects neurons against oxygen-glucose deprivation/reoxygenation-induced injury through activation of peroxisome proliferator-activated receptor-γ function.

    Science.gov (United States)

    Liu, Zun-Jing; Liu, Hong-Qiang; Xiao, Cheng; Fan, Hui-Zhen; Huang, Qing; Liu, Yun-Hai; Wang, Yu

    2014-11-01

    The turmeric derivative curcumin protects against cerebral ischemic injury. We previously demonstrated that curcumin activates peroxisome proliferator-activated receptor-γ (PPARγ), a ligand-activated transcription factor involved in both neuroprotective and anti-inflammatory signaling pathways. This study tested whether the neuroprotective effects of curcumin against oxygen-glucose deprivation/reoxygenation (OGD/R)-induced injury of rat cortical neurons are mediated (at least in part) by PPARγ. Curcumin (10 μM) potently enhanced PPARγ expression and transcriptional activity following OGD/R. In addition, curcumin markedly increased neuronal viability, as evidenced by decreased lactate dehydrogenase release and reduced nitric oxide production, caspase-3 activity, and apoptosis. These protective effects were suppressed by coadministration of the PPARγ antagonist 2-chloro-5-nitrobenzanilide (GW9662) and by prior transfection of a small-interfering RNA (siRNA) targeting PPARγ, treatments that had no toxic effects on healthy neurons. Curcumin reduced OGD/R-induced accumulation of reactive oxygen species and inhibited the mitochondrial apoptosis pathway, as indicated by reduced release of cytochrome c and apoptosis-inducing factor and maintenance of both the mitochondrial membrane potential and the Bax/Bcl-2 ratio. Again, GW9662 or PPARγ siRNA transfection mitigated the protective effects of curcumin on mitochondrial function. Curcumin suppressed IκB kinase phosphorylation and IκB degradation, thereby inhibiting nuclear factor-κ B (NF-κB) nuclear translocation, effects also blocked by GW9662 or PPARγ siRNA. Immunoprecipitation experiments revealed that PPARγ interacted with NF-κB p65 and inhibited NF-κB activation. The present study provides strong evidence that at least some of the neuroprotective effects of curcumin against OGD/R are mediated by PPARγ activation.

  20. Peroxisome Proliferator-Activated Receptor γCoactivator 1 α and Insulin Resistance%PGC-1α与胰岛素抵抗

    Institute of Scientific and Technical Information of China (English)

    马慧娟

    2011-01-01

    Peroxisome proliferator-activated receptor "y coactivator la ( PGC-la) is a nuclear transcription co-activator factor. PGC-la can play different functions when combined with different transcription factors. Additionally, genetic and environmental factors can affect the expression of PGC-la. The expression of PGC-la noticeably decreased in patients with insulin resistance and type 2 diabetes. The expression of PGC-la and insulin sensitivity decreased with high lipid intervention. However, physical exercise can increase the expression and improve insulin resistance. The gene polymorphism of PGC-la is closely related to insulin resistance and type 2 diabetes.%过氧化物酶体增生物激活受体y共激活因子1α(PGC-1α),是一种核转录共激活因子,它与不同的转录因子结合发挥不同的功能.PGC-1α在胰岛素抵抗和2型糖尿病人群的表达下降.环境和遗传因素均可影响PGC-1α的表达,高脂使PGC-1α表达下降,降低胰岛素敏感性,而运动可增加PGC-1α表达,改善胰岛素抵抗.PGC-1α的基因多态性与胰岛素抵抗、2型糖尿病密切相关.

  1. Activation of peroxisome proliferator-activated receptor β/δ attenuates acute ischemic stroke on middle cerebral ischemia occlusion in rats.

    Science.gov (United States)

    Chao, Xiaodong; Xiong, Chunlei; Dong, Weifeng; Qu, Yan; Ning, Weidong; Liu, Wei; Han, Feng; Ma, Yijie; Wang, Rencong; Fei, Zhou; Han, Hua

    2014-07-01

    Peroxisome proliferator-activated receptor (PPAR)-β/δ is a transcription factor that belongs to the nuclear hormone receptor family. There is little information about the effects of the immediate administration of specific ligands of PPAR-β/δ (GW0742) in animal models of acute ischemic stroke. Using a rat model of middle cerebral ischemia occlusion (MCAO) in vivo, we have investigated the effect of pretreatment with GW0742 before MCAO. The neuroprotective effect of GW0742 against acute ischemic stroke was evaluated by the neurologic deficit score (NDS), dry-wet weight, and 2,3,5-triphenyltetrazolium chloride staining. The levels of interleukin (IL)-1β, nuclear factor (NF)-κB, and tumor necrosis factor (TNF)-α were detected by an enzyme-linked immunosorbent assay. The expressions of inducible nitric oxide synthase (iNOS), Bax, and Bcl-2 were detected by Western blot. The apoptotic cells were counted by in situ terminal deoxyribonucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay. The pretreatment with GW0742 significantly increased the expression of Bcl-2, and significantly decreased in the volume of infarction, NDS, edema, expressions of IL-1β, NF-κB, TNFα, and Bax, contents of iNOS and the apoptotic cells in infarct cerebral hemisphere compared with rats in the vehicle group at 24 hours after MCAO. The study suggests the neuroprotective effect of the PPAR-β/δ ligand GW0742 in acute ischemic stroke by a mechanism that may involve its anti-inflammatory and antiapoptotic action. Crown Copyright © 2014. Published by Elsevier Inc. All rights reserved.

  2. Identification of Modulators of the Nuclear Receptor Peroxisome Proliferator-Activated Receptor α (PPARα in a Mouse Liver Gene Expression Compendium.

    Directory of Open Access Journals (Sweden)

    Keiyu Oshida

    Full Text Available The nuclear receptor family member peroxisome proliferator-activated receptor α (PPARα is activated by therapeutic hypolipidemic drugs and environmentally-relevant chemicals to regulate genes involved in lipid transport and catabolism. Chronic activation of PPARα in rodents increases liver cancer incidence, whereas suppression of PPARα activity leads to hepatocellular steatosis. Analytical approaches were developed to identify biosets (i.e., gene expression differences between two conditions in a genomic database in which PPARα activity was altered. A gene expression signature of 131 PPARα-dependent genes was built using microarray profiles from the livers of wild-type and PPARα-null mice after exposure to three structurally diverse PPARα activators (WY-14,643, fenofibrate and perfluorohexane sulfonate. A fold-change rank-based test (Running Fisher’s test (p-value ≤ 10-4 was used to evaluate the similarity between the PPARα signature and a test set of 48 and 31 biosets positive or negative, respectively for PPARα activation; the test resulted in a balanced accuracy of 98%. The signature was then used to identify factors that activate or suppress PPARα in an annotated mouse liver/primary hepatocyte gene expression compendium of ~1850 biosets. In addition to the expected activation of PPARα by fibrate drugs, di(2-ethylhexyl phthalate, and perfluorinated compounds, PPARα was activated by benzofuran, galactosamine, and TCDD and suppressed by hepatotoxins acetaminophen, lipopolysaccharide, silicon dioxide nanoparticles, and trovafloxacin. Additional factors that activate (fasting, caloric restriction or suppress (infections PPARα were also identified. This study 1 developed methods useful for future screening of environmental chemicals, 2 identified chemicals that activate or suppress PPARα, and 3 identified factors including diets and infections that modulate PPARα activity and would be hypothesized to affect chemical

  3. Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors.

    Science.gov (United States)

    Qian, Guofeng; Fan, Wei; Ahlemeyer, Barbara; Karnati, Srikanth; Baumgart-Vogt, Eveline

    2015-01-01

    Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat), whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and related gene expression

  4. Down-regulated peroxisome proliferator-activated receptor γ (PPARγ) in lung epithelial cells promotes a PPARγ agonist-reversible proinflammatory phenotype in chronic obstructive pulmonary disease (COPD).

    Science.gov (United States)

    Lakshmi, Sowmya P; Reddy, Aravind T; Zhang, Yingze; Sciurba, Frank C; Mallampalli, Rama K; Duncan, Steven R; Reddy, Raju C

    2014-03-07

    Chronic obstructive pulmonary disease (COPD) is a progressive inflammatory condition and a leading cause of death, with no available cure. We assessed the actions in pulmonary epithelial cells of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear hormone receptor with anti-inflammatory effects, whose role in COPD is largely unknown. We found that PPARγ was down-regulated in lung tissue and epithelial cells of COPD patients, via both reduced expression and phosphorylation-mediated inhibition, whereas pro-inflammatory nuclear factor-κB (NF-κB) activity was increased. Cigarette smoking is the main risk factor for COPD, and exposing airway epithelial cells to cigarette smoke extract (CSE) likewise down-regulated PPARγ and activated NF-κB. CSE also down-regulated and post-translationally inhibited the glucocorticoid receptor (GR-α) and histone deacetylase 2 (HDAC2), a corepressor important for glucocorticoid action and whose down-regulation is thought to cause glucocorticoid insensitivity in COPD. Treating epithelial cells with synthetic (rosiglitazone) or endogenous (10-nitro-oleic acid) PPARγ agonists strongly up-regulated PPARγ expression and activity, suppressed CSE-induced production and secretion of inflammatory cytokines, and reversed its activation of NF-κB by inhibiting the IκB kinase pathway and by promoting direct inhibitory binding of PPARγ to NF-κB. In contrast, PPARγ knockdown via siRNA augmented CSE-induced chemokine release and decreases in HDAC activity, suggesting a potential anti-inflammatory role of endogenous PPARγ. The results imply that down-regulation of pulmonary epithelial PPARγ by cigarette smoke promotes inflammatory pathways and diminishes glucocorticoid responsiveness, thereby contributing to COPD pathogenesis, and further suggest that PPARγ agonists may be useful for COPD treatment.

  5. Peroxisome proliferator-activated receptor-gamma inhibits transformed growth of non-small cell lung cancer cells through selective suppression of Snail.

    Science.gov (United States)

    Choudhary, Rashmi; Li, Howard; Winn, Robert A; Sorenson, Amber L; Weiser-Evans, Mary C M; Nemenoff, Raphael A

    2010-03-01

    Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPARgamma) inhibits transformed growth of non-small cell lung cancer (NSCLC) cell lines in vitro and in vivo. We have demonstrated that activation of PPARgamma promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-kappaB. The Snail family of transcription factors, which includes Snail (Snail1), Slug (Snail2), and ZEB1, is an important regulator of epithelial-mesenchymal transition, as well as cell survival. The goal of this study was to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARgamma activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARgamma activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 and matrix metaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARgamma activators.

  6. Peroxisome Proliferator-Activated Receptor-γ Inhibits Transformed Growth of Non-Small Cell Lung Cancer Cells through Selective Suppression of Snail

    Directory of Open Access Journals (Sweden)

    Rashmi Choudhary

    2010-03-01

    Full Text Available Work from our laboratory and others has demonstrated that activation of the nuclear receptor peroxisome proliferator-activated receptor-γ (PPARγ inhibits transformed growth of non-small cell lung cancer (NSCLC cell lines in vitro and in vivo. We have demonstrated that activation of PPARγ promotes epithelial differentiation of NSCLC by increasing expression of E-cadherin, as well as inhibiting expression of COX-2 and nuclear factor-κB. The Snail family of transcription factors, which includes Snail (Snail1, Slug (Snail2, and ZEB1, is an important regulator of epithelial-mesenchymal transition, as well as cell survival. The goal of this study was to determine whether the biological responses to rosiglitazone, a member of the thiazolidinedione family of PPARγ activators, are mediated through the regulation of Snail family members. Our results indicate that, in two independent NSCLC cell lines, rosiglitazone specifically decreased expression of Snail, with no significant effect on either Slug or ZEB1. Suppression of Snail using short hairpin RNA silencing mimicked the effects of PPARγ activation, in inhibiting anchorage-independent growth, promoting acinar formation in three-dimensional culture, and inhibiting invasiveness. This was associated with the increased expression of E-cadherin and decreased expression of COX-2 and matrix metaloproteinases. Conversely, overexpression of Snail blocked the biological responses to rosiglitazone, increasing anchorage-independent growth, invasiveness, and promoting epithelial-mesenchymal transition. The suppression of Snail expression by rosiglitazone seemed to be independent of GSK-3 signaling but was rather mediated through suppression of extracellular signal-regulated kinase activity. These findings suggest that selective regulation of Snail may be critical in mediating the antitumorigenic effects of PPARγ activators.

  7. High density lipoprotein suppresses lipoprotein associated phospholipase A2 in human monocytes-derived macrophages through peroxisome proliferator-activated receptor-γ pathway

    Institute of Scientific and Technical Information of China (English)

    HAN Guan-ping; REN Jing-yi; QIN Li; SONG Jun-xian; WANG Lan; CHEN Hong

    2012-01-01

    Background Lipoprotein-associated phospholipase A2 (Lp-PLA2) is mainly secreted by macrophages,serving as a specific marker of atherosclerotic plaque and exerting pro-atherogenic effects.It is known that high-density lipoprotein (HDL) plays an important role against atherosclerosis by inhibiting pro-inflammatory factors,however,the relationship between HDL and Lp-PLA2 remains elusive.Methods In this study,reverse transcription-polymerase chain reaction (RT-PCR),Western blotting,and a platelet-activating factor (PAF) acetylhydrolase assay were performed to determine the Lp-PLA2 mRNA level,protein expression and activity in human monocyte-derived macrophages upon HDL treatment of different concentrations and durations.To investigate the underlying mechanism of HDL-induced Lp-PLA2 action,pioglitazone,a peroxisome proliferator-activated receptor-y (PPARy) ligand,was introduced to human monocyte-derived macrophages and mRNA and protein levels of Lp-PLA2,as well as its activity,were determined.Results Lp-PLA2 mRNA levels,protein expression and activity were significantly inhibited in response to HDL treatment in a dose and time dependent manner in human monocyte-derived macrophages.Pioglitazone treatment (1-10 ng/ml) upregulated the Lp-PLA2 mRNA level,protein expression and activity in human monocyte-derived macrophages,while the effects were markedly reversed by HDL.In addition,pioglitazone resulted in a significant increase in PPARY phosphorylation in human monocyte-derived macrophages,which could be inhibited by HDL.Conclusion These findings indicate that HDL suppresses the expression and activity of Lp-PLA2 in human monocyte-derived macrophages,and the underlying mechanisms may be mediated through the PPARY pathway.

  8. Analysis of the heat shock response in mouse liver reveals transcriptional dependence on the nuclear receptor peroxisome proliferator-activated receptor α (PPARα

    Directory of Open Access Journals (Sweden)

    Jonnalagadda Sudhakar

    2010-01-01

    Full Text Available Abstract Background The nuclear receptor peroxisome proliferator-activated receptor alpha (PPARα regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. Many of these genes are also transcriptionally regulated by heat shock (HS through activation by HS factor-1 (HSF1. We hypothesized that there are interactions on a genetic level between PPARα and the HS response mediated by HSF1. Results Wild-type and PPARα-null mice were exposed to HS, the PPARα agonist WY-14,643 (WY, or both; gene and protein expression was examined in the livers of the mice 4 or 24 hrs after HS. Gene expression profiling identified a number of Hsp family members that were altered similarly in both mouse strains. However, most of the targets of HS did not overlap between strains. A subset of genes was shown by microarray and RT-PCR to be regulated by HS in a PPARα-dependent manner. HS also down-regulated a large set of mitochondrial genes specifically in PPARα-null mice that are known targets of PPARγ co-activator-1 (PGC-1 family members. Pretreatment of PPARα-null mice with WY increased expression of PGC-1β and target genes and prevented the down-regulation of the mitochondrial genes by HS. A comparison of HS genes regulated in our dataset with those identified in wild-type and HSF1-null mouse embryonic fibroblasts indicated that although many HS genes are regulated independently of both PPARα and HSF1, a number require both factors for HS responsiveness. Conclusions These findings demonstrate that the PPARα genotype has a dramatic effect on the transcriptional targets of HS and support an expanded role for PPARα in the regulation of proteome maintenance genes after exposure to diverse forms of environmental stress including HS.

  9. Altered promoter recycling rates contribute to dominant-negative activity of human peroxisome proliferator-activated receptor-gamma mutations associated with diabetes.

    Science.gov (United States)

    Li, Gang; Leff, Todd

    2007-04-01

    The transcription factor peroxisome proliferator-activated receptor-gamma (PPARgamma) plays an important role in regulating lipid and glucose metabolism and improves insulin sensitivity in diabetic patients when activated by thiazolidinedione drugs. Several loss-of-function mutations in PPARgamma have been identified that cause lipodystrophy and diabetes in humans. Because affected individuals are heterozygotes and have one normal PPARgamma allele, it is of interest to know whether these mutations act in a dominant-negative fashion to inhibit the activity of the wild-type (WT) receptor. Here we compare the molecular phenotypes of two previously identified PPARgamma mutations: P467L, reported to be dominant negative; and F388L, reported to be devoid of dominant-negative activity. We developed a competitive chromatin immunoprecipitation assay to measure the relative ability of mutant PPARgamma to compete with WT receptor for binding to a PPAR regulatory element (PPRE)-containing promoter. By determining the ratio of mutant and WT receptors bound to a PPRE over time, we estimated the relative promoter turnover rate of each receptor. This assay demonstrated that PPARgamma bearing the P467L had a reduced promoter turnover rate compared with the F388L receptor, and over time out-competed the WT receptor for promoter binding sites. We propose that the P467L receptor is dominant negative because in a cell containing both WT and mutant receptors, the majority of the PPAR-regulated promoters will be occupied by the transcriptionally defective mutant receptor. In contrast, the F388L mutation lacks dominant-negative activity because its more rapid promoter turnover rate prevented it from out-competing the WT receptor for promoter binding sites.

  10. Effect of peroxisome proliferator-activated receptor-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue.

    Science.gov (United States)

    Toyoda, Takuya; Kamei, Yasutomi; Kato, Hirotsugu; Sugita, Satoshi; Takeya, Motohiro; Suganami, Takayoshi; Ogawa, Yoshihiro

    2008-06-01

    This study was designed to examine the effect of peroxisome proliferator-activated receptor-alpha (PPAR-alpha) ligands on the inflammatory changes induced by the interaction between adipocytes and macrophages in obese adipose tissue. PPAR-alpha ligands (Wy-14,643 and fenofibrate) were added to 3T3-L1 adipocytes, RAW264 macrophages, or co-culture of 3T3-L1 adipocytes and RAW264 macrophages in vitro, and monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-alpha) mRNA expression and secretion were examined. PPAR-alpha ligands were administered to genetically obese ob/ob mice for 2 weeks. Moreover, the effect of PPAR-alpha ligands was also evaluated in the adipose tissue explants and peritoneal macrophages obtained from PPAR-alpha-deficient mice. In the co-culture of 3T3-L1 adipocytes and RAW264 macrophages, PPAR-alpha ligands reduced MCP-1 and TNF-alpha mRNA expression and secretion in vitro relative to vehicle-treated group. The anti-inflammatory effect of Wy-14,643 was observed in adipocytes treated with macrophage-conditioned media or mouse recombinant TNF-alpha and in macrophages treated with adipocyte-conditioned media or palmitate. Systemic administration of PPAR-alpha ligands inhibited the inflammatory changes in adipose tissue from ob/ob mice. Wy-14,643 also exerted an anti-inflammatory effect in the adipose tissue explants but not in peritoneal macrophages obtained from PPAR-alpha-deficient mice. This study provides evidence for the anti-inflammatory effect of PPAR-alpha ligands in the interaction between adipocytes and macrophages in obese adipose tissue, thereby improving the dysregulation of adipocytokine production and obesity-related metabolic syndrome.

  11. Transcriptional activation of peroxisome proliferator-activated receptor-{gamma} requires activation of both protein kinase A and Akt during adipocyte differentiation

    Energy Technology Data Exchange (ETDEWEB)

    Kim, Sang-pil [Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine (Korea, Republic of); Ha, Jung Min; Yun, Sung Ji; Kim, Eun Kyoung [MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine (Korea, Republic of); Chung, Sung Woon [Department of Thoracic and Cardiovascular Surgery, Pusan National University School of Medicine (Korea, Republic of); Hong, Ki Whan; Kim, Chi Dae [MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine (Korea, Republic of); Bae, Sun Sik, E-mail: sunsik@pusan.ac.kr [MRC for Ischemic Tissue Regeneration, Medical Research Institute, and Department of Pharmacology, Pusan National University School of Medicine (Korea, Republic of)

    2010-08-13

    Research highlights: {yields} Elevated cAMP activates both PKA and Epac. {yields} PKA activates CREB transcriptional factor and Epac activates PI3K/Akt pathway via Rap1. {yields} Akt modulates PPAR-{gamma} transcriptional activity in concert with CREB. -- Abstract: Peroxisome proliferator-activated receptor-{gamma} (PPAR-{gamma}) is required for the conversion of pre-adipocytes. However, the mechanism underlying activation of PPAR-{gamma} is unclear. Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-{gamma}. Hormonal induction of adipogenesis was blocked by a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002), by a protein kinase A (PKA) inhibitor (H89), and by a Rap1 inhibitor (GGTI-298). Transcriptional activity of PPAR-{gamma} was markedly enhanced by 3-isobutyl-1-methylxanthine (IBMX), but not insulin and dexamethasone. In addition, IBMX-induced PPAR-{gamma} transcriptional activity was blocked by PI3K/Akt, PKA, or Rap1 inhibitors. 8-(4-Chlorophenylthio)-2'-O-methyl-cAMP (8-pCPT-2'-O-Me-cAMP) which is a specific agonist for exchanger protein directly activated by cAMP (Epac) significantly induced the activation of Akt. Furthermore, knock-down of Akt1 markedly attenuated PPAR-{gamma} transcriptional activity. These results indicate that both PKA and Akt signaling pathways are required for transcriptional activation of PPAR-{gamma}, suggesting post-translational activation of PPAR-{gamma} might be critical step for adipogenic gene expression.

  12. Microparticles engineered to highly express peroxisome proliferator-activated receptor-γ decreased inflammatory mediator production and increased adhesion of recipient monocytes.

    Directory of Open Access Journals (Sweden)

    Julie Sahler

    Full Text Available Circulating blood microparticles are submicron vesicles released primarily by megakaryocytes and platelets that act as transcellular communicators. Inflammatory conditions exhibit elevated blood microparticle numbers compared to healthy conditions. Direct functional consequences of microparticle composition, especially internal composition, on recipient cells are poorly understood. Our objective was to evaluate if microparticle composition could impact the function of recipient cells, particularly during inflammatory provocation. We therefore engineered the composition of megakaryocyte culture-derived microparticles to generate distinct microparticle populations that were given to human monocytes to assay for influences recipient cell function. Herein, we tested the responses of monocytes exposed to either control microparticles or microparticles that contain the anti-inflammatory transcription factor, peroxisome proliferator-activated receptor-γ (PPARγ. In order to normalize relative microparticle abundance from two microparticle populations, we implemented a novel approach that utilizes a Nanodrop Spectrophotometer to assay for microparticle density rather than concentration. We found that when given to peripheral blood mononuclear cells, microparticles were preferentially internalized by CD11b+ cells, and furthermore, microparticle composition had a profound functional impact on recipient monocytes. Specifically, microparticles containing PPARγ reduced activated monocyte production of the proinflammatory cytokines interleukin-8 and monocyte chemotactic protein-1 compared to activated monocytes exposed to control microparticles. Additionally, treatment with PPARγ microparticles greatly increased monocyte cell adherence. This change in morphology occurred simultaneously with increased production of the key extracellular matrix protein, fibronectin and increased expression of the fibronectin-binding integrin, ITGA5. PPARγ microparticles

  13. Cloning and expression characterization of peroxisome proliferator-activated receptors (PPARs) with their agonists, dietary lipids, and ambient salinity in rabbitfish Siganus canaliculatus.

    Science.gov (United States)

    You, Cuihong; Jiang, Danli; Zhang, Qinghao; Xie, Dizhi; Wang, Shuqi; Dong, Yewei; Li, Yuanyou

    2017-04-01

    Rabbitfish Siganus canaliculatus is the first marine teleost reported to have the ability of biosynthesizing C20-22 long-chain polyunsaturated fatty acids (LC-PUFA) from C18 precursors, and thus provides a model for studying the regulatory mechanisms of LC-PUFA biosynthesis in teleosts. To investigate the possible roles of peroxisome proliferator-activated receptors (PPARs), critical transcription factors involved in the regulation of lipid metabolism, in the regulation of LC-PUFA biosynthesis in rabbitfish, the PPAR genes were cloned and their expression characterization with PPAR agonists, dietary lipid resource, and ambient salinity were examined. Three cDNA sequences respectively encoding 477, 516 and 519 amino acids of PPARα, PPARβ, and PPARγ isoforms were obtained. PPARα exhibited a wide tissue expression with its highest levels in the heart and brain; PPARβ was predominantly expressed in the gills, while PPARγ was highly expressed in the intestine and gills. In rabbitfish primary hepatocytes, both the PPAR agonists 2-bromopalmitate (2-Bro) and fenofibrate (FF) increased the expression of PPARγ, SREBP1c and Elovl5, whereas FF depressed the expression of Δ6/Δ5 Fad. Moreover, a higher hepatic PPARβ expression was observed in fish fed diets with vegetable oils (VO) than that with fish oil (FO), in the former the expression of PPARα, PPARβ, and PPARγ were increased at the low ambient salinity (10ppt), where an increasing expression of Δ5/Δ6 Fad, Δ4 Fad and Elovl5 genes was previously reported. These results suggest that PPARs might be involved in the upregulation of LC-PUFA biosynthesis with dietary VO and low ambient salinity in rabbitfish.

  14. Expression of peroxisome proliferator-activated receptor gamma (PPARgamma) in human transitional bladder cancer and its role in inducing cell death.

    Science.gov (United States)

    Guan, Y F; Zhang, Y H; Breyer, R M; Davis, L; Breyer, M D

    1999-10-01

    The present study examined the expression and role of the thiazolidinedione (TZD)-activated transcription factor, peroxisome proliferator-activated receptor gamma (PPARgamma), in human bladder cancers. In situ hybridization shows that PPARgamma mRNA is highly expressed in all human transitional epithelial cell cancers (TCCa's) studied (n=11). PPARgamma was also expressed in five TCCa cell lines as determined by RNase protection assays and immunoblot. Retinoid X receptor alpha (RXRalpha), a 9-cis-retinoic acid stimulated (9-cis-RA) heterodimeric partner of PPARgamma, was also co-expressed in all TCCa tissues and cell lines. Treatment of the T24 bladder cancer cells with the TZD PPARgamma agonist troglitazone, dramatically inhibited 3H-thymidine incorporation and induced cell death. Addition of the RXRalpha ligands, 9-cis-RA or LG100268, sensitized T24 bladder cancer cells to the lethal effect of troglitazone and two other PPAR- activators, ciglitazone and 15-deoxy-delta(12,14)-PGJ2 (15dPGJ(2)). Troglitazone treatment increased expression of two cyclin-dependent kinase inhibitors, p21(WAF1/CIP1) and p16(INK4), and reduced cyclin D1 expression, consistent with G1 arrest. Troglitazone also induced an endogenous PPARgamma target gene in T24 cells, adipocyte-type fatty acid binding protein (A-FABP), the expression of which correlates with bladder cancer differentiation. In situ hybridization shows that A-FABP expression is localized to normal uroepithelial cells as well as some TCCa's. Taken together, these results demonstrate that PPARgamma is expressed in human TCCa where it may play a role in regulating TCCa differentiation and survival, thereby providing a potential target for therapy of uroepithelial cancers.

  15. Telmisartan inhibits the proinflammatory effects of homocysteine on human endothelial cells through activation of the peroxisome proliferator-activated receptor-δ pathway.

    Science.gov (United States)

    Xu, Shanghua; Song, Huanhuan; Huang, Maozhi; Wang, Kefeng; Xu, Changsheng; Xie, Liangdi

    2014-09-01

    The aim of this study was to investigate the inhibition capacity of telmisartan to endothelial inflammation induced by homocysteine (Hcy) and discuss the proposed mechanism in vitro. Human umbilical vein endothelial cells (HUVECs) were prepared by collagenase digestion and cultured in vitro. An increase in monocyte chemoattractant protein-1 (MCP-1) and vascular cell adhesion molecule-1 (VCAM-1) was analyzed by reverse transcription-polymerase chain reaction (RT-PCR) as markers of Hcy-induced endothelial inflammation. HL-60 cell adhesion to HUVECs was measured by rose bengal staining. Nuclear, cytosolic and total nuclear transcription factor-κB (NF-κB) p65 levels were analyzed by western blotting. Peroxisome proliferator-activated receptor-δ (PPARδ) expression by HUVECs exposed to Hcy with or without telmisartan pretreatment was analyzed by RT-PCR and western blotting. Hcy significantly increased the levels of MCP-1 mRNA, VCAM-1 mRNA and monocyte binding to HUVECs. These effects were significantly attenuated by pretreatment with telmisartan and PPARδ agonists. The effect of telmisartan was inhibited by PPARδ antagonists. The Hcy-mediated downregulation of PPARδ mRNA and protein of HUVECs was inhibited by telmisartan. Hcy-mediated upregulation of NF-κB p65 protein levels in nuclear extracts was inhibited by telmisartan and PPARδ agonists. In conclusion, telmisartan exerts potent anti-inflammatory effects in endothelial cells, probably via a binary mechanism involving PPARδ activation and inhibition of the nuclear translocation of NF-κB.

  16. A Novel Cytosolic Isoform of Mitochondrial Trans-2-Enoyl-CoA Reductase Enhances Peroxisome Proliferator-Activated Receptor α Activity

    Directory of Open Access Journals (Sweden)

    Dong-Gyu Kim

    2014-06-01

    Full Text Available BackgroundMitochondrial trans-2-enoyl-CoA reductase (MECR is involved in mitochondrial synthesis of fatty acids and is highly expressed in mitochondria. MECR is also known as nuclear receptor binding factor-1, which was originally reported with yeast two-hybrid screening as a binding protein of the nuclear hormone receptor peroxisome proliferator-activated receptor α (PPARα. However, MECR and PPARα are localized at different compartment, mitochondria, and the nucleus, respectively. Therefore, the presence of a cytosolic or nuclear isoform of MECR is necessary for functional interaction between MECR and PPARα.MethodsTo identify the expression pattern of MECR and the cytosolic form of MECR (cMECR, we performed reverse transcription polymerase chain reaction (RT-PCR with various tissue samples from Sprague-Dawley rats. To confirm the interaction between cMECR and PPARα, we performed several binding assays such as yeast two-hybrid, coimmunoprecipitation, and bimolecular fluorescence complementation. To observe subcellular localization of these proteins, immunocytochemistry was performed. A luciferase assay was used to measure PPARα activity.ResultsWe provide evidence of an alternatively spliced variant of the rat MECR gene that yields cMECR. The cMECR lacks the N-terminal 76 amino acids of MECR and shows uniform distribution in the cytoplasm and nucleus of HeLa cells. cMECR directly bound PPARα in the nucleus and increased PPARα-dependent luciferase activity in HeLa cells.ConclusionWe found the cytosolic form of MECR (cMECR was expressed in the cytosolic and/or nuclear region, directly binds with PPARα, and enhances PPARα activity.

  17. Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist inhibits collagen synthesis in human hypertrophic scar fibroblasts by targeting Smad3 via miR-145

    Energy Technology Data Exchange (ETDEWEB)

    Zhu, Hua-Yu; Li, Chao; Zheng, Zhao; Zhou, Qin; Guan, Hao; Su, Lin-Lin; Han, Jun-Tao; Zhu, Xiong-Xiang; Wang, Shu-yue; Li, Jun, E-mail: lijunfmmu@163.com; Hu, Da-Hai, E-mail: hudahaifmmu@aliyun.com

    2015-03-27

    The transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) functions to regulate cell differentiation and lipid metabolism. Recently, its agonist has been documented to regulate extracellular matrix production in human dermal fibroblasts. This study explored the underlying molecular mechanisms and gene interactions in hypertrophic scar fibroblasts (HSFBs) in vitro. HSFBs were cultured and treated with or without PPAR-γ agonist or antagonist for gene expression. Bioinformatical analysis predicted that miR-145 could target Smad3 expression. Luciferase assay was used to confirm such an interaction. The data showed that PPAR-γ agonist troglitazone suppressed expression of Smad3 and Col1 in HSFBs. PPAR-γ agonist induced miR-145 at the gene transcriptional level, which in turn inhibited Smad3 expression and Col1 level in HSFBs. Furthermore, ELISA data showed that Col1 level in HSFBs was controlled by a feedback regulation mechanism involved in PPAR-γ agonist and antagonist-regulated expression of miR-145 and Smad3 in HSFBs. These findings indicate that PPAR-γ-miR-145-Smad3 axis plays a role in regulation of collagen synthesis in HSFBs. - Highlights: • PPAR-γ agonist inhibits collagen synthesis in HSFBs. • Smad3 and type I collagen expression are decreased by PPAR-γ agonist. • miR-145 expression is increased by PPAR-γ agonist in HSFBs. • Increased miR-145 inhibits collagen synthesis by targeting Smad3. • miR-145 regulates collagen synthesis.

  18. Peroxisome proliferator-activated receptor gamma (PPARγ) in yellow catfish Pelteobagrus fulvidraco: molecular characterization, mRNA expression and transcriptional regulation by insulin in vivo and in vitro.

    Science.gov (United States)

    Zheng, Jia-Lang; Zhuo, Mei-Qin; Luo, Zhi; Pan, Ya-Xiong; Song, Yu-Feng; Huang, Chao; Zhu, Qing-Ling; Hu, Wei; Chen, Qi-Liang

    2015-02-01

    Peroxisome proliferator-activated receptor gamma (PPARγ) is ligand-inducible transcription factor and has important roles in lipid metabolism, cell proliferation and inflammation. In the present study, yellow catfish Pelteobagrus fulvidraco PPARγ cDNA was isolated from liver by RT-PCR and RACE, and its molecular characterization and transcriptional regulation by insulin in vivo and in vitro were determined. The generation of PPARγ1 and PPARγ2 was due to alternative promoter of PPARγ gene. PPARγ1 and PPARγ2 mRNA covered 2426 bp and 2537 bp, respectively, with an open reading frame (ORF) of 1584 bp encoding 527 amino acid residues. Yellow catfish PPARγ gene was organized in a manner similar to that of their mammalian homologs, implying a modular organization of the protein's domains. A comparison between the yellow catfish PPARγ amino acid sequence and the correspondent sequences of several other species revealed the identity of 55-76.2%. Two PPARγ transcripts (PPARγ1 and PPARγ2) mRNAs were expressed in a wide range of tissues, but the abundance of each PPARγ mRNA showed the tissue- and developmental stage-dependent expression patterns. Intraperitoneal injection of insulin in vivo significantly stimulated the mRNA expression of total PPARγ and PPARγ1, but not PPARγ2 in the liver of yellow catfish. In contrast, incubation of hepatocytes with insulin in vitro increased the mRNA levels of PPARγ1, PPARγ2 and total PPARγ. To our knowledge, for the first time, the present study provides evidence that PPARγ1 and PPARγ2 are differentially expressed with and among tissues during different developmental stages and also regulated by insulin both in vivo and in vitro, which serves to increase our understanding on PPARγ physiological function in fish.

  19. Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy.

    Science.gov (United States)

    Hirano, Ken-ichi; Tanaka, Tatsuya; Ikeda, Yoshihiko; Yamaguchi, Satoshi; Zaima, Nobuhiro; Kobayashi, Kazuhiro; Suzuki, Akira; Sakata, Yasuhiko; Sakata, Yasushi; Kobayashi, Kunihisa; Toda, Tatsushi; Fukushima, Norihide; Ishibashi-Ueda, Hatsue; Tavian, Daniela; Nagasaka, Hironori; Hui, Shu-Ping; Chiba, Hitoshi; Sawa, Yoshiki; Hori, Masatsugu

    2014-01-10

    Adipose triglyceride lipase (ATGL, also known as PNPLA2) is an essential molecule for hydrolysis of intracellular triglyceride (TG). Genetic ATGL deficiency is a rare multi-systemic neutral lipid storage disease. Information regarding its clinical profile and pathophysiology, particularly for cardiac involvement, is still very limited. A previous middle-aged ATGL-deficient patient in our institute (Case 1) with severe heart failure required cardiac transplantation (CTx) and exhibited a novel phenotype, "Triglyceride deposit cardiomyovasculopathy (TGCV)". Here, we tried to elucidate molecular mechanism underlying TGCV. The subjects were two cases with TGCV, including our second case who was a 33-year-old male patient (Case 2) with congestive heart failure requiring CTx. Case 2 was homozygous for a point mutation in the 5' splice donor site of intron 5 in the ATGL, which results in at least two types of mRNAs due to splicing defects. The myocardium of both patients (Cases 1 and 2) showed up-regulation of peroxisome proliferated activated receptors (PPARs), key transcription factors for metabolism of long chain fatty acids (LCFAs), which was in contrast to these molecules' lower expression in ATGL-targeted mice. We investigated the intracellular metabolism of LCFAs under human ATGL-deficient conditions using patients' passaged skin fibroblasts as a model. ATGL-deficient cells showed higher uptake and abnormal intracellular transport of LCFA, resulting in massive TG accumulation. We used these findings from cardiac specimens and cell-biological experiments to construct a hypothetical model to clarify the pathophysiology of the human disorder. In patients with TGCV, even when hydrolysis of intracellular TG is defective, the marked up-regulation of PPARγ and related genes may lead to increased uptake of LCFAs, the substrates for TG synthesis. This potentially vicious cycle of LCFAs could explain the massive accumulation of TG and severe clinical course for this rare

  20. Diabetes mellitus, superoxide dismutase and peroxisome proliferator activated receptor gamma polymorphisms modify the outcome of end-stage renal disease patients of Han Chinese origin.

    Science.gov (United States)

    Chao, Chia-Ter; Huang, Jenq-Wen; Chiang, Chih-Kang; Chen, Yen-Ching; Fang, Cheng-Chung; Hu, Fu-Chang; Chang, Chen-Chih; Yen, Chung-Jen

    2016-12-07

    Increased oxidative stress significantly modifies the outcome of patients with diabetes mellitus (DM) and end-stage renal disease (ESRD), and is counteracted by anti-oxidative capacity. However, whether anti-oxidant single nucleotide polymorphisms (SNPs) influence the outcome of ESRD individuals with or without DM has not been tested before. We prospectively enrolled multi-center ESRD patients of Han Chinese origin betwen 2002 and 2003, recording their anti-oxidant (superoxide dismutase [SOD2], glutathione peroxidase [GPX1]) and peroxisome proliferator activated receptor-γ (PPAR-γ) genotyping results, and stratified based on DM. They were followed up until 2008, with risk factors for mortality analyzed by Cox proportional hazard regression. We discovered that diabetic ESRD carriers of CC genotype of SOD2 exon 2 had an increased risk of mortality compared to non-diabetic ones with other genotypes (hazard ratio [HR] 4.04, p = 0.04), while GPX1 SNPs had no influence. Interactions between SOD2 and PPAR-γ SNPs regarding the mortality influence were also detected (for SOD2 CC genotype x PPAR-γexon 6 CT genotype, HR 3.19, p = 0.008), suggesting the importance of considering a combination panel of SNPs on patient survival. This might be the largest study focusing on the relationship between anti-oxidant SNPs and the outcomes of diabetic ESRD patients of Han Chinese origin. More studies are needed to validate our findings. This article is protected by copyright. All rights reserved.

  1. Protective effect of ghrelin on left ventricular remodeling in spontaneously hypertensive rats is associated with the peroxisome proliferator-activated receptor gamma-dependent pathway

    Institute of Scientific and Technical Information of China (English)

    LI Zhao; ZHU Xiao-ying; LI Meng; BAI Ying-long; HU Jian

    2008-01-01

    Background Studies suggested that exogenous ghrelin administration could prevent eady left ventricular remodeling in rats with myocardial infarction.We investigated herein whether ghrelin attenuated left ventricular remodeling induced by hypertension and whether ghrelin's effect was mediated through the peroxisome proliferator-activated receptor gamma (PPAR-γ)-dependent pathway.Methods Spontaneously hypertensive rats (8-week-old males) were randomly divided into three groups with 12 rats in each:ghrelin group (received ghrelin 100 μg/kg subcutaneously (sc) twice daily);ghrelin+GW9662 group (received the PPAR-γ antagonist GW9662 at 2 mg/kg sc,and then ghrelin as above);saline controls.Normal male Wistar Kyoto rats (n=12) served as normal controls.Four weeks later,the effects of ghrelin on cardiac remodeling were evaluated by echocardiographic,hemodynamic,and histopathological examination,and gene expression analysis (PPAR-γ protein and mRNA expression).The serum levels of C-reactive protein (CRP) and tumor necrosis factor (TNF)αa were detected by enzyme linked immunosorbent assay.Results Ghrelin prevented ventricular remodeling,increased PPAR-y expression in the myocardium,suppressed collagen I and collagen III mRNA expression,and also decreased the serum levels of TNF-α,but not CRP.All abovementioned effects of ghrelin were inhibited by GW9662.Conclusion Ghrelin inhibited ventricular remodeling induced by hypertension,and the preventive effects of ghrelin may be mediated by the anti-inflammatory actions of the PPAR-y-dependent pathway.

  2. Statin induction of liver fatty acid-binding protein (L-FABP) gene expression is peroxisome proliferator-activated receptor-alpha-dependent.

    Science.gov (United States)

    Landrier, Jean-François; Thomas, Charles; Grober, Jacques; Duez, Hélène; Percevault, Frédéric; Souidi, Maâmar; Linard, Christine; Staels, Bart; Besnard, Philippe

    2004-10-29

    Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5'-deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position -67/-55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPARalpha agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPARalpha-null animals demonstrating the direct implication of PPARalpha in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPARalpha mRNA levels both in vitro and in vivo and activated the mouse PPARalpha promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPARalpha. Moreover, PPARalpha might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.

  3. Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR family.

    Directory of Open Access Journals (Sweden)

    Christopher Weidner

    Full Text Available Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita flowers extract (CFE for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD-fed C57BL/6 mice with CFE (200 mg/kg/d for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders.

  4. Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR) family.

    Science.gov (United States)

    Weidner, Christopher; Wowro, Sylvia J; Rousseau, Morten; Freiwald, Anja; Kodelja, Vitam; Abdel-Aziz, Heba; Kelber, Olaf; Sauer, Sascha

    2013-01-01

    Given the significant increases in the incidence of metabolic diseases, efficient strategies for preventing and treating of these common disorders are urgently needed. This includes the development of phytopharmaceutical products or functional foods to prevent or cure metabolic diseases. Plant extracts from edible biomaterial provide a potential resource of structurally diverse molecules that can synergistically interfere with complex disorders. In this study we describe the safe application of ethanolic chamomile (Matricaria recutita) flowers extract (CFE) for the treatment and prevention of type 2 diabetes and associated disorders. We show in vitro that this extract activates in particular nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) and its isotypes. In a cellular context, in human primary adipocytes CFE administration (300 µg/ml) led to specific expression of target genes of PPARγ, whereas in human hepatocytes CFE-induced we detected expression changes of genes that were regulated by PPARα. In vivo treatment of insulin-resistant high-fat diet (HFD)-fed C57BL/6 mice with CFE (200 mg/kg/d) for 6 weeks considerably reduced insulin resistance, glucose intolerance, plasma triacylglycerol, non-esterified fatty acids (NEFA) and LDL/VLDL cholesterol. Co-feeding of lean C57BL/6 mice a HFD with 200 mg/kg/d CFE for 20 weeks showed effective prevention of fatty liver formation and hepatic inflammation, indicating additionally hepatoprotective effects of the extract. Moreover, CFE treatment did not reveal side effects, which have otherwise been associated with strong synthetic PPAR-targeting molecules, such as weight gain, liver disorders, hemodilution or bone cell turnover. Taken together, modulation of PPARs and other factors by chamomile flowers extract has the potential to prevent or treat type 2 diabetes and related disorders.

  5. Peroxisome proliferator-activated receptor γ polymorphism Pro12Ala Is associated with nephropathy in type 2 diabetes: evidence from meta-analysis of 18 studies.

    Science.gov (United States)

    Zhang, Hui; Zhu, Shimiao; Chen, Jing; Tang, Yang; Hu, Hailong; Mohan, Viswanathan; Venkatesan, Radha; Wang, Jianmin; Chen, Haiping

    2012-06-01

    Insulin resistance plays a part in diabetic nephropathy (DN). The association between the peroxisome proliferator-activated receptor γ Pro to Ala alteration at codon 12 (Pro12Ala) polymorphism and the risk of insulin resistance has been confirmed. The association between the polymorphism and DN risk has also been widely studied recently, but no consensus was available up to now. A systematic search of electronic databases (MEDLINE, Embase, and China National Knowledge Infrastructure) and reference lists of relevant articles was carried out, and then 18 case-control studies involving 3,361 DN cases and 5,825 control subjects were identified. In the overall analysis, the Ala12 variant was observed to be significantly associated with decreased DN risk (odds ratio 0.76 [95% CI 0.61-0.93]). Some evidence of heterogeneity among the included studies was detected, which could be explained by the difference of ethnicity and stage of DN. Subgroup analyses stratified by ethnicity and stage of DN were performed, and results indicated the Pro12Ala polymorphism was associated with the risk of DN in Caucasians but no similar association was observed in Asians. Additionally, we observed that Ala12 was associated with decreased risk of albuminuria. With only a few of subjects were available, we failed to detect statistically significant association between the polymorphism and end-stage renal disease (ESRD). Our results indicated that the Ala12 variant is a significantly protective factor for DN. Future research should focus on the effect of Pro12Ala polymorphism on ESRD and gathering data of Africans.

  6. Expression of peroxisome proliferator activated receptor-gamma in non-small cell lung carcinoma: correlation with histological type and grade.

    Science.gov (United States)

    Theocharis, Stamatios; Kanelli, Helen; Politi, Ekaterini; Margeli, Alexandra; Karkandaris, Christos; Philippides, Theodoros; Koutselinis, Antonios

    2002-06-01

    Peroxisome Proliferator Activated Receptor-gamma (PPAR-gamma) is a ligand-activated transcription factor belonging to the steroid receptor superfamily. It is a key regulator of adipogenic differentiation and glucose homeostasis, the ligands of which have also been demonstrated to induce differentiation in human breast, lung and colon cancer cell lines. In the present study, PPAR-gamma expression in cases of non-small cell lung carcinoma (NSCLC) was examined immunohistochemically and was correlated with tumor histological type and grade. Primary tumor samples from 147 patients with NSCLC were immunostained using a monoclonal antibody against PPAR-gamma. Positive PPAR-gamma immunostaining was prominent in 61 out of 147 cases (42%) and negative in the rest. PPAR-gamma positivity was prominent in 37 out of 79 cases (47%) of squamous cell lung carcinoma and in 24 out of 68 ones (35%) of lung adenocarcinoma. PPAR-gamma positivity was most frequently observed in squamous cell tumors (P=0.021) and in tumors of high histological grade of both histological types (P=0.041). Well-differentiated adenocarcinoma cases presented increased frequency for PPAR-gamma positivity compared with moderately and poorly differentiated ones (P=0.001). The intensity and pattern of PPAR-gamma staining in tumor cells were not correlated with histopathological parameters in PPAR-gamma positive cases of NSCLC examined. Our findings support evidence for participation of this protein in the biological mechanisms underlying the carcinogenic evolution in the lung, suggesting also the importance of specific PPAR-gamma ligands as future therapeutic approach in lung cancer.

  7. Activation of β-Adrenoceptors by Dobutamine May Induce a Higher Expression of Peroxisome Proliferator-Activated Receptors δ (PPARδ in Neonatal Rat Cardiomyocytes

    Directory of Open Access Journals (Sweden)

    Ming-Ting Chou

    2012-01-01

    Full Text Available Recent evidence showed the role of peroxisome proliferator-activated receptors (PPARs in cardiac function. Cardiac contraction induced by various agents is critical in restoring the activity of peroxisome proliferator-activated receptors δ (PPARδ in cardiac myopathy. Because dobutamine is an agent widely used to treat heart failure in emergency setting, this study is aimed to investigate the change of PPARδ in response to dobutamine. Neonatal rat cardiomyocytes were used to examine the effects of dobutamine on PPARδ expression levels and cardiac troponin I (cTnI phosphorylation via Western blotting analysis. We show that treatment with dobutamine increased PPARδ expression and cTnI phosphorylation in a time- and dose-dependent manner in neonatal rat cardiomyocytes. These increases were blocked by the antagonist of β1-adrenoceptors. Also, the action of dobutamine was related to the increase of calcium ions and diminished by chelating intracellular calcium. Additionally, dobutamine-induced action was reduced by the inhibition of downstream messengers involved in this calcium-related pathway. Moreover, deletion of PPARδ using siRNA generated the reduction of cTnI phosphorylation in cardiomyocytes treated with dobutamine. Thus, we concluded that PPARδ is increased by dobutamine in cardiac cells.

  8. Tesaglitazar, a dual peroxisome proliferator-activated receptor alpha/gamma agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance

    DEFF Research Database (Denmark)

    Schuster, H.; Fagerberg, B.; Edwards, S.

    2008-01-01

    Aim: To determine the effects of the peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar on serum levels of apolipoprotein (apo) A-I, apoB, and apoCIII in non-diabetic insulin-resistant subjects. Methods: This randomized, double-blind, multicentre, placebo-controlle......Aim: To determine the effects of the peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar on serum levels of apolipoprotein (apo) A-I, apoB, and apoCIII in non-diabetic insulin-resistant subjects. Methods: This randomized, double-blind, multicentre, placebo...... associated with insulin resistance. (C) 2007 Elsevier Ireland Ltd. All rights reserved Udgivelsesdato: 2008/3......-controlled trial examined the effect of tesaglitazar (0.1, 0.25, 0.5, and 1 mg) once daily for 12 weeks on apolipoprotein levels in 390 abdominally obese subjects with hypertriglyceridaemia. Results: Tesaglitazar dose-dependently increased serum concentrations of apoA-I (p

  9. Peroxisomes in Different Skeletal Cell Types during Intramembranous and Endochondral Ossification and Their Regulation during Osteoblast Differentiation by Distinct Peroxisome Proliferator-Activated Receptors.

    Directory of Open Access Journals (Sweden)

    Guofeng Qian

    Full Text Available Ossification defects leading to craniofacial dysmorphism or rhizomelia are typical phenotypes in patients and corresponding knockout mouse models with distinct peroxisomal disorders. Despite these obvious skeletal pathologies, to date no careful analysis exists on the distribution and function of peroxisomes in skeletal tissues and their alterations during ossification. Therefore, we analyzed the peroxisomal compartment in different cell types of mouse cartilage and bone as well as in primary cultures of calvarial osteoblasts. The peroxisome number and metabolism strongly increased in chondrocytes during endochondral ossification from the reserve to the hypertrophic zone, whereas in bone, metabolically active osteoblasts contained a higher numerical abundance of this organelle than osteocytes. The high abundance of peroxisomes in these skeletal cell types is reflected by high levels of Pex11β gene expression. During culture, calvarial pre-osteoblasts differentiated into secretory osteoblasts accompanied by peroxisome proliferation and increased levels of peroxisomal genes and proteins. Since many peroxisomal genes contain a PPAR-responsive element, we analyzed the gene expression of PPARɑ/ß/ɣ in calvarial osteoblasts and MC3T3-E1 cells, revealing higher levels for PPARß than for PPARɑ and PPARɣ. Treatment with different PPAR agonists and antagonists not only changed the peroxisomal compartment and associated gene expression, but also induced complex alterations of the gene expression patterns of the other PPAR family members. Studies in M3CT3-E1 cells showed that the PPARß agonist GW0742 activated the PPRE-mediated luciferase expression and up-regulated peroxisomal gene transcription (Pex11, Pex13, Pex14, Acox1 and Cat, whereas the PPARß antagonist GSK0660 led to repression of the PPRE and a decrease of the corresponding mRNA levels. In the same way, treatment of calvarial osteoblasts with GW0742 increased in peroxisome number and

  10. 过氧化物酶体增殖物激活受体γ激动剂拮抗人皮肤成纤维细胞转化生长因子β1机制研究%Mechanism underlying the inhibitory effects of peroxisome proliferator-activated receptor γ agonists on transforming growth factor β1 in adult skin fibroblasts

    Institute of Scientific and Technical Information of China (English)

    杨崇志; 张会堂; 王公升; 周海全; 马驰; 胡大海

    2010-01-01

    目的 了解过氧化物酶体增殖物激活受体γ(PPARγ)激动剂拈抗TGF-β1促皮肤瘢痕化的效应机制.方法 体外培养正常成人皮肤Fb,根据培养基中所加刺激物不同分为空白对照组(无血清DMEM培养基),TGF-β1组(DMEM培养基加入含终浓度10 ng/mL TGF-β1作用48 h),曲格列酮组(DMEM培养基加入含终浓度10μmol/L曲格列酮作用2 h,再加入10 ng/mL TGF-β1作用48h),15-脱氧前列腺素J2(15d-PGJ2)组(DMEM培养基加入含终浓度10 μmol/L 15d-PGJ2作用2 h,再加入10 ng/mL TGF-β1作用48 h).应用蛋白质印迹法检测结缔组织生长因子(CTGF)的表达,实时荧光RT-PCR检测CTGF、基质金属蛋白酶1(MMP-1)及血小板源性生长因子(PDGF)的mRNA水平变化.对数据进行单因素方差分析.结果 TGF-β1组的CTGF蛋白和mRNA表达水平均高于空白对照组,曲格列酮组和15d-PGJ2组的CTGF蛋白及mRNA表达水平低于TGF-β1组.空白对照组、TGF-β1组、曲格列酮组、15d-PGJ 2组MMP-1 mRNA表达水平分别为1.281±0.195、0.193±0.051、0.417±0.043、0.485±0.027,其中TGF-β1组低于空白对照组(F=12.811,P<0.01),曲格列酮组、15d-PGJ2组高于TGF-β1组(F=12.811,P值均小于0.01).空白对照组、TGF-β1组、曲格列酮组、15d-PGJ2组PDGF mRNA表达水平分别为0.349±0.057、1.044±0.237、0.677±0.055、0.511±0.017,其中TGF-β1组高于空白对照组(F=16.848,P<0.01),曲格列酮组、15d-PGJ2组低于TGF-β1组(F=16.848,P值均小于0.01).结论 激活后的PPARγ对TGF-β1下游反应因子CTGF的抑制作用,可能是其拮抗TGF-β1促皮肤瘢痕化的主要机制,而对细胞因子MMP-1、PDGF的影响可能也是其机制之一.%Objective To study the mechanism underlying the inhibitory effects of peroxisome proliferator-activated receptor γ (PPARγ) agonists on transforming growth factor β 1 (TGF-β1)-induced scarring of skin. Methods Fibroblasts isolated from healthy adult skin were cultured in vitro and divided into blank

  11. ACTIVATION ASSAY FOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR- ALPHA (PPARÁ) BY PERFLUOROALKYL ACIDS (PFAAS) IN COS-1 CELLS

    Science.gov (United States)

    PFAAs have been found to elicit various physiological effects including peroxisome proliferation, indicating the mechanism of action for these chemicals could involve PPAR. This study investigates the ability of PFAAs to bind and activate mouse and human PPARα in COS-1 cell...

  12. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians

    DEFF Research Database (Denmark)

    Ek, J; Andersen, G; Urhammer, S A;

    2001-01-01

    We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non-insulin-dependent) dia......We examined whether the Pro12-Ala polymorphism of the human peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene was related to altered insulin sensitivity among glucose-tolerant subjects or a lower accumulated incidence or prevalence of IGT and Type II (non...

  13. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians