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

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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

Identification of plant extracts with potential antidiabetic properties: effect on human peroxisome proliferator-activated receptor (PPAR), adipocyte differentiation and insulin-stimulated glucose uptake

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Christensen, Kathrine B; Minet, Ariane; Svenstrup, Henrik

2009-01-01

Thiazolidinediones (TZDs) are insulin sensitizing drugs used to treat type 2 diabetes. The primary target of the TZDs is the peroxisome proliferator-activated receptor (PPAR) gamma, a key regulator of adipogenesis and glucose homeostasis. Currently prescribed TZDs are full PPARgamma agonists, and...

Retinoid X receptor and peroxisome proliferator-activated receptor activate an estrogen responsive gene independent of the estrogen receptor.

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Nuñez, S B; Medin, J A; Braissant, O; Kemp, L; Wahli, W; Ozato, K; Segars, J H

1997-03-14

Estrogen receptors regulate transcription of genes essential for sexual development and reproductive function. Since the retinoid X receptor (RXR) is able to modulate estrogen responsive genes and both 9-cis RA and fatty acids influenced development of estrogen responsive tumors, we hypothesized that estrogen responsive genes might be modulated by RXR and the fatty acid receptor (peroxisome proliferator-activated receptor, PPAR). To test this hypothesis, transfection assays in CV-1 cells were performed with an estrogen response element (ERE) coupled to a luciferase reporter construct. Addition of expression vectors for RXR and PPAR resulted in an 11-fold increase in luciferase activity in the presence of 9-cis RA. Furthermore, mobility shift assays demonstrated binding of RXR and PPAR to the vitellogenin A2-ERE and an ERE in the oxytocin promoter. Methylation interference assays demonstrated that specific guanine residues required for RXR/PPAR binding to the ERE were similar to residues required for ER binding. Moreover, RXR domain-deleted constructs in transfection assays showed that activation required RXR since an RXR delta AF-2 mutant completely abrogated reporter activity. Oligoprecipitation binding studies with biotinylated ERE and (35)S-labeled in vitro translated RXR constructs confirmed binding of delta AF-2 RXR mutant to the ERE in the presence of baculovirus-expressed PPAR. Finally, in situ hybridization confirmed RXR and PPAR mRNA expression in estrogen responsive tissues. Collectively, these data suggest that RXR and PPAR are present in reproductive tissues, are capable of activating estrogen responsive genes and suggest that the mechanism of activation may involve direct binding of the receptors to estrogen response elements.

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

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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.

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

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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...

Pleiotropic Actions of Peroxisome Proliferator-Activated Receptors (PPARs in Dysregulated Metabolic Homeostasis, Inflammation and Cancer: Current Evidence and Future Perspectives

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Antonio Simone Laganà

2016-06-01

Full Text Available Background: Peroxisome proliferator-activated receptors (PPARs have demonstrated a lot of important effects in the regulation of glucose and lipid metabolism and in the correct functioning of adipose tissue. Recently, many studies have evaluated a possible effect of PPARs on tumor cells. The purpose of this review is to describe the effects of PPARs, their action and their future prospective; Methods: Narrative review aimed to synthesize cutting-edge evidence retrieved from searches of computerized databases; Results: PPARs play a key role in metabolic diseases, which include several cardiovascular diseases, insulin resistance, type 2 diabetes, metabolic syndrome, impaired immunity and the increasing risk of cancer; in particular, PPARα and PPARβ/δ mainly enable energy combustion, while PPARγ contributes to energy storage by enhancing adipogenesis; Conclusion: PPAR agonists could represent interesting types of molecules that can treat not only metabolic diseases, but also inflammation and cancer. Additional research is needed for the identification of high-affinity, high-specificity agonists for the treatment of obesity, type 2 diabetes (T2DM and other metabolic diseases. Further studies are needed also to elucidate the role of PPARs in cancer.

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

Signaling cross-talk between peroxisome proliferator-activated receptor/retinoid X receptor and estrogen receptor through estrogen response elements.

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Keller, H; Givel, F; Perroud, M; Wahli, W

1995-07-01

Peroxisome proliferator-activated receptors (PPARs) and retinoid X receptors (RXRs) are nuclear hormone receptors that are activated by fatty acids and 9-cis-retinoic acid, respectively. PPARs and RXRs form heterodimers that activate transcription by binding to PPAR response elements (PPREs) in the promoter of target genes. The PPREs described thus far consist of a direct tandem repeat of the AGGTCA core element with one intervening nucleotide. We show here that the vitellogenin A2 estrogen response element (ERE) can also function as a PPRE and is bound by a PPAR/RXR heterodimer. Although this heterodimer can bind to several other ERE-related palindromic response elements containing AGGTCA half-sites, only the ERE is able to confer transactivation of test reporter plasmids, when the ERE is placed either close to or at a distance from the transcription initiation site. Examination of natural ERE-containing promoters, including the pS2, very-low-density apolipoprotein II and vitellogenin A2 genes, revealed considerable differences in the binding of PPAR/RXR heterodimers to these EREs. In their natural promoter context, these EREs did not allow transcriptional activation by PPARs/RXRs. Analysis of this lack of stimulation of the vitellogenin A2 promoter demonstrated that PPARs/RXRs bind to the ERE but cannot transactivate due to a nonpermissive promoter structure. As a consequence, PPARs/RXRs inhibit transactivation by the estrogen receptor through competition for ERE binding. This is the first example of signaling cross-talk between PPAR/RXR and estrogen receptor.

Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor Alpha Selective

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Li, J.; Kennedy, L; Shi, Y; Tao, S; Ye, X; Chen, S; Wang, Y; Hernandez, A; Wang, W; et al.

2010-01-01

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and {approx}410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

Prenatal polycyclic aromatic hydrocarbon, adiposity, peroxisome proliferator-activated receptor (PPAR γ methylation in offspring, grand-offspring mice.

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Zhonghai Yan

Full Text Available 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.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.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.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.Greater prenatal PAH exposure was associated with increased weight, fat mass, adipose gene expression and epigenetic changes in progeny.

Statins Activate Human PPAR Promoter and Increase PPAR mRNA Expression and Activation in HepG2 Cells

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Makoto Seo

2008-01-01

Full Text Available Statins increase peroxisome proliferator-activated receptor (PPAR mRNA expression, but the mechanism of this increased PPAR production remains elusive. To examine the regulation of PPAR production, we examined the effect of 7 statins (atorvastatin, cerivastatin, fluvastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin on human PPAR promoter activity, mRNA expression, nuclear protein levels, and transcriptional activity. The main results are as follows. (1 Majority of statins enhanced PPAR promoter activity in a dose-dependent manner in HepG2 cells transfected with the human PPAR promoter. This enhancement may be mediated by statin-induced HNF-4. (2 PPAR mRNA expression was increased by statin treatment. (3 The PPAR levels in nuclear fractions were increased by statin treatment. (4 Simvastatin, pravastatin, and cerivastatin markedly enhanced transcriptional activity in 293T cells cotransfected with acyl-coenzyme A oxidase promoter and PPAR/RXR expression vectors. In summary, these data demonstrate that PPAR production and activation are upregulated through the PPAR promoter activity by statin treatment.

Liver X receptor and peroxisome proliferator-activated receptor as integrators of lipid homeostasis and immunity.

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Kidani, Yoko; Bensinger, Steven J

2012-09-01

Lipid metabolism has emerged as an important modulator of innate and adaptive immune cell fate and function. The lipid-activated transcription factors peroxisome proliferator-activated receptor (PPAR) α, β/δ, γ and liver X receptor (LXR) are members of the nuclear receptor superfamily that have a well-defined role in regulating lipid homeostasis and metabolic diseases. Accumulated evidence over the last decade indicates that PPAR and LXR signaling also influence multiple facets of inflammation and immunity, thereby providing important crosstalk between metabolism and immune system. Herein, we provide a brief introduction to LXR and PPAR biology and review recent discoveries highlighting the importance of PPAR and LXR signaling in the modulation of normal and pathologic states of immunity. We also examine advances in our mechanistic understanding of how nuclear receptors impact immune system function and homeostasis. Finally, we discuss whether LXRs and PPARs could be pharmacologically manipulated to provide novel therapeutic approaches for modulation of the immune system under pathologic inflammation or in the context of allergic and autoimmune disease. © 2012 John Wiley & Sons A/S.

Pharmacologic implications of peroxisome proliferator activated receptors (PPAR Implicaciones farmacológicas de los receptores activados por los proliferadores de peroxisomas (PPAR

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Luis Carlos Mejía Rivera

2001-01-01

Full Text Available PPAR are a group of proteins, members of the receptors located within the nucleus. These receptors modulate DNA transcriptional activity by binding to specific response elements on target genes. To date, three main types of PPAR have been identified designed α, δand γthese receptors are involved in the regulation of diferent metabolic processes, being the group of receptors more intensely studied. PPARαare greatly involved in both catabolism of fatty acids and transport of extracellular lipids; fibrates, their agonists, are of proved usefulness in some dyslipidemias. Thiazolidinediones used as antihyperglicemiant agents are PPARγagonists, but their relationship with carbohydrate metabolism is not yet clear; nevertheless, their use in the management of type 2 diabetes mellitus is of increasing importance. On the other hand, nonsteroidal anti-inflammatory agents are somehow related with PPARδfunctions; up to date a molecular and epidemiologic relationship of these drugs and receptors with colon cancer has been established. Los receptores activados por los proliferadores de peroxisomas (PPAR son un grupo de proteínas pertenecientes a la familia de receptores de ubicación nuclear que se comportan como factores que modulan la transcripción del DNA al unirse a elementos de respuesta específicos de ciertos genes blanco. Hasta el momento se han descrito tres tipos principales de PPAR designados como α, δ, y γ; estos receptores se encuentran involucrados en la regulación de diferentes procesos metabólicos; por esto se han convertido en uno de los grupos de receptores más intensamente estudiados. Los PPARα participan tanto en el catabolismo de los ácidos grasos como en el transporte extracelular de lípidos; los fibratos, sus agonistas, tienen utilidad ampliamente demostrada en el manejo de algunas dislipidemias. Las tiazolidindionas utilizadas como fármacos antihiperglicemiantes son agonistas de los PPARγ; todav

Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases

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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.

Effects of peroxisome proliferator activated receptors (PPAR-γ and -α agonists on cochlear protection from oxidative stress.

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Marijana Sekulic-Jablanovic

Full Text Available Various insults cause ototoxicity in mammals by increasing oxidative stress leading to apoptosis of auditory hair cells (HCs. The thiazolidinediones (TZDs; e.g., pioglitazone and fibrate (e.g., fenofibrate drugs are used for the treatment of diabetes and dyslipidemia. These agents target the peroxisome proliferator-activated receptors, PPARγ and PPARα, which are transcription factors that influence glucose and lipid metabolism, inflammation, and organ protection. In this study, we explored the effects of pioglitazone and other PPAR agonists to prevent gentamicin-induced oxidative stress and apoptosis in mouse organ of Corti (OC explants. Western blots showed high levels of PPARγ and PPARα proteins in mouse OC lysates. Immunofluorescence assays indicated that PPARγ and PPARα proteins are present in auditory HCs and other cell types in the mouse cochlea. Gentamicin treatment induced production of reactive oxygen species (ROS, lipid peroxidation, caspase activation, PARP-1 cleavage, and HC apoptosis in cultured OCs. Pioglitazone mediated its anti-apoptotic effects by opposing the increase in ROS induced by gentamicin, which inhibited the subsequent formation of 4-hydroxy-2-nonenal (4-HNE and activation of pro-apoptotic mediators. Pioglitazone mediated its effects by upregulating genes that control ROS production and detoxification pathways leading to restoration of the reduced:oxidized glutathione ratio. Structurally diverse PPAR agonists were protective of HCs. Pioglitazone (PPARγ-specific, tesaglitazar (PPARγ/α-specific, and fenofibric acid (PPARα-specific all provided >90% protection from gentamicin toxicity by regulation of overlapping subsets of genes controlling ROS detoxification. This study revealed that PPARs play important roles in the cochlea, and that PPAR-targeting drugs possess therapeutic potential as treatment for hearing loss.

Revealing a steroid receptor ligand as a unique PPAR[gamma] agonist

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Lin, Shengchen; Han, Ying; Shi, Yuzhe; Rong, Hui; Zheng, Songyang; Jin, Shikan; Lin, Shu-Yong; Lin, Sheng-Cai; Li, Yong (Pitt); (Xiamen)

2012-06-28

Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) regulates metabolic homeostasis and is a molecular target for anti-diabetic drugs. We report here the identification of a steroid receptor ligand, RU-486, as an unexpected PPAR{gamma} agonist, thereby uncovering a novel signaling route for this steroid drug. Similar to rosiglitazone, RU-486 modulates the expression of key PPAR{gamma} target genes and promotes adipocyte differentiation, but with a lower adipogenic activity. Structural and functional studies of receptor-ligand interactions reveal the molecular basis for a unique binding mode for RU-486 in the PPAR{gamma} ligand-binding pocket with distinctive properties and epitopes, providing the molecular mechanisms for the discrimination of RU-486 from thiazolidinediones (TZDs) drugs. Our findings together indicate that steroid compounds may represent an alternative approach for designing non-TZD PPAR{gamma} ligands in the treatment of insulin resistance.

Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPAR

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Saoirse E. O'Sullivan

2009-01-01

Full Text Available The aim of the present study was to examine whether endocannabinoids cause PPAR-mediated vascular actions. Functional vascular studies were carried out in rat aortae. Anandamide and N-arachidonoyl-dopamine (NADA, but not palmitoylethanolamide, caused significant vasorelaxation over time (2 hours. Vasorelaxation to NADA, but not anandamide, was inhibited by CB1 receptor antagonism (AM251, 1 M, and vasorelaxation to both anandamide and NADA was inhibited by PPAR antagonism (GW9662, 1 M. Pharmacological inhibition of de novo protein synthesis, nitric oxide synthase, and super oxide dismutase abolished the responses to anandamide and NADA. Removal of the endothelium partly inhibited the vasorelaxant responses to anandamide and NADA. Inhibition of fatty acid amide hydrolase (URB597, 1 M inhibited the vasorelaxant response to NADA, but not anandamide. These data indicate that endocannabinoids cause time-dependent, PPAR-mediated vasorelaxation. Activation of PPAR in the vasculature may represent a novel mechanism by which endocannabinoids are involved in vascular regulation.

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

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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.

Fatty Acid Amide Hydrolase (FAAH) Inhibition Enhances Memory Acquisition through Activation of PPAR-alpha Nuclear Receptors

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Mazzola, Carmen; Medalie, Julie; Scherma, Maria; Panlilio, Leigh V.; Solinas, Marcello; Tanda, Gianluigi; Drago, Filippo; Cadet, Jean Lud; Goldberg, Steven R.; Yasar, Sevil

2009-01-01

Inhibitors of fatty acid amide hydrolase (FAAH) increase endogenous levels of anandamide (a cannabinoid CB[subscript 1]-receptor ligand) and oleoylethanolamide and palmitoylethanolamide (OEA and PEA, ligands for alpha-type peroxisome proliferator-activated nuclear receptors, PPAR-alpha) when and where they are naturally released in the brain.…

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

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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.

Role of Peroxisome Proliferator-Activated Receptors in Inflammation Control

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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.

Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist inhibits collagen synthesis in human hypertrophic scar fibroblasts by targeting Smad3 via miR-145

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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.

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

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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)-d...

Gemfibrozil, a lipid lowering drug, inhibits the activation of primary human microglia via peroxisome proliferator-activated receptor β.

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Jana, Malabendu; Pahan, Kalipada

2012-08-01

Microglial activation participates in the pathogenesis of various neuroinflammatory and neurodegenerative diseases. However, mechanisms by which microglial activation could be controlled are poorly understood. Peroxisome proliferator-activated receptors (PPAR) are transcription factors belonging to the nuclear receptor super family with diverse effect. This study underlines the importance of PPARβ/δ in mediating the anti-inflammatory effect of gemfibrozil, an FDA-approved lipid-lowering drug, in primary human microglia. Bacterial lipopolysachharides (LPS) induced the expression of various proinflammatory molecules and upregulated the expression of microglial surface marker CD11b in human microglia. However, gemfibrozil markedly suppressed proinflammatory molecules and CD11b in LPS-stimulated microglia. Human microglia expressed PPAR-β and -γ, but not PPAR-α. Interestingly, either antisense knockdown of PPAR-β or antagonism of PPAR-β by a specific chemical antagonist abrogated gemfibrozil-mediated inhibition of microglial activation. On the other hand, blocking of PPAR-α and -γ had no effect on gemfibrozil-mediated anti-inflammatory effect in microglia. These results highlight the fact that gemfibrozil regulates microglial activation by inhibiting inflammatory gene expression in a PPAR-β dependent pathway and further reinforce its therapeutic application in several neuroinflammatory and neurodegenerative diseases.

Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians

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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......-insulin-dependent) diabetes mellitus among Scandinavian Caucasians....

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

Genomic organization of the mouse peroxisome proliferator-activated receptor beta/delta gene

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Larsen, Leif K; Amri, Ez-Zoubir; Mandrup, Susanne

2002-01-01

Peroxisome proliferator-activated receptor (PPAR) beta/delta is ubiquitously expressed, but the level of expression differs markedly between different cell types. In order to determine the molecular mechanisms governing PPARbeta/delta gene expression, we have isolated and characterized the mouse...

Abscisic Acid Regulates Inflammation via Ligand-binding Domain-independent Activation of Peroxisome Proliferator-activated Receptor γ*

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Bassaganya-Riera, Josep; Guri, Amir J.; Lu, Pinyi; Climent, Montse; Carbo, Adria; Sobral, Bruno W.; Horne, William T.; Lewis, Stephanie N.; Bevan, David R.; Hontecillas, Raquel

2011-01-01

Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E2 and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation. PMID:21088297

Abscisic acid regulates inflammation via ligand-binding domain-independent activation of peroxisome proliferator-activated receptor gamma.

Science.gov (United States)

Bassaganya-Riera, Josep; Guri, Amir J; Lu, Pinyi; Climent, Montse; Carbo, Adria; Sobral, Bruno W; Horne, William T; Lewis, Stephanie N; Bevan, David R; Hontecillas, Raquel

2011-01-28

Abscisic acid (ABA) has shown efficacy in the treatment of diabetes and inflammation; however, its molecular targets and the mechanisms of action underlying its immunomodulatory effects remain unclear. This study investigates the role of peroxisome proliferator-activated receptor γ (PPAR γ) and lanthionine synthetase C-like 2 (LANCL2) as molecular targets for ABA. We demonstrate that ABA increases PPAR γ reporter activity in RAW 264.7 macrophages and increases ppar γ expression in vivo, although it does not bind to the ligand-binding domain of PPAR γ. LANCL2 knockdown studies provide evidence that ABA-mediated activation of macrophage PPAR γ is dependent on lancl2 expression. Consistent with the association of LANCL2 with G proteins, we provide evidence that ABA increases cAMP accumulation in immune cells. ABA suppresses LPS-induced prostaglandin E(2) and MCP-1 production via a PPAR γ-dependent mechanism possibly involving activation of PPAR γ and suppression of NF-κB and nuclear factor of activated T cells. LPS challenge studies in PPAR γ-expressing and immune cell-specific PPAR γ null mice demonstrate that ABA down-regulates toll-like receptor 4 expression in macrophages and T cells in vivo through a PPAR γ-dependent mechanism. Global transcriptomic profiling and confirmatory quantitative RT-PCR suggest novel candidate targets and demonstrate that ABA treatment mitigates the effect of LPS on the expression of genes involved in inflammation, metabolism, and cell signaling, in part, through PPAR γ. In conclusion, ABA decreases LPS-mediated inflammation and regulates innate immune responses through a bifurcating pathway involving LANCL2 and an alternative, ligand-binding domain-independent mechanism of PPAR γ activation.

The Role of Peroxisome Proliferator-Activated Receptors in the Development and Physiology of Gametes and Preimplantation Embryos

Directory of Open Access Journals (Sweden)

Jaou-Chen Huang

2008-01-01

Full Text Available In several species, a family of nuclear receptors, the peroxisome proliferator-activated receptors (PPARs composed of three isotypes, is expressed in somatic cells and germ cells of the ovary as well as the testis. Invalidation of these receptors in mice or stimulation of these receptors in vivo or in vitro showed that each receptor has physiological roles in the gamete maturation or the embryo development. In addition, synthetic PPARγ ligands are recently used to induce ovulation in women with polycystic ovary disease. These results reveal the positive actions of PPAR in reproduction. On the other hand, xenobiotics molecules (in herbicides, plasticizers, or components of personal care products, capable of activating PPAR, may disrupt normal PPAR functions in the ovary or the testis and have consequences on the quality of the gametes and the embryos. Despite the recent data obtained on the biological actions of PPARs in reproduction, relatively little is known about PPARs in gametes and embryos. This review summarizes the current knowledge on the expression and the function of PPARs as well as their partners, retinoid X receptors (RXRs, in germ cells and preimplantation embryos. The effects of natural and synthetic PPAR ligands will also be discussed from the perspectives of reproductive toxicology and assisted reproductive technology.

Fisetin up-regulates the expression of adiponectin in 3T3-L1 adipocytes via the activation of silent mating type information regulation 2 homologue 1 (SIRT1)-deacetylase and peroxisome proliferator-activated receptors (PPARs).

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Jin, Taewon; Kim, Oh Yoen; Shin, Min-Jeong; Choi, Eun Young; Lee, Sung Sook; Han, Ye Sun; Chung, Ji Hyung

2014-10-29

Adiponectin, an adipokine, has been described as showing physiological benefits against obesity-related malfunctions and vascular dysfunction. Several natural compounds that promote the expression and secretion of adipokines in adipocytes could be useful for treating metabolic disorders. This study investigated the effect of fisetin, a dietary flavonoid, on the regulation of adiponectin in adipocytes using 3T3-L1 preadipocytes. The expression and secretion of adiponectin increased in 3T3-L1 cells upon treatment with fisetin in a dose-dependent manner. Fisetin-induced adiponectin secretion was inhibited by peroxisome proliferator-activated receptor (PPAR) antagonists. It was also revealed that fisetin increased the activities of PPARs and silent mating type information regulation 2 homologue 1 (SIRT1) in a dose-dependent manner. Furthermore, the up-regulation of adiponectin and the activation of PPARs induced by fisetin were prevented by a SIRT1 inhibitor. Fisetin also promoted deacetylation of PPAR γ coactivator 1 (PGC-1) and its interaction with PPARs. SIRT knockdown by siRNA significantly decreased both adiponectin production and PPARs-PGC-1 interaction. These results provide evidence that fisetin promotes the gene expression of adiponectin through the activation of SIRT1 and PPARs in adipocytes.

Cow's milk increases the activities of human nuclear receptors peroxisome proliferator-activated receptors alpha and delta and retinoid X receptor alpha involved in the regulation of energy homeostasis, obesity, and inflammation.

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Suhara, W; Koide, H; Okuzawa, T; Hayashi, D; Hashimoto, T; Kojo, H

2009-09-01

The nuclear peroxisome proliferator-activated receptors (PPAR) have been shown to play crucial roles in regulating energy homeostasis including lipid and carbohydrate metabolism, inflammatory responses, and cell proliferation, differentiation, and survival. Because PPAR agonists have the potential to prevent or ameliorate diseases such as hyperlipidemia, diabetes, atherosclerosis, and obesity, we have explored new natural agonists for PPAR. For this purpose, cow's milk was tested for agonistic activity toward human PPAR subtypes using a reporter gene assay. Milk increased human PPARalpha activity in a dose-dependent manner with a 3.2-fold increase at 0.5% (vol/vol). It also enhanced human PPARdelta activity in a dose-dependent manner with an 11.5-fold increase at 0.5%. However, it only slightly affected human PPARgamma activity. Ice cream, butter, and yogurt also increased the activities of PPARalpha and PPARdelta, whereas vegetable cream affected activity of PPARdelta but not PPARalpha. Skim milk enhanced the activity of PPAR to a lesser degree than regular milk. Milk and fresh cream increased the activity of human retinoid X receptor (RXR)alpha as well as PPARalpha and PPARdelta, whereas neither affected vitamin D3 receptor, estrogen receptors alpha and beta, or thyroid receptors alpha and beta. Both milk and fresh cream were shown by quantitative real-time PCR to increase the quantity of mRNA for uncoupling protein 2 (UCP2), an energy expenditure gene, in a dose-dependent manner. The increase in UCP2 mRNA was found to be reduced by treatment with PPARdelta-short interfering (si)RNA. This study unambiguously clarified at the cellular level that cow's milk increased the activities of human PPARalpha, PPARdelta, and RXRalpha. The possible role in enhancing the activities of PPARalpha, PPARdelta, and RXRalpha, and the health benefits of cow's milk were discussed.

Peroxisome Proliferator-Activated Receptor- Is a Potent Target for Prevention and Treatment in Human Prostate and Testicular Cancer

Directory of Open Access Journals (Sweden)

Masahide Matsuyama

2008-01-01

Full Text Available Peroxisome proliferator-activated receptor- (PPAR- is a ligand-activated transcriptional factor belonging to steroid receptor superfamily. PPAR- plays a role in both adipocyte differentiation and tumorigenesis. Up to date, PPAR- is expressed in various cancer tissues, and PPAR- ligand induces growth arrest of these cancer cells. In this study, we examined the expression of PPAR- in prostate cancer (PC and testicular cancer (TC by RT-PCR and immunohistochemistry, and we also examined the effect of PPAR- ligand in these cells by MTT assay, hoechest staining, and flow cytometry. PPAR- expression was significantly more extensive and intense in malignant tissues than in normal tissues. PPAR- ligand induced the reduction of malignant cell viability through apoptosis. These results demonstrated that the generated PPAR- in PC and TC cells might play an important role in the tumorigenesis. PPAR- may become a new target in the treatment of PC and TC.

Expression of Peroxisomes-Proliferate Activated Receptors-γ in Diabetics, Obese and Normal Subjects

International Nuclear Information System (INIS)

Afzal, N.

2016-01-01

Background: Current research in type 2 diabetes mellitus focuses on the role of Peroxisome-Proliferator Activated Receptors (PPARs) in the pathogenesis of the Insulin Resistance Syndrome (IRS), which are pre-diabetic lesion and the hallmark of fully developed type 2 diabetes mellitus. This study aims at identifying the abnormal status of the PPAR-g in adipose tissues of type 2 diabetes mellitus patients, when compared with matched normal controls. Methods: This cross-sectional study was conducted in Ayub Medical College, Abbottabad, from 2012 to 2014. Sample included three equal groups of patients. Group-1 with diagnosed type 2 diabetes mellitus, aged 40-65 years, acting as the test group, Group-2 included non-diabetic obese, and Group-3 with normal subjects. Transcription Factor Assay for Peroxisome Proliferator Activated Receptor Gamma (gamma PPAR) was done on ELISA Technique from Nuclear Extract procured from Adipose Tissue of the subjects. Results: Mean age of enrolled participants was 48.93 SD±6.52.years. Patients ranged between ages of 40 years to 67 years. The mean values of PPAR in normal, obese and diabetic group were 1.72 SD±0.28, 1.282 SE±0.18 and 1.283 SE±0.18 respectively. The difference in mean values of PPAR was significant ρ<0.05. Conclusion: The levels of PPAR-g in patients with type 2 Diabetes Mellitus and Obese cases are significantly lower than normal controls. (author)

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

PPARs and the Cardiovascular System

Science.gov (United States)

Hamblin, Milton; Chang, Lin; Fan, Yanbo; Zhang, Jifeng

2009-01-01

Abstract Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone-receptor superfamily. Originally cloned in 1990, PPARs were found to be mediators of pharmacologic agents that induce hepatocyte peroxisome proliferation. PPARs also are expressed in cells of the cardiovascular system. PPARγ appears to be highly expressed during atherosclerotic lesion formation, suggesting that increased PPARγ expression may be a vascular compensatory response. Also, ligand-activated PPARγ decreases the inflammatory response in cardiovascular cells, particularly in endothelial cells. PPARα, similar to PPARγ, also has pleiotropic effects in the cardiovascular system, including antiinflammatory and antiatherosclerotic properties. PPARα activation inhibits vascular smooth muscle proinflammatory responses, attenuating the development of atherosclerosis. However, PPARδ overexpression may lead to elevated macrophage inflammation and atherosclerosis. Conversely, PPARδ ligands are shown to attenuate the pathogenesis of atherosclerosis by improving endothelial cell proliferation and survival while decreasing endothelial cell inflammation and vascular smooth muscle cell proliferation. Furthermore, the administration of PPAR ligands in the form of TZDs and fibrates has been disappointing in terms of markedly reducing cardiovascular events in the clinical setting. Therefore, a better understanding of PPAR-dependent and -independent signaling will provide the foundation for future research on the role of PPARs in human cardiovascular biology. Antioxid. Redox Signal. 11, 1415–1452. PMID:19061437

Peroxisome Proliferator-Activated Receptor-γ in Thyroid Autoimmunity

Directory of Open Access Journals (Sweden)

Silvia Martina Ferrari

2015-01-01

Full Text Available Peroxisome proliferator-activated receptor- (PPAR- γ expression has been shown in thyroid tissue from patients with thyroiditis or Graves’ disease and furthermore in the orbital tissue of patients with Graves’ ophthalmopathy (GO, such as in extraocular muscle cells. An increasing body of evidence shows the importance of the (C-X-C motif receptor 3 (CXCR3 and cognate chemokines (C-X-C motif ligand (CXCL9, CXCL10, and CXCL11, in the T helper 1 immune response and in inflammatory diseases such as thyroid autoimmune disorders. PPAR-γ agonists show a strong inhibitory effect on the expression and release of CXCR3 chemokines, in vitro, in various kinds of cells, such as thyrocytes, and in orbital fibroblasts, preadipocytes, and myoblasts from patients with GO. Recently, it has been demonstrated that rosiglitazone is involved in a higher risk of heart failure, stroke, and all-cause mortality in old patients. On the contrary, pioglitazone has not shown these effects until now; this favors pioglitazone for a possible use in patients with thyroid autoimmunity. However, further studies are ongoing to explore the use of new PPAR-γ agonists in the treatment of thyroid autoimmune disorders.

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...

Activation of RXR–PPAR heterodimers by organotin environmental endocrine disruptors

Science.gov (United States)

le Maire, Albane; Grimaldi, Marina; Roecklin, Dominique; Dagnino, Sonia; Vivat-Hannah, Valérie; Balaguer, Patrick; Bourguet, William

2009-01-01

The nuclear receptor retinoid X receptor-α (RXR-α)–peroxisome proliferator-activated receptor-γ (PPAR-γ) heterodimer was recently reported to have a crucial function in mediating the deleterious effects of organotin compounds, which are ubiquitous environmental contaminants. However, because organotins are unrelated to known RXR-α and PPAR-γ ligands, the mechanism by which these compounds bind to and activate the RXR-α–PPAR-γ heterodimer at nanomolar concentrations has remained elusive. Here, we show that tributyltin (TBT) activates all three RXR–PPAR-α, -γ, -δ heterodimers, primarily through its interaction with RXR. In addition, the 1.9 Å resolution structure of the RXR-α ligand-binding domain in complex with TBT shows a covalent bond between the tin atom and residue Cys 432 of helix H11. This interaction largely accounts for the high binding affinity of TBT, which only partly occupies the RXR-α ligand-binding pocket. Our data allow an understanding of the binding and activation properties of the various organotins and suggest a mechanism by which these tin compounds could affect other nuclear receptor signalling pathways. PMID:19270714

Discovery of a Series of Imidazo[4,5-b]pyridines with Dual Activity at Angiotensin II Type 1 Receptor and Peroxisome Proliferator-Activated Receptor-[gamma

Energy Technology Data Exchange (ETDEWEB)

Casimiro-Garcia, Agustin; Filzen, Gary F.; Flynn, Declan; Bigge, Christopher F.; Chen, Jing; Davis, Jo Ann; Dudley, Danette A.; Edmunds, Jeremy J.; Esmaeil, Nadia; Geyer, Andrew; Heemstra, Ronald J.; Jalaie, Mehran; Ohren, Jeffrey F.; Ostroski, Robert; Ellis, Teresa; Schaum, Robert P.; Stoner, Chad (Pfizer)

2013-03-07

Mining of an in-house collection of angiotensin II type 1 receptor antagonists to identify compounds with activity at the peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}) revealed a new series of imidazo[4,5-b]pyridines 2 possessing activity at these two receptors. Early availability of the crystal structure of the lead compound 2a bound to the ligand binding domain of human PPAR{gamma} confirmed the mode of interaction of this scaffold to the nuclear receptor and assisted in the optimization of PPAR{gamma} activity. Among the new compounds, (S)-3-(5-(2-(1H-tetrazol-5-yl)phenyl)-2,3-dihydro-1H-inden-1-yl)-2-ethyl-5-isobutyl-7-methyl-3H-imidazo[4,5-b]pyridine (2l) was identified as a potent angiotensin II type I receptor blocker (IC{sub 50} = 1.6 nM) with partial PPAR{gamma} agonism (EC{sub 50} = 212 nM, 31% max) and oral bioavailability in rat. The dual pharmacology of 2l was demonstrated in animal models of hypertension (SHR) and insulin resistance (ZDF rat). In the SHR, 2l was highly efficacious in lowering blood pressure, while robust lowering of glucose and triglycerides was observed in the male ZDF rat.

Induction of human adiponectin gene transcription by telmisartan, angiotensin receptor blocker, independently on PPAR-γ activation

International Nuclear Information System (INIS)

Moriuchi, Akie; Yamasaki, Hironori; Shimamura, Mika; Kita, Atsushi; Kuwahara, Hironaga; Fujishima, Keiichiro; Satoh, Tsuyoshi; Fukushima, Keiko; Fukushima, Tetsuya; Hayakawa, Takao; Mizuguchi, Hiroyuki; Nagayama, Yuji; Abiru, Norio; Kawasaki, Eiji; Eguchi, Katsumi

2007-01-01

Adiponectin, an adipose tissue-specific plasma protein, has been shown to ameliorate insulin resistance and inhibit the process of atherosclerosis. Recently, several reports have stated that angiotensin type 1 receptor blockers (ARBs), increase adiponectin plasma level, and ameliorate insulin resistance. Telmisartan, a subclass of ARBs, has been shown to be a partial agonist of the peroxisome proliferator-activated receptor (PPAR)-γ, and to increase the plasma adiponectin level. However, the transcriptional regulation of the human adiponectin gene by telmisartan has not been determined yet. To elucidate the effect of telmisartan on adiponectin, the stimulatory regulation of human adiponectin gene by telmisartan was investigated in 3T3-L1 adipocytes, utilizing adenovirus-mediated luciferase reporter gene-transferring technique. This study indicates that telmisartan may stimulate adiponectin transcription independent of PPAR-γ

Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor α.

Science.gov (United States)

Takao, Koichi; Noguchi, Kaori; Hashimoto, Yosuke; Shirahata, Akira; Sugita, Yoshiaki

2015-01-01

A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ(9)-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists.

Angiotensin II receptor blocker telmisartan enhances running endurance of skeletal muscle through activation of the PPAR-δ/AMPK pathway.

Science.gov (United States)

Feng, Xiaoli; Luo, Zhidan; Ma, Liqun; Ma, Shuangtao; Yang, Dachun; Zhao, Zhigang; Yan, Zhencheng; He, Hongbo; Cao, Tingbing; Liu, Daoyan; Zhu, Zhiming

2011-07-01

Clinical trials have shown that angiotensin II receptor blockers reduce the new onset of diabetes in hypertensives; however, the underlying mechanisms remain unknown. We investigated the effects of telmisartan on peroxisome proliferator activated receptor γ (PPAR-δ) and the adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway in cultured myotubes, as well as on the running endurance of wild-type and PPAR-δ-deficient mice. Administration of telmisartan up-regulated levels of PPAR-δ and phospho-AMPKα in cultured myotubes. However, PPAR-δ gene deficiency completely abolished the telmisartan effect on phospho-AMPKαin vitro. Chronic administration of telmisartan remarkably prevented weight gain, enhanced running endurance and post-exercise oxygen consumption, and increased slow-twitch skeletal muscle fibres in wild-type mice, but these effects were absent in PPAR-δ-deficient mice. The mechanism is involved in PPAR-δ-mediated stimulation of the AMPK pathway. Compared to the control mice, phospho-AMPKα level in skeletal muscle was up-regulated in mice treated with telmisartan. In contrast, phospho-AMPKα expression in skeletal muscle was unchanged in PPAR-δ-deficient mice treated with telmisartan. These findings highlight the ability of telmisartan to improve skeletal muscle function, and they implicate PPAR-δ as a potential therapeutic target for the prevention of type 2 diabetes. © 2011 The Authors Journal of Cellular and Molecular Medicine © 2011 Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.

The PPAR{gamma} ligand ciglitazone regulates androgen receptor activation differently in androgen-dependent versus androgen-independent human prostate cancer cells

Energy Technology Data Exchange (ETDEWEB)

Moss, Patrice E.; Lyles, Besstina E.; Stewart, LaMonica V., E-mail: lstewart@mmc.edu

2010-12-10

The androgen receptor (AR) regulates growth and progression of androgen-dependent as well as androgen-independent prostate cancer cells. Peroxisome proliferator-activated receptor gamma (PPAR{gamma}) agonists have been reported to reduce AR activation in androgen-dependent LNCaP prostate cancer cells. To determine whether PPAR{gamma} ligands are equally effective at inhibiting AR activity in androgen-independent prostate cancer, we examined the effect of the PPAR{gamma} ligands ciglitazone and rosiglitazone on C4-2 cells, an androgen- independent derivative of the LNCaP cell line. Luciferase-based reporter assays and Western blot analysis demonstrated that PPAR{gamma} ligand reduced dihydrotestosterone (DHT)-induced increases in AR activity in LNCaP cells. However, in C4-2 cells, these compounds increased DHT-induced AR driven luciferase activity. In addition, ciglitazone did not significantly alter DHT-mediated increases in prostate specific antigen (PSA) protein or mRNA levels within C4-2 cells. siRNA-based experiments demonstrated that the ciglitazone-induced regulation of AR activity observed in C4-2 cells was dependent on the presence of PPAR{gamma}. Furthermore, overexpression of the AR corepressor cyclin D1 inhibited the ability of ciglitazone to induce AR luciferase activity in C4-2 cells. Thus, our data suggest that both PPAR{gamma} and cyclin D1 levels influence the ability of ciglitazone to differentially regulate AR signaling in androgen-independent C4-2 prostate cancer cells.

Novel time-dependent vascular actions of {delta}{sup 9}-tetrahydrocannabinol mediated by peroxisome proliferator-activated receptor gamma

Energy Technology Data Exchange (ETDEWEB)

O' Sullivan, Saoirse E [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Tarling, Elizabeth J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Bennett, Andrew J [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Kendall, David A [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom); Randall, Michael D [School of Biomedical Sciences, E Floor, Queen' s Medical Centre, University of Nottingham, Nottingham NG7 2UH (United Kingdom)

2005-11-25

Cannabinoids have widespread effects on the cardiovascular system, only some of which are mediated via G-protein-coupled cell surface receptors. The active ingredient of cannabis, {delta}{sup 9}-tetrahydrocannabinol (THC), causes acute vasorelaxation in various arteries. Here we show for the first time that THC also causes slowly developing vasorelaxation through activation of peroxisome proliferator-activated receptors gamma (PPAR{gamma}). In vitro, THC (10 {mu}M) caused time-dependent vasorelaxation of rat isolated arteries. Time-dependent vasorelaxation to THC was similar to that produced by the PPAR{gamma} agonist rosiglitazone and was inhibited by the PPAR{gamma} antagonist GW9662 (1 {mu}M), but not the cannabinoid CB{sub 1} receptor antagonist AM251 (1 {mu}M). Time-dependent vasorelaxation to THC requires an intact endothelium, nitric oxide, production of hydrogen peroxide, and de novo protein synthesis. In transactivation assays in cultured HEK293 cells, THC-activated PPAR{gamma}, transiently expressed in combination with retinoid X receptor {alpha} and a luciferase reporter gene, in a concentration-dependent manner (100 nM-10 {mu}M). In vitro incubation with THC (1 or 10 {mu}M, 8 days) stimulated adipocyte differentiation in cultured 3T3L1 cells, a well-accepted property of PPAR{gamma} ligands. The present results provide strong evidence that THC is a PPAR{gamma} ligand, stimulation of which causes time-dependent vasorelaxation, implying some of the pleiotropic effects of cannabis may be mediated by nuclear receptors.

Regulation of the human SLC25A20 expression by peroxisome proliferator-activated receptor alpha in human hepatoblastoma cells

Energy Technology Data Exchange (ETDEWEB)

Tachibana, Keisuke, E-mail: nya@phs.osaka-u.ac.jp [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Takeuchi, Kentaro; Inada, Hirohiko [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Yamasaki, Daisuke [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Ishimoto, Kenji [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Tanaka, Toshiya; Hamakubo, Takao; Sakai, Juro; Kodama, Tatsuhiko [Laboratory for System Biology and Medicine, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro, Tokyo 153-8904 (Japan); Doi, Takefumi [Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871 (Japan); The Center for Advanced Medical Engineering and Informatics, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan); Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871 (Japan)

2009-11-20

Solute carrier family 25, member 20 (SLC25A20) is a key molecule that transfers acylcarnitine esters in exchange for free carnitine across the mitochondrial membrane in the mitochondrial {beta}-oxidation. The peroxisome proliferator-activated receptor alpha (PPAR{alpha}) is a ligand-activated transcription factor that plays an important role in the regulation of {beta}-oxidation. We previously established tetracycline-regulated human cell line that can be induced to express PPAR{alpha} and found that PPAR{alpha} induces the SLC25A20 expression. In this study, we analyzed the promoter region of the human slc25a20 gene and showed that PPAR{alpha} regulates the expression of human SLC25A20 via the peroxisome proliferator responsive element.

Role of peroxisome proliferators-activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease

Institute of Scientific and Technical Information of China (English)

Eric R Kallwitz; Alan McLachlan; Scott J Cotler

2008-01-01

Nonalcoholic fatty liver disease (NAFLD) is highly prevalent and can result in nonalcoholic steatohepatitis (NASH) and progressive liver disease including cirrhosis and hepatocellular carcinoma. A growing body of literature implicates the peroxisorne proliferators- activated receptors (PPARs) in the pathogenesis and treatment of NAFLD. These nuclear hormone receptors impact on hepatic triglyceride accumulation and insulin resistance. The aim of this review is to describe the data linking PPARα and PPARγ to NAFLD/NASH and to discuss the use of PPAR ligands for the treatment of NASH.

PPAR-γ activation increases insulin secretion through the up-regulation of the free fatty acid receptor GPR40 in pancreatic β-cells.

Directory of Open Access Journals (Sweden)

Hyo-Sup Kim

Full Text Available BACKGROUND: It has been reported that peroxisome proliferator-activated receptor (PPAR-γ and their synthetic ligands have direct effects on pancreatic β-cells. We investigated whether PPAR-γ activation stimulates insulin secretion through the up-regulation of GPR40 in pancreatic β-cells. METHODS: Rat insulinoma INS-1 cells and primary rat islets were treated with rosiglitazone (RGZ and/or adenoviral PPAR-γ overexpression. OLETF rats were treated with RGZ. RESULTS: PPAR-γ activation with RGZ and/or adenoviral PPAR-γ overexpression increased free fatty acid (FFA receptor GPR40 expression, and increased insulin secretion and intracellular calcium mobilization, and was blocked by the PLC inhibitors, GPR40 RNA interference, and GLUT2 RNA interference. As a downstream signaling pathway of intracellular calcium mobilization, the phosphorylated levels of CaMKII and CREB, and the downstream IRS-2 and phospho-Akt were significantly increased. Despite of insulin receptor RNA interference, the levels of IRS-2 and phospho-Akt was still maintained with PPAR-γ activation. In addition, the β-cell specific gene expression, including Pdx-1 and FoxA2, increased in a GPR40- and GLUT2-dependent manner. The levels of GPR40, phosphorylated CaMKII and CREB, and β-cell specific genes induced by RGZ were blocked by GW9662, a PPAR-γ antagonist. Finally, PPAR-γ activation up-regulated β-cell gene expressions through FoxO1 nuclear exclusion, independent of the insulin signaling pathway. Based on immunohistochemical staining, the GLUT2, IRS-2, Pdx-1, and GPR40 were more strongly expressed in islets from RGZ-treated OLETF rats compared to control islets. CONCLUSION: These observations suggest that PPAR-γ activation with RGZ and/or adenoviral overexpression increased intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene up-regulation.

Steroid receptor coactivator 1 deficiency increases MMTV-neu mediated tumor latency and differentiation specific gene expression, decreases metastasis, and inhibits response to PPAR ligands

International Nuclear Information System (INIS)

Han, Ji Seung; Crowe, David L

2010-01-01

The peroxisome proliferator activated receptor (PPAR) subgroup of the nuclear hormone receptor superfamily is activated by a variety of natural and synthetic ligands. PPARs can heterodimerize with retinoid X receptors, which have homology to other members of the nuclear receptor superfamily. Ligand binding to PPAR/RXRs results in recruitment of transcriptional coactivator proteins such as steroid receptor coactivator 1 (SRC-1) and CREB binding protein (CBP). Both SRC-1 and CBP are histone acetyltransferases, which by modifying nucleosomal histones, produce more open chromatin structure and increase transcriptional activity. Nuclear hormone receptors can recruit limiting amounts of coactivators from other transcription factor binding sites such as AP-1, thereby inhibiting the activity of AP-1 target genes. PPAR and RXR ligands have been used in experimental breast cancer therapy. The role of coactivator expression in mammary tumorigenesis and response to drug therapy has been the subject of recent studies. We examined the effects of loss of SRC-1 on MMTV-neu mediated mammary tumorigenesis. SRC-1 null mutation in mammary tumor prone mice increased the tumor latency period, reduced tumor proliferation index and metastasis, inhibited response to PPAR and RXR ligands, and induced genes involved in mammary gland differentiation. We also examined human breast cancer cell lines overexpressing SRC-1 or CBP. Coactivator overexpression increased cellular proliferation with resistance to PPAR and RXR ligands and remodeled chromatin of the proximal epidermal growth factor receptor promoter. These results indicate that histone acetyltransferases play key roles in mammary tumorigenesis and response to anti-proliferative therapies

Telmisartan prevented cognitive decline partly due to PPAR-γ activation

International Nuclear Information System (INIS)

Mogi, Masaki; Li Jianmei; Tsukuda, Kana; Iwanami, Jun; Min, Li-Juan; Sakata, Akiko; Fujita, Teppei; Iwai, Masaru; Horiuchi, Masatsugu

2008-01-01

Telmisartan is a unique angiotensin receptor blocker (ARB) and partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ. Here, we investigated the preventive effect of telmisartan on cognitive decline in Alzheimer disease. In ddY mice, intracerebroventricular injection of Aβ 1-40 significantly attenuated their cognitive function evaluated by shuttle avoidance test. Pretreatment with a non-hypotensive dose of telmisartan significantly inhibited such cognitive decline. Interestingly, co-treatment with GW9662, a PPAR-γ antagonist, partially inhibited this improvement of cognitive decline. Another ARB, losartan, which has less PPAR-γ agonistic effect, also inhibited Aβ-injection-induced cognitive decline; however the effect was smaller than that of telmisartan and was not affected by GW9662. Immunohistochemical staining for Aβ showed the reduced Aβ deposition in telmisartan-treated mice. However, this reduction was not observed in mice co-administered GW9662. These findings suggest that ARB has a preventive effect on cognitive impairment in Alzheimer disease, and telmisartan, with PPAR-γ activation, could exert a stronger effect

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

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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.

Transcriptional activation of peroxisome proliferator-activated receptor-γ requires activation of both protein kinase A and Akt during adipocyte differentiation

International Nuclear Information System (INIS)

Kim, Sang-pil; Ha, Jung Min; Yun, Sung Ji; Kim, Eun Kyoung; Chung, Sung Woon; Hong, Ki Whan; Kim, Chi Dae; Bae, Sun Sik

2010-01-01

Research highlights: → Elevated cAMP activates both PKA and Epac. → PKA activates CREB transcriptional factor and Epac activates PI3K/Akt pathway via Rap1. → Akt modulates PPAR-γ transcriptional activity in concert with CREB. -- Abstract: Peroxisome proliferator-activated receptor-γ (PPAR-γ) is required for the conversion of pre-adipocytes. However, the mechanism underlying activation of PPAR-γ is unclear. Here we showed that cAMP-induced activation of protein kinase A (PKA) and Akt is essential for the transcriptional activation of PPAR-γ. 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-γ was markedly enhanced by 3-isobutyl-1-methylxanthine (IBMX), but not insulin and dexamethasone. In addition, IBMX-induced PPAR-γ 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-γ transcriptional activity. These results indicate that both PKA and Akt signaling pathways are required for transcriptional activation of PPAR-γ, suggesting post-translational activation of PPAR-γ might be critical step for adipogenic gene expression.

Activation of Central PPAR-γ Attenuates Angiotensin II-Induced Hypertension

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Yu, Yang; Xue, Bao-Jian; Wei, Shun-Guang; Zhang, Zhi-Hua; Beltz, Terry G; Guo, Fang; Johnson, Alan Kim; Felder, Robert B

2015-01-01

Inflammation and renin-angiotensin system activity in the brain contribute to hypertension through effects on fluid intake, vasopressin release, and sympathetic nerve activity. We recently reported that activation of brain peroxisome proliferator-activated receptor (PPAR)-γ in heart failure rats reduced inflammation and renin-angiotensin system activity in the hypothalamic paraventricular nucleus and ameliorated the peripheral manifestations of heart failure. We hypothesized that activation of brain PPAR-γ might have beneficial effects in angiotensin II-induced hypertension. Sprague-Dawley rats received a 2-week subcutaneous infusion of angiotensin II (120 ng/kg/min) combined with a continuous intracerebroventricular infusion of vehicle, the PPAR-γ agonist pioglitazone (3 nmol/h) or the PPAR-γ antagonist GW9662 (7 nmol/h). Angiotensin II+vehicle rats had increased mean blood pressure, increased sympathetic drive as indicated by the mean blood pressure response to ganglionic blockade, and increased water consumption. PPAR-γ mRNA in subfornical organ and hypothalamic paraventricular nucleus was unchanged, but PPAR-γ DNA binding activity was reduced. mRNA for interleukin-1β, tumor necrosis factor-α, cyclooxygenase-2 and angiotensin II type-1 receptor was augmented in both nuclei, and hypothalamic paraventricular nucleus neuronal activity was increased. The plasma vasopressin response to a 6-hour water restriction also increased. These responses to angiotensin II were exacerbated by GW9662 and ameliorated by pioglitazone, which increased PPAR-γ mRNA and PPAR-γ DNA binding activity in subfornical organ and hypothalamic paraventricular nucleus. Pioglitazone and GW9662 had no effects on control rats. The results suggest that activating brain PPAR-γ to reduce central inflammation and brain renin-angiotensin system activity may be a useful adjunct in the treatment of angiotensin II-dependent hypertension. PMID:26101342

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

International Nuclear Information System (INIS)

Yan Zhencheng; Liu Daoyan; Zhang Lili; Shen Chenyi; Ma Qunli; Cao Tingbing; Wang Lijuan; Nie Hai; Zidek, Walter; Tepel, Martin; Zhu Zhiming

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-δ (PPAR-δ)-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 < 0.05). Adipocyte hypertrophy induced by high-fat diet was accompanied by increased CB1 expression in adipose tissue, whereas exercise significantly reduced CB1 expression (each p < 0.05). CB1 receptor expression and adipocyte differentiation were directly regulated by PPAR-δ. Adipocyte hypertrophy induced by high-fat diet was accompanied by reduced PPAR-δ. Furthermore, selective silencing of PPAR-δ by RNA interference in 3T3-L1-preadipocyte cells significantly increased CB1 expression from 1.00 ± 0.06 (n = 3) to 1.91 ± 0.06 (n = 3; p < 0.01) and increased adipocyte differentiation, whereas adenovirus-mediated overexpression of PPAR-δ significantly reduced CB1 expression to 0.39 ± 0.03 (n = 3; p < 0.01) and reduced adipocyte differentiation. In the presence of the CB1 antagonist rimonabant adipocyte differentiation in stimulated 3T3 L1 preadipocyte cells was significantly reduced. The study indicates that high-fat diet-induced hypertrophy of adipocytes is associated with increased CB1 receptor expression which is directly regulated by PPAR-δ. Both CB1 and PPAR-δ are intimately involved in therapeutic interventions against a most important cardiovascular risk factor

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

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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...

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...

Cytotoxic activities of amentoflavone against human breast and cervical cancers are mediated by increasing of PTEN expression levels due to peroxisomes proliferate-activated receptor {gamma} activation

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Lee, Eunjung; Shin, Soyoung; Lee, Jeeyoung; Lee, So Jung; Kim, Jinkyoung; Yoon, Doyoung; Kim, Yangmee [Konkuk Univ., Seoul (Korea, Republic of); Woo, Eunrhan [Chosun Univ., Gwangju (Korea, Republic of)

2012-07-15

Human peroxisomes proliferate-activated receptor gamma (hPPAR{gamma}) has been implicated in numerous pathologies, including obesity, diabetes, and cancer. Previously, we verified that amentoflavone is an activator of hPPAR{gamma} and probed the molecular basis of its action. In this study, we investigated the mechanism of action of amentoflavone in cancer cells and demonstrated that amentoflavone showed strong cytotoxicity against MCF-7 and HeLa cancer cell lines. We showed that hPPAR{gamma} expression in MCF-7 and HeLa cells is specifically stimulated by amentoflavone, and suggested that amentoflavone-induced cytotoxic activities are mediated by activation of hPPAR{gamma} in these two cancer cell lines. Moreover, amentoflavone increased PTEN levels in these two cancer cell lines, indicating that the cytotoxic activities of amentoflavone are mediated by increasing of PTEN expression levels due to hPPAR{gamma} activation.

PPAR, PTEN, and the Fight against Cancer

Directory of Open Access Journals (Sweden)

Rosemary E. Teresi

2008-01-01

Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR is a ligand-activated transcription factor, which belongs to the family of nuclear hormone receptors. Recent in vitro studies have shown that PPAR can regulate the transcription of phosphatase and tensin homolog on chromosome ten (PTEN, a known tumor suppressor. PTEN is a susceptibility gene for a number of disorders, including breast and thyroid cancer. Activation of PPAR through agonists increases functional PTEN protein levels that subsequently induces apoptosis and inhibits cellular growth, which suggests that PPAR may be a tumor suppressor. Indeed, several in vivo studies have demonstrated that genetic alterations of PPAR can promote tumor progression. These results are supported by observations of the beneficial effects of PPAR agonists in the in vivo cancer setting. These studies signify the importance of PPAR and PTEN's interaction in cancer prevention.

Peroxisome proliferator-activated receptor gamma signaling in human sperm physiology.

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Liu, Li-Li; Xian, Hua; Cao, Jing-Chen; Zhang, Chong; Zhang, Yong-Hui; Chen, Miao-Miao; Qian, Yi; Jiang, Ming

2015-01-01

Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of the PPARs, which are transcription factors of the steroid receptor superfamily. PPARγ acts as an important molecule for regulating energy homeostasis, modulates the hypothalamic-pituitary-gonadal (HPG) axis, and is reciprocally regulated by HPG. In the human, PPARγ protein is highly expressed in ejaculated spermatozoa, implying a possible role of PPARγ signaling in regulating sperm energy dissipation. PPARγ protein is also expressed in Sertoli cells and germ cells (spermatocytes). Its activation can be induced during capacitation and the acrosome reaction. This mini-review will focus on how PPARγ signaling may affect fertility and sperm quality and the potential reversibility of these adverse effects.

Bezafibrate induces a mitochondrial derangement in human cell lines: a PPAR-independent mechanism for a peroxisome proliferator.

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Scatena, R; Bottoni, P; Vincenzoni, F; Messana, I; Martorana, G E; Nocca, G; De Sole, P; Maggiano, N; Castagnola, M; Giardina, B

2003-11-01

Bezafibrate is a hypolipidemic drug that belongs to the group of peroxisome proliferators because it binds to peroxisome proliferator-activated receptors type alpha (PPARs). Peroxisome proliferators produce a myriad of extraperoxisomal effects, which are not necessarily dependent on their interaction with PPARs. An investigation on the peculiar activities of bezafibrate could clarify some of the molecular events and the relationship with the biochemical and pharmacological properties of this class of compounds. In this view, the human acute promyelocytic leukemia HL-60 cell line and human rabdomiosarcoma TE-671 cell line were cultured in media containing bezafibrate and a number of observations such as spectrophotometric analysis of mitochondrial respiratory chain enzymes, NMR metabolite determinations, phosphofructokinase enzymatic analysis, and differentiation assays were carried on. Bezafibrate induced a derangement of NADH cytochrome c reductase activity accompanied by metabolic alterations, mainly a shift to anaerobic glycolysis and an increase of fatty acid oxidation, as shown by NMR analysis of culture supernatants where acetate, lactate, and alanine levels increased. On the whole, the present results suggest a biochemical profile and a therapeutic role of this class of PPARs ligands more complex than those previously proposed.

Time-dependent therapeutic roles of nitazoxanide on high-fat diet/streptozotocin-induced diabetes in rats: effects on hepatic peroxisome proliferator-activated receptor-gamma receptors.

Science.gov (United States)

Elaidy, Samah M; Hussain, Mona A; El-Kherbetawy, Mohamed K

2018-05-01

Targeting peroxisome proliferator-activated receptor-gamma (PPAR-γ) is an approved strategy in facing insulin resistance (IR) for diabetes mellitus (DM) type 2. The PPAR-γ modulators display improvements in the insulin-sensitizing and adverse effects of the traditional thiazolidinediones. Nitazoxanide (NTZ) is proposed as a PPAR-γ receptor ligand with agonistic post-transcriptional effects. Currently, NTZ antidiabetic activities versus pioglitazone (PIO) in a high-fat diet/streptozotocin rat model of type 2 diabetes was explored. Diabetic adult male Wistar rats were treated orally with either PIO (2.7 mg·kg -1 ·day -1 ) or NTZ (200 mg·kg -1 ·day -1 ) for 14, 21, and 28 days. Body masses, fasting blood glucose, IR, lipid profiles, and liver and kidney functions of rats were assayed. Hepatic glucose metabolism and PPAR-γ protein expression levels as well as hepatic, pancreatic, muscular, and renal histopathology were evaluated. Significant time-dependent euglycemic and insulin-sensitizing effects with preservation of liver and kidney functions were offered by NTZ. Higher hepatic levels of glucose-6-phosphatase and glucose-6-phosphate dehydrogenase enzymes and PPAR-γ protein expressions were acquired by NTZ and PIO, respectively. NTZ could be considered an oral therapeutic strategy for DM type 2. Further systematic NTZ/PPAR-γ receptor subtype molecular activations are recommended. Simultaneous use of NTZ with other approved antidiabetics should be explored.

Evaluation of glucose metabolism and reproductive hormones in polycystic ovary syndrome on the basis of peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala genotype.

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Tok, E C; Aktas, A; Ertunc, D; Erdal, E M; Dilek, S

2005-06-01

Peroxisome proliferator-activated receptor (PPAR)-gamma2 Pro12Ala polymorphism has been suggested as a protective factor for polycystic ovary syndrome (PCOS). In this study, we aimed to investigate metabolic features and reproductive hormones in women with PCOS and compare these features with control women on the basis of Pro12Ala genotype. This study involved 60 randomly selected women with PCOS and 60 controls. Main outcome measures were anthropometric measures, variables of glucose metabolism and reproductive hormones. All the patients were genotyped for Pro12Ala variant of PPAR-gamma2 gene. Patients with Pro12Ala polymorphism were more obese in both groups. Furthermore, they had lower fasting insulin levels, were less insulin-resistant and were less glucose-intolerant as demonstrated by 2 h glucose concentrations. However, there was no difference in reproductive hormone levels on the basis of Pro12Ala genotype. Both control women and women with PCOS had significant differences in glucose metabolism on the basis of PPAR-gamma2 Pro12Ala polymorphism. Pro12Ala variant may break the process that leads to PCOS in susceptible women, instead of being a direct causal relationship between Pro12Ala polymorphism and PCOS.

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...

Screening of Peroxisome Proliferator-Activated Receptors (PPARs) α, γ and α Gene Polymorphisms for Obesity and Metabolic Syndrome Association in the Multi-Ethnic Malaysian Population.

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Chia, Phee-Phee; Fan, Sook-Ha; Say, Yee-How

2015-11-05

This study aimed to investigate the association of peroxisome proliferator-activated receptor (PPAR) genes PPARα L162V, PPARγ2 C161T and PPARδ T294C single nucleotide polymorphisms (SNPs) with obesity and metabolic syndrome (Met-S) in a multi-ethnic population in Kampar, Malaysia. Socio-demographic data, anthropometric and biochemical measurements (plasma lipid profile, adiponectin and interleukin-6 [IL-6] levels) were taken from 307 participants (124 males; 180 obese; 249 Met-S; 97 Malays, 85 ethnic Chinese, 55 ethnic Indians). The overall minor allele frequencies were .08, .22 and .30 for PPAR α L162V, γ C161T, δ T294C, respectively. All SNPs were not associated with obesity, Met-S and obesity with/without Met-S by χ(2) analysis, ethnicity-stratified and logistic regression analyses. Nevertheless, participants with V162 allele of PPARα had significantly higher IL-6, while those with T161 allele of PPARγ2 had significantly lower HOMA-IR. All PPAR SNPs were not associated with obesity and Met-S in the suburban population of Kampar, Malaysia, where only PPARα V162 and PPARγ2 T161 alleles were associated with plasma IL-6 and HOMA-IR, respectively.

Peroxisome Proliferator-Activated Receptor-γ Ligands: Potential Pharmacological Agents for Targeting the Angiogenesis Signaling Cascade in Cancer

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Costas Giaginis

2008-01-01

Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ has currently been considered as molecular target for the treatment of human metabolic disorders. Experimental data from in vitro cultures, animal models, and clinical trials have shown that PPAR-γ ligand activation regulates differentiation and induces cell growth arrest and apoptosis in a variety of cancer types. Tumor angiogenesis constitutes a multifaceted process implicated in complex downstream signaling pathways that triggers tumor growth, invasion, and metastasis. In this aspect, accumulating in vitro and in vivo studies have provided extensive evidence that PPAR-γ ligands can function as modulators of the angiogenic signaling cascade. In the current review, the crucial role of PPAR-γ ligands and the underlying mechanisms participating in tumor angiogenesis are summarized. Targeting PPAR-γ may prove to be a potential therapeutic strategy in combined treatments with conventional chemotherapy; however, special attention should be taken as there is also substantial evidence to support that PPAR-γ ligands can enhance angiogenic phenotype in tumoral cells.

Impaired peroxisome proliferator-activated receptor γ function through mutation of a conserved salt bridge (R425C) in familial partial lipodystrophy

NARCIS (Netherlands)

Jeninga, E.H.; van Beekum, P.O; van Dijk, A.D.J.; Hamers, N.; Bonvin, A.M.J.J.; Berger, R.; Kalkhoven, E.

2007-01-01

The nuclear receptor peroxisome proliferator-activated receptor (PPAR) γ plays a key role in the regulation of glucose and lipid metabolism in adipocytes by regulating their differentiation, maintenance, and function. A heterozygous mutation in the PPARG gene, which changes an arginine residue at

Identification and characterization of PPAR? ligands in the hippocampus

OpenAIRE

Roy, Avik; Kundu, Madhuchhanda; Jana, Malabendu; Mishra, Rama K.; Yung, Yeni; Luan, Chi-Hao; Gonzalez, Frank J.; Pahan, Kalipada

2016-01-01

Peroxisome proliferator-activated receptor alpha (PPAR?) regulates hepatic fatty acid catabolism and mediates the metabolic response to starvation. Recently, we have found that PPAR? is constitutively activated in nuclei of hippocampal neurons and controls plasticity via direct transcriptional activation of CREB. Here, three endogenous ligands of PPAR?, 3-hydroxy-(2,2)-dimethyl butyrate, hexadecanamide, and 9-octadecenamide were discovered in mouse brain hippocampus. Mass spectrometric detect...

Attenuation of Immune-Mediated Renal Injury by Telmisartan, an Angiotensin Receptor Blocker and a Selective PPAR-γ Activator

Directory of Open Access Journals (Sweden)

Yuki Hamano

2011-09-01

Full Text Available Background/Aims: Anti-glomerular basement membrane (GBM nephritis is characterized by activation of the renin-angiotensin system. This study aimed to determine the question of whether a temporary angiotensin II blockade at the initial stage of anti-GBM nephritis is able to attenuate the disease as well as differences in renoprotection among angiotensin II receptor blockers (ARBs with distinct peroxisome proliferator-activated receptor (PPAR-γ-modulating activities. Methods: C57BL/6J mice were immunized with rabbit IgG, followed by intravenous injection of rabbit anti-mouse antibodies. Mice were then treated with telmisartan, losartan, and telmisartan + GW9662 (a PPAR-γ antagonist for 5 days, or hydralazine for 9 days. On days 8 and 13, mice were sacrificed to obtain tissues for histological analysis. Results: The temporary administration of telmisartan significantly suppressed glomerular damage compared to hydralazine. Losartan showed a similar effect but was less effective. Co-administration of GW9662 attenuated the renoprotective effect of telmisartan, almost to levels observed with losartan. In particular, it limited the decreased infiltration of inflammatory cells and preservation of capillaries in the glomeruli induced by telmisartan. Conclusion: Temporary angiotensin II blockade at the initial stage of anti-GBM disease dramatically inhibited its progression. In addition to a class effect of ARBs, telmisartan modified inflammation and endothelial damage in the kidney through its PPAR-γ-agonistic action.

Telmisartan protects against diabetic vascular complications in a mouse model of obesity and type 2 diabetes, partially through peroxisome proliferator activated receptor-{gamma}-dependent activity

Energy Technology Data Exchange (ETDEWEB)

Toyama, Kensuke; Nakamura, Taishi; Kataoka, Keiichiro [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Yasuda, Osamu [Department of Cardiovascular Clinical and Translational Research, Kumamoto University Hospital, Kumamoto (Japan); Fukuda, Masaya; Tokutomi, Yoshiko; Dong, Yi-Fei [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Ogawa, Hisao [Department of Cardiovascular Medicine, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan); Kim-Mitsuyama, Shokei, E-mail: kimmitsu@gpo.kumamoto-u.ac.jp [Department of Pharmacology and Molecular Therapeutics, Kumamoto University Graduate School of Medical Sciences, Kumamoto (Japan)

2011-07-08

Highlights: {yields} Telmisartan, an angiotensin receptor blocker, acts as a partial PPAR{gamma} agonist. {yields} The protective effects of telmisartan against diabetic vascular injury were associated with attenuation of vascular NF{kappa}B activation and TNF {alpha}. {yields} PPAR{gamma} activity of telmisartan was involved in the normalization of vascular PPAR{gamma} downregulation in diabetic mice. {yields} We provided the first evidence indicating that PPAR{gamma} activity of telmisartan contributed to the protective effects of telmisartan against diabetic vascular complication. -- Abstract: Experimental and clinical data support the notion that peroxisome proliferator-activated receptor {gamma} (PPAR{gamma}) activation is associated with anti-atherosclerosis as well as anti-diabetic effect. Telmisartan, an angiotensin receptor blocker (ARB), acts as a partial PPAR{gamma} agonist. We hypothesized that telmisartan protects against diabetic vascular complications, through PPAR{gamma} activation. We compared the effects of telmisartan, telmisartan combined with GW9662 (a PPAR{gamma} antagonist), and losartan with no PPAR{gamma} activity on vascular injury in obese type 2 diabetic db/db mice. Compared to losartan, telmisartan significantly ameliorated vascular endothelial dysfunction, downregulation of phospho-eNOS, and coronary arterial remodeling in db/db mice. More vascular protective effects of telmisartan than losartan were associated with greater anti-inflammatory effects of telmisartan, as shown by attenuation of vascular nuclear factor kappa B (NF{kappa}B) activation and tumor necrosis factor {alpha}. Coadministration of GW9662 with telmisartan abolished the above mentioned greater protective effects of telmisartan against vascular injury than losartan in db/db mice. Thus, PPAR{gamma} activity appears to be involved in the vascular protective effects of telmisartan in db/db mice. Moreover, telmisartan, but not losartan, prevented the downregulation of

Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor-β.

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Jana, Malabendu; Mondal, Susanta; Gonzalez, Frank J; Pahan, Kalipada

2012-10-05

An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(-/-) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases.

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

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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.

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

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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.

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

Leptin rapidly activates PPARs in C2C12 muscle cells

International Nuclear Information System (INIS)

Bendinelli, Paola; Piccoletti, Roberta; Maroni, Paola

2005-01-01

Experimental evidence suggests that leptin operates on the tissues, including skeletal muscle, also by modulating gene expression. Using electrophoretic mobility shift assays, we have shown that physiological doses of leptin promptly increase the binding of C2C12 cell nuclear extracts to peroxisome proliferator-activated receptor (PPAR) response elements in oligonucleotide probes and that all three PPAR isoforms participate in DNA-binding complexes. We pre-treated C2C12 cells with AACOCF 3 , a specific inhibitor of cytosolic phospholipase A 2 (cPLA 2 ), an enzyme that supplies ligands to PPARs, and found that it abrogates leptin-induced PPAR DNA-binding activity. Leptin treatment significantly increased cPLA 2 activity, evaluated as the release of [ 3 H]arachidonic acid from pre-labelled C2C12 cells, as well as phosphorylation. Further, using MEK1 inhibitor PD-98059 we showed that leptin activates cPLA 2 through ERK induction. These results support a direct effect of leptin on skeletal muscle cells, and suggest that the hormone may modulate muscle transcription also by precocious activation of PPARs through ERK-cPLA 2 pathway

Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats

DEFF Research Database (Denmark)

Boberg, Julie; Metzdorff, Stine Broeng; Wortziger, Rasmus Henrik Sorgenfryd

2008-01-01

of obesity and insulin resistance. These effects could be related to chemical interaction with nuclear receptors such as the peroxisome proliferator activated receptors (PPARs). As several testosterone-reducing drugs are PPAR activators, we aimed to examine whether four PPAR agonists were able to affect...

Activation of PPAR by Rosiglitazone Does Not Negatively Impact Male Sex Steroid Hormones in Diabetic Rats

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Mahmoud Mansour

2009-01-01

Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR activation decreased serum testosterone (T in women with hyperthecosis and/or polycystic ovary syndrome and reduced the conversion of androgens to estradiol (E2 in female rats. This implies modulation of female sex steroid hormones by PPAR. It is not clear if PPAR modulates sex steroid hormones in diabetic males. Because PPAR activation by thiazolidinedione increased insulin sensitivity in type 2 diabetes, understanding the long term impact of PPAR activation on steroid sex hormones in males is critical. Our objective was to determine the effect of PPAR activation on serum and intratesticular T, luteinizing hormone (LH, follicle stimulating hormone (FSH and E2 concentrations in male Zucker diabetic fatty (ZDF rats treated with the PPAR agonist rosiglitazone (a thiazolidinedione. Treatment for eight weeks increased PPAR mRNA and protein in the testis and elevated serum adiponectin, an adipokine marker for PPAR activation. PPAR activation did not alter serum or intratesticular T concentrations. In contrast, serum T level but not intratesticular T was reduced by diabetes. Neither diabetes nor PPAR activation altered serum E2 or gonadotropins FSH and LH concentrations. The results suggest that activation of PPAR by rosiglitazone has no negative impact on sex hormones in male ZDF rats.

Gemfibrozil, a Lipid-lowering Drug, Increases Myelin Genes in Human Oligodendrocytes via Peroxisome Proliferator-activated Receptor-β*

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Jana, Malabendu; Mondal, Susanta; Gonzalez, Frank J.; Pahan, Kalipada

2012-01-01

An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2′,3′-cyclic-nucleotide 3′-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α in either gemfibrozil-treated or untreated human oligodendrocytes, and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-α(−/−) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(−/−) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases. PMID:22879602

Rosiglitazone, a Peroxisome Proliferator-Activated Receptor (PPAR)-γ Agonist, Attenuates Inflammation Via NF-κB Inhibition in Lipopolysaccharide-Induced Peritonitis.

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Zhang, Yun-Fang; Zou, Xun-Liang; Wu, Jun; Yu, Xue-Qing; Yang, Xiao

2015-12-01

We assessed the anti-inflammatory effect of peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, in a lipopolysaccharide (LPS)-induced peritonitis rat model. LPS was intraperitoneally injected into rats to establish peritonitis model. Male Sprague-Dawley (SD) rats were assigned to normal saline (the solvent of LPS), LPS, rosiglitazone plus LPS, and rosiglitazone alone. A simple peritoneal equilibrium test was performed with 20 ml 4.25 % peritoneal dialysis fluid. We measured the leukocyte count in dialysate and ultrafiltration volume. Peritoneal membrane histochemical staining was performed, and peritoneal thickness was assessed. CD40 and intercellular adhesion molecule-1 messenger RNA (ICAM-1 mRNA) levels in rat visceral peritoneum were detected by reverse transcription (RT)-PCR. IL-6 in rat peritoneal dialysis effluent was measured using enzyme-linked immunosorbent assay. The phosphorylation of NF-κB-p65 and IκBα was analyzed by Western blot. LPS administration resulted in increased peritoneal thickness and decreased ultrafiltration volume. Rosiglitazone pretreatment significantly decreased peritoneal thickness. In addition to CD40 and ICAM-1 mRNA expression, the IL-6, p-p65, and p-IκBα protein expressions were enhanced in LPS-administered animals. Rosiglitazone pretreatment significantly decreased ICAM-1 mRNA upregulation, secretion of IL-6 protein, and phosphorylation of NF-κB-p65 and IκBα without decreasing CD40 mRNA expression. Rosiglitazone has a protective effect in peritonitis, simultaneously decreasing NF-κB phosphorylation, suggesting that NF-κB signaling pathway mediated peritoneal inflammation induced by LPS. PPAR-γ might be considered a potential therapeutic target against peritonitis.

Nifedipine, a calcium channel blocker, inhibits advanced glycation end product (AGE)-elicited mesangial cell damage by suppressing AGE receptor (RAGE) expression via peroxisome proliferator-activated receptor-gamma activation

International Nuclear Information System (INIS)

Matsui, Takanori; Yamagishi, Sho-ichi; Takeuchi, Masayoshi; Ueda, Seiji; Fukami, Kei; Okuda, Seiya

2009-01-01

The interaction between advanced glycation end products (AGE) and their receptor RAGE mediates the progressive alteration in renal architecture and loss of renal function in diabetic nephropathy. Oxidative stress generation and inflammation also play a central role in diabetic nephropathy. This study investigated whether and how nifedipine, a calcium channel blocker (CCB), blocked the AGE-elicited mesangial cell damage in vitro. Nifedipine, but not amlodipine, a control CCB, down-regulated RAGE mRNA levels and subsequently reduced reactive oxygen species (ROS) generation in AGE-exposed mesangial cells. AGE increased mRNA levels of vascular cell adhesion molecule-1 (VCAM-1) and induced monocyte chemoattractant protein-1 (MCP-1) production in mesangial cells, both of which were prevented by the treatment with nifedipine, but not amlodipine. The beneficial effects of nifedipine on AGE-exposed mesangial cells were blocked by the simultaneous treatment of GW9662, an inhibitor of peroxisome proliferator-activated receptor-γ (PPAR-γ). Although nifedipine did not affect expression levels of PPAR-γ, it increased the PPAR-γ transcriptional activity in mesangial cells. Our present study provides a unique beneficial aspect of nifedipine on diabetic nephropathy; it could work as an anti-inflammatory agent against AGE by suppressing RAGE expression in cultured mesangial cells via PPAR-γ activation.

Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-α-mediated downregulation of cholesterol 7α-hydroxylase and sterol 27-hydroxylase expression

NARCIS (Netherlands)

Post, S.M.; Duez, H.; Gervois, P.P.; Staels, B.; Kuipers, F.; Princen, H.M.G.

2001-01-01

Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased

Fibrates suppress bile acid synthesis via peroxisome proliferator-activated receptor-alpha-mediated downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase expression

NARCIS (Netherlands)

Post, SM; Duez, H; Gervois, PP; Staels, B; Kuipers, F; Princen, HMG

2001-01-01

Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased

Fatty acids activate a chimera of the clofibric acid-activated receptor and the glucocorticoid receptor.

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Göttlicher, M; Widmark, E; Li, Q; Gustafsson, J A

1992-01-01

Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Nature (London) 347, 645-650], which encodes a 97% similar protein with a particularly well-conserved putative ligand-binding domain. To search for physiologically occurring activators, we established a transcriptional transactivation assay by stably expressing in CHO cells a chimera of rat PPAR and the human glucocorticoid receptor that activates expression of the placental alkaline phosphatase reporter gene under the control of the mouse mammary tumor virus promoter. Testing of compounds related to lipid metabolism or peroxisomal proliferation revealed that 150 microM concentrations of arachidonic or linoleic acid but not of dehydroepiandrosterone, cholesterol, or 25-hydroxy-cholesterol, activate the receptor chimera. In addition, saturated fatty acids induce the reporter gene. Shortening the chain length to n = 6 or introduction of an omega-terminal carboxylic group abolished the activation potential of the fatty acid. In conclusion, the present results indicate that fatty acids can regulate gene expression mediated by a member of the steroid nuclear receptor superfamily. Images PMID:1316614

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

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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.

Effects of Rosiglitazone on the Expression of PPAR-γ and on the ...

African Journals Online (AJOL)

Purpose: Peroxisome proliferator-activated receptor (PPAR)-γ ligand is known to repress the expression of pro-inflammatory mediators. However, it is unclear how it affects PPAR-γ expression and the inflammatory response in the human lung. We investigated the effects of rosiglitazone (synthetic PPAR-γ ligand) on the ...

Peroxisome Proliferator-Activated Receptor-γ in Amyotrophic Lateral Sclerosis and Huntington’s Disease

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Mahmoud Kiaei

2008-01-01

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.

Antidiabetic effects of chamomile flowers extract in obese mice through transcriptional stimulation of nutrient sensors of the peroxisome proliferator-activated receptor (PPAR family.

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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.

Activation of peroxisome proliferator-activated receptor-alpha and -gamma in auricular tissue from heart failure patients.

Science.gov (United States)

Gómez-Garre, Dulcenombre; Herraíz, Marta; González-Rubio, Ma Luisa; Bernal, Rosa; Aragoncillo, Paloma; Carbonell, Amparo; Rufilanchas, Juan José; Fernández-Cruz, Arturo

2006-03-01

Peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of lipid and energy metabolism in cardiomyocytes, have recently been proposed to modulate cardiovascular pathophysiological responses in experimental models. However, there is little information about the functional activity of PPARs in human heart failure. To investigate PPAR-alpha and -gamma expression and activity, and the association with ET-1 production and fibrosis, in cardiac biopsies from patients with end-stage heart failure due to ischemic cardiomyopathy (ICM) in comparison and from non-failing donor hearts. All samples were obtained during cardiac transplantation. Morphological analysis (by Masson trichrome and image analysis) did not detect fibrosis in the left atrium from non-failing donors (NFLA) or from ICM patients (FLA). However, left ventricles from failing hearts (FLV) contained a greater number of fibrotic areas (NFLA: 3.21+/-1.15, FLA: 1.63+/-0.83, FLV: 14.5+/-3.45%; n = 9, PPPAP-gamma mRNA (by RT-PCR) and protein (by Western blot) levels were higher in the ventricles from failing hearts compared with the atrium from failing and non-failing hearts. Electrophoretic mobility shift assays showed that PPAR-alpha and PPAP-gamma were not activated in the ventricles (NFLA: 1.00+/-0.11, FLA: 1.89+/-0.24, FLV: 0.95+/-0.07; n = 9, PPPAP-gamma are selectively activated in the atria from ICM patients and might be functionally important in the maintenance of atrial morphology.

Peroxisome Proliferator-Activated Receptor α Activation Suppresses Cytochrome P450 Induction Potential in Mice Treated with Gemfibrozil.

Science.gov (United States)

Shi, Cunzhong; Min, Luo; Yang, Julin; Dai, Manyun; Song, Danjun; Hua, Huiying; Xu, Gangming; Gonzalez, Frank J; Liu, Aiming

2017-09-01

Gemfibrozil, a peroxisome proliferator-activated receptor α (PPARα) agonist, is widely used for hypertriglyceridaemia and mixed hyperlipidaemia. Drug-drug interaction of gemfibrozil and other PPARα agonists has been reported. However, the role of PPARα in cytochrome P450 (CYP) induction by fibrates is not well known. In this study, wild-type mice were first fed gemfibrozil-containing diets (0.375%, 0.75% and 1.5%) for 14 days to establish a dose-response relationship for CYP induction. Then, wild-type mice and Pparα-null mice were treated with a 0.75% gemfibrozil-containing diet for 7 days. CYP3a, CYP2b and CYP2c were induced in a dose-dependent manner by gemfibrozil. In Pparα-null mice, their mRNA level, protein level and activity were induced more than those in wild-type mice. So, gemfibrozil induced CYP, and this action was inhibited by activated PPARα. These data suggested that the induction potential of CYPs was suppressed by activated PPARα, showing a potential role of this receptor in drug-drug interactions and metabolic diseases treated with fibrates. © 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

Effect of PPAR γ activators on hypertrophic cardiac myocytes in vitro

International Nuclear Information System (INIS)

Wu Shimin; Zhou Xin; Ye Ping; Wang Qiong; Gao Yue; Liu Yongxue

2004-01-01

Objective: To investigate the effects of peroxisome proliferator-activated receptor γ (PPAR γ) activators pioglitazone and 15-deoxy-Δ 12,14 prostaglandin J 2 (15d-PGJ 2 ) on hypertrophic cardiac myocytes (MC) of neonatal rats in vitro. Methods; With the stimulation of angiotensin II(Ang II), a model of hypertrophy of MC was established. With the method of reverse transcription-polymerase chain reaction (RT-PCR), mRNA expression of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) was amplified; with the aid of NIH Image J software the surface area of MC was analyzed and with 3 H-leucine incorporation, the synthesizing rate of protein in MC was measured. Results: Increases in surface area of MC, mRNA expression of ANP and BNP and 3 H-leucine incorporation in MC were observed in the model of cardiac hypertrophy. Pioglitazone and 15d-PGJ 2 , two kinds of PPAR γ activators, inhibited the above changes in a dose-dependent manner. Conclusion: It is suggested that PPAR γ activators inhibit hypertrophy of cardiac myocytes and PPAR γ-dependent pathway be involved in the inhibitory course

PPAR-γ in the Cardiovascular System

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Sheng Zhong Duan

2008-01-01

Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ, an essential transcriptional mediator of adipogenesis, lipid metabolism, insulin sensitivity, and glucose homeostasis, is increasingly recognized as a key player in inflammatory cells and in cardiovascular diseases (CVD such as hypertension, cardiac hypertrophy, congestive heart failure, and atherosclerosis. PPAR-γ agonists, the thiazolidinediones (TZDs, increase insulin sensitivity, lower blood glucose, decrease circulating free fatty acids and triglycerides, lower blood pressure, reduce inflammatory markers, and reduce atherosclerosis in insulin-resistant patients and animal models. Human genetic studies on PPAR-γ have revealed that functional changes in this nuclear receptor are associated with CVD. Recent controversial clinical studies raise the question of deleterious action of PPAR-γ agonists on the cardiovascular system. These complex interactions of metabolic responsive factors and cardiovascular disease promise to be important areas of focus for the future.

Anti-kindling Effect of Bezafibrate, a Peroxisome Proliferator-activated Receptors Alpha Agonist, in Pentylenetetrazole Induced Kindling Seizure Model.

Science.gov (United States)

Saha, Lekha; Bhandari, Swati; Bhatia, Alka; Banerjee, Dibyajyoti; Chakrabarti, Amitava

2014-12-01

Studies in the animals suggested that Peroxisome proliferators activated receptors (PPARs) may be involved in seizure control and selective agonists of PPAR α or PPAR γ raise seizure thresholds. The present study was contemplated with the aim of evaluating the anti kindling effects and the mechanism of bezafibrate, a Peroxisome proliferator-activated receptors α (PPAR-α) agonist in pentylenetetrazole (PTZ) induced kindling model of seizures in rats. In a PTZ kindled Wistar rat model, different doses of bezafibrate (100 mg/kg, 200 mg/kg and 300 mg/kg) were administered intraperitoneally 30 minutes before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The parameters measured were the latency to develop kindling and incidence of kindling, histopathological study of hippocampus, hippocampal lipid peroxidation studies, serum neuron specific enolase, and hippocampal DNA fragmentation study. In this study, bezafibrate significantly reduced the incidence of kindling in PTZ treated rats and exhibited a marked prolongation in the latencies to seizures. In the present study bezafibrate decreased the thiobarbituric acid-reactive substance i.e. Malondialdehyde levels, increased the reduced glutathione levels, catalase and superoxide dismutase activity in the brain. This added to its additional neuroprotective effects. Bezafibrate also reduced the neuronal damage and apoptosis in hippocampal area of the brain. Therefore bezafibrate exerted anticonvulsant properties in PTZ induced kindling model in rats. These findings may provide insights into the understanding of the mechanism of bezafibrate as an anti kindling agent and could offer a useful support to the basic antiepileptic therapy in preventing the development of PTZ induced seizures, suggesting its potential for therapeutic applications in temporal lobe epilepsy.

Discovery of an Oxybenzylglycine Based Peroxisome Proliferator Activated Receptor [alpha] Selective Agonist 2-((3-((2-(4-Chlorophenyl)-5-methyloxazol-4-yl)methoxy)benzyl)(methoxycarbonyl)amino)acetic Acid (BMS-687453)

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Li, Jun; Kennedy, Lawrence J.; Shi, Yan; Tao, Shiwei; Ye, Xiang-Yang; Chen, Stephanie Y.; Wang, Ying; Hernndez, Andrs S.; Wang, Wei; Devasthale, Pratik V.; Chen, Sean; Lai, Zhi; Zhang, Hao; Wu, Shung; Smirk, Rebecca A.; Bolton, Scott A.; Ryono, Denis E.; Zhang, Huiping; Lim, Ngiap-Kie; Chen, Bang-Chi; Locke, Kenneth T.; O’Malley, Kevin M.; Zhang, Litao; Srivastava, Rai Ajit; Miao, Bowman; Meyers, Daniel S.; Monshizadegan, Hossain; Search, Debra; Grimm, Denise; Zhang, Rongan; Harrity, Thomas; Kunselman, Lori K.; Cap, Michael; Kadiyala, Pathanjali; Hosagrahara, Vinayak; Zhang, Lisa; Xu, Carrie; Li, Yi-Xin; Muckelbauer, Jodi K.; Chang, Chiehying; An, Yongmi; Krystek, Stanley R.; Blanar, Michael A.; Zahler, Robert; Mukherjee, Ranjan; Cheng, Peter T.W.; Tino, Joseph A. (BMS)

2010-04-12

An 1,3-oxybenzylglycine based compound 2 (BMS-687453) was discovered to be a potent and selective peroxisome proliferator activated receptor (PPAR) {alpha} agonist, with an EC{sub 50} of 10 nM for human PPAR{alpha} and 410-fold selectivity vs human PPAR{gamma} in PPAR-GAL4 transactivation assays. Similar potencies and selectivity were also observed in the full length receptor co-transfection assays. Compound 2 has negligible cross-reactivity against a panel of human nuclear hormone receptors including PPAR{delta}. Compound 2 demonstrated an excellent pharmacological and safety profile in preclinical studies and thus was chosen as a development candidate for the treatment of atherosclerosis and dyslipidemia. The X-ray cocrystal structures of the early lead compound 12 and compound 2 in complex with PPAR{alpha} ligand binding domain (LBD) were determined. The role of the crystal structure of compound 12 with PPAR{alpha} in the development of the SAR that ultimately resulted in the discovery of compound 2 is discussed.

Assessment of chitosan-affected metabolic response by peroxisome proliferator-activated receptor bioluminescent imaging-guided transcriptomic analysis.

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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.

PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression possibly through PPAR{gamma} activation in the liver

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Oishi, Katsutaka, E-mail: k-ooishi@aist.go.jp [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Uchida, Daisuke [Biological Clock Research Group, Biomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Ibaraki (Japan); Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Ibaraki (Japan); Ohkura, Naoki [Department of Clinical Molecular Biology, Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa (Japan); Horie, Shuichi [Department of Clinical Biochemistry, Kagawa Nutrition University, Sakado, Saitama (Japan)

2010-10-15

Research highlights: {yields} PPAR{alpha} deficiency augments a ketogenic diet-induced circadian PAI-1 expression. {yields} Hepatic expressions of PPAR{gamma} and PCG-1{alpha} are induced by a ketogenic diet. {yields} PPAR{gamma} antagonist attenuates a ketogenic diet-induced PAI-1 expression. {yields} Ketogenic diet advances the phase of circadian clock in a PPAR{alpha}-independent manner. -- Abstract: An increased level of plasminogen activator inhibitor-1 (PAI-1) is considered a risk factor for cardiovascular diseases, and PAI-1 gene expression is under the control of molecular circadian clocks in mammals. We recently showed that PAI-1 expression is augmented in a phase-advanced circadian manner in mice fed with a ketogenic diet (KD). To determine whether peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) is involved in hypofibrinolytic status induced by a KD, we examined the expression profiles of PAI-1 and circadian clock genes in PPAR{alpha}-null KD mice. Chronic administration of bezafibrate induced the PAI-1 gene expression in a PPAR{alpha}-dependent manner. Feeding with a KD augmented the circadian expression of PAI-1 mRNA in the hearts and livers of wild-type (WT) mice as previously described. The KD-induced mRNA expression of typical PPAR{alpha} target genes such as Cyp4A10 and FGF21 was damped in PPAR{alpha}-null mice. However, plasma PAI-1 concentrations were significantly more elevated in PPAR{alpha}-null KD mice in accordance with hepatic mRNA levels. These observations suggest that PPAR{alpha} activation is dispensable for KD-induced PAI-1 expression. We also found that hyperlipidemia, fatty liver, and the hepatic expressions of PPAR{gamma} and its coactivator PCG-1{alpha} were more effectively induced in PPAR{alpha}-null, than in WT mice on a KD. Furthermore, KD-induced hepatic PAI-1 expression was significantly suppressed by supplementation with bisphenol A diglycidyl ether, a PPAR{gamma} antagonist, in both WT and PPAR

PPARs Signaling and Cancer in the Gastrointestinal System

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Valerio Pazienza

2012-01-01

Full Text Available Nowadays, the study of the peroxisome proliferators activated receptors (PPARs as potential targets for cancer prevention and therapy has gained a strong interest. From a biological point of view, the overall responsibility of PPARs in cancer development and progression is still controversial since several studies report both antiproliferative and tumor-promoting actions for these signaling molecules in human cancer cells and animal models. In this paper, we discuss PPARs functions in the context of different types of gastrointestinal cancer.

Anti-diabetic action of Punica granatum flower extract: Activation of PPAR-γ and identification of an active component

International Nuclear Information System (INIS)

Huang, Tom H.W.; Peng Gang; Kota, Bhavani P.; Li, George Q.; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao

2005-01-01

Peroxisome proliferator-activated receptor (PPAR)-γ activators are widely used in the treatment of type 2 diabetes because they improve the sensitivity of insulin receptors. Punica granatum flower (PGF) has been used as an anti-diabetic medicine in Unani medicinal literature. The mechanism of actions is, however, unknown. In the current study, we demonstrated that 6-week oral administration of methanol extract from PGF (500 mg/kg, daily) inhibited glucose loading-induced increase of plasma glucose levels in Zucker diabetic fatty rats (ZDF), a genetic animal model for type 2 diabetes, whereas it did not inhibit the increase in Zucker lean rats (ZL). The treatment did not lower the plasma glucose levels in fasted ZDF and ZL rats. Furthermore, RT-PCR results demonstrated that the PGF extract treatment in ZDF rats enhanced cardiac PPAR-γ mRNA expression and restored the down-regulated cardiac glucose transporter (GLUT)-4 (the insulin-dependent isoform of GLUTs) mRNA. These results suggest that the anti-diabetic activity of PGF extract may result from improved sensitivity of the insulin receptor. From the in vitro studies, we demonstrated that the PGF extract enhanced PPAR-γ mRNA and protein expression and increased PPAR-γ-dependent mRNA expression and activity of lipoprotein lipase in human THP-1-differentiated macrophage cells. Phytochemical investigation demonstrated that gallic acid in PGF extract is mostly responsible for this activity. Thus, our findings indicate that PPAR-γ is a molecular target for PGF extract and its prominent component gallic acid, and provide a better understanding of the potential mechanism of the anti-diabetic action of PGF

Transcriptional Control of Vascular Smooth Muscle Cell Proliferation by Peroxisome Proliferator-Activated Receptor-γ: Therapeutic Implications for Cardiovascular Diseases

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Florence Gizard

2008-01-01

Full Text Available Proliferation of vascular smooth muscle cells (SMCs is a critical process for the development of atherosclerosis and complications of procedures used to treat atherosclerotic diseases, including postangioplasty restenosis, vein graft failure, and transplant vasculopathy. Peroxisome proliferator-activated receptor (PPAR γ is a member of the nuclear hormone receptor superfamily and the molecular target for the thiazolidinediones (TZD, used clinically to treat insulin resistance in patients with type 2 diabetes. In addition to their efficacy to improve insulin sensitivity, TZD exert a broad spectrum of pleiotropic beneficial effects on vascular gene expression programs. In SMCs, PPARγ is prominently upregulated during neointima formation and suppresses the proliferative response to injury of the arterial wall. Among the molecular target genes regulated by PPARγ in SMCs are genes encoding proteins involved in the regulation of cell-cycle progression, cellular senescence, and apoptosis. This inhibition of SMC proliferation is likely to contribute to the prevention of atherosclerosis and postangioplasty restenosis observed in animal models and proof-of-concept clinical studies. This review will summarize the transcriptional target genes regulated by PPARγ in SMCs and outline the therapeutic implications of PPARγ activation for the treatment and prevention of atherosclerosis and its complications.

Peroxisome Proliferator-Activated Receptors as Mediators of Phthalate-Induced Effects in the Male and Female Reproductive Tract: Epidemiological and Experimental Evidence

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Giuseppe Latini

2008-01-01

Full Text Available There is growing evidence that male as well as female reproductive function has been declining in human and wildlife populations over the last 40 years. Several factors such as lifestyle or environmental xenobiotics other than genetic factors may play a role in determining adverse effects on reproductive health. Among the environmental xenobiotics phthalates, a family of man-made pollutants are suspected to interfere with the function of the endocrine system and therefore to be endocrine disruptors. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs. Toxicological studies have shown that phthalates can activate a subset of PPARs. Here, we analyze the epidemiological and experimental evidence linking phthalate exposure to both PPAR activation and adverse effects on male and female reproductive health.

Expression of Peroxisome Proliferator-Activated Receptor-γ in Key Neuronal Subsets Regulating Glucose Metabolism and Energy Homeostasis

OpenAIRE

Sarruf, David A.; Yu, Fang; Nguyen, Hong T.; Williams, Diana L.; Printz, Richard L.; Niswender, Kevin D.; Schwartz, Michael W.

2008-01-01

In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-γ agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARγ is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARγ distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spa...

Genomewide analyses define different modes of transcriptional regulation by peroxisome proliferator-activated receptor-β/δ (PPARβ/δ.

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Till Adhikary

Full Text Available 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.

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.

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

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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

Examination of adipose depot-specific PPAR moieties

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Dodson, M.V., E-mail: dodson@wsu.edu [Department of Animal Sciences, Washington State University, Pullman, WA 99164 (United States); Vierck, J.L. [Department of Animal Sciences, Washington State University, Pullman, WA 99164 (United States); Hausman, G.J. [USDA-ARS, Richard B. Russell Agricultural Research Station, Athens, GA 30604 (United States); Guan, L.L. [Department of Agricultural, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, T6G 2P5 Canada (Canada); Fernyhough, M.E. [The Hartz Mountain Corporation, Secaucus, NJ 07094 (United States); Poulos, S.P. [The Coca-Cola Company, Research and Technology, Atlanta, GA 30313 (United States); Mir, P.S. [Agriculture and Agri-Food Canada Research Centre, Lethbridge, CA T1J 4B1 (United States); Jiang, Z. [Department of Animal Sciences, Washington State University, Pullman, WA 99164 (United States)

2010-04-02

Molecular mechanisms of peroxisome proliferator activated receptors (PPARs) are being defined rapidly, as illustrated by the volume of papers published. Much of the research is directed towards a clinical end-point/application; however, the non-homogeneous nature of adipose depots in laboratory animals is spurring similar research in domestic meat animals (such as beef cattle). Moreover, the size of adipose depots in meat animals remains an attractive feature for using them to obtain cells for PPAR research. Examination of meat-animal depot-specific PPAR moieties may provide novel information about adipocyte regulation that might be extrapolated to all animals.

Examination of adipose depot-specific PPAR moieties

International Nuclear Information System (INIS)

Dodson, M.V.; Vierck, J.L.; Hausman, G.J.; Guan, L.L.; Fernyhough, M.E.; Poulos, S.P.; Mir, P.S.; Jiang, Z.

2010-01-01

Molecular mechanisms of peroxisome proliferator activated receptors (PPARs) are being defined rapidly, as illustrated by the volume of papers published. Much of the research is directed towards a clinical end-point/application; however, the non-homogeneous nature of adipose depots in laboratory animals is spurring similar research in domestic meat animals (such as beef cattle). Moreover, the size of adipose depots in meat animals remains an attractive feature for using them to obtain cells for PPAR research. Examination of meat-animal depot-specific PPAR moieties may provide novel information about adipocyte regulation that might be extrapolated to all animals.

PPAR-α, a lipid-sensing transcription factor, regulates blood-brain barrier efflux transporter expression.

Science.gov (United States)

More, Vijay R; Campos, Christopher R; Evans, Rebecca A; Oliver, Keith D; Chan, Gary Ny; Miller, David S; Cannon, Ronald E

2017-04-01

Lipid sensor peroxisome proliferator-activated receptor alpha (PPAR- α) is the master regulator of lipid metabolism. Dietary release of endogenous free fatty acids, fibrates, and certain persistent environmental pollutants, e.g. perfluoroalkyl fire-fighting foam components, are peroxisome proliferator-activated receptor alpha ligands. Here, we define a role for peroxisome proliferator-activated receptor alpha in regulating the expression of three ATP-driven drug efflux transporters at the rat and mouse blood-brain barriers: P-glycoprotein (Abcb1), breast cancer resistance protein (Bcrp/Abcg2), and multidrug resistance-associated protein 2 (Mrp2/Abcc2). Exposing isolated rat brain capillaries to linoleic acid, clofibrate, or PKAs increased the transport activity and protein expression of the three ABC transporters. These effects were blocked by the PPAR- α antagonist, GW6471. Dosing rats with 20 mg/kg or 200 mg/kg of clofibrate decreased the brain accumulation of the P-glycoprotein substrate, verapamil, by 50% (in situ brain perfusion; effects blocked by GW6471) and increased P-glycoprotein expression and activity in capillaries ex vivo. Fasting C57Bl/6 wild-type mice for 24 h increased both serum lipids and brain capillary P-glycoprotein transport activity. Fasting did not alter P-glycoprotein activity in PPAR- α knockout mice. These results indicate that hyperlipidemia, lipid-lowering fibrates and exposure to certain fire-fighting foam components activate blood-brain barrier peroxisome proliferator-activated receptor alpha, increase drug efflux transporter expression and reduce drug delivery to the brain.

Calcitriol Inhibits HCV Infection via Blockade of Activation of PPAR and Interference with Endoplasmic Reticulum-Associated Degradation

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Yu-Min Lin

2018-01-01

Full Text Available Vitamin D has been identified as an innate anti-hepatitis C virus (HCV agent but the possible mechanisms for this issue remain unclear. Here, we clarified the mechanisms of calcitriol-mediated inhibition of HCV infection. Calcitriol partially inhibited HCV infection, nitric oxide (NO release and lipid accumulation in Huh7.5 human hepatoma cells via the activation of vitamin D receptor (VDR. When cells were pretreated with the activators of peroxisome proliferator-activated receptor (PPAR-α (Wy14643 and -γ (Ly171883, the calcitriol-mediated HCV suppression was reversed. Otherwise, three individual stimulators of PPAR-α/β/γ blocked the activation of VDR. PPAR-β (linoleic acid reversed the inhibition of NO release, whereas PPAR-γ (Ly171883 reversed the inhibitions of NO release and lipid accumulation in the presence of calcitriol. The calcitriol-mediated viral suppression, inhibition of NO release and activation of VDR were partially blocked by an inhibitor of endoplasmic reticulum-associated degradation (ERAD, kifunensine. Furthermore, calcitriol blocked the HCV-induced expressions of apolipoprotein J and 78 kDa glucose-regulated protein, which was restored by pretreatment of kifunensine. These results indicated that the calcitriol-mediated HCV suppression was associated with the activation of VDR, interference with ERAD process, as well as blockades of PPAR, lipid accumulation and nitrative stress.

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.

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

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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.

PPARs: Key Regulators of Airway Inflammation and Potential Therapeutic Targets in Asthma

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Asoka Banno

2018-01-01

Full Text Available Asthma affects approximately 300 million people worldwide, significantly impacting quality of life and healthcare costs. While current therapies are effective in controlling many patients' symptoms, a large number continue to experience exacerbations or treatment-related adverse effects. Alternative therapies are thus urgently needed. Accumulating evidence has shown that the peroxisome proliferator-activated receptor (PPAR family of nuclear hormone receptors, comprising PPARα, PPARβ/δ, and PPARγ, is involved in asthma pathogenesis and that ligand-induced activation of these receptors suppresses asthma pathology. PPAR agonists exert their anti-inflammatory effects primarily by suppressing pro-inflammatory mediators and antagonizing the pro-inflammatory functions of various cell types relevant to asthma pathophysiology. Experimental findings strongly support the potential clinical benefits of PPAR agonists in the treatment of asthma. We review current literature, highlighting PPARs' key role in asthma pathogenesis and their agonists' therapeutic potential. With additional research and rigorous clinical studies, PPARs may become attractive therapeutic targets in this disease.

Differential activation of catalase expression and activity by PPAR agonists: Implications for astrocyte protection in anti-glioma therapy☆

Science.gov (United States)

Khoo, Nicholas K.H.; Hebbar, Sachin; Zhao, Weiling; Moore, Steven A.; Domann, Frederick E.; Robbins, Mike E.

2013-01-01

Glioma survival is dismal, in part, due to an imbalance in antioxidant expression and activity. Peroxisome proliferator-activated receptor (PPAR) agonists have antineoplastic properties which present new redox-dependent targets for glioma anticancer therapies. Herein, we demonstrate that treatment of primary cultures of normal rat astrocytes with PPAR agonists increased the expression of catalase mRNA protein, and enzymatic activity. In contrast, these same agonists had no effect on catalase expression and activity in malignant rat glioma cells. The increase in steady-state catalase mRNA observed in normal rat astrocytes was due, in part, to de novo mRNA synthesis as opposed to increased catalase mRNA stability. Moreover, pioglitazone-mediated induction of catalase activity in normal rat astrocytes was completely blocked by transfection with a PPARγ-dominant negative plasmid. These data suggest that defects in PPAR-mediated signaling and gene expression may represent a block to normal catalase expression and induction in malignant glioma. The ability of PPAR agonists to differentially increase catalase expression and activity in normal astrocytes but not glioma cells suggests that these compounds might represent novel adjuvant therapeutic agents for the treatment of gliomas. PMID:24024139

The Natural Compound Dansameum Reduces foam Cell Formation by Downregulating CD36 and Peroxisome Proliferator-activated Receptor-gamma; Expression.

Science.gov (United States)

Park, Kang-Seo; Ahn, Sang Hyun; Lee, Kang Pa; Park, Sun-Young; Cheon, Jin Hong; Choi, Jun-Yong; Kim, Kibong

2018-01-01

Atherosclerosis-induced vascular disorders are major causes of death in most western countries. During the development of atherosclerotic lesions, foam cell formation is essential and formed through the expression of CD36 and the peroxisome proliferator-activated receptor gamma (PPAR-γ). To investigate whether dansameum extract (DSE) could show anti-atherosclerotic effect through down-regulating cellular redox state including CD36 and PARP-γ expression in oxidative low-density lipoprotein (oxLDL)-treated RAW264.7 cells and on differentiated foam cells in ApoE Knockout (ApoE-/-) mice. The Korean polyherbal medicine DSE was prepared from three plants in the following proportions: 40 g of Salvia miltiorrhiza root, 4 g of Amomumxanthioides fruit, and 4 g of Santalum album lignum. The immunohistochemistry and reverse transcription-polymerase chain reaction was used for analysis of protein and mRNA involved in foam cell formation. We first showed that effects of DSE on foam cell formation in both oxLDL-induced RAW264.7 cells and in blood vessels from apolipoprotein E deficientApoE-/- mice with high fat diet-fed. DSE treatment significantly reduced the expression of CD36 and PPAR-γ in oxLDL-stimulated RAW264.7 cells and ApoE-/-mice, in the latter case by regulating heme oxygenase-1. Furthermore, DSE treatment also reduced cellular lipid content in vitro and in vivo experiments. Our data suggest that DSE may have anti-atherosclerotic properties through regulating foam cell formation. Dansameum extract (DSE) Regulates the expression of CD36 and peroxisome proliferator-activated receptor gamma in oxidative low-density lipoprotein-stimulated RAW264.7 Cells and ApoE Knockout (ApoE Knockout [ApoE-/-]) miceDSE Regulates Cholesterol Levels in the Serum of ApoE-deficient (ApoE-/-) miceDSE Reduced the Formation of Foam Cells by Regulating heme oxygenase-1 in ApoE-/- mice with high fat diet-fed. Abbreviations used: DSE: Dansameum extract, PPAR-γ: Peroxisome proliferator-activated

NAD(P)H oxidase/nitric oxide interactions in peroxisome proliferator activated receptor (PPAR)α-mediated cardiovascular effects

International Nuclear Information System (INIS)

Newaz, Mohammad; Blanton, Ahmad; Fidelis, Paul; Oyekan, Adebayo

2005-01-01

Activation of peroxisome proliferator activated receptor (PPAR)α and its protective role in cardiovascular function has been reported but the exact mechanism(s) involved is not clear. As we have shown that PPARα ligands increased nitric oxide (NO) production and cardiovascular function is controlled by a balance between NO and free radicals, we hypothesize that PPARα activation tilts the balance between NO and free radicals and that this mechanism defines the protective effects of PPARα ligands on cardiovascular system. Systolic blood pressure (SBP) was greater in PPARα knockout (KO) mice compared with its wild type (WT) litter mates (130 ± 10 mmHg versus 107 ± 4 mmHg). L-NAME (100 mg/L p.o.), the inhibitor of NO production abolished the difference between PPARα KO and WT mice. In kidney homogenates, tissue lipid hydroperoxide generation was greater in KO mice (11.8 ± 1.4 pM/mg versus 8.3 ± 0.6 pM/mg protein). This was accompanied by a higher total NOS activity (46 ± 6%, p 2+ -dependent NOS activity in kidney homogenates of untreated PPARα WT compared with the KO mice. Clofibrate, a PPARα ligand, increased NOS activity in WT but not KO mice. Bezafibrate (30 mg/kg) reduced SBP in conscious rats (19 ± 4%, p < 0.05), increased urinary NO excretion (4.06 ± 0.53-7.07 ± 1.59 μM/24 h; p < 0.05) and reduced plasma 8-isoprostane level (45.8 ± 15 μM versus 31.4 ± 8 μM), and NADP(H) oxidase activity (16 ± 5%). Implantation of DOCA pellet (20 mg s.c.) in uninephrectomized mice placed on 1% NaCl drinking water increased SBP by a margin that was markedly greater in KO mice (193 ± 13 mmHg versus 130 ± 12 mmHg). In the rat, DOCA increased SBP and NAD(P)H oxidase activity and both effects were diminished by clofibrate. In addition, clofibrate reduced ET-1 production in DOCA/salt hypertensive rats. Thus, apart from inhibition of ET-1 production, PPARα activation exerts protective actions in hypertension via a mechanism that involves NO production and

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.

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,

Bixin regulates mRNA expression involved in adipogenesis and enhances insulin sensitivity in 3T3-L1 adipocytes through PPAR{gamma} activation

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Takahashi, Nobuyuki; Goto, Tsuyoshi; Taimatsu, Aki; Egawa, Kahori; Katoh, Sota; Kusudo, Tatsuya; Sakamoto, Tomoya; Ohyane, Chie; Lee, Joo-Young; Kim, Young-il; Uemura, Taku; Hirai, Shizuka [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 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 611-0011 (Japan)

2009-12-25

Insulin resistance is partly due to suppression of insulin-induced glucose uptake into adipocytes. The uptake is dependent on adipocyte differentiation, which is controlled at mRNA transcription level. The peroxisome proliferator-activated receptor (PPAR), a ligand-regulated nuclear receptor, is involved in the differentiation. Many food-derived compounds serve as ligands to activate or inactivate PPAR. In this study, we demonstrated that bixin and norbixin (annatto extracts) activate PPAR{gamma} by luciferase reporter assay using GAL4-PPAR chimera proteins. To examine the effects of bixin on adipocytes, 3T3-L1 adipocytes were treated with bixin or norbixin. The treatment induced mRNA expression of PPAR{gamma} target genes such as adipocyte-specific fatty acid-binding protein (aP2), lipoprotein lipase (LPL), and adiponectin in differentiated 3T3-L1 adipocytes and enhanced insulin-dependent glucose uptake. The observations indicate that bixin acts as an agonist of PPAR{gamma} and enhances insulin sensitivity in 3T3-L1 adipocytes, suggesting that bixin is a valuable food-derived compound as a PPAR ligand to regulate lipid metabolism and to ameliorate metabolic syndrome.

Peroxisome proliferator-activated receptor {alpha} agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

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Antonelli, Alessandro, E-mail: a.antonelli@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Ferrari, Silvia Martina, E-mail: sm.ferrari@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Frascerra, Silvia, E-mail: lafrasce@gmail.com [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Corrado, Alda, E-mail: dala_res@hotmail.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Pupilli, Cinzia, E-mail: c.pupilli@dfc.unifi.it [Endocrinology Unit, Azienda Ospedaliera Careggi and University of Florence, Viale Morgagni 85, I-50134, Florence (Italy); Bernini, Giampaolo, E-mail: g.bernini@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Benvenga, Salvatore, E-mail: s.benvenga@me.nettuno.it [Department of Clinical and Experimental Medicine, Section of Endocrinology, University of Messina, Piazza Pugliatti 1, I-98122, Messina (Italy); Ferrannini, Ele, E-mail: eferrannini@med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy); Fallahi, Poupak, E-mail: poupak@int.med.unipi.it [Department of Internal Medicine, University of Pisa-School of Medicine, Via Roma 67, I-56100, Pisa (Italy)

2011-07-01

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR){alpha} activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPAR{alpha} and PPAR{gamma} activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN){gamma} and tumor necrosis factor (TNF){alpha}. IFN{gamma} stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNF{alpha} alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFN{gamma} and TNF{alpha} had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPAR{alpha} activators inhibited the secretion of both chemokines (stimulated with IFN{gamma} and TNF{alpha}) at a level higher (for CXCL10, about 60-72%) than PPAR{gamma} agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFN{gamma} and TNF{alpha} in GD and normal thyrocytes. Furthermore we first show that PPAR{alpha} activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPAR{alpha} may be involved in the modulation of the immune response in the thyroid.

Phytol directly activates peroxisome proliferator-activated receptor α (PPARα) and regulates gene expression involved in lipid metabolism in PPARα-expressing HepG2 hepatocytes

International Nuclear Information System (INIS)

Goto, Tsuyoshi; Takahashi, Nobuyuki; Kato, Sota; Egawa, Kahori; Ebisu, Shogo; Moriyama, Tatsuya; Fushiki, Tohru; Kawada, Teruo

2005-01-01

The peroxisome proliferator-activated receptor (PPAR) is one of the indispensable transcription factors for regulating lipid metabolism in various tissues. In our screening for natural compounds that activate PPAR using luciferase assays, a branched-carbon-chain alcohol (a component of chlorophylls), phytol, has been identified as a PPARα-specific activator. Phytol induced the increase in PPARα-dependent luciferase activity and the degree of in vitro binding of a coactivator, SRC-1, to GST-PPARα. Moreover, the addition of phytol upregulated the expression of PPARα-target genes at both mRNA and protein levels in PPARα-expressing HepG2 hepatocytes. These findings indicate that phytol is functional as a PPARα ligand and that it stimulates the expression of PPARα-target genes in intact cells. Because PPARα activation enhances circulating lipid clearance, phytol may be important in managing abnormalities in lipid metabolism

Involvement of the Retinoid X Receptor Ligand in the Anti-Inflammatory Effect Induced by Peroxisome Proliferator-Activated Receptor Agonist In Vivo

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Atsuki Yamamoto

2011-01-01

Full Text Available Peroxisome proliferator-activated receptor γ (PPARγ forms a heterodimeric DNA-binding complex with retinoid X receptors (RXRs. It has been reported that the effect of the PPAR agonist is reduced in hepatocyte RXR-deficient mice. Therefore, it is suggested that the endogenous RXR ligand is involved in the PPARγ agonist-induced anti-inflammatory effect. However, the participation of the RXR ligand in the PPARγ-induced anti-inflammatory effect is unknown. Here, we investigated the influence of RXR antagonist on the anti-inflammatory effect of PPARγ agonist pioglitazone in carrageenan test. In addition, we also examined the influence of PPAR antagonist on the anti-inflammatory effect induced by RXR agonist NEt-3IP. The RXR antagonist suppressed the antiedema effect of PPARγ agonist. In addition, the anti-inflammatory effect of RXR agonist was suppressed by PPARγ antagonist. PPARγ agonist-induced anti-inflammatory effects were reversed by the RXR antagonist. Thus, we showed that the endogenous RXR ligand might contribute to the PPARγ agonist-induced anti-inflammatory effect.

PPAR2Pro12Ala Polymorphism and Human Health

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Weimin He

2009-01-01

Full Text Available The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPAR is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPAR have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPAR, Pro12Ala of PPAR2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPAR2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPAR2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPAR2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies.

A role for central nervous system PPAR-γ in the regulation of energy balance.

Science.gov (United States)

Ryan, Karen K; Li, Bailing; Grayson, Bernadette E; Matter, Emily K; Woods, Stephen C; Seeley, Randy J

2011-05-01

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences. PPAR-γ is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain. Here we report a previously unknown role for central nervous system (CNS) PPAR-γ in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-γ, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-γ and the viral transcriptional activator VP16 (VP16-PPAR-γ), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-γ with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.

Synthesis of Phthalimide Derivatives as Potential PPAR-γ Ligands

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So Hyeon Eom

2016-06-01

Full Text Available Paecilocin A, a phthalide derivative isolated from the jellyfish-derived fungus Paecilomyces variotii, activates PPAR-γ (Peroxisome proliferator-activated receptor gamma in rat liver Ac2F cells. Based on a SAR (Structure-activity relationships study and in silico analysis of paecilocin A-mimetic derivatives, additional N-substituted phthalimide derivatives were synthesized and evaluated for PPAR-γ agonistic activity in both murine liver Ac2F cells and in human liver HepG2 cells by luciferase assay, and for adipogenic activity in 3T3-L1 cells. Docking simulation indicated PD6 was likely to bind most strongly to the ligand binding domain of PPAR-γ by establishing crucial H-bonds with key amino acid residues. However, in in vitro assays, PD1 and PD2 consistently displayed significant PPAR-γ activation in Ac2F and HepG2 cells, and adipogenic activity in 3T3-L1 preadipocytes.

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; J. Bressan

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...

PPAR{gamma} regulates the expression of cholesterol metabolism genes in alveolar macrophages

Energy Technology Data Exchange (ETDEWEB)

Baker, Anna D.; Malur, Anagha; Barna, Barbara P.; Kavuru, Mani S. [Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University (United States); Malur, Achut G. [Department of Microbiology and Immunology, East Carolina University (United States); Thomassen, Mary Jane, E-mail: thomassenm@ecu.edu [Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, East Carolina University (United States); Department of Microbiology and Immunology, East Carolina University (United States)

2010-03-19

Peroxisome proliferator-activated receptor-gamma (PPAR{gamma}) is a nuclear transcription factor involved in lipid metabolism that is constitutively expressed in the alveolar macrophages of healthy individuals. PPAR{gamma} has recently been implicated in the catabolism of surfactant by alveolar macrophages, specifically the cholesterol component of surfactant while the mechanism remains unclear. Studies from other tissue macrophages have shown that PPAR{gamma} regulates cholesterol influx, efflux, and metabolism. PPAR{gamma} promotes cholesterol efflux through the liver X receptor-alpha (LXR{alpha}) and ATP-binding cassette G1 (ABCG1). We have recently shown that macrophage-specific PPAR{gamma} knockout (PPAR{gamma} KO) mice accumulate cholesterol-laden alveolar macrophages that exhibit decreased expression of LXR{alpha} and ABCG1 and reduced cholesterol efflux. We hypothesized that in addition to the dysregulation of these cholesterol efflux genes, the expression of genes involved in cholesterol synthesis and influx was also dysregulated and that replacement of PPAR{gamma} would restore regulation of these genes. To investigate this hypothesis, we have utilized a Lentivirus expression system (Lenti-PPAR{gamma}) to restore PPAR{gamma} expression in the alveolar macrophages of PPAR{gamma} KO mice. Our results show that the alveolar macrophages of PPAR{gamma} KO mice have decreased expression of key cholesterol synthesis genes and increased expression of cholesterol receptors CD36 and scavenger receptor A-I (SRA-I). The replacement of PPAR{gamma} (1) induced transcription of LXR{alpha} and ABCG1; (2) corrected suppressed expression of cholesterol synthesis genes; and (3) enhanced the expression of scavenger receptors CD36. These results suggest that PPAR{gamma} regulates cholesterol metabolism in alveolar macrophages.

Identification of bioactive compounds from flowers of black elder (Sambucus nigra L.) that activate the human peroxisome proliferator-activated receptor (PPAR) gamma

DEFF Research Database (Denmark)

Christensen, Kathrine B; Petersen, Rasmus K; Kristiansen, Karsten

2010-01-01

Obesity is one of the predisposing factors for the development of overt Type 2 diabetes (T2D). T2D is caused by a combination of insulin resistance and beta-cell failure and can be treated with insulin sensitizing drugs that target the nuclear receptor peroxisome proliferator-activated receptor (...

Involvement of PPAR-γ in the neuroprotective and anti-inflammatory effects of angiotensin type 1 receptor inhibition: effects of the receptor antagonist telmisartan and receptor deletion in a mouse MPTP model of Parkinson's disease

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Garrido-Gil Pablo

2012-02-01

Full Text Available Abstract Background Several recent studies have shown that angiotensin type 1 receptor (AT1 antagonists such as candesartan inhibit the microglial inflammatory response and dopaminergic cell loss in animal models of Parkinson's disease. However, the mechanisms involved in the neuroprotective and anti-inflammatory effects of AT1 blockers in the brain have not been clarified. A number of studies have reported that AT1 blockers activate peroxisome proliferator-activated receptor gamma (PPAR γ. PPAR-γ activation inhibits inflammation, and may be responsible for neuroprotective effects, independently of AT1 blocking actions. Methods We have investigated whether oral treatment with telmisartan (the most potent PPAR-γ activator among AT1 blockers provides neuroprotection against dopaminergic cell death and neuroinflammation, and the possible role of PPAR-γ activation in any such neuroprotection. We used a mouse model of parkinsonism induced by the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and co-administration of the PPAR-γ antagonist GW9662 to study the role of PPAR-γ activation. In addition, we used AT1a-null mice lesioned with MPTP to study whether deletion of AT1 in the absence of any pharmacological effect of AT1 blockers provides neuroprotection, and investigated whether PPAR-γ activation may also be involved in any such effect of AT1 deletion by co-administration of the PPAR-γ antagonist GW9662. Results We observed that telmisartan protects mouse dopaminergic neurons and inhibits the microglial response induced by administration of MPTP. The protective effects of telmisartan on dopaminergic cell death and microglial activation were inhibited by co-administration of GW9662. Dopaminergic cell death and microglial activation were significantly lower in AT1a-null mice treated with MPTP than in mice not subjected to AT1a deletion. Interestingly, the protective effects of AT1 deletion were also inhibited by co

Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

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Katrin Hack

Full Text Available We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787 retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

Restoration of Endothelial Function in Pparα−/− Mice by Tempol

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Neerupma Silswal

2015-01-01

Full Text Available Peroxisome proliferator activated receptor alpha (PPARα is one of the PPAR isoforms belonging to the nuclear hormone receptor superfamily that regulates genes involved in lipid and lipoprotein metabolism. PPARα is present in the vascular wall and is thought to be involved in protection against vascular disease. To determine if PPARα contributes to endothelial function, conduit and cerebral resistance arteries were studied in Pparα−/− mice using isometric and isobaric tension myography, respectively. Aortic contractions to PGF2α and constriction of middle cerebral arteries to phenylephrine were not different between wild type (WT and Pparα−/−; however, relaxation/dilation to acetylcholine (ACh was impaired. There was no difference in relaxation between WT and Pparα−/− aorta to treatment with a nitric oxide (NO surrogate indicating impairment in endothelial function. Endothelial NO levels as well as NO synthase expression were reduced in Pparα−/− aortas, while superoxide levels were elevated. Two-week feeding with the reactive oxygen species (ROS scavenger, tempol, normalized ROS levels and rescued the impaired endothelium-mediated relaxation in Pparα−/− mice. These results suggest that Pparα−/− mice have impaired endothelial function caused by decreased NO bioavailability. Therefore, activation of PPARα receptors may be a therapeutic target for maintaining endothelial function and protection against cardiovascular disease.

Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages

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Mayi, Therese Hervee; Rigamonti, Elena [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Pattou, Francois [Univ Lille Nord de France, F-59000 Lille (France); Department of Endocrine Surgery, University Hospital, Lille (France); U859 Biotherapies for Diabetes, INSERM, Lille (France); Staels, Bart, E-mail: bart.staels@pasteur-lille.fr [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France); Chinetti-Gbaguidi, Giulia [Univ Lille Nord de France, F-59000 Lille (France); INSERM UR1011, F-59000 Lille (France); UDSL, F-59000 Lille (France); Institut Pasteur de Lille, F-59019 Lille (France)

2011-01-07

Research highlights: {yields} Synthetic LXR ligands decreased visfatin expression in human macrophages. {yields} LXR activation leads to a modest and transient decrease of NAD{sup +} concentration. {yields} LXR activation decreased PPAR{gamma}-induced visfatin in human macrophages. -- Abstract: Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR){gamma} are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPAR{gamma} target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD{sup +} concentration was observed. Interestingly, LXR activation decreased the PPAR{gamma}-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPAR{gamma} pathways in human macrophages.

Salacia oblonga root improves postprandial hyperlipidemia and hepatic steatosis in Zucker diabetic fatty rats: Activation of PPAR-α

International Nuclear Information System (INIS)

Hsun-Wei Huang, Tom; Peng Gang; Qian Li, George; Yamahara, Johji; Roufogalis, Basil D.; Li Yuhao

2006-01-01

Salacia oblonga (SO) root is an Ayurvedic medicine with anti-diabetic and anti-obese properties. Peroxisome proliferator-activated receptor (PPAR)-α, a nuclear receptor, plays an important role in maintaining the homeostasis of lipid metabolism. Here, we demonstrate that chronic oral administration of the water extract from the root of SO to Zucker diabetic fatty (ZDF) rats, a genetic model of type 2 diabetes and obesity, lowered plasma triglyceride and total cholesterol (TC) levels, increased plasma high-density lipoprotein levels and reduced the liver contents of triglyceride, non-esterified fatty acids (NEFA) and the ratio of fatty droplets to total tissue. By contrast, the extract had no effect on plasma triglyceride and TC levels in fasted ZDF rats. After olive oil administration to ZDF the extract also inhibited the increase in plasma triglyceride levels. These results suggest that SO extract improves postprandial hyperlipidemia and hepatic steatosis in ZDF rats. Additionally, SO treatment enhanced hepatic expression of PPAR-α mRNA and protein, and carnitine palmitoyltransferase-1 and acyl-CoA oxidase mRNAs in ZDF rats. In vitro, SO extract and its main component mangiferin activated PPAR-α luciferase activity in human embryonic kidney 293 cells and lipoprotein lipase mRNA expression and enzyme activity in THP-1 differentiated macrophages; these effects were completely suppressed by a selective PPAR-α antagonist MK-886. The findings from both in vivo and in vitro suggest that SO extract functions as a PPAR-α activator, providing a potential mechanism for improvement of postprandial hyperlipidemia and hepatic steatosis in diabetes and obesity

PPAR-α Ligands as Potential Therapeutic Agents for Wet Age-Related Macular Degeneration

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Marisol del V Cano

2008-01-01

Full Text Available The peroxisome proliferator-activated receptors (PPAR's are members of the steroid/thyroid nuclear receptor, superfamily of transcription factors. There are currently three known PPAR subtypes, α, β, and γ. The PPARs are now recognized participants in a number of biological pathways some of which are implicated in the pathogenesis of age-related macular degeneration (AMD. These include immune modulation, lipid regulation, and oxidant/antioxidant pathways important to the onset and progression of “dry” AMD, and vascular endothelial growth factor (VEGF mediated pathways that stimulate choroidal neovascularization (CNV, characteristic of “wet” AMD. PPAR-α is found in retina and also on vascular cells important to formation of CNV. At this time, however, relatively little is known about potential contributions of PPAR-α to the pathogenesis of dry and wet AMD. This review examines current literature for potential roles of PPAR-α in the pathogenesis and potential treatment of AMD with emphasis on prevention and treatment of wet AMD.

PPARs, Obesity, and Inflammation

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Rinke Stienstra

2007-01-01

Full Text Available The worldwide prevalence of obesity and related metabolic disorders is rising rapidly, increasing the burden on our healthcare system. Obesity is often accompanied by excess fat storage in tissues other than adipose tissue, including liver and skeletal muscle, which may lead to local insulin resistance and may stimulate inflammation, as in steatohepatitis. In addition, obesity changes the morphology and composition of adipose tissue, leading to changes in protein production and secretion. Some of these secreted proteins, including several proinflammatory mediators, may be produced by macrophages resident in the adipose tissue. The changes in inflammatory status of adipose tissue and liver with obesity feed a growing recognition that obesity represents a state of chronic low-level inflammation. Various molecular mechanisms have been implicated in obesity-induced inflammation, some of which are modulated by the peroxisome proliferator-activated receptors (PPARs. PPARs are ligand-activated transcription factors involved in the regulation of numerous biological processes, including lipid and glucose metabolism, and overall energy homeostasis. Importantly, PPARs also modulate the inflammatory response, which makes them an interesting therapeutic target to mitigate obesity-induced inflammation and its consequences. This review will address the role of PPARs in obesity-induced inflammation specifically in adipose tissue, liver, and the vascular wall.

Opposite Interplay Between the Canonical WNT/β-Catenin Pathway and PPAR Gamma: A Potential Therapeutic Target in Gliomas.

Science.gov (United States)

Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

2018-06-01

In gliomas, the canonical Wingless/Int (WNT)/β-catenin pathway is increased while peroxisome proliferator-activated receptor gamma (PPAR-γ) is downregulated. The two systems act in an opposite manner. This review focuses on the interplay between WNT/β-catenin signaling and PPAR-γ and their metabolic implications as potential therapeutic target in gliomas. Activation of the WNT/β-catenin pathway stimulates the transcription of genes involved in proliferation, invasion, nucleotide synthesis, tumor growth, and angiogenesis. Activation of PPAR-γ agonists inhibits various signaling pathways such as the JAK/STAT, WNT/β-catenin, and PI3K/Akt pathways, which reduces tumor growth, cell proliferation, cell invasiveness, and angiogenesis. Nonsteroidal anti-inflammatory drugs, curcumin, antipsychotic drugs, adiponectin, and sulforaphane downregulate the WNT/β-catenin pathway through the upregulation of PPAR-γ and thus appear to provide an interesting therapeutic approach for gliomas. Temozolomide (TMZ) is an antiangiogenic agent. The downstream action of this opposite interplay may explain the TMZ-resistance often reported in gliomas.

Identification and expression analysis of peroxisome proliferator-activated receptors cDNA in a reptile, the leopard gecko (Eublepharis macularius).

Science.gov (United States)

Kato, Keisuke; Oka, Yoshitaka; Park, Min Kyun

2008-05-01

Despite the physiological and evolutionary significance of lipid metabolism in amniotes, the molecular mechanisms involved have been unclear in reptiles. To elucidate this, we investigated peroxisome proliferators-activated receptors (PPARs) in the leopard gecko (Eublepharis macularius). PPARs belong to a nuclear hormone-receptor family mainly involved in lipid metabolism. Although PPARs have been widely studied in mammals, little information about them is yet available from reptiles. We identified in the leopard gecko partial cDNA sequences of PPARalpha and beta, and full sequences of two isoforms of PPARgamma. This is the first report of reptilian PPARgamma mRNA isoforms. We also evaluated the organ distribution of expression of these genes by using RT-PCR and competitive PCR. The expression level of PPARalpha mRNA was highest in the large intestine, and moderate in the liver and kidney. The expression level of PPARbeta mRNA was highest in the kidney and large intestine, and moderate in the liver. Similarly to the expression of human PPARgamma isoforms, PPARgammaa was expressed ubiquitously, whereas the expression of PPARgammab was restricted. The highest levels of their expression, however, were observed in the large intestine, rather than in the adipose tissue as in mammals. Taken together, these results showed that the profile of PPARbeta mRNA expression in the leopard gecko is similar to that in mammals, and that those of PPAR alpha and gamma are species specific. This may reflect adaptation to annual changes in lipid storage due to seasonal food availability.

PPAR Agonists for the Prevention and Treatment of Lung Cancer

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Sowmya P. Lakshmi

2017-01-01

Full Text Available Lung cancer is the most common and most fatal of all malignancies worldwide. Furthermore, with more than half of all lung cancer patients presenting with distant metastases at the time of initial diagnosis, the overall prognosis for the disease is poor. There is thus a desperate need for new prevention and treatment strategies. Recently, a family of nuclear hormone receptors, the peroxisome proliferator-activated receptors (PPARs, has attracted significant attention for its role in various malignancies including lung cancer. Three PPARs, PPARα, PPARβ/δ, and PPARγ, display distinct biological activities and varied influences on lung cancer biology. PPARα activation generally inhibits tumorigenesis through its antiangiogenic and anti-inflammatory effects. Activated PPARγ is also antitumorigenic and antimetastatic, regulating several functions of cancer cells and controlling the tumor microenvironment. Unlike PPARα and PPARγ, whether PPARβ/δ activation is anti- or protumorigenic or even inconsequential currently remains an open question that requires additional investigation. This review of current literature emphasizes the multifaceted effects of PPAR agonists in lung cancer and discusses how they may be applied as novel therapeutic strategies for the disease.

Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor α Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver

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Ito, Yuki; Nakamura, Toshiki; Yanagiba, Yukie; Ramdhan, Doni Hikmat; Yamagishi, Nozomi; Naito, Hisao; Kamijima, Michihiro; Gonzalez, Frank J.; Nakajima, Tamie

2012-01-01

Dibutylphthalate (DBP), di(2-ethylhexyl)phthalate (DEHP), and di(2-ethylhexyl)adipate (DEHA) are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR) α, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPARα by these plasticizers using wild-type (mPPARα) and humanized PPARα (hPPARα) mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control), 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg), DEHP (977, 1953 mg/kg), and DEHA (926, 1853 mg/kg), respectively. Generally, hepatic PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR) more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR. PMID:22792086

Plasticizers May Activate Human Hepatic Peroxisome Proliferator-Activated Receptor α Less Than That of a Mouse but May Activate Constitutive Androstane Receptor in Liver

Directory of Open Access Journals (Sweden)

Yuki Ito

2012-01-01

Full Text Available Dibutylphthalate (DBP, di(2-ethylhexylphthalate (DEHP, and di(2-ethylhexyladipate (DEHA are used as plasticizers. Their metabolites activate peroxisome proliferator-activated receptor (PPAR α, which may be related to their toxicities. However, species differences in the receptor functions between rodents and human make it difficult to precisely extrapolate their toxicity from animal studies to human. In this paper, we compared the species differences in the activation of mouse and human hepatic PPARα by these plasticizers using wild-type (mPPARα and humanized PPARα (hPPARα mice. At 12 weeks old, each genotyped male mouse was classified into three groups, and fed daily for 2 weeks per os with corn oil (vehicle control, 2.5 or 5.0 mmol/kg DBP (696, 1392 mg/kg, DEHP (977, 1953 mg/kg, and DEHA (926, 1853 mg/kg, respectively. Generally, hepatic PPARα of mPPARα mice was more strongly activated than that of hPPARα mice when several target genes involving β-oxidation of fatty acids were evaluated. Interestingly, all plasticizers also activated hepatic constitutive androstane receptor (CAR more in hPPARα mice than in mPPARα mice. Taken together, these plasticizers activated mouse and human hepatic PPARα as well as CAR. The activation of PPARα was stronger in mPPARα mice than in hPPARα mice, while the opposite was true of CAR.

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

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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

Immunoregulatory mechanisms of macrophage PPAR-γ in mice with experimental inflammatory bowel disease.

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Hontecillas, R; Horne, W T; Climent, M; Guri, A J; Evans, C; Zhang, Y; Sobral, B W; Bassaganya-Riera, J

2011-05-01

Peroxisome proliferator-activated receptor-γ (PPAR-γ) is widely expressed in macrophages and has been identified as a putative target for the development of novel therapies against inflammatory bowel disease (IBD). Computational simulations identified macrophages as key targets for therapeutic interventions against IBD. This study aimed to characterize the mechanisms underlying the beneficial effects of macrophage PPAR-γ in IBD. Macrophage-specific PPAR-γ deletion significantly exacerbated clinical activity and colonic pathology, impaired the splenic and mesenteric lymph node regulatory T-cell compartment, increased percentages of lamina propria (LP) CD8+ T cells, increased surface expression of CD40, Ly6C, and Toll-like receptor 4 (TLR-4) in LP macrophages, and upregulated expression of colonic IFN-γ, CXCL9, CXCL10, IL-22, IL1RL1, CCR1, suppressor of cytokine signaling 3, and MHC class II in mice with IBD. Moreover, macrophage PPAR-γ was required for accelerating pioglitazone-mediated recovery from dextran sodium sulfate (DSS) colitis, providing a cellular target for the anti-inflammatory effects of PPAR-γ agonists in IBD.

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

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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.

The Contribution of Peroxisome Proliferator-Activated Receptor Alpha to the Relationship Between Toxicokinetics and Toxicodynamics of Trichloroethylene.

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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

Efficacy of peroxisome proliferator activated receptor agonist in the treatment of virus-associated haemophagocytic syndrome in a rabbit model.

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Hsieh, Wen-Chuan; Lan, Bau-Shin; Chen, Yi-Ling; Chang, Yao; Chuang, Huai-Chia; Su, Ih-Jen

2010-01-01

Virus-associated haemophagocytic syndrome (VAHS) is a fatal complication of viral infections, such as Epstein-Barr virus and H5N1 influenza, that results from macrophage activation and pro inflammatory cytokine injuries. The high comorbidity and mortality of current therapy urgently demands an ideal agent based on VAHS pathogenesis. Peroxisome proliferator activated receptor (PPAR) agonists, regulators of metabolic syndrome, can exhibit immunomodulatory effects on macrophage activation and cytokine secretion. In this study, we adopted rosiglitazone, a PPAR-gamma agonist, for VAHS control in a Herpesvirus papio (HVP)-infected rabbit model. Various doses of rosiglitazone were orally administered to rabbits on day 7 or day 20 after intravenous challenge with 5 x 10(7) copies of HVP. The rabbits that received 4 mg/day rosiglitazone had significantly increased survival when treated at an early stage of infection (P<0.01), whereas a higher dose (8 mg/day) was required at the advanced stage of the disease (P<0.05). All rosiglitazone-treated rabbits had significantly improved laboratory parameters and plasma tumour necrosis factor-alpha levels. Importantly, rosiglitazone could also inhibit viral replication in vitro and in vivo. PPAR agonists could represent a potentially new agent for the therapy of VAHS.

Modulating Estrogen Receptor-related Receptor-α Activity Inhibits Cell Proliferation*

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Bianco, Stéphanie; Lanvin, Olivia; Tribollet, Violaine; Macari, Claire; North, Sophie; Vanacker, Jean-Marc

2009-01-01

High expression of the estrogen receptor-related receptor (ERR)-α in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRα reduces the proliferation of various cell lines and blocks the G1/S transition of the cell cycle in an ERR...

Src is activated by the nuclear receptor peroxisome proliferator-activated receptor β/δ in ultraviolet radiation-induced skin cancer.

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Montagner, Alexandra; Delgado, Maria B; Tallichet-Blanc, Corinne; Chan, Jeremy S K; Sng, Ming K; Mottaz, Hélén; Degueurce, Gwendoline; Lippi, Yannick; Moret, Catherine; Baruchet, Michael; Antsiferova, Maria; Werner, Sabine; Hohl, Daniel; Saati, Talal Al; Farmer, Pierre J; Tan, Nguan S; Michalik, Liliane; Wahli, Walter

2014-01-01

Although non-melanoma skin cancer (NMSC) is the most common human cancer and its incidence continues to rise worldwide, the mechanisms underlying its development remain incompletely understood. Here, we unveil a cascade of events involving peroxisome proliferator-activated receptor (PPAR) β/δ and the oncogene Src, which promotes the development of ultraviolet (UV)-induced skin cancer in mice. UV-induced PPARβ/δ activity, which directly stimulated Src expression, increased Src kinase activity and enhanced the EGFR/Erk1/2 signalling pathway, resulting in increased epithelial-to-mesenchymal transition (EMT) marker expression. Consistent with these observations, PPARβ/δ-null mice developed fewer and smaller skin tumours, and a PPARβ/δ antagonist prevented UV-dependent Src stimulation. Furthermore, the expression of PPARβ/δ positively correlated with the expression of SRC and EMT markers in human skin squamous cell carcinoma (SCC), and critically, linear models applied to several human epithelial cancers revealed an interaction between PPARβ/δ and SRC and TGFβ1 transcriptional levels. Taken together, these observations motivate the future evaluation of PPARβ/δ modulators to attenuate the development of several epithelial cancers.

Structure-dependent binding and activation of perfluorinated compounds on human peroxisome proliferator-activated receptor γ

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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.

Peroxisome proliferator-activated receptors (PPARs-independent functions of fish oil on glucose and lipid metabolism in diet-induced obese mice

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Wakutsu Masaki

2010-09-01

Full Text Available Abstract Background Fish oil is known to improve lifestyle-related diseases. These effects occur partly via activation of PPARs by the n-3 polyunsaturated fatty acids included abundantly in fish oil. We investigated fish oil functions on glucose and lipid metabolism that are both dependent on and independent of PPARs pathway. Methods Mice were fed a diet containing 30 en% beef tallow (B diet for twelve weeks to induce obesity. The mice were then divided into two groups which were fed either a B diet or a diet containing 30 en% fish oil (F diet. Each group was further divided into two groups which were administered PPARα and γ antagonists or vehicle once a day for three weeks. Results The F diet groups showed lower triglyceride levels in plasma and liver than the B diet groups, but PPARs antagonists did not affect the triglyceride levels in either diet groups. The F diet groups also showed improvement of glucose tolerance compared with the B diet groups. However, PPARs antagonists made glucose tolerance worse in the F diet group but improved it in the B diet group. Therefore, by the administration of antagonists, glucose tolerance was inversely regulated between the B and F diets, and hypolipidemic action in the plasma and liver of the F diet group was not affected. Conclusion These results suggest that fish oil decreases lipid levels in plasma and liver via PPARs pathway-independent mechanism, and that glucose tolerance is inversely regulated by PPARs antagonists under diets containing different oils.

Peroxisome proliferator-activated receptors, estrogenic responses and biotransformation system in the liver of salmon exposed to tributyltin and second messenger activator

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Pavlikova, Nela [Department of Biology, Norwegian University of Science and Technology (NTNU), Hogskoleringen 5, 7491 Trondheim (Norway); RECETOX Research Centre for Environmental Chemistry and Ecotoxicology, Masaryk University, Kamenice 3, CZ62500 Brno (Czech Republic); Kortner, Trond M. [Department of Biology, Norwegian University of Science and Technology (NTNU), Hogskoleringen 5, 7491 Trondheim (Norway); Arukwe, Augustine, E-mail: arukwe@bio.ntnu.no [Department of Biology, Norwegian University of Science and Technology (NTNU), Hogskoleringen 5, 7491 Trondheim (Norway)

2010-08-15

The mechanisms by which organotin compounds produce modulations of the endocrine systems and other biological responses are not fully understood. In this study, juvenile salmon were force-fed diet containing TBT (0: solvent control, 0.1, 1 and 10 mg/kg fish) for 72 h. Subsequently, fish exposed to solvent control and 10 mg TBT were exposed to waterborne concentration (200 {mu}g/l) of the adenylate cyclase (AC) stimulator, forskolin for 2 and 4 h. The overall aim of the study was to explore whether TBT endocrine disruptive effects involve second messenger activation. Liver was sampled from individual fish (n = 8) at the end of the exposures. The transcription patterns of peroxisome proliferator-activated receptor (PPAR) isotype and acyl-coenzyme A oxidase 1 (ACOX1), aromatase isoform, estrogen receptor-{alpha} (ER{alpha}), pregnane X receptor (PXR), CYP3A and glutathione S-transferase (GST) genes were measured by quantitative polymerase chain reaction (qPCR). Our data showed a consistent increase in PPAR{alpha}, PPAR{beta} and PPAR{gamma} mRNA and protein expression after TBT exposure that were inversely correlated with ACOX1 mRNA levels. Forskolin produced PPAR isotype-specific mRNA and protein effects that were modulated by TBT. ACOX1 expression was decreased (at 2 h) and increased (at 4 h) by forskolin and the presence of TBT potentiated these effects. TBT apparently increased mRNA and protein levels of cyp19a, compared to the solvent control, whereas cyp19b mRNA levels were unaffected by TBT treatment. Combined TBT and forskolin exposure produced respective decrease and increase of mRNA levels of cyp19a and cyp19b, compared with control. TBT decreased ER{alpha} mRNA at low dose (1 mg/kg) and forskolin exposure alone produced a consistent decrease of ER{alpha} mRNA levels that were not affected by the presence of TBT. Interestingly, PXR and CYP3A mRNA levels were differentially affected, either decreased or increased, after exposure to TBT and forskolin, singly

Examining the safety of PPAR agonists - current trends and future prospects.

Science.gov (United States)

Bortolini, Michele; Wright, Matthew B; Bopst, Martin; Balas, Bogdana

2013-01-01

The peroxisome proliferator-activated receptor (PPAR)-α and -γ agonists, fibrates and glitazones, are effective treatments for dyslipidemia and type 2 diabetes mellitus, respectively, but exhibit class-related, as well as compound-specific safety characteristics. This article reviews the profiles of PPAR-α, PPAR-γ, and dual PPAR-α/γ agonists with regard to class-related and compound-specific efficacy and adverse effects. We explore how learnings from first-generation drugs are being applied to develop safer PPAR-targeted therapies. The finding that rosiglitazone may increase risk for cardiovascular events has led to regulatory guidelines requiring demonstration of cardiovascular safety in appropriate outcome trials for new type 2 diabetes mellitus drugs. The emerging data on the possibly increased risk of bladder cancer with pioglitazone may prompt the need for post-approval safety studies for new drugs. Since PPAR-α and -γ affect key cardiometabolic risk factors (diabetic dyslipidemia, insulin resistance, hyperglycemia, and inflammation) in a complementary fashion, combining their benefits has emerged as a particularly attractive option. New PPAR-targeted therapies that balance the relative potency and/or activity toward PPAR-α and -γ have shown promise in retaining efficacy while reducing potential side effects.

PPAR Agonists and Metabolic Syndrome: An Established Role?

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Margherita Botta

2018-04-01

Full Text Available Therapeutic approaches to metabolic syndrome (MetS are numerous and may target lipoproteins, blood pressure or anthropometric indices. Peroxisome proliferator-activated receptors (PPARs are involved in the metabolic regulation of lipid and lipoprotein levels, i.e., triglycerides (TGs, blood glucose, and abdominal adiposity. PPARs may be classified into the α, β/δ and γ subtypes. The PPAR-α agonists, mainly fibrates (including newer molecules such as pemafibrate and omega-3 fatty acids, are powerful TG-lowering agents. They mainly affect TG catabolism and, particularly with fibrates, raise the levels of high-density lipoprotein cholesterol (HDL-C. PPAR-γ agonists, mainly glitazones, show a smaller activity on TGs but are powerful glucose-lowering agents. Newer PPAR-α/δ agonists, e.g., elafibranor, have been designed to achieve single drugs with TG-lowering and HDL-C-raising effects, in addition to the insulin-sensitizing and antihyperglycemic effects of glitazones. They also hold promise for the treatment of non-alcoholic fatty liver disease (NAFLD which is closely associated with the MetS. The PPAR system thus offers an important hope in the management of atherogenic dyslipidemias, although concerns regarding potential adverse events such as the rise of plasma creatinine, gallstone formation, drug–drug interactions (i.e., gemfibrozil and myopathy should also be acknowledged.

Evolutionary Pattern and Regulation Analysis to Support Why Diversity Functions Existed within PPAR Gene Family Members

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Tianyu Zhou

2015-01-01

Full Text Available Peroxisome proliferators-activated receptor (PPAR gene family members exhibit distinct patterns of distribution in tissues and differ in functions. The purpose of this study is to investigate the evolutionary impacts on diversity functions of PPAR members and the regulatory differences on gene expression patterns. 63 homology sequences of PPAR genes from 31 species were collected and analyzed. The results showed that three isolated types of PPAR gene family may emerge from twice times of gene duplication events. The conserved domains of HOLI (ligand binding domain of hormone receptors domain and ZnF_C4 (C4 zinc finger in nuclear in hormone receptors are essential for keeping basic roles of PPAR gene family, and the variant domains of LCRs may be responsible for their divergence in functions. The positive selection sites in HOLI domain are benefit for PPARs to evolve towards diversity functions. The evolutionary variants in the promoter regions and 3′ UTR regions of PPARs result into differential transcription factors and miRNAs involved in regulating PPAR members, which may eventually affect their expressions and tissues distributions. These results indicate that gene duplication event, selection pressure on HOLI domain, and the variants on promoter and 3′ UTR are essential for PPARs evolution and diversity functions acquired.

Evolutionary Pattern and Regulation Analysis to Support Why Diversity Functions Existed within PPAR Gene Family Members.

Science.gov (United States)

Zhou, Tianyu; Yan, Xiping; Wang, Guosong; Liu, Hehe; Gan, Xiang; Zhang, Tao; Wang, Jiwen; Li, Liang

2015-01-01

Peroxisome proliferators-activated receptor (PPAR) gene family members exhibit distinct patterns of distribution in tissues and differ in functions. The purpose of this study is to investigate the evolutionary impacts on diversity functions of PPAR members and the regulatory differences on gene expression patterns. 63 homology sequences of PPAR genes from 31 species were collected and analyzed. The results showed that three isolated types of PPAR gene family may emerge from twice times of gene duplication events. The conserved domains of HOLI (ligand binding domain of hormone receptors) domain and ZnF_C4 (C4 zinc finger in nuclear in hormone receptors) are essential for keeping basic roles of PPAR gene family, and the variant domains of LCRs may be responsible for their divergence in functions. The positive selection sites in HOLI domain are benefit for PPARs to evolve towards diversity functions. The evolutionary variants in the promoter regions and 3' UTR regions of PPARs result into differential transcription factors and miRNAs involved in regulating PPAR members, which may eventually affect their expressions and tissues distributions. These results indicate that gene duplication event, selection pressure on HOLI domain, and the variants on promoter and 3' UTR are essential for PPARs evolution and diversity functions acquired.

Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity

International Nuclear Information System (INIS)

Liu, Wei-Xin; Wang, Ting; Zhou, Feng; Wang, Ying; Xing, Jun-Wei; Zhang, Shen; Gu, Shou-Zhi; Sang, Li-Xuan; Dai, Cong; Wang, Hai-Lan

2015-01-01

Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. - Highlights: • Obesity down-regulates PPAR-γ in the colon. • Down-regulated colonic PPAR-γ may facilitate inflammatory

Voluntary exercise prevents colonic inflammation in high-fat diet-induced obese mice by up-regulating PPAR-γ activity

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Liu, Wei-Xin, E-mail: weixinliu@yahoo.com [Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Wang, Ting; Zhou, Feng; Wang, Ying; Xing, Jun-Wei; Zhang, Shen [Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Gu, Shou-Zhi [Department of Anatomy, Seirei Christopher College, Hamamatsu 433-8558 (Japan); Sang, Li-Xuan [Department of Cadre Ward II, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Dai, Cong [Department of Gastroenterology, First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning (China); Wang, Hai-Lan [Guangdong Province Hospital for Occupational Disease Prevention and Treatment, Guangzhou 510300, Guangdong (China)

2015-04-10

Obesity is associated with increased colonic inflammation, which elevates the risk of colon cancer. Although exercise exerts anti-inflammatory actions in multiple chronic diseases associated with inflammation, it is unknown whether this strategy prevents colonic inflammation in obesity. We hypothesized that voluntary exercise would suppress colonic inflammation in high-fat diet (HFD)-induced obesity by modulation of peroxisome proliferator-activated receptor (PPAR)-γ. Male C57Bl/6J mice fed either a control diet (6.5% fat, CON) or a high-fat diet (24% fat, HFD) were divided into sedentary, voluntary exercise or voluntary exercise with PPAR-γ antagonist GW9662 (10 mg/kg/day). All interventions took place for 12 weeks. Compared with CON-sedentary group, HFD-sedentary mice gained significantly more body weight and exhibited metabolic disorders. Molecular studies revealed that HFD-sedentary mice had increased expression of inflammatory mediators and activation of nuclear factor (NF)-κB in the colons, which were associated with decreased expression and activity of PPAR-γ. Voluntary exercise markedly attenuated body weight gain, improved metabolic disorders, and normalized the expression of inflammatory mediators and activation of NF-κB in the colons in HFD-mice while having no effects in CON-animals. Moreover, voluntary exercise significantly increased expression and activity of PPAR-γ in the colons in both HFD- and CON-animals. However, all of these beneficial effects induced by voluntary exercise were abolished by GW9662, which inhibited expression and activity of PPAR-γ. The results suggest that decreased PPAR-γ activity in the colon of HFD-induced obesity may facilitate the inflammatory response and colon carcinogenesis. Voluntary exercise prevents colonic inflammation in HFD-induced obesity by up-regulating PPAR-γ activity. - Highlights: • Obesity down-regulates PPAR-γ in the colon. • Down-regulated colonic PPAR-γ may facilitate inflammatory

Activation of PPAR{delta} up-regulates fatty acid oxidation and energy uncoupling genes of mitochondria and reduces palmitate-induced apoptosis in pancreatic {beta}-cells

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Wan, Jun; Jiang, Li; Lue, Qingguo; Ke, Linqiu [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China); Li, Xiaoyu [State Key Laboratory of Oral Diseases, Sichuan University, No. 14, 3rd Section, Renmin South Road, Chengdu, Sichuan 610041 (China); Tong, Nanwei, E-mail: buddyjun@hotmail.com [Department of Endocrinology, West China Hospital of Sichuan University, 37 Guoxue Lane, Chengdu, Sichuan 610041 (China)

2010-01-15

Recent evidence indicates that decreased oxidative capacity, lipotoxicity, and mitochondrial aberrations contribute to the development of insulin resistance and type 2 diabetes. The goal of this study was to investigate the effects of peroxisome proliferator-activated receptor {delta} (PPAR{delta}) activation on lipid oxidation, mitochondrial function, and insulin secretion in pancreatic {beta}-cells. After HIT-T15 cells (a {beta}-cell line) were exposed to high concentrations of palmitate and GW501516 (GW; a selective agonist of PPAR{delta}), we found that administration of GW increased the expression of PPAR{delta} mRNA. GW-induced activation of PPAR{delta} up-regulated carnitine palmitoyltransferase 1 (CPT1), long-chain acyl-CoA dehydrogenase (LCAD), pyruvate dehydrogenase kinase 4 (PDK4), and uncoupling protein 2 (UCP2); alleviated mitochondrial swelling; attenuated apoptosis; and reduced basal insulin secretion induced by increased palmitate in HIT cells. These results suggest that activation of PPAR{delta} plays an important role in protecting pancreatic {beta}-cells against aberrations caused by lipotoxicity in metabolic syndrome and diabetes.

PPAR gamma Pro(12)Ala polymorphism and risk of acute coronary syndrome in a prospective study of Danes

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Vogel, Ulla Birgitte; Segel, Stine; Dethlefsen, Claus

2009-01-01

Background: Acute coronary syndrome (ACS) is a major cause of morbidity and mortality in the western world. Peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the regulation of the energy balance, adipocyte differentiation and lipid biosynthesis. The aim...... was to investigate if the polymorphism PPAR gamma 2 Pro(12)Ala, which encodes a less efficient transcription factor, was associated with risk of acute coronary disease and if there were interactions between this polymorphism and factors that modify PPAR gamma activity, such as alcohol intake, smoking, and use of non...

Dietary modulators of peroxisome proliferator-activated receptors: implications for the prevention and treatment of metabolic syndrome.

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

2008-01-01

In its simplest form, obesity is a state characterized by nutrient overabundance leading to hypertrophy of storage cells in white adipose tissue and the deposition of excess lipids into key metabolic regions, such as skeletal muscle and liver. Ever so steadily, this condition begins to manifest itself as progressive insulin resistance and thus ensues a myriad of other chronic diseases, such as type 2 diabetes, cardiovascular disease, and hypertension, which all fall into the realm of the metabolic syndrome. To offset imbalances in nutrient availability, however, it appears that nature has developed the peroxisome proliferator-activated receptors (PPARs), a family of endogenous lipid sensors that adeptly modulate our rates of macronutrient oxidation and regulate the systemic inflammatory response, which itself is tightly linked to the development of obesity-induced chronic disease. By understanding how PPARs alpha, delta and gamma act jointly to maintain metabolic homeostasis and reduce the chronic inflammation associated with obesity, we may one day discover that the machinery needed to defeat obesity and control the devastating consequences of the metabolic syndrome have been with us the entire time.

Activation of β-Adrenoceptors by Dobutamine May Induce a Higher Expression of Peroxisome Proliferator-Activated Receptors δ (PPARδ in Neonatal Rat Cardiomyocytes

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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.

Effects of L-carnitine against oxidative stress in human hepatocytes: involvement of peroxisome proliferator-activated receptor alpha

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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

Gamma (γ) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (γ) expression in SW 480 human colon cancer cell lines

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Campbell, Sharon E; Stone, William L; Whaley, Sarah G; Qui, Min; Krishnan, Koyamangalath

2003-01-01

Background Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of γ-tocopherol is higher than α-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used α-tocopherol. Recent epidemiological, experimental and molecular studies suggest that γ-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied α-tocopherol. γ-Tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor γ (PPARγ) is a promising molecular target for colon cancer prevention. Upregulation of PPARγ activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARγ ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both α and γ tocopherol on the expression of PPARγ mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines. Results We have discovered that the α and γ isoforms of vitamin E upregulate PPARγ mRNA and protein expression in the SW480 colon cancer cell lines. γ-Tocopherol is a better modulator of PPARγ expression than α-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, γ-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of �

Gamma (γ) tocopherol upregulates peroxisome proliferator activated receptor (PPAR) gamma (γ) expression in SW 480 human colon cancer cell lines

International Nuclear Information System (INIS)

Campbell, Sharon E; Stone, William L; Whaley, Sarah G; Qui, Min; Krishnan, Koyamangalath

2003-01-01

Tocopherols are lipid soluble antioxidants that exist as eight structurally different isoforms. The intake of γ-tocopherol is higher than α-tocopherol in the average US diet. The clinical results of the effects of vitamin E as a cancer preventive agent have been inconsistent. All published clinical trials with vitamin E have used α-tocopherol. Recent epidemiological, experimental and molecular studies suggest that γ-tocopherol may be a more potent chemopreventive form of vitamin E compared to the more-studied α-tocopherol. γ-Tocopherol exhibits differences in its ability to detoxify nitrogen dioxide, growth inhibitory effects on selected cancer cell lines, inhibition of neoplastic transformation in embryonic fibroblasts, and inhibition of cyclooxygenase-2 (COX-2) activity in macrophages and epithelial cells. Peroxisome proliferator activator receptor γ (PPARγ) is a promising molecular target for colon cancer prevention. Upregulation of PPARγ activity is anticarcinogenic through its effects on downstream genes that affect cellular proliferation and apoptosis. The thiazolidine class of drugs are powerful PPARγ ligands. Vitamin E has structural similarity to the thiazolidine, troglitazone. In this investigation, we tested the effects of both α and γ tocopherol on the expression of PPARγ mRNA and protein in SW 480 colon cancer cell lines. We also measured the intracellular concentrations of vitamin E in SW 480 colon cancer cell lines. We have discovered that the α and γ isoforms of vitamin E upregulate PPARγ mRNA and protein expression in the SW480 colon cancer cell lines. γ-Tocopherol is a better modulator of PPARγ expression than α-tocopherol at the concentrations tested. Intracellular concentrations increased as the vitamin E concentration added to the media was increased. Further, γ-tocopherol-treated cells have higher intracellular tocopherol concentrations than those treated with the same concentrations of α-tocopherol. Our data suggest that

Mixed tocopherols prevent mammary tumorigenesis by inhibiting estrogen action and activating PPAR-γ

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Lee, Hong Jin; Ju, Jihyeung; Paul, Shiby; So, Jae-Young; DeCastro, Andrew; Smolarek, Amanda; Lee, Mao-Jung; Yang, Chung S.; Newmark, Harold L.; Suh, Nanjoo

2009-01-01

Purpose Tocopherols are lipophilic antioxidants present in vegetable oils. Although the antioxidant and anticancer activities of α-tocopherol (vitamin E) have been studied for decades, recent intervention studies with α-tocopherol have been negative for protection from cancer in humans. The tocopherols consist of 4 isoforms, α, β, γ, and δ variants, and recent attention is being made to other isoforms. In the present study, we investigated the inhibitory effect of a tocopherol mixture rich in γ- and δ-tocopherols against mammary tumorigenesis. Experimental Design Female Sprague Dawley rats were treated with N-methyl-N-nitrosourea (NMU), and then fed diets containing 0.1%, 0.3%, or 0.5% mixed tocopherols rich in γ- and δ-tocopherols for 9 weeks. Tumor burden and multiplicity were determined, and the levels of markers of inflammation, proliferation and apoptosis were evaluated in the serum and in mammary tumors. The regulation of nuclear receptor signaling by tocopherols was studied in mammary tumors and in breast cancer cells. Results Dietary administration of 0.1%, 0.3%, or 0.5% mixed tocopherols suppressed mammary tumor growth by 38%, 50%, or 80%, respectively. Tumor multiplicity was also significantly reduced in all three mixed tocopherol groups. Mixed tocopherols increased the expression of p21, p27, caspase-3 and peroxisome proliferator activated receptor-γ (PPAR-γ), and inhibited AKT and estrogen signaling in mammary tumors. Our mechanistic study found that γ- and δ-tocopherols, but not α-tocopherol, activated PPAR-γ and antagonized estrogen action in breast cancer. Conclusion The results suggest that γ- and δ-tocopherols may be effective agents for the prevention of breast cancer. PMID:19509159

Peroxisome proliferator-activated receptor ligands regulate lipid content, metabolism, and composition in fetal lungs of diabetic rats.

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Kurtz, M; Capobianco, E; Careaga, V; Martinez, N; Mazzucco, M B; Maier, M; Jawerbaum, A

2014-03-01

Maternal diabetes impairs fetal lung development. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors relevant in lipid homeostasis and lung development. This study aims to evaluate the effect of in vivo activation of PPARs on lipid homeostasis in fetal lungs of diabetic rats. To this end, we studied lipid concentrations, expression of lipid metabolizing enzymes and fatty acid composition in fetal lungs of control and diabetic rats i) after injections of the fetuses with Leukotriene B4 (LTB4, PPARα ligand) or 15deoxyΔ(12,14)prostaglandin J2 (15dPGJ2, PPARγ ligand) and ii) fed during pregnancy with 6% olive oil- or 6% safflower oil-supplemented diets, enriched with PPAR ligands were studied. Maternal diabetes increased triglyceride concentrations and decreased expression of lipid-oxidizing enzymes in fetal lungs of diabetic rats, an expression further decreased by LTB4 and partially restored by 15dPGJ2 in lungs of male fetuses in the diabetic group. In lungs of female fetuses in the diabetic group, maternal diets enriched with olive oil increased triglyceride concentrations and fatty acid synthase expression, while those enriched with safflower oil increased triglyceride concentrations and fatty acid transporter expression. Both olive oil- and safflower oil-supplemented diets decreased cholesterol and cholesteryl ester concentrations and increased the expression of the reverse cholesterol transporter ATP-binding cassette A1 in fetal lungs of female fetuses of diabetic rats. In fetal lungs of control and diabetic rats, the proportion of polyunsaturated fatty acids increased with the maternal diets enriched with olive and safflower oils. Our results revealed important changes in lipid metabolism in fetal lungs of diabetic rats, and in the ability of PPAR ligands to modulate the composition of lipid species relevant in the lung during the perinatal period.

Peroxisome proliferator-activated receptor α activation induces hepatic steatosis, suggesting an adverse effect.

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Fang Yan

Full Text Available 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

Molecular cloning and tissue distribution of peroxisome proliferator-activated receptor-alpha (PPARα) and gamma (PPARγ) in the pigeon (Columba livia domestica).

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Xie, P; Yuan, C; Wang, C; Zou, X-T; Po, Z; Tong, H-B; Zou, J-M

2014-01-01

1. Peroxisome proliferator-activated receptors (PPAR) are involved in lipid metabolism through transcriptional regulation of target gene expression. The objective of the current study was to clone and characterise the PPARα and PPARγ genes in pigeon. 2. The full-length of 1941-bp PPARα and 1653-bp PPARγ were cloned from pigeons. The two genes were predicted to encode 468 and 475 amino acids, respectively. Both proteins contained two C4-type zinc fingers, a nuclear hormone receptor DNA-binding region signature and a HOLI domain (ligand binding domain of hormone receptors), and had high identities with other corresponding avian genes. 3. Using quantitative real-time PCR, pigeon PPARα gene expression was shown to be high in kidney, liver, gizzard and duodenum whereas PPARγ was predominantly expressed in adipose tissue.

Modulation of PPAR-γ by Nutraceutics as Complementary Treatment for Obesity-Related Disorders and Inflammatory Diseases

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D. Ortuño Sahagún

2012-01-01

Full Text Available A direct correlation between adequate nutrition and health is a universally accepted truth. The Western lifestyle, with a high intake of simple sugars, saturated fat, and physical inactivity, promotes pathologic conditions. The main adverse consequences range from cardiovascular disease, type 2 diabetes, and metabolic syndrome to several cancers. Dietary components influence tissue homeostasis in multiple ways and many different functional foods have been associated with various health benefits when consumed. Natural products are an important and promising source for drug discovery. Many anti-inflammatory natural products activate peroxisome proliferator-activated receptors (PPAR; therefore, compounds that activate or modulate PPAR-gamma (PPAR-γ may help to fight all of these pathological conditions. Consequently, the discovery and optimization of novel PPAR-γ agonists and modulators that would display reduced side effects is of great interest. In this paper, we present some of the main naturally derived products studied that exert an influence on metabolism through the activation or modulation of PPAR-γ, and we also present PPAR-γ-related diseases that can be complementarily treated with nutraceutics from functional foods.

Oxymatrine attenuates hepatic steatosis in non-alcoholic fatty liver disease rats fed with high fructose diet through inhibition of sterol regulatory element binding transcription factor 1 (Srebf1) and activation of peroxisome proliferator activated receptor alpha (Pparα).

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Shi, Li-juan; Shi, Lei; Song, Guang-yao; Zhang, He-fang; Hu, Zhi-juan; Wang, Chao; Zhang, Dong-hui

2013-08-15

The aim of this study was to examine the therapeutic effect of oxymatrine, a monomer isolated from the medicinal plant Sophora flavescens Ait, on the hepatic lipid metabolism in non-alcoholic fatty liver (NAFLD) rats and to explore the potential mechanism. Rats were fed with high fructose diet for 8 weeks to establish the NAFLD model, then were given oxymatrine treatment (40, 80, and 160 mg/kg, respectively) for another 8 weeks. Body weight gain, liver index, serum and liver lipids, and histopathological evaluation were measured. Enzymatic activity and gene expression of the key enzymes involved in the lipogenesis and fatty acid oxidation were assayed. The results showed that oxymatrine treatment reduced body weight gain, liver weight, liver index, dyslipidemia, and liver triglyceride level in a dose dependant manner. Importantly, the histopathological examination of liver confirmed that oxymatrine could decrease the liver lipid accumulation. The treatment also decreased the fatty acid synthase (FAS) enzymatic activity and increased the carnitine palmitoyltransferase 1A (CPT1A) enzymatic activity. Besides, oxymatrine treatment decreased the mRNA expression of sterol regulatory element binding transcription factor 1(Srebf1), fatty acid synthase (Fasn), and acetyl CoA carboxylase (Acc), and increased the mRNA expression of peroxisome proliferator activated receptor alpha (Pparα), carnitine palmitoyltransferase 1A (Cpt1a), and acyl CoA oxidase (Acox1) in high fructose diet induced NAFLD rats. These results suggested that the therapeutic effect of oxymatrine on the hepatic steatosis in high fructose diet induced fatty liver rats is partly due to down-regulating Srebf1 and up-regulating Pparα mediated metabolic pathways simultaneously. © 2013 Elsevier B.V. All rights reserved.

Giardia muris infection in mice is associated with a protective interleukin 17A response and induction of peroxisome proliferator-activated receptor alpha.

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Dreesen, Leentje; De Bosscher, Karolien; Grit, Grietje; Staels, Bart; Lubberts, Erik; Bauge, Eric; Geldhof, Peter

2014-08-01

The protozoan parasite Giardia duodenalis (Giardia lamblia) is one of the most commonly found intestinal pathogens in mammals, including humans. In the current study, a Giardia muris-mouse model was used to analyze cytokine transcription patterns and histological changes in intestinal tissue at different time points during infection in C57BL/6 mice. Since earlier work revealed the upregulation of peroxisome proliferator-activated receptors (PPARs) in Giardia-infected calves, a second aim was to investigate the potential activation of PPARs in the intestines of infected mice. The most important observation in all mice was a strong upregulation of il17a starting around 1 week postinfection. The significance of interleukin 17A (IL-17A) in orchestrating a protective immune response was further demonstrated in an infection trial or experiment using IL-17 receptor A (IL-17RA) knockout (KO) mice: whereas in wild-type (WT) mice, cyst secretion dropped significantly after 3 weeks of infection, the IL-17RA KO mice were unable to clear the infection. Analysis of the intestinal response further indicated peroxisome proliferator-activated receptor alpha (PPARα) induction soon after the initial contact with the parasite, as characterized by the transcriptional upregulation of ppara itself and several downstream target genes such as pltp and cpt1. Overall, PPARα did not seem to have any influence on the immune response against G. muris, since PPARα KO animals expressed il-17a and could clear the infection similar to WT controls. In conclusion, this study shows for the first time the importance of IL-17 production in the clearance of a G. muris infection together with an early induction of PPARα. The effect of the latter, however, is still unclear. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The effect of n-3 long chain fatty acids supplementation on plasma peroxisome proliferator activated receptor gamma and thyroid hormones in obesity

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Parizad Taraghijou

2012-01-01

Full Text Available Background: Peroxisome proliferator-activated receptor gamma (PPAR γ is a transcription factor, which is abundantly expressed in adipose tissue and has a direct link to adiposity. It seems that long-chain polyunsaturated fatty acids (LC-PUFAs can regulate PPAR γ expression. The purpose of this study was to investigate the effects of n-3LC PUFA supplementation on plasma levels of PPAR γ and thyroid hormones in obesity. Materials and Methods: In a randomized double-blind controlled trial, 66 subjects with obesity were assigned to 2 groups. Participants in intervention group consumed omega3 capsules contained 1000 mg n-3 fatty acids (180 mg of eicosapentaenoic acid [EPA] and 120 mg of docosahexaenoic acid [DHA] and placebo group consumed placebo capsules contained paraffin twice a day for 4 wk. Fasting blood samples and weight measurements were collected at the baseline and at the end of the trial. Plasma PPAR γ and thyroid hormones were measured by ELISA. Data were analyzed using a repeated measure model-two factor for comparing two groups in two times. Results: No significant changes were observed in PPAR γ levels between and within the groups after supplementation (P>0.05. N-3LC PUFA supplementation significantly increased T4 levels after 4 wk (P<0.05 but T3 and TSH did not change significantly. Conclusion: Our study showed that n-3LC PUFAs supplementation increased T4 levels. However, no significant changes in T3, TSH and PPAR γ plasma levels were observed in obese adults.

Inhibitory effect on hepatitis B virus in vitro by a peroxisome proliferator-activated receptor-γ ligand, rosiglitazone

International Nuclear Information System (INIS)

Wakui, Yuta; Inoue, Jun; Ueno, Yoshiyuki; Fukushima, Koji; Kondo, Yasuteru; Kakazu, Eiji; Obara, Noriyuki; Kimura, Osamu; Shimosegawa, Tooru

2010-01-01

Although chronic infection of hepatitis B virus (HBV) is currently managed with nucleot(s)ide analogues or interferon-α, 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 PPARα ligand, bezafibrate, and a PPARγ 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 PPARγ, reduced the suppressive effect of rosiglitazone on HBV. Moreover, rosiglitazone showed a synergistic effect on HBV replication with lamivudine or interferon-α-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.

Ligand activation of peroxisome proliferator-activated receptor-β/δ suppresses liver tumorigenesis in hepatitis B transgenic mice

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Balandaram, Gayathri; Kramer, Lance R.; Kang, Boo-Hyon; Murray, Iain A.; Perdew, Gary H.; Gonzalez, Frank J.; Peters, Jeffrey M.

2016-01-01

Highlights: • The role of PPARβ/δ in HBV-induced liver cancer was examined. • PPARβ/δ inhibits steatosis, inflammation, tumor multiplicity and promotes apoptosis. • Kupffer cell PPARβ/δ mediates these effects independent of DNA binding. - Abstract: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) inhibits steatosis and inflammation, known risk factors for liver cancer. In this study, the effect of ligand activation of PPARβ/δ in modulating liver tumorigenesis in transgenic hepatitis B virus (HBV) mice was examined. Activation of PPARβ/δ in HBV mice reduced steatosis, the average number of liver foci, and tumor multiplicity. Reduced expression of hepatic CYCLIN D1 and c-MYC, tumor necrosis factor alpha (Tnfa) mRNA, serum levels of alanine aminotransaminase, and an increase in apoptotic signaling was also observed following ligand activation of PPARβ/δ in HBV mice compared to controls. Inhibition of Tnfa mRNA expression was not observed in wild-type hepatocytes. Ligand activation of PPARβ/δ inhibited lipopolysaccharide (LPS)-induced mRNA expression of Tnfa in wild-type, but not in Pparβ/δ-null Kupffer cells. Interestingly, LPS-induced expression of Tnfa mRNA was also inhibited in Kupffer cells from a transgenic mouse line that expressed a DNA binding mutant form of PPARβ/δ compared to controls. Combined, these results suggest that ligand activation of PPARβ/δ attenuates hepatic tumorigenesis in HBV transgenic mice by inhibiting steatosis and cell proliferation, enhancing hepatocyte apoptosis, and modulating anti-inflammatory activity in Kupffer cells.

Immunoregulatory mechanisms of macrophage PPAR γ in mice with experimental inflammatory bowel disease

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Hontecillas, Raquel; Horne, William T.; Climent, Montse; Guri, Amir J.; Evans, C.; Zhang, Y.; Sobral, Bruno W.; Bassaganya-Riera, Josep

2010-01-01

Peroxisome proliferator-activated receptor γ (PPAR γ) is widely expressed in macrophages and has been identified as a putative target for the development of novel therapies against inflammatory bowel disease (IBD). Computational simulations identified macrophages as key targets for therapeutic interventions against IBD. This study aimed to characterize the mechanisms underlying the beneficial effects of macrophage PPAR γ in IBD. Macrophage-specific PPAR γ deletion significantly exacerbated clinical activity and colonic pathology, impaired the splenic and mesenteric lymph node regulatory T cell compartment, increased percentages of LP CD8+ T cells, increased surface expression of CD40, Ly6C, and TLR-4 in LP macrophages, and upregulated expression of colonic IFN-γ, CXCL9, CXCL10, IL-22, IL1RL1, CCR1, suppressor of cytokine signaling 3 and MCH class II in mice with IBD. Moreover, macrophage PPAR γ was required for accelerating pioglitazone-mediated recovery from DSS colitis, providing a cellular target for the anti-inflammatory effects of PPAR γ agonists in IBD. PMID:21068720

Should We Use PPAR Agonists to Reduce Cardiovascular Risk?

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Jennifer G. Robinson

2008-01-01

Full Text Available Trials of peroxisome proliferator-activated receptor (PPAR agonists have shown mixed results for cardiovascular prevention. Fibrates are PPAR- agonists that act primarily to improve dyslipidemia. Based on low- and high-density lipoprotein cholesterol (LDL and HDL effects, gemfibrozil may be of greater cardiovascular benefit than expected, fenofibrate performed about as expected, and bezafibrate performed worse than expected. Increases in both cardiovascular and noncardiovascular serious adverse events have been observed with some fibrates. Thiazolidinediones (TZDs are PPAR- agonists used to improve impaired glucose metabolism but also influence lipids. Pioglitazone reduces atherosclerotic events in diabetic subjects, but has no net cardiovascular benefit due to increased congestive heart failure risk. Rosiglitazone may increase the risk of atherosclerotic events, and has a net harmful effect on the cardiovascular system when congestive heart failure is included. The primary benefit of TZDs appears to be the prevention of diabetic microvascular complications. Dual PPAR-/ agonists have had unacceptable adverse effects but more selective agents are in development. PPAR- and pan-agonists are also in development. It will be imperative to prove that future PPAR agonists not only prevent atherosclerotic events but also result in a net reduction on total cardiovascular events without significant noncardiovascular adverse effects with long-term use.

Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

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Tenenbaum Alexander

2012-11-01

Full Text Available Abstract All fibrates are peroxisome proliferators-activated receptors (PPARs-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C. However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones are used to treat type 2 diabetes mellitus (T2DM. They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates. Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants

Balanced pan-PPAR activator bezafibrate in combination with statin: comprehensive lipids control and diabetes prevention?

Science.gov (United States)

Tenenbaum, Alexander; Fisman, Enrique Z

2012-11-14

All fibrates are peroxisome proliferators-activated receptors (PPARs)-alpha agonists with ability to decrease triglyceride and increase high density lipoprotein- cholesterol (HDL-C). However, bezafibrate has a unique characteristic profile of action since it activates all three PPAR subtypes (alpha, gamma and delta) at comparable doses. Therefore, bezafibrate operates as a pan-agonist for all three PPAR isoforms. Selective PPAR gamma agonists (thiazolidinediones) are used to treat type 2 diabetes mellitus (T2DM). They improve insulin sensitivity by up-regulating adipogenesis, decreasing free fatty acid levels, and reversing insulin resistance. However, selective PPAR gamma agonists also cause water retention, weight gain, peripheral edema, and congestive heart failure. The expression of PPAR beta/ delta in essentially all cell types and tissues (ubiquitous presence) suggests its potential fundamental role in cellular biology. PPAR beta/ delta effects correlated with enhancement of fatty acid oxidation, energy consumption and adaptive thermogenesis. Together, these data implicate PPAR beta/delta in fuel combustion and suggest that pan-PPAR agonists that include a component of PPAR beta/delta activation might offset some of the weight gain issues seen with selective PPAR gamma agonists, as was demonstrated by bezafibrate studies. Suggestively, on the whole body level all PPARs acting as one orchestra and balanced pan-PPAR activation seems as an especially attractive pharmacological goal. Conceptually, combined PPAR gamma and alpha action can target simultaneously insulin resistance and atherogenic dyslipidemia, whereas PPAR beta/delta properties may prevent the development of overweight. Bezafibrate, as all fibrates, significantly reduced plasma triglycerides and increased HDL-C level (but considerably stronger than other major fibrates). Bezafibrate significantly decreased prevalence of small, dense low density lipoproteins particles, remnants, induced

Peroxisome Proliferator-Activated Receptor-α Activation Decreases Mean Arterial Pressure, Plasma Interleukin-6, and COX-2 While Increasing Renal CYP4A Expression in an Acute Model of DOCA-Salt Hypertension

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Dexter L. Lee

2011-01-01

Full Text Available Peroxisome proliferator-activated receptor-alpha (PPAR-α activation by fenofibrate reduces blood pressure and sodium retention during DOCA-salt hypertension. PPAR-α activation reduces the expression of inflammatory cytokines, such as interleukin-6 (IL-6. Fenofibrate also induces cytochrome P450 4A (CYP4A and increases 20-hydroxyeicosatetraenoic acid (20-HETE production. This study tested whether the administration of fenofibrate would reduce blood pressure by attenuating plasma IL-6 and renal expression of cyclooxygenase-2 (COX-2, while increasing expression of renal CYP4A during 7 days of DOCA-salt hypertension. We performed uni-nephrectomy on 12–14 week old male Swiss Webster mice and implanted biotelemetry devices in control, DOCA-salt (1.5 mg/g treated mice with or without fenofibrate (500 mg/kg/day in corn oil, intragastrically. Fenofibrate significantly decreased mean arterial pressure and plasma IL-6. In kidney homogenates, fenofibrate increased CYP4A and decreased COX-2 expression. There were no differences in renal cytochrome P450, family 2, subfamily c, polypeptide 23 (CYP2C23 and soluble expoxide hydrolase (sEH expression between the groups. Our results suggest that the blood pressure lowering effect of PPAR-α activation by fenofibrate involves the reduction of plasma IL-6 and COX-2, while increasing CYP4A expression during DOCA-salt hypertension. Our results may also suggest that PPAR-α activation protects the kidney against renal injury via decreased COX-2 expression.

The Role of PPAR Receptors and Leukotriene B4 Receptors in Mediating the Effects of LY293111 in Pancreatic Cancer

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Thomas E. Adrian

2008-01-01

Full Text Available Pancreatic cancer is a devastating disease in which current therapies are inadequate. Separate lines of research have identified the 5-lipoxygenase/leukotriene B4 receptor pathway and the PPAR pathway as potential targets for prevention or treatment of this disease. LY293111 was originally designed as a potent leukotriene B4 receptor antagonist for treatment of inflammatory conditions. LY293111 was also known to have inhibitory effects on 5-lipoxygenase, which is upstream of the production of leukotrienes. LY293111 was shown to have potent anticancer effects in pancreatic cancer and several other solid malignancies, where it caused cell cycle arrest and marked apoptosis. Subsequently, it came to light that LY293111 exhibited PPAR agonist activity in addition to its effects on the 5-lipoxygenase pathway. This raises the question of which of the two targets is of greatest importance with regard to the anticancer effects of this agent. The evidence to date is not conclusive, but suggests that the effects of LY293111 may be mediated by both LTB4 receptors and PPAR.

Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists.

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

2011-01-01

The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.

Deletion of PPAR-γ in immune cells enhances susceptibility to antiglomerular basement membrane disease

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Cristen Chafin

2010-10-01

Full Text Available Cristen Chafin2, Sarah Muse2, Raquel Hontecillas5, Josep Bassaganya-Riera5, David L Caudell2, Samuel K Shimp III4, M Nichole Rylander4, John Zhang6, Liwu Li3, Christopher M Reilly1,21Virginia College of Osteopathic Medicine, 2Department of Biomedical Sciences and Pathobiology, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 3Department of Biological Sciences, 4Department of Mechanical Engineering, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 5Nutritional Immunology and Molecular Medicine Laboratory, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA; 6Medical University of SC, Charleston, SC, USAAbstract: Activation of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPAR-γ has been shown to be immunoregulatory in autoimmune diseases by inhibiting production of a number of inflammatory mediators. We investigated whether PPAR-γ gene deletion in hematopoietic cells would alter disease pathogenesis in the antiglomerular basement membrane (anti-GBM mouse model. PPAR-γ+/+ and PPAR-γ-/- mice were immunized with rabbit antimouse GBM antibodies and lipopolysaccharide and evaluated for two weeks. Although both the PPAR-γ+/+ and PPAR-γ-/- mice had IgG deposition in the glomerulus and showed proteinuria two weeks after injection, glomerular and tubulointerstitial disease in PPAR-γ-/- mice were significantly more severe compared with the PPAR-γ+/+ animals. We observed that the PPAR-γ-/- mice had decreased CD4+CD25+ regulatory T cells and an increased CD8+:CD4+ ratio as compared with the PPAR-γ+/+ mice, suggesting that PPAR-γ has a role in the regulation of T cells. Furthermore, plasma interleukin-6 levels were significantly increased in the PPAR-γ-/- mice at two weeks as compared with the PPAR-γ+/+ animals. Taken together, these studies show that

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

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...... in epithelial cells from inflamed mucosa in vitro. Rosiglitazone enema treatment was well tolerated and reduced the Mayo ulcerative colitis score from 8.9 to 4.3 (P levels in the epithelial cells of the patients, indicating PPAR...

Modulating Estrogen Receptor-related Receptor-α Activity Inhibits Cell Proliferation*

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Bianco, Stéphanie; Lanvin, Olivia; Tribollet, Violaine; Macari, Claire; North, Sophie; Vanacker, Jean-Marc

2009-01-01

High expression of the estrogen receptor-related receptor (ERR)-α in human tumors is correlated to a poor prognosis, suggesting an involvement of the receptor in cell proliferation. In this study, we show that a synthetic compound (XCT790) that modulates the activity of ERRα reduces the proliferation of various cell lines and blocks the G1/S transition of the cell cycle in an ERRα-dependent manner. XCT790 induces, in a p53-independent manner, the expression of the cell cycle inhibitor p21waf/cip1 at the protein, mRNA, and promoter level, leading to an accumulation of hypophosphorylated Rb. Finally, XCT790 reduces cell tumorigenicity in Nude mice. PMID:19546226

Regulation of PPAR{gamma} function by TNF-{alpha}

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Ye Jianping [Pennington Biomedical Research Center, Louisiana State University System, 6400 Perkins Road, Baton Rouge, LA 70808 (United States)], E-mail: yej@pbrc.edu

2008-09-26

The nuclear receptor PPAR{gamma} is a lipid sensor that regulates lipid metabolism through gene transcription. Inhibition of PPAR{gamma} activity by TNF-{alpha} is involved in pathogenesis of insulin resistance, atherosclerosis, inflammation, and cancer cachexia. PPAR{gamma} activity is regulated by TNF-{alpha} at pre-translational and post-translational levels. Activation of serine kinases including IKK, ERK, JNK, and p38 may be involved in the TNF-regulation of PPAR{gamma}. Of the four kinases, IKK is a dominant signaling molecule in the TNF-regulation of PPAR{gamma}. IKK acts through at least two mechanisms: inhibition of PPAR{gamma} expression and activation of PPAR{gamma} corepressor. In this review article, literature is reviewed with a focus on the mechanisms of PPAR{gamma} inhibition by TNF-{alpha}.

Functional Role of PPARs in Ruminants: Potential Targets for Fine-Tuning Metabolism during Growth and Lactation

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Chen, Shuowen; Khan, Muhammad J.; Loor, Juan J.

2013-01-01

Characterization and biological roles of the peroxisome proliferator-activated receptor (PPAR) isotypes are well known in monogastrics, but not in ruminants. However, a wealth of information has accumulated in little more than a decade on ruminant PPARs including isotype tissue distribution, response to synthetic and natural agonists, gene targets, and factors affecting their expression. Functional characterization demonstrated that, as in monogastrics, the PPAR isotypes control expression of genes involved in lipid metabolism, anti-inflammatory response, development, and growth. Contrary to mouse, however, the PPARγ gene network appears to controls milk fat synthesis in lactating ruminants. As in monogastrics, PPAR isotypes in ruminants are activated by long-chain fatty acids, therefore, making them ideal candidates for fine-tuning metabolism in this species via nutrients. In this regard, using information accumulated in ruminants and monogastrics, we propose a model of PPAR isotype-driven biological functions encompassing key tissues during the peripartal period in dairy cattle. PMID:23737762

Cloning retinoid and peroxisome proliferator-activated nuclear receptors of the Pacific oyster and in silico binding to environmental chemicals.

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Susanne Vogeler

Full Text Available Disruption of nuclear receptors, a transcription factor superfamily regulating gene expression in animals, is one proposed mechanism through which pollution causes effects in aquatic invertebrates. Environmental pollutants have the ability to interfere with the receptor's functions through direct binding and inducing incorrect signals. Limited knowledge of invertebrate endocrinology and molecular regulatory mechanisms, however, impede the understanding of endocrine disruptive effects in many aquatic invertebrate species. Here, we isolated three nuclear receptors of the Pacific oyster, Crassostrea gigas: two isoforms of the retinoid X receptor, CgRXR-1 and CgRXR-2, a retinoic acid receptor ortholog CgRAR, and a peroxisome proliferator-activated receptor ortholog CgPPAR. Computer modelling of the receptors based on 3D crystal structures of human proteins was used to predict each receptor's ability to bind to different ligands in silico. CgRXR showed high potential to bind and be activated by 9-cis retinoic acid and the organotin tributyltin (TBT. Computer modelling of CgRAR revealed six residues in the ligand binding domain, which prevent the successful interaction with natural and synthetic retinoid ligands. This supports an existing theory of loss of retinoid binding in molluscan RARs. Modelling of CgPPAR was less reliable due to high discrepancies in sequence to its human ortholog. Yet, there are suggestions of binding to TBT, but not to rosiglitazone. The effect of potential receptor ligands on early oyster development was assessed after 24h of chemical exposure. TBT oxide (0.2μg/l, all-trans retinoic acid (ATRA (0.06 mg/L and perfluorooctanoic acid (20 mg/L showed high effects on development (>74% abnormal developed D-shelled larvae, while rosiglitazone (40 mg/L showed no effect. The results are discussed in relation to a putative direct (TBT disruption effect on nuclear receptors. The inability of direct binding of ATRA to CgRAR suggests

PPARs Link Early Life Nutritional Insults to Later Programmed Hypertension and Metabolic Syndrome

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You-Lin Tain

2015-12-01

Full Text Available Hypertension is an important component of metabolic syndrome. Adulthood hypertension and metabolic syndrome can be programmed in response to nutritional insults in early life. Peroxisome proliferator-activated receptors (PPARs serve as a nutrient-sensing signaling linking nutritional programming to hypertension and metabolic syndrome. All three members of PPARs, PPARα, PPARβ/δ, and PPARγ, are expressed in the kidney and involved in blood pressure control. This review provides an overview of potential clinical applications of targeting on the PPARs in the kidney to prevent programmed hypertension and metabolic syndrome, with an emphasis on the following areas: mechanistic insights to interpret programmed hypertension; the link between the PPARs, nutritional insults, and programmed hypertension and metabolic syndrome; the impact of PPAR signaling pathway in a maternal high-fructose model; and current experimental studies on early intervention by PPAR modulators to prevent programmed hypertension and metabolic syndrome. Animal studies employing a reprogramming strategy via targeting PPARs to prevent hypertension have demonstrated interesting results. It is critical that the observed effects on developmental reprogramming in animal models are replicated in human studies, to halt the globally-growing epidemic of metabolic syndrome-related diseases.

Angiopoietin-like 4 mediates PPAR delta effect on lipoprotein lipase-dependent fatty acid uptake but not on beta-oxidation in myotubes.

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Marius R Robciuc

Full Text Available Peroxisome proliferator-activated receptor (PPAR delta is an important regulator of fatty acid (FA metabolism. Angiopoietin-like 4 (Angptl4, a multifunctional protein, is one of the major targets of PPAR delta in skeletal muscle cells. Here we investigated the regulation of Angptl4 and its role in mediating PPAR delta functions using human, rat and mouse myotubes. Expression of Angptl4 was upregulated during myotubes differentiation and by oleic acid, insulin and PPAR delta agonist GW501516. Treatment with GW501516 or Angptl4 overexpression inhibited both lipoprotein lipase (LPL activity and LPL-dependent uptake of FAs whereas uptake of BSA-bound FAs was not affected by either treatment. Activation of retinoic X receptor (RXR, PPAR delta functional partner, using bexarotene upregulated Angptl4 expression and inhibited LPL activity in a PPAR delta dependent fashion. Silencing of Angptl4 blocked the effect of GW501516 and bexarotene on LPL activity. Treatment with GW501516 but not Angptl4 overexpression significantly increased palmitate oxidation. Furthermore, Angptl4 overexpression did not affect the capacity of GW501516 to increase palmitate oxidation. Basal and insulin stimulated glucose uptake, glycogen synthesis and glucose oxidation were not significantly modulated by Angptl4 overexpression. Our findings suggest that FAs-PPARdelta/RXR-Angptl4 axis controls the LPL-dependent uptake of FAs in myotubes, whereas the effect of PPAR delta activation on beta-oxidation is independent of Angptl4.

Peroxisome proliferator-activated receptor γ is expressed in hippocampal neurons and its activation prevents β-amyloid neurodegeneration: role of Wnt signaling

International Nuclear Information System (INIS)

Inestrosa, Nibaldo C.; Godoy, Juan A.; Quintanilla, Rodrigo A.; Koenig, Cecilia S.; Bronfman, Miguel

2005-01-01

The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-β-peptide (Aβ), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPARγ is present in rat hippocampal neurons in culture. (2) Activation of PPARγ by troglitazone and rosiglitazone protects rat hippocampal neurons against Aβ-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPARγ agonists, including troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic Aβ-induced rise in bulk-free Ca 2+ . (4) PPARγ activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3β (GSK-3β) and an increase of the cytoplasmic and nuclear β-catenin levels. We conclude that the activation of PPARγ prevents Aβ-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPARγ and the Wnt signaling pathway. More important, the fact that the activation of PPARγ attenuated Aβ-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective

Discovery of novel PPAR ligands by a virtual screening approach based on pharmacophore modeling, 3D shape, and electrostatic similarity screening

DEFF Research Database (Denmark)

Markt, Patrick; Petersen, Rasmus K; Flindt, Esben N

2008-01-01

Peroxisome proliferator-activated receptors (PPARs) are important targets for drugs used in the treatment of atherosclerosis, dyslipidaemia, obesity, type 2 diabetes, and other diseases caused by abnormal regulation of the glucose and lipid metabolism. We applied a virtual screening workflow base...

Antidepressant-like effect of atorvastatin in the forced swimming test in mice: the role of PPAR-gamma receptor and nitric oxide pathway.

Science.gov (United States)

Shahsavarian, Arash; Javadi, Shiva; Jahanabadi, Samane; Khoshnoodi, Mina; Shamsaee, Javad; Shafaroodi, Hamed; Mehr, Shahram Ejtemaei; Dehpour, Ahmadreza

2014-12-15

Atorvastatin is a synthetic and lipophilic statin which has been reported to have a positive role in reducing depression. The potential antidepressant-like effects of atorvastatin and the possible involvement of peroxisome proliferator-activated receptor gamma (PPAR_γ) and nitric oxide system were determined using forced swimming test (FST) in mice was studied. Atorvastatin (0.01, 0.1 and 1 mg/kg, p.o.) was administered 1 h before FST. To assess the involvement of PPAR_γ in the possible antidepressant effect of atorvastatin, pioglitazone, a PPAR_γ agonist (5 mg/kg), and GW-9662, a specific PPAR_γ antagonist (2 mg/kg), was co-administered with atorvastatin (0.01 mg/kg, p.o.) and then FST was performed. The possible role of nitric oxide pathway was determined by using co-administration of a non-specific NOS inhibitor, N-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg, i.p.), and a NO precursor, L-arginine (750 mg/kg, i.p.) with sub-effective doses of atorvastatin and pioglitazone. Immobility time was significantly decreased after atorvastatin administration (0.1 and 1 mg/kg, p.o.). Administration of pioglitazone or L-NAME in combination with the sub-effective dose of atorvastatin (0.01 mg/kg, p.o.) reduced the immobility time in the FST compared to drugs alone, showing the participation of these pathways; while co-administration of non-effective doses of atorvastatin and pioglitazone with GW9662 or L-arginine reversed antidepressant-like effect of atorvastatin in FST. Data from concurrent use of GW9662 and atorvastatin also demonstrated that the antidepressant effect of atorvastatin was significantly reversed by GW9662. The antidepressant-like effect of atorvastatin on mice in the FST is mediated at least in part through PPAR_γ receptors and NO pathway. Copyright © 2014 Elsevier B.V. All rights reserved.

Evaluation of Whether Gemfibrozil is a Peroxisome Proliferator in Fish

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Gemfibrozil is a pharmaceutical that indirectly modulates cholesterol biosynthesis through effects on peroxisome proliferator-activated receptors (PPAR), which are transcriptional cofactors that regulate expression of genes related to lipid metabolism. An enzyme found in the pero...

In vitro Screening and Evaluation of 37 Traditional Chinese Medicines for Their Potential to Activate Peroxisome Proliferator-Activated Receptors-γ.

Science.gov (United States)

Gao, Die; Zhang, Yonglan; Yang, Fengqing; Lin, Yexin; Zhang, Qihui; Xia, Zhining

2016-01-01

Peroxisome proliferator-activated receptors (PPAR)-γ is widely used as an attractive target for the treatment of type 2 diabetes mellitus. Thiazolidinediones, the agonists of PPARγ, has been popularly utilized as insulin sensitizers in the therapy of type 2 diabetes whereas numerous severe side-effects may also occur concomitantly. The PPARγ activation activity of different polar extracts, including petroleum ether, ethyl acetate, n-butanol, residual of ethanol, the precipitate part of water and the supernatant of water extracts, from 37 traditional Chinese medicines were systematically evaluated. HeLa cells were transiently co-transfected with the re-constructed plasmids of GAL4-PPARγ-ligand binding domain and pGL4.35. The activation of PPARγ by different polarity extracts were evaluated based on the PPARγ transactivation assay and rosiglitazone was used as positive control. Seven medicines (root bark of Lycium barbarum, Anoectochilus sroxburghii, the rhizome of Phragmites australis, Pterocephalus hookeri, Polygonatum sibiricum, fruit of Gleditsia sinensis, and Epimedium brevicornu) were able to significantly activate PPARγ. As seven medicines were able to activate PPARγ, the anti-diabetic activity of them is likely to be mediated by this nuclear receptor. Lots of the tested medicinal products had activation effects on activating PPARγEthyl acetate extracts of root bark of L.barbarum, rhizome of P.saustralis and fruit of G.siasinensis showed good PPARγ activation effect similar or higher than that of positive control, 0.5 μg/mL rosiglitazonePetroleum ether extracts of A.roxburghii, P. hookeri, P. sibiricum, E.brevicornu also can significantly activate PPARγ, the effects of them were higher than t0.5 μg/mL rosiglitazoneSchisandra chinensis (Turcz.) Baill., the fruit Cornus officinalis Siebold and Zucc., Alisma plantago-aquatica L. and the root of Trichosanthes Kirilowii Maxim., traditional anti-diabetic mediciness in China, had no effects on the

The Role of PPARs in Placental Immunology: A Systematic Review of the Literature

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Stefan Hutter

2013-01-01

Full Text Available Pregnancy is a state of immunotolerance, and pregnancy outcome is strongly linked to the correct activation and balancing of the maternal immune system. Besides abortion as possible result of improper early pregnancy development, other pregnancy associated conditions like preeclampsia (PE, intrauterine growth retardation (IUGR, preterm labour, or gestational diabetes mellitus (GDM are linked to immunologic overactivation and dysregulation. Both the innate and the adaptive immune system, and therefore B and T lymphocytes, natural killer cells (NK, macrophages and dendritic cells (DCs are all involved in trophoblast invasion, pregnancy maintenance, and development of pregnancy disorders. Peroxisome proliferator activated receptors (PPARs are nuclear transcription factors with three known isotypes: PPAR, PPARβ/δ, and PPARγ. They are expressed in most human organs and their function extends from regulating metabolism, homeostasis, and carcinogenesis to immune response. In the recent years, PPARs have been identified in most reproductive tissues and in all lines of immune cells. Only in few cases, the role of PPARs in reproductive immunology has been elucidated though the role of PPARs in immune answer and immunotolerance is evident. Within this paper we would like to give an update on today’s knowledge about PPARs and immune cells in reproduction and highlight interesting interferences in regard of future therapeutic targets.

PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

International Nuclear Information System (INIS)

Rogue, Alexandra; Anthérieu, Sébastien; Vluggens, Aurore; Umbdenstock, Thierry; Claude, Nancy; Moureyre-Spire, Catherine de la; Weaver, Richard J.; Guillouzo, André

2014-01-01

Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Energy Technology Data Exchange (ETDEWEB)

Rogue, Alexandra [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France); Biologie Servier, Gidy (France); Anthérieu, Sébastien; Vluggens, Aurore [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France); Umbdenstock, Thierry [Technologie Servier, Orléans (France); Claude, Nancy [Institut de Recherches Servier, Courbevoie (France); Moureyre-Spire, Catherine de la; Weaver, Richard J. [Biologie Servier, Gidy (France); Guillouzo, André, E-mail: Andre.Guillouzo@univ-rennes1.fr [Inserm UMR 991, 35043 Rennes Cedex (France); Université de Rennes 1, Faculté des Sciences Pharmaceutiques et Biologiques, 35043 Rennes Cedex (France)

2014-04-01

Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. Conclusion: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients. - Highlights: • There is no pharmacological agent approved for the treatment of NAFLD. • This study demonstrates that PPAR agonists can reduce fatty acid-induced steatosis. • Some nuclear receptors appear to be potent actors in the control

Environmental enrichment, age and PPARα interact to regulate proliferation in neurogenic niches

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Margarita ePerez-Martin

2016-03-01

Full Text Available Peroxisome proliferator-activated receptor alpha (PPARα ligands have been shown to modulate recovery after brain insults such as ischemia and irradiation by enhancing neurogenesis. In the present study, we investigated the effect of the genetic deletion of PPARα receptors on the proliferative rate of neural precursor cells (NPC in the adult brain. The study was performed in aged Pparα-/- mice exposed to nutritional (treats and environmental (games enrichments for 20 days. We performed immunohistochemical analyses of cells containing the replicating cell DNA marker 5-bromo-2’-deoxyuridine (BrdU+ and the immature neuronal marker doublecortin (Dcx+ in the main neurogenic zones of the adult brain: subgranular zone of dentate gyrus (SGZ, subventricular zone of lateral ventricles (SVZ and/or hypothalamus. Results indicated a reduction in the number of BrdU+ cells in the neurogenic zones analyzed as well as Dcx+ cells in the SGZ during aging (2, 6, 18 months. Pparα deficiency alleviated the age-related reduction of NPC proliferation (BrdU+ cells in the SVZ of the 18-months-old mice. While no genotype effect on NPC proliferation was detected in the SGZ during aging, an accentuated reduction in the number of Dcx+ cells was observed in the SGZ of the 6-months-old Pparα-/- mice. Exposing the 18-months-old mice to nutritional and environmental enrichments reversed the Pparα-/--induced impairment of NPC proliferation in the neurogenic zones analyzed. The enriched environment did not modify the number of SGZ Dcx+ cells in the 18 months old Pparα-/- mice. These results identify PPARα receptors as a potential target to counteract the naturally observed decline in adult NPC proliferation associated with aging and impoverished environments.

Effects of pioglitazone mediated activation of PPAR-γ on CIDEC and obesity related changes in mice.

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Bilal Haider Shamsi

Full Text Available OBJECTIVE: Obesity is a metabolic disorder that can lead to high blood pressure, increased blood cholesterol and triglycerides, insulin resistance, and diabetes mellitus. The aim was to study the effects of pioglitazone mediated sensitization of peroxisome proliferator-activated receptor gamma (PPAR-γ on the relationship of Cell death-inducing DFFA-like effector C (CIDEC with obesity related changes in mice. METHODS: Sixty C57B/L6 mice weighing 10-12g at 3 weeks of age were randomly divided into 3 groups. Mice in Group 1 were fed on normal diet (ND while Group 2 mice were given high fat diet (HFD, and Group 3 mice were given high fat diet and treated with Pioglitazone (HFD+P. Body weight, length and level of blood sugar were measured weekly. Quantitative real-time PCR, fluorescence microscopy, and ELISA were performed to analyze the expression of CIDEC and PPAR-γ in visceral adipose tissue (VAT and subcutaneous adipose tissue (SAT. RESULTS: Body weight and length of mice increased gradually with time in all groups. Blood sugar in HFD mice started to increase significantly from the mid of late phase of obesity while pioglitazone attenuated blood sugar level in HFD+P mice. The mRNA expressions and protein levels of PPAR-γ and CIDEC genes started to increase in HFD mice as compared to ND mice and decreased gradually during the late phase of obesity in VAT. Pioglitazone enhanced the expression of PPAR-γ and CIDEC genes in HFD+P mice even during the late phase of obesity. CONCLUSION: It is insinuated that VAT is associated with late phase obesity CIDEC decrease and insulin resistance, while pioglitazone enhances CIDEC through activation of PPAR-γ, increases its expression, and decreases lipolysis, hence preventing an increase of blood sugar in mice exposed to HFD.

Peroxisomal proliferator activated receptor-γ deficiency in a Canadian kindred with familial partial lipodystrophy type 3 (FPLD3

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Cao Henian

2006-01-01

Full Text Available Abstract Background Familial partial lipodystrophy (Dunnigan type 3 (FPLD3, Mendelian Inheritance in Man [MIM] 604367 results from heterozygous mutations in PPARG encoding peroxisomal proliferator-activated receptor-γ. Both dominant-negative and haploinsufficiency mechanisms have been suggested for this condition. Methods We present a Canadian FPLD3 kindred with an affected mother who had loss of fat on arms and legs, but no increase in facial, neck, suprascapular or abdominal fat. She had profound insulin resistance, diabetes, severe hypertriglyceridemia and relapsing pancreatitis, while her pre-pubescent daughter had normal fat distribution but elevated plasma triglycerides and C-peptide and depressed high-density lipoprotein cholesterol. Results The mother and daughter were each heterozygous for PPARG nonsense mutation Y355X, whose protein product in vitro was transcriptionally inactive with no dominant-negative activity against the wild-type receptor. In addition the mutant protein appeared to be markedly unstable. Conclusion Taken together with previous studies of human PPARG mutations, these findings suggest that PPAR-γ deficiency due either to haploinsufficiency or to substantial activity loss due to dominant negative interference of the normal allele product's function can each contribute to the FPLD3 phenotype.

PPAR ligands improve impaired metabolic pathways in fetal hearts of diabetic rats.

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Kurtz, Melisa; Capobianco, Evangelina; Martinez, Nora; Roberti, Sabrina Lorena; Arany, Edith; Jawerbaum, Alicia

2014-10-01

In maternal diabetes, the fetal heart can be structurally and functionally affected. Maternal diets enriched in certain unsaturated fatty acids can activate the nuclear receptors peroxisome proliferator-activated receptors (PPARs) and regulate metabolic and anti-inflammatory pathways during development. Our aim was to investigate whether PPARα expression, lipid metabolism, lipoperoxidation, and nitric oxide (NO) production are altered in the fetal hearts of diabetic rats, and to analyze the putative effects of in vivo PPAR activation on these parameters. We found decreased PPARα expression in the hearts of male but not female fetuses of diabetic rats when compared with controls. Fetal treatments with the PPARα ligand leukotriene B4 upregulated the expression of PPARα and target genes involved in fatty acid oxidation in the fetal hearts. Increased concentrations of triglycerides, cholesterol, and phospholipids were found in the hearts of fetuses of diabetic rats. Maternal treatments with diets supplemented with 6% olive oil or 6% safflower oil, enriched in unsaturated fatty acids that can activate PPARs, led to few changes in lipid concentrations, but up-regulated PPARα expression in fetal hearts. NO production, which was increased in the hearts of male and female fetuses in the diabetic group, and lipoperoxidation, which was increased in the hearts of male fetuses in the diabetic group, was reduced by the maternal treatments supplemented with safflower oil. In conclusion, impaired PPARα expression, altered lipid metabolism, and increased oxidative and nitridergic pathways were evidenced in hearts of fetuses of diabetic rats and were regulated in a gender-dependent manner by treatments enriched with PPAR ligands. © 2014 Society for Endocrinology.

Anti-hypertensive and cardioprotective effects of a novel apitherapy formulation via upregulation of peroxisome proliferator-activated receptor-α and -γ in spontaneous hypertensive rats.

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Sun, Yanru; Han, Mingfeng; Shen, Zhenhuang; Huang, Haibo; Miao, Xiaoqing

2018-02-01

Ventricular remodeling is associated with many heart diseases, and ventricular remodeling induced by hypertension can be fatal independent of hypertension. In this study, we prepared a novel apitherapy formulation, designated Bao-Yuan-Ling (BYL), which contained propolis, royal jelly, and bee venom, to treat spontaneous hypertensive rats (SHRs). We then evaluated the pharmacology of BYL and the potential mechanisms through which BYL affects hypertension and ventricular remodeling. We found that BYL treatment could reduce blood pressure in SHRs. Thereafter, we found that BYL treatment reduced serum levels of angiotensin II, endothelin 1, and transforming growth factor-β and improved the myocardial structure. Moreover, the results of quantitative real-time polymerase chain reaction indicated that BYL treatment could upregulate the mRNA expression of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ. Thus, we could conclude that BYL had hypotensive and cardioprotective effects in SHRs, potentially through improvement of myocardial energy metabolism.

Anti-hypertensive and cardioprotective effects of a novel apitherapy formulation via upregulation of peroxisome proliferator-activated receptor-α and -γ in spontaneous hypertensive rats

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Yanru Sun

2018-02-01

Full Text Available Ventricular remodeling is associated with many heart diseases, and ventricular remodeling induced by hypertension can be fatal independent of hypertension. In this study, we prepared a novel apitherapy formulation, designated Bao-Yuan-Ling (BYL, which contained propolis, royal jelly, and bee venom, to treat spontaneous hypertensive rats (SHRs. We then evaluated the pharmacology of BYL and the potential mechanisms through which BYL affects hypertension and ventricular remodeling. We found that BYL treatment could reduce blood pressure in SHRs. Thereafter, we found that BYL treatment reduced serum levels of angiotensin II, endothelin 1, and transforming growth factor-β and improved the myocardial structure. Moreover, the results of quantitative real-time polymerase chain reaction indicated that BYL treatment could upregulate the mRNA expression of peroxisome proliferator-activated receptor (PPAR-α and PPAR-γ. Thus, we could conclude that BYL had hypotensive and cardioprotective effects in SHRs, potentially through improvement of myocardial energy metabolism.

Essential Oil of Pinus koraiensis Exerts Antiobesic and Hypolipidemic Activity via Inhibition of Peroxisome Proliferator-Activated Receptors Gamma Signaling.

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Ko, Hyun-Suk; Lee, Hyo-Jeong; Lee, Hyo-Jung; Sohn, Eun Jung; Yun, Miyong; Lee, Min-Ho; Kim, Sung-Hoon

2013-01-01

Our group previously reported that essential oil of Pinus koraiensis (EOPK) exerts antihyperlipidemic effects via upregulation of low-density lipoprotein receptor and inhibition of acyl-coenzyme A. In the present study, we investigated the antiobesity and hypolipidemic mechanism of EOPK using in vitro 3T3-L1 cells and in vivo HFD-fed rats. EOPK markedly suppressed fat accumulation and intracellular triglyceride associated with downregulation of adipogenic transcription factor expression, including PPAR γ and CEBP α in the differentiated 3T3-L1 adipocytes. Additionally, EOPK attenuated the expression levels of FABP and GPDH as target genes of PPAR γ during adipocyte differentiation. Furthermore, PPAR γ inhibitor GW9662 enhanced the decreased expression of FABP and PPAR γ and fat accumulation induced by EOPK. To confirm the in vitro activity of EOPK, animal study was performed by administering normal diet, HFD, and/or EOPK at the dose of 100 or 200 mg/kg for 6 weeks. Consistently, EOPK significantly suppressed body weight gain, serum triglyceride, total cholesterol, LDL cholesterol, and AI value and increased HDL cholesterol in a dose-dependent manner. Immunohistochemistry revealed that EOPK treatment abrogated the expression of PPAR γ in the liver tissue sections of EOPK-treated rats. Taken together, our findings suggest that EOPK has the antiobesic and hypolipidemic potential via inhibition of PPAR γ -related signaling.

Interactions between TGF-β1, canonical WNT/β-catenin pathway and PPAR γ in radiation-induced fibrosis.

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Vallée, Alexandre; Lecarpentier, Yves; Guillevin, Rémy; Vallée, Jean-Noël

2017-10-27

Radiation therapy induces DNA damage and inflammation leading to fibrosis. Fibrosis can occur 4 to 12 months after radiation therapy. This process worsens with time and years. Radiation-induced fibrosis is characterized by fibroblasts proliferation, myofibroblast differentiation, and synthesis of collagen, proteoglycans and extracellular matrix. Myofibroblasts are non-muscle cells that can contract and relax. Myofibroblasts evolve towards irreversible retraction during fibrosis process. In this review, we discussed the interplays between transforming growth factor-β1 (TGF-β1), canonical WNT/β-catenin pathway and peroxisome proliferator-activated receptor gamma (PPAR γ) in regulating the molecular mechanisms underlying the radiation-induced fibrosis, and the potential role of PPAR γ agonists. Overexpression of TGF-β and canonical WNT/β-catenin pathway stimulate fibroblasts accumulation and myofibroblast differentiation whereas PPAR γ expression decreases due to the opposite interplay of canonical WNT/β-catenin pathway. Both TGF-β1 and canonical WNT/β-catenin pathway stimulate each other through the Smad pathway and non-Smad pathways such as phosphatidylinositol 3-kinase/serine/threonine kinase (PI3K/Akt) signaling. WNT/β-catenin pathway and PPAR γ interact in an opposite manner. PPAR γ agonists decrease β-catenin levels through activation of inhibitors of the WNT pathway such as Smad7, glycogen synthase kinase-3 (GSK-3 β) and dickkopf-related protein 1 (DKK1). PPAR γ agonists also stimulate phosphatase and tensin homolog (PTEN) expression, which decreases both TGF-β1 and PI3K/Akt pathways. PPAR γ agonists by activating Smad7 decrease Smads pathway and then TGF-β signaling leading to decrease radiation-induced fibrosis. TGF-β1 and canonical WNT/β-catenin pathway promote radiation-induced fibrosis whereas PPAR γ agonists can prevent radiation-induced fibrosis.

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor suppressor in hepatocellular carcinoma.

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Liu, Rui; Zhang, Haiyang; Zhang, Yan; Li, Shuang; Wang, Xinyi; Wang, Xia; Wang, Cheng; Liu, Bin; Zen, Ke; Zhang, Chen-Yu; Zhang, Chunni; Ba, Yi

2017-04-01

Peroxisome proliferator-activated receptor gamma coactivator-1 alpha plays a crucial role in regulating the biosynthesis of mitochondria, which is closely linked to the energy metabolism in various tumors. This study investigated the regulatory role of peroxisome proliferator-activated receptor gamma coactivator-1 alpha in the pathogenesis of hepatocellular carcinoma. In this study, the changes of peroxisome proliferator-activated receptor gamma coactivator-1 alpha messenger RNA levels between normal human liver and hepatocellular carcinoma tissue were examined by quantitative reverse transcription polymerase chain reaction. Knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by RNA interference in the human liver cell line L02, while overexpression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha was conducted by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha complementary DNA in the human hepatocarcinoma cell line HepG2. Cellular morphological changes were observed via optical and electron microscopy. Cellular apoptosis was determined by Hoechst 33258 staining. In addition, the expression levels of 21,400 genes in tissues and cells were detected by microarray. It was shown that peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression was significantly downregulated in hepatocellular carcinoma compared with normal liver tissues. After knockdown of peroxisome proliferator-activated receptor gamma coactivator-1 alpha expression in L02 cells, cells reverted to immature and dedifferentiated morphology exhibiting cancerous tendency. Apoptosis occurred in the HepG2 cells after transfection by adenovirus encoding peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Microarray analysis showed consistent results. The results suggest that peroxisome proliferator-activated receptor gamma coactivator-1 alpha acts as a tumor

Activation of PPARs α, β/δ, and γ Impairs TGF-β1-Induced Collagens' Production and Modulates the TIMP-1/MMPs Balance in Three-Dimensional Cultured Chondrocytes

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Paul-Emile Poleni

2010-01-01

Full Text Available Background and Purpose. We investigated the potency of Peroxisome Proliferators-Activated Receptors (PPARs α, β/δ, and γ agonists to modulate Transforming Growth Factor-β1 (TGF-β1- induced collagen production or changes in Tissue Inhibitor of Matrix Metalloproteinase- (TIMP- 1/Matrix Metalloproteinase (MMP balance in rat chondrocytes embedded in alginate beads. Experimental Approach. Collagen production was evaluated by quantitative Sirius red staining, while TIMP-1 protein levels and global MMP (-1, -2, -3, -7, and -9 or specific MMP-13 activities were measured by ELISA and fluorigenic assays in culture media, respectively. Levels of mRNA for type II collagen, TIMP-1, and MMP-3 & 13 were quantified by real-time PCR. Key Results. TGF-β1 increased collagen deposition and type II collagen mRNA levels, while inducing TIMP-1 mRNA and protein expression. In contrast, it decreased global MMP or specific MMP-13 activities, while decreasing MMP-3 or MMP-13 mRNA levels. PPAR agonists reduced most of the effects of TGF-β1 on changes in collagen metabolism and TIMP-1/MMP balance in rat in a PPAR-dependent manner, excepted for Wy14643 on MMP activities. Conclusions and Implications. PPAR agonists reduce TGF-β1-modulated ECM turnover and inhibit chondrocyte activities crucial for collagen biosynthesis, and display a different inhibitory profile depending on selectivity for PPAR isotypes.

Induction of mitochondrial biogenesis and respiration is associated with mTOR regulation in hepatocytes of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA)

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Hagland, Hanne R.; Nilsson, Linn I.H. [Department of Biomedicine, University of Bergen (Norway); Burri, Lena [Institute of Medicine, University of Bergen, Haukeland University Hospital (Norway); Nikolaisen, Julie [Department of Biomedicine, University of Bergen (Norway); Berge, Rolf K. [Institute of Medicine, University of Bergen, Haukeland University Hospital (Norway); Department of Heart Disease, Haukeland University Hospital (Norway); Tronstad, Karl J., E-mail: karl.tronstad@biomed.uib.no [Department of Biomedicine, University of Bergen (Norway)

2013-01-11

Highlights: Black-Right-Pointing-Pointer We investigated mechanisms of mitochondrial regulation in rat hepatocytes. Black-Right-Pointing-Pointer Tetradecylthioacetic acid (TTA) was employed to activate mitochondrial oxidation. Black-Right-Pointing-Pointer Mitochondrial biogenesis and respiration were induced. Black-Right-Pointing-Pointer It was confirmed that PPAR target genes were induced. Black-Right-Pointing-Pointer The mechanism involved activation mTOR. -- Abstract: The hypolipidemic effect of peroxisome proliferator-activated receptor (PPAR) activators has been explained by increasing mitochondrial fatty acid oxidation, as observed in livers of rats treated with the pan-PPAR activator tetradecylthioacetic acid (TTA). PPAR-activation does, however, not fully explain the metabolic adaptations observed in hepatocytes after treatment with TTA. We therefore characterized the mitochondrial effects, and linked this to signalling by the metabolic sensor, the mammalian target of rapamycin (mTOR). In hepatocytes isolated from TTA-treated rats, the changes in cellular content and morphology were consistent with hypertrophy. This was associated with induction of multiple mitochondrial biomarkers, including mitochondrial DNA, citrate synthase and mRNAs of mitochondrial proteins. Transcription analysis further confirmed activation of PPAR{alpha}-associated genes, in addition to genes related to mitochondrial biogenesis and function. Analysis of mitochondrial respiration revealed that the capacity of both electron transport and oxidative phosphorylation were increased. These effects coincided with activation of the stress related factor, ERK1/2, and mTOR. The protein level and phosphorylation of the downstream mTOR actors eIF4G and 4E-BP1 were induced. In summary, TTA increases mitochondrial respiration by inducing hypertrophy and mitochondrial biogenesis in rat hepatocytes, via adaptive regulation of PPARs as well as mTOR.

24-Methylenecycloartanyl ferulate, a major compound of γ-oryzanol, promotes parvin-beta expression through an interaction with peroxisome proliferator-activated receptor-gamma 2 in human breast cancer cells

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Kim, Heon Woong; Lim, Eun Joung; Jang, Hwan Hee; Cui, XueLei; Kang, Da Rae; Lee, Sung Hyen; Kim, Haeng Ran; Choe, Jeong Sook; Yang, Young Mok; Kim, Jung Bong; Park, Jong Hwan

2015-01-01

Parvin-β is an adaptor protein that binds to integrin-linked kinase (ILK) and is significantly downregulated in breast tumors and breast cancer cell lines. We treated the breast cancer cell line MCF7 with 24-methylenecycloartanyl ferulate (24-MCF), a γ-oryzanol compound. We observed upregulation of parvin-β (GenBank Accession No. (AF237769)) and peroxisome proliferator-activated receptor (PPAR)-γ2 (GenBank Accession No. (NM-015869)). Among γ-oryzanol compounds, only treatment with 24-MCF led to the formation of reverse transcription-PCR products of parvin-β (650 and 500 bp) and PPAR-γ2 (580 bp) in MCF7 cells, but not in T47D, SK-BR-3, or MDA-MB-231 cells. 24-MCF treatment increased the mRNA and protein levels of parvin-β in MCF7 cells in a dose-dependent manner. We hypothesized that there is a correlation between parvin-β expression and induction of PPAR-γ2. This hypothesis was investigated by using a promoter-reporter assay, chromatin immunoprecipitation, and an electrophoretic mobility shift assay. 24-MCF treatment induced binding of PPAR-γ2 to a peroxisome proliferator response element-like cis-element (ACTAGGACAAAGGACA) in the parvin-β promoter in MCF7 cells in a dose-dependent manner. 24-MCF treatment significantly decreased anchorage-independent growth and inhibited cell movement in comparison to control treatment with dimethyl sulfoxide. 24-MCF treatment reduced the levels of GTP-bound Rac1 and Cdc42. Evaluation of Akt1 inhibition by 24-MCF revealed that the half maximal effective concentration was 33.3 μM. Docking evaluations revealed that 24-MCF binds to the ATP-binding site of Akt1(PDB ID: (3OCB)) and the compound binding energy is -8.870 kcal/mol. Taken together, our results indicate that 24-MCF treatment increases parvin-β expression, which may inhibit ILK downstream signaling. - Highlights: • Treatment with 24-MCF increases gene expression of parvin-β and PPAR-ϒ2 in MCF7 cells. • PPAR-ϒ2 interacts with the parvin-β gene via

24-Methylenecycloartanyl ferulate, a major compound of γ-oryzanol, promotes parvin-beta expression through an interaction with peroxisome proliferator-activated receptor-gamma 2 in human breast cancer cells

Energy Technology Data Exchange (ETDEWEB)

Kim, Heon Woong; Lim, Eun Joung; Jang, Hwan Hee [Department of Agro-Food Resources, National Academy of Agricultural Science, Rural Department Administration, Wanju-gun, Jeollabuk-do 565-851 (Korea, Republic of); Cui, XueLei [Research Institute of Medical Science, KonKuk University, School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701 (Korea, Republic of); Kang, Da Rae [Department of Infection & Immunology, School of Medicine, KonKuk University 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701 (Korea, Republic of); Lee, Sung Hyen; Kim, Haeng Ran; Choe, Jeong Sook [Department of Agro-Food Resources, National Academy of Agricultural Science, Rural Department Administration, Wanju-gun, Jeollabuk-do 565-851 (Korea, Republic of); Yang, Young Mok [Department of Pathology, School of Medicine and Institute of Biomedical Science and Technology, Konkuk University, Seoul 143-701 (Korea, Republic of); Kim, Jung Bong, E-mail: jungbkim@korea.kr [Department of Agro-Food Resources, National Academy of Agricultural Science, Rural Department Administration, Wanju-gun, Jeollabuk-do 565-851 (Korea, Republic of); Park, Jong Hwan, E-mail: nihpark@yahoo.com [Research Institute of Medical Science, KonKuk University, School of Medicine, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701 (Korea, Republic of)

2015-12-25

Parvin-β is an adaptor protein that binds to integrin-linked kinase (ILK) and is significantly downregulated in breast tumors and breast cancer cell lines. We treated the breast cancer cell line MCF7 with 24-methylenecycloartanyl ferulate (24-MCF), a γ-oryzanol compound. We observed upregulation of parvin-β (GenBank Accession No. (AF237769)) and peroxisome proliferator-activated receptor (PPAR)-γ2 (GenBank Accession No. (NM-015869)). Among γ-oryzanol compounds, only treatment with 24-MCF led to the formation of reverse transcription-PCR products of parvin-β (650 and 500 bp) and PPAR-γ2 (580 bp) in MCF7 cells, but not in T47D, SK-BR-3, or MDA-MB-231 cells. 24-MCF treatment increased the mRNA and protein levels of parvin-β in MCF7 cells in a dose-dependent manner. We hypothesized that there is a correlation between parvin-β expression and induction of PPAR-γ2. This hypothesis was investigated by using a promoter-reporter assay, chromatin immunoprecipitation, and an electrophoretic mobility shift assay. 24-MCF treatment induced binding of PPAR-γ2 to a peroxisome proliferator response element-like cis-element (ACTAGGACAAAGGACA) in the parvin-β promoter in MCF7 cells in a dose-dependent manner. 24-MCF treatment significantly decreased anchorage-independent growth and inhibited cell movement in comparison to control treatment with dimethyl sulfoxide. 24-MCF treatment reduced the levels of GTP-bound Rac1 and Cdc42. Evaluation of Akt1 inhibition by 24-MCF revealed that the half maximal effective concentration was 33.3 μM. Docking evaluations revealed that 24-MCF binds to the ATP-binding site of Akt1(PDB ID: (3OCB)) and the compound binding energy is -8.870 kcal/mol. Taken together, our results indicate that 24-MCF treatment increases parvin-β expression, which may inhibit ILK downstream signaling. - Highlights: • Treatment with 24-MCF increases gene expression of parvin-β and PPAR-ϒ2 in MCF7 cells. • PPAR-ϒ2 interacts with the parvin-β gene via

Atherogenic ω-6 Lipids Modulate PPAR- EGR-1 Crosstalk in Vascular Cells

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Jia Fei

2011-01-01

Full Text Available Atherogenic ω-6 lipids are physiological ligands of peroxisome proliferator-activated receptors (PPARs and elicit pro- and antiatherogenic responses in vascular cells. The objective of this study was to investigate if ω-6 lipids modulated the early growth response-1 (Egr-1/PPAR crosstalk thereby altering vascular function. Rat aortic smooth muscle cells (RASMCs were exposed to ω-6 lipids, linoleic acid (LA, or its oxidized form, 13-HPODE (OxLA in the presence or absence of a PPARα antagonist (MK886 or PPARγ antagonist (GW9662 or PPAR-specific siRNA. Our results demonstrate that ω-6 lipids, induced Egr-1 and monocyte chemotactic protein-1 (MCP-1 mRNA and protein levels at the acute phase (1–4 hrs when PPARα was downregulated and at subacute phase (4–12 hrs by modulating PPARγ, thus resulting in altered monocyte adhesion to RASMCs. We provide novel insights into the mechanism of action of ω-6 lipids on Egr-1/PPAR interactions in vascular cells and their potential in altering vascular function.

Ω-3 fatty acids prevent hepatic steatosis, independent of PPAR-α activity, in a murine model of parenteral nutrition-associated liver disease.

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Prince, Esther; Lazare, Farrah B; Treem, William R; Xu, Jiliu; Iqbal, Jahangir; Pan, Xiaoyue; Josekutty, Joby; Walsh, Meghan; Anderson, Virginia; Hussain, M Mahmood; Schwarz, Steven M

2014-07-01

ω-3 Fatty acids (FAs), natural ligands for the peroxisome proliferator-activated receptor-α (PPAR-α), attenuate parenteral nutrition-associated liver disease (PNALD). However, the mechanisms underlying the protective role of ω-3 FAs are still unknown. The aim of this study was to determine the effects of ω-3 FAs on hepatic triglyceride (TG) accumulation in a murine model of PNALD and to investigate the role of PPAR-α and microsomal triglyceride transfer protein (MTP) in this experimental setting. 129S1/SvImJ wild-type or 129S4/SvJaePparatm/Gonz/J PPAR-α knockout mice were fed chow and water (controls); oral, fat-free PN solution only (PN-O); PN-O plus intraperitoneal (IP) ω-6 FA-predominant supplements (PN-ω-6); or PN-O plus IP ω-3 FA (PN-ω-3). Control and PN-O groups received sham IP injections of 0.9% NaCl. Hepatic histology, TG and cholesterol, MTP activity, and PPAR-α messenger RNA were assessed after 19 days. In all experimental groups, PN feeding increased hepatic TG and MTP activity compared with controls. Both PN-O and PN-ω-6 groups accumulated significantly greater amounts of TG when compared with PN-ω-3 mice. Studies in PPAR-α null animals showed that PN feeding increases hepatic TG as in wild-type mice. PPAR-α null mice in the PN-O and PN-ω-6 groups demonstrated variable degrees of hepatic steatosis, whereas no evidence of hepatic fat accumulation was found after 19 days of oral PN plus IP ω-3 FAs. PN induces TG accumulation (steatosis) in wild-type and PPAR-α null mice. In PN-fed wild-type and PPAR-α null mice given IP ω-3 FAs, reduced hepatic TG accumulation and absent steatosis are found. Prevention of steatosis by ω-3 FAs results from PPAR-α-independent pathways. © 2013 American Society for Parenteral and Enteral Nutrition.

Cloning of peroxisome proliferators activated receptors in the cobia (Rachycentron canadum) and their expression at different life-cycle stages under cage aquaculture.

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Tsai, Mei-Ling; Chen, Houng-Yung; Tseng, Mei-Cheuh; Chang, Rey-Chang

2008-12-01

We present the cDNA sequences and tissue mRNA expression of peroxisome proliferator-activated receptor (PPAR) alpha, beta and gamma isotypes in the cobia (Rachycentron canadum), a warm water pelagic fish that is becoming a fish of choice for offshore cage farming. RT-PCR and real-time PCR showed that PPARalpha mRNA predominated in red muscle, heart and liver whereas PPARbeta was expressed mainly in liver and pyloric caeca. In contrast, PPARgamma transcripts were detected in all of the tissues examined, with the highest level occurring in visceral fat depot. Our 52-wk time-series investigation showed that while the mRNA expression of PPARgamma in the cobia was positively (P cobia.

The Antifibrosis Effects of Peroxisome Proliferator-Activated Receptor δ on Rat Corneal Wound Healing after Excimer Laser Keratectomy

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Yun Gu

2014-01-01

Full Text Available Corneal stromal fibrosis characterized by myofibroblasts and abnormal extracellular matrix (ECM is usually the result of inappropriate wound healing. The present study tested the hypothesis that the ligand activation of peroxisome proliferator-activated receptor (PPAR δ had antifibrosis effects in a rat model of corneal damage. Adult Sprague-Dawley rats underwent bilateral phototherapeutic keratectomy (PTK. The eyes were randomized into four groups: PBS, GW501516 (a selective agonist of PPARδ, GSK3787 (a selective antagonist of PPARδ, or GW501516 combined with GSK3787. The agents were subconjunctivally administered twice a week until sacrifice. The cellular aspects of corneal wound healing were evaluated with in vivo confocal imaging and postmortem histology. A myofibroblast marker (α-smooth muscle actin and ECM production (fibronectin, collagen type III and collagen type I were examined by immunohistochemistry and RT-PCR. At the early stages of wound healing, GW501516 inhibited reepithelialization and promoted angiogenesis. During the remodeling phase of wound healing, GW501516 attenuated the activation and proliferation of keratocytes, which could be reversed by GSK3787. GW501516 decreased transdifferentiation from keratocytes into myofibroblasts, ECM synthesis, and corneal haze. These results demonstrate that GW501516 controls corneal fibrosis and suggest that PPARδ may potentially serve as a therapeutic target for treating corneal scars.

Molecular Recognition of PPAR gamma by Kinase Cdk5/p25: Insights from a Combination of Protein-Protein Docking and Adaptive Biasing Force Simulations

NARCIS (Netherlands)

Mottin, Melina; Telles de Souza, Paulo C; Skaf, Munir S

2015-01-01

The peroxisome proliferator-activated receptor gamma (PPAR gamma) is an important transcription factor that plays a major role in the regulation of glucose and lipid metabolisms and has, therefore, many implications in modern-life metabolic disorders such as diabetes, obesity, and cardiovascular

Mode of action of ethyl tertiary-butyl ether hepatotumorigenicity in the rat: Evidence for a role of oxidative stress via activation of CAR, PXR and PPAR signaling pathways

Energy Technology Data Exchange (ETDEWEB)

Kakehashi, Anna, E-mail: anna@med.osaka-cu.ac.jp [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Hagiwara, Akihiro; Imai, Norio [DIMS Institute of Medical Science, Inc., 64 Goura, Nishiazai, Azai-cho, Ichinomiya, Aichi 491-0113 (Japan); Nagano, Kasuke [Nagano Toxicologic-Pathology Consulting, Ochiai, Hadano, Kanagawa 257-0025 (Japan); Nishimaki, Fukumi [Biofuel Assessment Group, New Fuels Dept., Japan Petroleum Energy Center (JPEC), 4-3-9 Toranomon, Minato-ku, Tokyo 105-0001 (Japan); Banton, Marcy [Toxicology and Risk Assessment, LyondellBasell Industries, LyondellBasell Corporate HSE/Product Safety, One Houston Center, Suite 700, 1221 McKinney Street, Houston, TX 770 10 (United States); Wei, Min [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Fukushima, Shoji [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan); Japan Bioassay Research Center, Japan Industrial Safety and Health Association, 2445 Hirasawa, Hadano, Kanagawa 257-0011 (Japan); Wanibuchi, Hideki [Department of Pathology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585 (Japan)

2013-12-01

To elucidate possible mode of action (MOA) and human relevance of hepatotumorigenicity in rats for ethyl tertiary-butyl ether (ETBE), male F344 rats were administered ETBE at doses of 0, 150 and 1000 mg/kg body weight twice a day by gavage for 1 and 2 weeks. For comparison, non-genotoxic carcinogen phenobarbital (PB) was applied at a dose of 500 ppm in diet. Significant increase of P450 total content and hydroxyl radical levels by low, high doses of ETBE and PB treatments at weeks 1 and 2, and 8-OHdG formation at week 2, accompanied accumulation of CYP2B1/2B2, CYP3A1/3A2 and CYP2C6, and downregulation of DNA oxoguanine glycosylase 1, induction of apoptosis and cell cycle arrest in hepatocytes, respectively. Up-regulation of CYP2E1 and CYP1A1 at weeks 1 and 2, and peroxisome proliferation at week 2 were found in high dose ETBE group. Results of proteome analysis predicted activation of upstream regulators of gene expression altered by ETBE including constitutive androstane receptor (CAR), pregnane-X-receptor (PXR) and peroxisome proliferator-activated receptors (PPARs). These results indicate that the MOA of ETBE hepatotumorigenicity in rats may be related to induction of oxidative stress, 8-OHdG formation, subsequent cell cycle arrest, and apoptosis, suggesting regenerative cell proliferation after week 2, predominantly via activation of CAR and PXR nuclear receptors by a mechanism similar to that of PB, and differentially by activation of PPARs. The MOA for ETBE hepatotumorigenicity in rats is unlikely to be relevant to humans. - Highlights: • We focus on MOA and human relevance of hepatotumorigenicity in rats for ETBE. • ETBE was administered to F344 rats for 1 and 2 weeks. • Oxidative stress formation, proliferation and apoptosis in the liver are analyzed. • ETBE-induced changes of gene and protein expression in the liver are examined. • The effects are compared with those induced by non-genotoxic carcinogen PB.

The molecular mechanisms of action of PPAR-γ agonists in the treatment of corneal alkali burns (Review)

Science.gov (United States)

Zhou, Hongyan; Zhang, Wensong; Bi, Miaomiao; Wu, Jie

2016-01-01

Corneal alkali burns (CAB) are characterized by injury-induced inflammation, fibrosis and neovascularization (NV), and may lead to blindness. This review evaluates the current knowledge of the molecular mechanisms responsible for CAB. The processes of cytokine production, chemotaxis, inflammatory responses, immune response, cell signal transduction, matrix metalloproteinase production and vascular factors in CAB are discussed. Previous evidence indicates that peroxisome proliferator-activated receptor γ (PPAR-γ) agonists suppress immune responses, inflammation, corneal fibrosis and NV. This review also discusses the role of PPAR-γ as an anti-inflammatory, anti-fibrotic and anti-angiogenic agent in the treatment of CAB, as well as the potential role of PPAR-γ in the pathological process of CAB. There have been numerous studies evaluating the clinical profiles of CAB, and the aim of this systematic review was to summarize the evidence regarding the treatment of CAB with PPAR-γ agonists. PMID:27499172

Waterborne gemfibrozil challenges the hepatic antioxidant defense system and down-regulates peroxisome proliferator-activated receptor beta (PPARβ) mRNA levels in male goldfish (Carassius auratus)

International Nuclear Information System (INIS)

Mimeault, C.; Trudeau, V.L.; Moon, T.W.

2006-01-01

The lipid regulator gemfibrozil (GEM) is one of many human pharmaceuticals found in the aquatic environment. We previously demonstrated that GEM bioconcentrates in blood and reduces plasma testosterone levels in goldfish (Carassius auratus). In this study, we address the potential of an environmentally relevant waterborne concentration of GEM (1.5 μg/l) to induce oxidative stress in goldfish liver and whether this may be linked to GEM acting as a peroxisome proliferator (PP). We also investigate the autoregulation of the peroxisome proliferator-activated receptors (PPARs) as a potential index of exposure. The three PPAR subtypes (α, β, and γ) were amplified from goldfish liver cDNA. Goldfish exposed to a concentration higher (1500 μg/l) than environmentally relevant for 14 and 28 days significantly reduce hepatic PPARβ mRNA levels (p < 0.001). Levels of CYP1A1 mRNA were unchanged. GEM exposure significantly induced the antioxidant defense enzymes catalase (p < 0.001), glutathione peroxidase (p < 0.001) and glutathione-S-transferase (p = 0.006) but not acyl-CoA oxidase or glutathione reductase. As GEM exposure failed to increase levels of thiobarbituric reactive substances (TBARS), we conclude that a sub-chronic exposure to GEM upregulates the antioxidant defense status of the goldfish as an adaptive response to this human pharmaceutical

Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway

Energy Technology Data Exchange (ETDEWEB)

Xu, Xiaolin [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China); Li, Qian [Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai (China); Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China); Wang, Yiqing [Department of Cardiothoracic Surgery, Huashan Hospital, Fudan University, Shanghai 200032 (China)

2013-11-15

Highlights: •Arctigenin enhanced cholesterol efflux in oxLDL-loaded THP-1 macrophages. •The expression of ABCA1, ABCG1 and apoE was upregulated in arctigenin-treated cells. •Arctigenin promoted the expression of PPAR-γ and LXR-α. •Inhibition of PPAR-γ or LXR-α reversed arctigenin-mediated biological effects. •Arctigenin promotes cholesterol efflux via activation of PPAR-γ/LXR-α/ABCA1 pathway. -- Abstract: Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α.

Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway

International Nuclear Information System (INIS)

Xu, Xiaolin; Li, Qian; Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian; Wang, Yiqing

2013-01-01

Highlights: •Arctigenin enhanced cholesterol efflux in oxLDL-loaded THP-1 macrophages. •The expression of ABCA1, ABCG1 and apoE was upregulated in arctigenin-treated cells. •Arctigenin promoted the expression of PPAR-γ and LXR-α. •Inhibition of PPAR-γ or LXR-α reversed arctigenin-mediated biological effects. •Arctigenin promotes cholesterol efflux via activation of PPAR-γ/LXR-α/ABCA1 pathway. -- Abstract: Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α

EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

International Nuclear Information System (INIS)

Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline; Sun, Jianmin; Jögi, Annika; Neumann, Drorit; Rönnstrand, Lars; Påhlman, Sven

2014-01-01

Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα + ) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells

EPO-independent functional EPO receptor in breast cancer enhances estrogen receptor activity and promotes cell proliferation

Energy Technology Data Exchange (ETDEWEB)

Reinbothe, Susann; Larsson, Anna-Maria; Vaapil, Marica; Wigerup, Caroline [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Sun, Jianmin [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Jögi, Annika [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Neumann, Drorit [Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel); Rönnstrand, Lars [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); Påhlman, Sven, E-mail: sven.pahlman@med.lu.se [Department of Laboratory Medicine, Translational Cancer Research, Medicon Village, Lund University, SE-223 81 Lund (Sweden); CREATE Health, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv (Israel)

2014-02-28

Highlights: • New anti-human EPOR antibody confirms full-length EPOR expression in breast cancer cells. • Proliferation of breast cancer cells is not affected by rhEPO treatment in vitro. • EPOR knockdown impairs proliferation of ERa positive breast cancer cells. • EPOR knockdown reduces AKT phosphorylation and ERa activity. - Abstract: The main function of Erythropoietin (EPO) and its receptor (EPOR) is the stimulation of erythropoiesis. Recombinant human EPO (rhEPO) is therefore used to treat anemia in cancer patients. However, clinical trials have indicated that rhEPO treatment might promote tumor progression and has a negative effect on patient survival. In addition, EPOR expression has been detected in several cancer forms. Using a newly produced anti-EPOR antibody that reliably detects the full-length isoform of the EPOR we show that breast cancer tissue and cells express the EPOR protein. rhEPO stimulation of cultured EPOR expressing breast cancer cells did not result in increased proliferation, overt activation of EPOR (receptor phosphorylation) or a consistent activation of canonical EPOR signaling pathway mediators such as JAK2, STAT3, STAT5, or AKT. However, EPOR knockdown experiments suggested functional EPO receptors in estrogen receptor positive (ERα{sup +}) breast cancer cells, as reduced EPOR expression resulted in decreased proliferation. This effect on proliferation was not seen in ERα negative cells. EPOR knockdown decreased ERα activity further supports a mechanism by which EPOR affects proliferation via ERα-mediated mechanisms. We show that EPOR protein is expressed in breast cancer cells, where it appears to promote proliferation by an EPO-independent mechanism in ERα expressing breast cancer cells.

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; Oude Elferink, Ronald P. J.; Kuipers, Folkert; Groen, Albert K.

2009-01-01

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

Cucurbitane Triterpenoid from Momordica charantia Induces Apoptosis and Autophagy in Breast Cancer Cells, in Part, through Peroxisome Proliferator-Activated Receptor γ Activation

Directory of Open Access Journals (Sweden)

Jing-Ru Weng

2013-01-01

Full Text Available Although the antitumor activity of the crude extract of wild bitter gourd (Momordica charantia L. has been reported, its bioactive constituents and the underlying mechanism remain undefined. Here, we report that 3β,7β-dihydroxy-25-methoxycucurbita-5,23-diene-19-al (DMC, a cucurbitane-type triterpene isolated from wild bitter gourd, induced apoptotic death in breast cancer cells through peroxisome proliferator-activated receptor (PPAR γ activation. Luciferase reporter assays indicated the ability of DMC to activate PPARγ, and pharmacological inhibition of PPARγ protected cells from DMC's antiproliferative effect. Western blot analysis indicated that DMC suppressed the expression of many PPARγ-targeted signaling effectors, including cyclin D1, CDK6, Bcl-2, XIAP, cyclooxygenase-2, NF-κB, and estrogen receptor α, and induced endoplasmic reticulum stress, as manifested by the induction of GADD153 and GRP78 expression. Moreover, DMC inhibited mTOR-p70S6K signaling through Akt downregulation and AMPK activation. The ability of DMC to activate AMPK in liver kinase (LK B1-deficient MDA-MB-231 cells suggests that this activation was independent of LKB1-regulated cellular metabolic status. However, DMC induced a cytoprotective autophagy presumably through mTOR inhibition, which could be overcome by the cotreatment with the autophagy inhibitor chloroquine. Together, the ability of DMC to modulate multiple PPARγ-targeted signaling pathways provides a mechanistic basis to account for the antitumor activity of wild bitter gourd.

Maraviroc attenuates trauma-hemorrhage-induced hepatic injury through PPAR gamma-dependent pathway in rats.

Directory of Open Access Journals (Sweden)

Fu-Chao Liu

Full Text Available Maraviroc is a CC-chemokine receptor 5 (CCR5 antagonist with potent antiviral and cancer preventive effects. Recent evidence suggests that the co-existence of CCR5 in various cell types is involved in inflammation. However, the effects that CCR5 antagonists produce in trauma-hemorrhage remain unknown. The peroxisome proliferator-activated receptor gamma (PPAR(γ pathway exerts anti-inflammatory effects in injury. In this study, we hypothesized that maraviroc administration in male rats, after trauma-hemorrhage, decreases cytokine production and protects against hepatic injury through a PPAR(γ-dependent pathway. Male Sprague-Dawley rats underwent trauma-hemorrhage (mean blood pressure maintained at approximately 35-40 mmHg for 90 minutes, followed by fluid resuscitation. During resuscitation, a single dose of maraviroc (3 mg/kg, intravenously with and without a PPAR(γ antagonist GW9662 (1 mg/kg, intravenously, GW9662 or vehicle was administered. Plasma alanine aminotransferase (ALT with aspartate aminotransferase (AST concentrations and various hepatic parameters were measured (n=8 rats/group at 24 hours after resuscitation. The results showed that trauma-hemorrhage increased hepatic myeloperoxidase activity, intercellular adhesion molecule-1 and interleukin-6 levels, and plasma ALT and AST concentrations. These parameters were significantly improved in the maraviroc-treated rats subjected to trauma-hemorrhage. Maraviroc treatment also increased hepatic PPAR(γ expression compared with vehicle-treated trauma-hemorrhaged rats. Co-administration of GW9662 with maraviroc abolished the maraviroc-induced beneficial effects on the above parameters and hepatic injury. These results suggest that the protective effect of maraviroc administration on alleviation of hepatic injury after trauma-hemorrhage, which is, at least in part, through PPAR(γ-dependent pathway.

Ligands for the peroxisome proliferator-activated receptor-γ have inhibitory effects on growth of human neuroblastoma cells in vitro

International Nuclear Information System (INIS)

Valentiner, Ursula; Carlsson, Margarita; Erttmann, Rudolf; Hildebrandt, Herbert; Schumacher, Udo

2005-01-01

The thiazolidinedione (TZD) or glitazone class of peroxisome proliferator-activated-γ (PPAR-γ) ligands not only induce adipocyte differentiation and increase insulin sensitivity, but also exert growth inhibitory effects on several carcinoma cell lines in vitro as well as in vivo. In the current study the in vitro effect of four PPAR-γ agonists (ciglitazone, pioglitazone, troglitazone, rosiglitazone) on the cell growth of seven human neuroblastoma cell lines (Kelly, LAN-1, LAN-5, LS, IMR-32, SK-N-SH, SH-SY5Y) was investigated. Growth rates were assessed by a colorimetric XTT-based assay kit. Expression of PPAR-γ protein was examined by immunohistochemistry and Western blot analysis. All glitazones inhibited in vitro growth and viability of the human neuroblastoma cell lines in a dose-dependent manner showing considerable effects only at high concentrations (10 μM and 100 μM). Effectiveness of the glitazones on neuroblastoma cell growth differed depending on the cell line and the agent. The presence of PPAR-γ protein was demonstrated in all cell lines. Our findings indicate that ligands for PPAR-γ may be useful therapeutic agents for the treatment of neuroblastoma. Thus the effect of glitazones on the growth of neuroblastoma should now be investigated in an in vivo animal model

Peroxisome Proliferator-Activated Receptor Ligands and Their Role in Chronic Myeloid Leukemia: Therapeutic Strategies.

Science.gov (United States)

Yousefi, Bahman; Samadi, Nasser; Baradaran, Behzad; Shafiei-Irannejad, Vahid; Zarghami, Nosratollah

2016-07-01

Imatinib therapy remains the gold standard for treatment of chronic myeloid leukemia; however, the acquired resistance to this therapeutic agent in patients has urged the scientists to devise modalities for overcoming this chemoresistance. For this purpose, initially therapeutic agents with higher tyrosine kinase activity were introduced, which had the potential for inhibiting even mutant forms of Bcr-Abl. Furthermore, coupling imatinib with peroxisome proliferator-activated receptor ligands also showed beneficial effects in chronic myeloid leukemia cell proliferation. These combination protocols inhibited cell growth and induced apoptosis as well as differentiation in chronic myeloid leukemia cell lines. In addition, peroxisome proliferator-activated receptors ligands increased imatinib uptake by upregulating the expression of human organic cation transporter 1. Taken together, peroxisome proliferator-activated receptors ligands are currently being considered as novel promising therapeutic candidates for chronic myeloid leukemia treatment, because they can synergistically enhance the efficacy of imatinib. In this article, we reviewed the potential of peroxisome proliferator-activated receptors ligands for use in chronic myeloid leukemia treatment. The mechanism of action of these therapeutics modalities are also presented in detail. © 2016 John Wiley & Sons A/S.

Endogenous fatty acid ethanolamides suppress nicotine-induced activation of mesolimbic dopamine neurons through nuclear receptors.

Science.gov (United States)

Melis, Miriam; Pillolla, Giuliano; Luchicchi, Antonio; Muntoni, Anna Lisa; Yasar, Sevil; Goldberg, Steven R; Pistis, Marco

2008-12-17

Nicotine stimulates the activity of mesolimbic dopamine neurons, which is believed to mediate the rewarding and addictive properties of tobacco use. Accumulating evidence suggests that the endocannabinoid system might play a major role in neuronal mechanisms underlying the rewarding properties of drugs of abuse, including nicotine. Here, we investigated the modulation of nicotine effects by the endocannabinoid system on dopamine neurons in the ventral tegmental area with electrophysiological techniques in vivo and in vitro. We discovered that pharmacological inhibition of fatty acid amide hydrolase (FAAH), the enzyme that catabolizes fatty acid ethanolamides, among which the endocannabinoid anandamide (AEA) is the best known, suppressed nicotine-induced excitation of dopamine cells. Importantly, this effect was mimicked by the administration of the FAAH substrates oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), but not methanandamide, the hydrolysis resistant analog of AEA. OEA and PEA are naturally occurring lipid signaling molecules structurally related to AEA, but devoid of affinity for cannabinoid receptors. They blocked the effects of nicotine by activation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), a nuclear receptor transcription factor involved in several aspects of lipid metabolism and energy balance. Activation of PPAR-alpha triggered a nongenomic stimulation of tyrosine kinases, which might lead to phosphorylation and negative regulation of neuronal nicotinic acetylcholine receptors. These data indicate for the first time that the anorexic lipids OEA and PEA possess neuromodulatory properties as endogenous ligands of PPAR-alpha in the brain and provide a potential new target for the treatment of nicotine addiction.

PPARs Expression in Adult Mouse Neural Stem Cells: Modulation of PPARs during Astroglial Differentiaton of NSC

Directory of Open Access Journals (Sweden)

A. Cimini

2007-01-01

Full Text Available PPAR isotypes are involved in the regulation of cell proliferation, death, and differentiation, with different roles and mechanisms depending on the specific isotype and ligand and on the differentiated, undifferentiated, or transformed status of the cell. Differentiation stimuli are integrated by key transcription factors which regulate specific sets of specialized genes to allow proliferative cells to exit the cell cycle and acquire specialized functions. The main differentiation programs known to be controlled by PPARs both during development and in the adult are placental differentiation, adipogenesis, osteoblast differentiation, skin differentiation, and gut differentiation. PPARs may also be involved in the differentiation of macrophages, brain, and breast. However, their functions in this cell type and organs still awaits further elucidation. PPARs may be involved in cell proliferation and differentiation processes of neural stem cells (NSC. To this aim, in this work the expression of the three PPAR isotypes and RXRs in NSC has been investigated.

Inverse Relationship between 15-Lipoxygenase-2 and PPAR-γ Gene Expression in Normal Epithelia Compared with Tumor Epithelia

Directory of Open Access Journals (Sweden)

Vemparala Subbarayan

2005-03-01

Full Text Available 15-Lipoxygenase-2 (15-LOX-2 synthesizes 15-S-hydroxyeicosatetraenoic acid (15-S-HETE, an endogenous ligand for the nuclear receptor, peroxisome proliferator-activated receptor-γ (PPAR-γ. Several studies have described an inverse relationship between 15-LOX-2 and PPAR-γ expression in normal versus tumor samples. To systematically determine if this is a ubiquitous phenomenon, we used a variety of epithelial and nonepithelial cells and some tissues to further evaluate the extent of this inverse relationship. The levels of mRNA or protein were measured by reverse transcriptase polymerase chain reaction or Western gray level intensity, whereas distribution was determined by in situ hybridization or immunofluorescence. 15-S-HETE was measured by liquid chromatography/tandem mass spectrometry. Normal epithelial cells/samples generally expressed high levels of 15-LOX-2 along with the enzyme product 15-S-HETE, but both levels were reduced in cancer cells/samples. In contrast, most cancer cells expressed high levels of PPAR-γ mRNA and protein, which were absent from normal epithelial cells. Overall, the inverse relationship between these two genes was primarily restricted to epithelial samples. Forced expression of PPAR-γ reduced 15-LOX-2 protein levels in normal cells, whereas forced expression of 15-LOX-2 in tumor cells suppressed PPAR-y protein levels. These results suggest that feedback mechanisms may contribute to the loss of 15-LOX-2 pathway components, which coincide with an increase in PPAR-γ in many epithelial cancers.

Peroxisome Proliferator-Activated Receptor γ Regulates the Expression of Lipid Phosphate Phosphohydrolase 1 in Human Vascular Endothelial Cells

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Yazi Huang

2014-01-01

Full Text Available Lipid phosphate phosphohydrolase 1 (LPP1, a membrane ectophosphohydrolase regulating the availability of bioactive lipid phosphates, plays important roles in cellular signaling and physiological processes such as angiogenesis and endothelial migration. However, the regulated expression of LPP1 remains largely unknown. Here, we aimed to examine a role of peroxisome proliferator-activated receptor γ (PPARγ in the transcriptional control of LPP1 gene expression. In human umbilical vein endothelial cells (HUVECs, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR demonstrated that activation of PPARγ increased the mRNA level of LPP1. Chromatin immunoprecipitation assay showed that PPARγ binds to the putative PPAR-responsive elements (PPREs within the 5′-flanking region of the human LPP1 gene. Genomic fragment containing 1.7-kilobase of the promoter region was cloned by using PCR. The luciferase reporter assays demonstrated that overexpression of PPARγ and rosiglitazone, a specific ligand for PPARγ, could significantly upregulate the reporter activity. However, site-directed mutagenesis of the PPRE motif abolished the induction. In conclusion, our results demonstrated that PPARγ transcriptionally activated the expression of LPP1 gene in ECs, suggesting a potential role of PPARγ in the metabolism of phospholipids.

Scaffold-based pan-agonist design for the PPARα, PPARβ and PPARγ receptors.

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Li-Song Zhang

Full Text Available As important members of nuclear receptor superfamily, Peroxisome proliferator-activated receptors (PPAR play essential roles in regulating cellular differentiation, development, metabolism, and tumorigenesis of higher organisms. The PPAR receptors have 3 identified subtypes: PPARα, PPARβ and PPARγ, all of which have been treated as attractive targets for developing drugs to treat type 2 diabetes. Due to the undesirable side-effects, many PPAR agonists including PPARα/γ and PPARβ/γ dual agonists are stopped by US FDA in the clinical trials. An alternative strategy is to design novel pan-agonist that can simultaneously activate PPARα, PPARβ and PPARγ. Under such an idea, in the current study we adopted the core hopping algorithm and glide docking procedure to generate 7 novel compounds based on a typical PPAR pan-agonist LY465608. It was observed by the docking procedures and molecular dynamics simulations that the compounds generated by the core hopping and glide docking not only possessed the similar functions as the original LY465608 compound to activate PPARα, PPARβ and PPARγ receptors, but also had more favorable conformation for binding to the PPAR receptors. The additional absorption, distribution, metabolism and excretion (ADME predictions showed that the 7 compounds (especially Cpd#1 hold high potential to be novel lead compounds for the PPAR pan-agonist. Our findings can provide a new strategy or useful insights for designing the effective pan-agonists against the type 2 diabetes.

Irbesartan increased PPAR{gamma} activity in vivo in white adipose tissue of atherosclerotic mice and improved adipose tissue dysfunction

Energy Technology Data Exchange (ETDEWEB)

Iwai, Masaru; Kanno, Harumi; Senba, Izumi; Nakaoka, Hirotomo; Moritani, Tomozo [Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295 (Japan); Horiuchi, Masatsugu, E-mail: horiuchi@m.ehime-u.ac.jp [Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295 (Japan)

2011-03-04

Research highlights: {yields} Atherosclerotic apolipoprotein E-deficient (ApoEKO) mice were treated with irbesartan. {yields} Irbesartan decreased white adipose tissue weight without affecting body weight. {yields} DNA-binding for PPAR{gamma} was increased in white adipose tissue in vivo by irbesartan. {yields} Irbesartan increased adipocyte number in white adipose tissue. {yields} Irbesatan increased the expression of adiponectin and leptin in white adipose tissue. -- Abstract: The effect of the PPAR{gamma} agonistic action of an AT{sub 1} receptor blocker, irbesartan, on adipose tissue dysfunction was explored using atherosclerotic model mice. Adult male apolipoprotein E-deficient (ApoEKO) mice at 9 weeks of age were treated with a high-cholesterol diet (HCD) with or without irbesartan at a dose of 50 mg/kg/day for 4 weeks. The weight of epididymal and retroperitoneal adipose tissue was decreased by irbesartan without changing food intake or body weight. Treatment with irbesartan increased the expression of PPAR{gamma} in white adipose tissue and the DNA-binding activity of PPAR{gamma} in nuclear extract prepared from adipose tissue. The expression of adiponectin, leptin and insulin receptor was also increased by irbesartan. These results suggest that irbesartan induced activation of PPAR{gamma} and improved adipose tissue dysfunction including insulin resistance.

Epidermis-type lipoxygenase 3 regulates adipocyte differentiation and peroxisome proliferator-activated receptor gamma activity

DEFF Research Database (Denmark)

Hallenborg, Philip; Jørgensen, Claus; Petersen, Rasmus K

2010-01-01

preadipocytes. Here, we show that forced expression of eLOX3 or addition of eLOX3 products stimulated adipogenesis under conditions that normally require an exogenous PPAR gamma ligand for differentiation. Hepoxilins, a group of oxidized arachidonic acid derivatives produced by eLOX3, bound to and activated...... PPAR gamma. Production of hepoxilins was increased transiently during the initial stages of adipogenesis. Furthermore, small interfering RNA-mediated or retroviral short hairpin RNA-mediated knockdown of eLOX3 expression abolished differentiation of 3T3-L1 preadipocytes. Finally, we demonstrate...... differentiation has remained enigmatic. Previously, we showed that lipoxygenase (LOX) activity is involved in activation of PPAR gamma during the early stages of adipocyte differentiation. Of the seven known murine LOXs, only the unconventional LOX epidermis-type lipoxygenase 3 (eLOX3) is expressed in 3T3-L1...

Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease.

Science.gov (United States)

Mohapatra, Saroj K; Guri, Amir J; Climent, Montse; Vives, Cristina; Carbo, Adria; Horne, William T; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-04-20

Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR gamma in IEC on progression of experimental inflammatory bowel disease (IBD). In the first phase, PPAR gamma flfl; Villin Cre- (VC-) and PPAR gamma flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR gamma. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR gamma in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR gamma null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR gamma in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR gamma null mice. Our results demonstrate that adequate expression of PPAR gamma in IEC is required for the regulation of mucosal immune responses and prevention of experimental IBD, possibly by modulation of

Immunoregulatory actions of epithelial cell PPAR gamma at the colonic mucosa of mice with experimental inflammatory bowel disease.

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Saroj K Mohapatra

Full Text Available BACKGROUND: Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR gamma in IEC on progression of experimental inflammatory bowel disease (IBD. METHODOLOGY/PRINCIPAL FINDINGS: In the first phase, PPAR gamma flfl; Villin Cre- (VC- and PPAR gamma flfl; Villin Cre+ (VC+ mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR gamma. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR gamma in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI or weight loss. In contrast, the IEC-specific PPAR gamma null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR gamma in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN of IEC-specific PPAR gamma null mice. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that adequate expression of PPAR gamma in IEC is required for the regulation of mucosal

Immunoregulatory Actions of Epithelial Cell PPAR γ at the Colonic Mucosa of Mice with Experimental Inflammatory Bowel Disease

Science.gov (United States)

Mohapatra, Saroj K.; Guri, Amir J.; Climent, Montse; Vives, Cristina; Carbo, Adria; Horne, William T.; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-01-01

Background Peroxisome proliferator-activated receptors are nuclear receptors highly expressed in intestinal epithelial cells (IEC) and immune cells within the gut mucosa and are implicated in modulating inflammation and immune responses. The objective of this study was to investigate the effect of targeted deletion of PPAR γ in IEC on progression of experimental inflammatory bowel disease (IBD). Methodology/Principal Findings In the first phase, PPAR γ flfl; Villin Cre- (VC-) and PPAR γ flfl; Villin Cre+ (VC+) mice in a mixed FVB/C57BL/6 background were challenged with 2.5% dextran sodium sulfate (DSS) in drinking water for 0, 2, or 7 days. VC+ mice express a transgenic recombinase under the control of the Villin-Cre promoter that causes an IEC-specific deletion of PPAR γ. In the second phase, we generated VC- and VC+ mice in a C57BL/6 background that were challenged with 2.5% DSS. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to phenotypically characterize lymphocyte and macrophage populations in blood, spleen and mesenteric lymph nodes. Global gene expression analysis was profiled using Affymetrix microarrays. The IEC-specific deficiency of PPAR γ in mice with a mixed background worsened colonic inflammatory lesions, but had no effect on disease activity (DAI) or weight loss. In contrast, the IEC-specific PPAR γ null mice in C57BL/6 background exhibited more severe inflammatory lesions, DAI and weight loss in comparison to their littermates expressing PPAR γ in IEC. Global gene expression profiling revealed significantly down-regulated expression of lysosomal pathway genes and flow cytometry results demonstrated suppressed production of IL-10 by CD4+ T cells in mesenteric lymph nodes (MLN) of IEC-specific PPAR γ null mice. Conclusions/Significance Our results demonstrate that adequate expression of PPAR γ in IEC is required for the regulation of mucosal immune responses and prevention of

Ombuin-3-O-β-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/β

Energy Technology Data Exchange (ETDEWEB)

Malek, Mastura Abd; Hoang, Minh-Hien; Jia, Yaoyao; Lee, Ji Hae; Jun, Hee Jin [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Lee, Dong-Ho [Department of Biotechnology, Graduate School of 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); Lee, Chul; Lee, Myung Koo [College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 361-763 (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 [Department of Biotechnology, Graduate School of Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of); Division of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, Seoul 136-713 (Korea, Republic of)

2013-01-25

Highlights: ► Ombuin-3-O-β-D-glucopyranoside is a dual ligand for PPARα and δ/β. ► Ombuin-3-O-β-D-glucopyranoside reduces cellular lipid levels in multiple cell types. ► Cells stimulated with ombuine up-regulated target genes in cholesterol efflux. ► Cells stimulated with ombuine regulated target fatty acid β-oxidation and synthesis. ► Ombuin-3-O-β-D-glucopyranoside could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: We demonstrated that ombuin-3-O-β-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/β. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/β but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/β. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/β with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages.

Ombuin-3-O-β-D-glucopyranoside from Gynostemma pentaphyllum is a dual agonistic ligand of peroxisome proliferator-activated receptors α and δ/β

International Nuclear Information System (INIS)

Malek, Mastura Abd; Hoang, Minh-Hien; Jia, Yaoyao; Lee, Ji Hae; Jun, Hee Jin; Lee, Dong-Ho; Lee, Hak Ju; Lee, Chul; Lee, Myung Koo; Hwang, Bang Yeon; Lee, Sung-Joon

2013-01-01

Highlights: ► Ombuin-3-O-β-D-glucopyranoside is a dual ligand for PPARα and δ/β. ► Ombuin-3-O-β-D-glucopyranoside reduces cellular lipid levels in multiple cell types. ► Cells stimulated with ombuine up-regulated target genes in cholesterol efflux. ► Cells stimulated with ombuine regulated target fatty acid β-oxidation and synthesis. ► Ombuin-3-O-β-D-glucopyranoside could ameliorate hyperlipidemia and hepatic steatosis. -- Abstract: We demonstrated that ombuin-3-O-β-D-glucopyranoside (ombuine), a flavonoid from Gynostemma pentaphyllum, is a dual agonist for peroxisome proliferator-activated receptors (PPARs) α and δ/β. Using surface plasmon resonance (SPR), time-resolved fluorescence resonance energy transfer (FRET) analyses, and reporter gene assays, we showed that ombuine bound directly to PPARα and δ/β but not to PPARγ or liver X receptors (LXRs). Cultured HepG2 hepatocytes stimulated with ombuine significantly reduced intracellular concentrations of triglyceride and cholesterol and downregulated the expression of lipogenic genes, including sterol regulatory element binding protein-1c (SREBP1c) and stearoyl-CoA desaturase-1 (SCD-1), with activation of PPARα and δ/β. Activation of LXRs by ombuine was confirmed by reporter gene assays, however, SPR and cell-based FRET assays showed no direct binding of ombuine to either of the LXRs suggesting LXR activation by ombuine may be operated via PPARα stimulation. Ombuine-stimulated macrophages showed significantly induced transcription of ATP binding cassette cholesterol transporter A1 (ABCA1) and G1 (ABCG1), the key genes in reverse cholesterol transport, which led to reduced cellular cholesterol concentrations. These results suggest that ombuine is a dual PPAR ligand for PPARα and δ/β with the ability to decrease lipid concentrations by reducing lipogenic gene expression in hepatocytes and inducing genes involved in cholesterol efflux in macrophages

Peroxisome Proliferator-Activated Receptor -β/δ, -γ Agonists and Resveratrol Modulate Hypoxia Induced Changes in Nuclear Receptor Activators of Muscle Oxidative Metabolism

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Timothy R. H. Regnault

2010-01-01

Full Text Available PPAR-α, PPAR-β, and PPAR-γ, and RXR in conjunction with PGC-1α and SIRT1, activate oxidative metabolism genes determining insulin sensitivity. In utero, hypoxia is commonly observed in Intrauterine Growth Restriction (IUGR, and reduced insulin sensitivity is often observed in these infants as adults. We sought to investigate how changes in oxygen tension might directly impact muscle PPAR regulation of oxidative genes. Following eight days in culture at 1% oxygen, C2C12 muscle myoblasts displayed a reduction of PGC-1α, PPAR-α, and RXR-α mRNA, as well as CPT-1b and UCP-2 mRNA. SIRT1 and PGC-1α protein was reduced, and PPAR-γ protein increased. The addition of a PPAR-β agonist (L165,041 for the final 24 hours of 1% treatment resulted in increased levels of UCP-2 mRNA and protein whereas Rosiglitazone induced SIRT1, PGC-1α, RXR-α, PPAR-α, CPT-1b, and UCP-2 mRNA and SIRT1 protein. Under hypoxia, Resveratrol induced SIRT1, RXR-α, PPAR-α mRNA, and PPAR-γ and UCP-2 protein. These findings demonstrate that hypoxia alters the components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription and translation. These results have implications for understanding selective hypoxia adaptation and how it might impact long-term muscle oxidative metabolism and insulin sensitivity.

The role of T cell PPAR gamma in mice with experimental inflammatory bowel disease.

Science.gov (United States)

Guri, Amir J; Mohapatra, Saroj K; Horne, William T; Hontecillas, Raquel; Bassaganya-Riera, Josep

2010-06-10

Peroxisome proliferator-activated receptor gamma (PPAR gamma) is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR gamma in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. PPAR gamma flfl; CD4 Cre+ (CD4cre) or Cre- (WT) mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN). Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. The deficiency of PPAR gamma in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+ FoxP3+ regulatory T cells (Treg) and IL10+ CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6) and IL-1beta, and suppressor of cytokine signaling 3 (SOCS-3) on day 7. Gene set enrichment analysis (GSEA) showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR gamma in T cells. The expression of PPAR gamma in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment of Treg to the mucosal inductive

The Role of T cell PPAR γ in mice with experimental inflammatory bowel disease

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Hontecillas Raquel

2010-06-01

Full Text Available Abstract Background Peroxisome proliferator-activated receptor γ (PPAR γ is a nuclear receptor whose activation has been shown to modulate macrophage and T cell-mediated inflammation. The objective of this study was to investigate the mechanisms by which the deletion of PPAR γ in T cells modulates immune cell distribution and colonic gene expression and the severity of experimental IBD. Methods PPAR γ flfl; CD4 Cre+ (CD4cre or Cre- (WT mice were challenged with 2.5% dextran sodium sulfate in their drinking water for 0, 2, or 7 days. Mice were scored on disease severity both clinically and histopathologically. Flow cytometry was used to assess lymphocyte and macrophage populations in the blood, spleen, and mesenteric lymph nodes (MLN. Global gene expression in colonic mucosa was profiled using Affymetrix microarrays. Results The deficiency of PPAR γ in T cells accelerated the onset of disease and body weight loss. Examination of colon histopathology revealed significantly greater epithelial erosion, leukocyte infiltration, and mucosal thickening in the CD4cre mice on day 7. CD4cre mice had more CD8+ T cells than WT mice and fewer CD4+FoxP3+ regulatory T cells (Treg and IL10+CD4+ T cells in blood and MLN, respectively. Transcriptomic profiling revealed around 3000 genes being transcriptionally altered as a result of DSS challenge in CD4cre mice. These included up-regulated mRNA expression of adhesion molecules, proinflammatory cytokines interleukin-6 (IL-6 and IL-1β, and suppressor of cytokine signaling 3 (SOCS-3 on day 7. Gene set enrichment analysis (GSEA showed that the ribosome and Krebs cycle pathways were downregulated while the apoptosis pathway was upregulated in colons of mice lacking PPAR γ in T cells. Conclusions The expression of PPAR γ in T cells is involved in preventing gut inflammation by regulating colonic expression of adhesion molecules and inflammatory mediators at later stages of disease while favoring the recruitment

Effect of folic acid and vitamin B12 on the expression of PPAR?, caspase-3 and caspase-8 mRNA in the abdominal aortas of rats with hyperlipidemia

OpenAIRE

LV, FENG-HUA; GAO, JIAN-ZHI; TENG, QING-LEI; ZHANG, JIN-YING

2013-01-01

Hyperlipidemia may lead to endothelial injury, due to its effects on homocysteine and vascular endothelial growth factor in the serum, and the mRNA expression levels of peroxisome proliferator-activated receptor-? (PPAR?), and caspase-3 and -8 in the vascular wall. In order to prevent and mitigate the high-fat state that results from endothelial injury, this study examined the effect of folic acid (FA) and vitamin B12 (VB12) on the expression of PPAR? and caspase-3 and -8 mRNA in the abdomina...

Peroxisome Proliferator-Activated Receptor Alpha Target Genes

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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.

The Pro12Ala Polymorphism of PPAR-γ Gene Is Associated with Sepsis Disease Severity and Outcome in Chinese Han Population

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Guoda Ma

2014-01-01

Full Text Available Peroxisome proliferator-activated receptor-γ (PPAR-γ is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the inflammatory response. Therefore, PPAR-γ has been suggested as a candidate gene for sepsis. In the present study, we investigated the association between the Pro12Ala polymorphism of PPAR-γ and sepsis in a Han Chinese population. A total of 308 patients with sepsis and 345 healthy controls were enrolled in this study. Genotyping was performed using the polymerase chain reaction-ligation detection reaction (PCR-LDR method. No significant differences were detected in the allele and genotype distributions of the PPAR-γ Pro12Ala SNP between septic patients and controls (P=0.622 for genotype; P=0.629 for allele. However, stratification by subtypes (sepsis, septic shock, and severe sepsis revealed a statistically significant difference in the frequency of the Ala allele and Ala-carrier genotype between the patients with the sepsis subtype and the healthy controls (P=0.014 for allele and P=0.012, for genotype. Moreover, significant differences were found in the frequency of the Ala allele and genotype between the sepsis survivors and nonsurvivors (all P=0.002. In the survivors, the PPAR-γ Pro12Ala genotype was significantly associated with decreased disease severity and recovery time (all P<0.001. Thus, genetic polymorphism is thought to play a role in the development and outcome of sepsis.

In Silico Identification of Potent PPAR-γ Agonists from Traditional Chinese Medicine: A Bioactivity Prediction, Virtual Screening, and Molecular Dynamics Study

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Kuan-Chung Chen

2014-01-01

Full Text Available The peroxisome proliferator-activated receptors (PPARs related to regulation of lipid metabolism, inflammation, cell proliferation, differentiation, and glucose homeostasis by controlling the related ligand-dependent transcription of networks of genes. They are used to be served as therapeutic targets against metabolic disorder, such as obesity, dyslipidemia, and diabetes; especially, PPAR-γ is the most extensively investigated isoform for the treatment of dyslipidemic type 2 diabetes. In this study, we filter compounds of traditional Chinese medicine (TCM using bioactivities predicted by three distinct prediction models before the virtual screening. For the top candidates, the molecular dynamics (MD simulations were also utilized to investigate the stability of interactions between ligand and PPAR-γ protein. The top two TCM candidates, 5-hydroxy-L-tryptophan and abrine, have an indole ring and carboxyl group to form the H-bonds with the key residues of PPAR-γ protein, such as residues Ser289 and Lys367. The secondary amine group of abrine also stabilized an H-bond with residue Ser289. From the figures of root mean square fluctuations (RMSFs, the key residues were stabilized in protein complexes with 5-Hydroxy-L-tryptophan and abrine as control. Hence, we propose 5-hydroxy-L-tryptophan and abrine as potential lead compounds for further study in drug development process with the PPAR-γ protein.

Phytohormone abscisic acid elicits antinociceptive effects in rats through the activation of opioid and peroxisome proliferator-activated receptors β/δ.

Science.gov (United States)

Mollashahi, Mahtab; Abbasnejad, Mehdi; Esmaeili-Mahani, Saeed

2018-08-05

The phytohormone abscisic acid exists in animal tissues particularly in the brain. However, its neurophysiological effects have not yet been fully clarified. This study was designed to evaluate the possible antinociceptive effects of abscisic acid on animal models of pain and determine its possible signaling mechanism. Tail-flick, hot-plate and formalin tests were used to assess the nociceptive threshold. All experiments were carried out on male Wistar rats. To determine the role of Peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and opioid receptors on the induction of abscisic acid antinociception, specific antagonists were injected 15 min before abscisic acid. The data showed that abscisic acid (5, 10 and 15 µg/rat, i.c.v.) significantly decreased pain responses in formalin test. In addition, it could also produce dose-dependent antinociceptive effect in tail-flick and hot-plate tests. Administration of PPARβ/δ antagonist (GSK0660, 80 nM, i.c.v.) significantly attenuated the antinociceptive effect of abscisic acid in all tests. The antinociceptive effects of abscisic acid were completely inhibited by naloxone (6 µg, i.c.v.) during the time course of tail-flick and hot-plate tests. The results indicated that the central injection of abscisic acid has potent pain-relieving property which is mediated partly via the PPAR β/δ and opioid signaling. Copyright © 2018 Elsevier B.V. All rights reserved.

Circadian rhythms, Wnt/beta-catenin pathway and PPAR alpha/gamma profiles in diseases with primary or secondary cardiac dysfunction

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Yves eLecarpentier

2014-11-01

Full Text Available Circadian clock mechanisms are far-from-equilibrium dissipative structures. Peroxisome proliferator-activated receptors (PPAR alpha, beta/delta and gamma play a key role in metabolic regulatory processes, particularly in heart muscle. Links between circadian rhythms (CRs and PPARs have been established. Mammalian CRs involve at least two critical transcription factors, CLOCK and BMAL1 (Gekakis et al., 1998; Hogenesch et al., 1998. PPAR gamma plays a major role in both glucose and lipid metabolisms and presents circadian properties which coordinate the interplay between metabolism and CRs. PPAR gamma is a major component of the vascular clock. Vascular PPAR gamma is a peripheral regulator of cardiovascular rhythms controlling circadian variations in blood pressure and heart rate through BMAL1. We focused our review on diseases with abnormalities of CRs and with primary or secondary cardiac dysfunction. Moreover, these diseases presented changes in the Wnt/beta-catenin pathway and PPARs, according to two opposed profiles. Profile 1 was defined as follows: inactivation of the Wnt/beta-catenin pathway with increased expression of PPAR gamma. Profile 2 was defined as follows: activation of the Wnt/beta-catenin pathway with decreased expression of PPAR gamma. A typical profile 1 disease is arrhythmogenic right ventricular cardiomyopathy, a genetic cardiac disease which presents mutations of the desmosomal proteins and is mainly characterized by fatty acid accumulation in adult cardiomyocytes mainly in the right ventricle. The link between PPAR gamma dysfunction and desmosomal genetic mutations occurs via inactivation of the Wnt/beta-catenin pathway presenting oscillatory properties. A typical profile 2 disease is type 2 diabetes, with activation of the Wnt/beta-catenin pathway and decreased expression of PPAR gamma. CRs abnormalities are present in numerous pathologies such as cardiovascular diseases, sympathetic/parasympathetic dysfunction

Arctigenin promotes cholesterol efflux from THP-1 macrophages through PPAR-γ/LXR-α signaling pathway.

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Xu, Xiaolin; Li, Qian; Pang, Liewen; Huang, Guoqian; Huang, Jiechun; Shi, Meng; Sun, Xiaotian; Wang, Yiqing

2013-11-15

Cholesterol efflux from macrophages is a critical mechanism to prevent the development of atherosclerosis. Here, we sought to investigate the effects of arctigenin, a bioactive component of Arctium lappa, on the cholesterol efflux in oxidized low-density lipoprotein (oxLDL)-loaded THP-1 macrophages. Our data showed that arctigenin significantly accelerated apolipoprotein A-I- and high-density lipoprotein-induced cholesterol efflux in both dose- and time-dependent manners. Moreover, arctigenin treatment enhanced the expression of ATP binding cassette transporter A1 (ABCA1), ABCG1, and apoE, all of which are key molecules in the initial step of cholesterol efflux, at both mRNA and protein levels. Arctigenin also caused a concentration-dependent elevation in the expression of peroxisome proliferator-activated receptor-gamma (PPAR-γ) and liver X receptor-alpha (LXR-α). The arctigenin-mediated induction of ABCA1, ABCG1, and apoE was abolished by specific inhibition of PPAR-γ or LXR-α using small interfering RNA technology. Our results collectively indicate that arctigenin promotes cholesterol efflux in oxLDL-loaded THP-1 macrophages through upregulation of ABCA1, ABCG1 and apoE, which is dependent on the enhanced expression of PPAR-γ and LXR-α. Copyright © 2013 Elsevier Inc. All rights reserved.

High sugar intake and development of skeletal muscle insulin resistance and inflammation in mice: a protective role for PPAR- δ agonism.

Science.gov (United States)

Benetti, Elisa; Mastrocola, Raffaella; Rogazzo, Mara; Chiazza, Fausto; Aragno, Manuela; Fantozzi, Roberto; Collino, Massimo; Minetto, Marco A

2013-01-01

Peroxisome Proliferator Activated Receptor (PPAR)- δ agonists may serve for treating metabolic diseases. However, the effects of PPAR- δ agonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR- δ agonist, GW0742 (1 mg/kg/day for 16 weeks), in male C57Bl6/J mice treated for 30 weeks with high-fructose corn syrup (HFCS), the major sweetener in foods and soft-drinks (15% wt/vol in drinking water). Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR- δ upregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR- δ activation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.

Peroxisome proliferator-activated receptors, estrogenic responses and biotransformation system in the liver of salmon exposed to tributyltin and second messenger activator

International Nuclear Information System (INIS)

Pavlikova, Nela; Kortner, Trond M.; Arukwe, Augustine

2010-01-01

The mechanisms by which organotin compounds produce modulations of the endocrine systems and other biological responses are not fully understood. In this study, juvenile salmon were force-fed diet containing TBT (0: solvent control, 0.1, 1 and 10 mg/kg fish) for 72 h. Subsequently, fish exposed to solvent control and 10 mg TBT were exposed to waterborne concentration (200 μg/l) of the adenylate cyclase (AC) stimulator, forskolin for 2 and 4 h. The overall aim of the study was to explore whether TBT endocrine disruptive effects involve second messenger activation. Liver was sampled from individual fish (n = 8) at the end of the exposures. The transcription patterns of peroxisome proliferator-activated receptor (PPAR) isotype and acyl-coenzyme A oxidase 1 (ACOX1), aromatase isoform, estrogen receptor-α (ERα), pregnane X receptor (PXR), CYP3A and glutathione S-transferase (GST) genes were measured by quantitative polymerase chain reaction (qPCR). Our data showed a consistent increase in PPARα, PPARβ and PPARγ mRNA and protein expression after TBT exposure that were inversely correlated with ACOX1 mRNA levels. Forskolin produced PPAR isotype-specific mRNA and protein effects that were modulated by TBT. ACOX1 expression was decreased (at 2 h) and increased (at 4 h) by forskolin and the presence of TBT potentiated these effects. TBT apparently increased mRNA and protein levels of cyp19a, compared to the solvent control, whereas cyp19b mRNA levels were unaffected by TBT treatment. Combined TBT and forskolin exposure produced respective decrease and increase of mRNA levels of cyp19a and cyp19b, compared with control. TBT decreased ERα mRNA at low dose (1 mg/kg) and forskolin exposure alone produced a consistent decrease of ERα mRNA levels that were not affected by the presence of TBT. Interestingly, PXR and CYP3A mRNA levels were differentially affected, either decreased or increased, after exposure to TBT and forskolin, singly and also in combination. GST mRNA was

Pioglitazone Attenuates Drug-Eluting Stent-Induced Proinflammatory State in Patients by Blocking Ubiquitination of PPAR

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Zhongxia Wang

2016-01-01

Full Text Available The inflammatory response after polymer-based drug-eluting stent (DES placement has recently emerged as a major concern. The biologic roles of peroxisome proliferator-activated receptor-γ (PPAR-γ activators thiazolidinedione (TZD remain controversial in cardiovascular disease. Herein, we investigated the antiinflammatory effects of pioglitazone (PIO on circulating peripheral blood mononuclear cells (MNCs in patients after coronary DES implantation. Methods and Results. Twenty-eight patients with coronary artery disease and who underwent DES implantations were randomly assigned to pioglitazone (30 mg/d; PIO or placebo (control; Con treatment in addition to optimal standard therapy. After 12 weeks of treatment, plasma concentrations of high-sensitivity C-reactive protein (hs-CRP, interleukin-6 (IL-6, tumor necrosis factor-α (TNF-α, and matrix metalloproteinase-9 (MMP-9 were significantly decreased in PIO group compared to the Con group (P=0.035, 0.011, 0.008, and 0.012, resp.. DES-induced mRNA expressions of IL-6, TNF-α, and MMP-9 in circulating MNC were significantly blocked by PIO (P=0.031, 0.012, and 0.007, resp.. In addition, PIO markedly inhibited DES-enhanced NF-κB function and DES-blocked PPAR-γ activity. Mechanically, DES induced PPAR-γ ubiquitination and degradation in protein level, which can be totally reversed by PIO. Conclusion. PIO treatment attenuated DES-induced PPAR loss, NF-κB activation, and proinflammation, indicating that PIO may have a novel direct protective role in modulating proinflammation in DES era.

Hepatic peroxisome proliferator-activated receptor α may have an important role in the toxic effects of di(2-ethylhexyl)phthalate on offspring of mice

International Nuclear Information System (INIS)

Hayashi, Yumi; Ito, Yuki; Yamagishi, Nozomi; Yanagiba, Yukie; Tamada, Hazuki; Wang, Dong; Ramdhan, Doni Hikmat; Naito, Hisao; Harada, Yukiko; Kamijima, Michihiro; Gonzales, Frank J.; Nakajima, Tamie

2011-01-01

Maternal exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with adverse effects on offspring, and the metabolites are agonists of peroxisome proliferator-activated receptor (PPAR) α, which exhibits species differences in expression and function. This study aimed to clarify the mechanism of DEHP-induced adverse effects on offspring in relation to maternal mouse and human PPARα. Male and female Sv/129 wild-type (mPPARα), Pparα-null and humanized PPARα (hPPARα) mice were treated with diets containing 0%, 0.01%, 0.05% (medium) or 0.1% (high) DEHP. After 4 weeks, males and females were mated. Dams were killed on gestational day 18 and postnatal day (PND) 2. High-dose DEHP decreased the number of total and live fetuses, and increased resorptions in mPPARα mice. In hPPARα mice, resorptions were increased above the medium dose, and the number of births was decreased at the high dose. The number of live pups on PND2 was decreased over the medium dose in mPPARα and at the high dose in hPPARα mice. No such findings were observed in Pparα-null mice. High-dose DEHP decreased plasma triglyceride in pregnant mPPARα mice, but not in Pparα-null and hPPARα ones. Above the medium dose in mPPARα mice significantly reduced hepatic microsomal triglyceride transfer protein (MTP) expression. Medium- and/or high-dose DEHP increased the levels of maternal PPARα target genes in mPPARα and hPPARα mice. Taken together, PPARα expression is required for the toxicity of DEHP in fetuses and pups and altered plasma triglyceride levels, through regulation of MTP may be important in mPPARα mice and not in hPPARα mice.

Galangin suppresses HepG2 cell proliferation by activating the TGF-β receptor/Smad pathway

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Wang, Yajun; Wu, Jun; Lin, Biyun; Li, Xv; Zhang, Haitao; Ding, Hang; Chen, Xiaoyi; Lan, Liubo; Luo, Hui

2014-01-01

Galangin can suppress hepatocellular carcinoma (HCC) cell proliferation. In this study, we demonstrated that galangin induced autophagy by activating the transforming growth factor (TGF)-β receptor/Smad pathway and increased TGF-β receptor I (RI), TGF-βRII, Smad1, Smad2, Smad3 and Smad4 levels but decreased Smad6 and Smad7 levels. Autophagy induced by galangin appears to depend on the TGF-β receptor/Smad signalling pathway because the down-regulation of Smad4 by siRNA or inhibition of TGF-β receptor activation by LY2109761 blocked galangin-induced autophagy. The down-regulation of Beclin1, autophagy-related gene (ATG) 16L, ATG12 and ATG3 restored HepG2 cell proliferation and prevented galangin-induced apoptosis. Our findings indicate a novel mechanism for galangin-induced autophagy via activation of the TGF-β receptor/Smad pathway. The induction of autophagy thus reflects the anti-proliferation effect of galangin on HCC cells

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

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Kersten, Sander; Stienstra, Rinke

2017-01-01

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

24-Methylenecycloartanyl ferulate, a major compound of γ-oryzanol, promotes parvin-beta expression through an interaction with peroxisome proliferator-activated receptor-gamma 2 in human breast cancer cells.

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Kim, Heon Woong; Lim, Eun Joung; Jang, Hwan Hee; Cui, XueLei; Kang, Da Rae; Lee, Sung Hyen; Kim, Haeng Ran; Choe, Jeong Sook; Yang, Young Mok; Kim, Jung Bong; Park, Jong Hwan

2015-12-25

Parvin-β is an adaptor protein that binds to integrin-linked kinase (ILK) and is significantly downregulated in breast tumors and breast cancer cell lines. We treated the breast cancer cell line MCF7 with 24-methylenecycloartanyl ferulate (24-MCF), a γ-oryzanol compound. We observed upregulation of parvin-β (GenBank Accession No. AF237769) and peroxisome proliferator-activated receptor (PPAR)-γ2 (GenBank Accession No. NM_015869). Among γ-oryzanol compounds, only treatment with 24-MCF led to the formation of reverse transcription-PCR products of parvin-β (650 and 500 bp) and PPAR-γ2 (580 bp) in MCF7 cells, but not in T47D, SK-BR-3, or MDA-MB-231 cells. 24-MCF treatment increased the mRNA and protein levels of parvin-β in MCF7 cells in a dose-dependent manner. We hypothesized that there is a correlation between parvin-β expression and induction of PPAR-γ2. This hypothesis was investigated by using a promoter-reporter assay, chromatin immunoprecipitation, and an electrophoretic mobility shift assay. 24-MCF treatment induced binding of PPAR-γ2 to a peroxisome proliferator response element-like cis-element (ACTAGGACAAAGGACA) in the parvin-β promoter in MCF7 cells in a dose-dependent manner. 24-MCF treatment significantly decreased anchorage-independent growth and inhibited cell movement in comparison to control treatment with dimethyl sulfoxide. 24-MCF treatment reduced the levels of GTP-bound Rac1 and Cdc42. Evaluation of Akt1 inhibition by 24-MCF revealed that the half maximal effective concentration was 33.3 μM. Docking evaluations revealed that 24-MCF binds to the ATP-binding site of Akt1(PDB ID: 3OCB) and the compound binding energy is -8.870 kcal/mol. Taken together, our results indicate that 24-MCF treatment increases parvin-β expression, which may inhibit ILK downstream signaling. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Clofibric acid, a peroxisome proliferator-activated receptor alpha ligand, inhibits growth of human ovarian cancer.

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Yokoyama, Yoshihito; Xin, Bing; Shigeto, Tatsuhiko; Umemoto, Mika; Kasai-Sakamoto, Akiko; Futagami, Masayuki; Tsuchida, Shigeki; Al-Mulla, Fahd; Mizunuma, Hideki

2007-04-01

Recent reports have shown that peroxisome proliferator-activated receptor (PPAR)alpha ligands reduce growth of some types of malignant tumors and prevent carcinogenesis. In this study, we investigated the inhibitory effect of clofibric acid (CA), a ligand for PPARalpha on growth of ovarian malignancy, in in vivo and in vitro experiments using OVCAR-3 and DISS cells derived from human ovarian cancer and aimed to elucidate the molecular mechanism of its antitumor effect. CA treatment significantly suppressed the growth of OVCAR-3 tumors xenotransplanted s.c. and significantly prolonged the survival of mice with malignant ascites derived from DISS cells as compared with control. CA also dose-dependently inhibited cell proliferation of cultured cell lines. CA treatment increased the expression of carbonyl reductase (CR), which promotes the conversion of prostaglandin E(2) (PGE(2)) to PGF(2alpha), in implanted OVCAR-3 tumors as well as cultured cells. CA treatment decreased PGE(2) level as well as vascular endothelial growth factor (VEGF) amount in both of OVCAR-3-tumor and DISS-derived ascites. Reduced microvessel density and induced apoptosis were found in solid OVCAR-3 tumors treated by CA. Transfection of CR expression vector into mouse ovarian cancer cells showed significant reduction of PGE(2) level as well as VEGF expression. These results indicate that CA produces potent antitumor effects against ovarian cancer in conjunction with a reduction of angiogenesis and induction of apoptosis. We conclude that CA could be an effective agent in ovarian cancer and should be tested alone and in combination with other anticancer drugs.

High Sugar Intake and Development of Skeletal Muscle Insulin Resistance and Inflammation in Mice: A Protective Role for PPAR-δ Agonism

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Elisa Benetti

2013-01-01

Full Text Available Peroxisome Proliferator Activated Receptor (PPAR-δ agonists may serve for treating metabolic diseases. However, the effects of PPAR-δ agonism within the skeletal muscle, which plays a key role in whole-body glucose metabolism, remain unclear. This study aimed to investigate the signaling pathways activated in the gastrocnemius muscle by chronic administration of the selective PPAR-δ agonist, GW0742 (1 mg/kg/day for 16 weeks, in male C57Bl6/J mice treated for 30 weeks with high-fructose corn syrup (HFCS, the major sweetener in foods and soft-drinks (15% wt/vol in drinking water. Mice fed with the HFCS diet exhibited hyperlipidemia, hyperinsulinemia, hyperleptinemia, and hypoadiponectinemia. In the gastrocnemius muscle, HFCS impaired insulin and AMP-activated protein kinase signaling pathways and reduced GLUT-4 and GLUT-5 expression and membrane translocation. GW0742 administration induced PPAR-δ upregulation and improvement in glucose and lipid metabolism. Diet-induced activation of nuclear factor-κB and expression of inducible-nitric-oxide-synthase and intercellular-adhesion-molecule-1 were attenuated by drug treatment. These effects were accompanied by reduction in the serum concentration of interleukin-6 and increase in muscular expression of fibroblast growth factor-21. Overall, here we show that PPAR-δ activation protects the skeletal muscle against the metabolic abnormalities caused by chronic HFCS exposure by affecting multiple levels of the insulin and inflammatory cascades.

Common angiotensin receptor blockers may directly modulate the immune system via VDR, PPAR and CCR2b

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Lee Robert E

2006-01-01

Full Text Available Abstract Background There have been indications that common Angiotensin Receptor Blockers (ARBs may be exerting anti-inflammatory actions by directly modulating the immune system. We decided to use molecular modelling to rapidly assess which of the potential targets might justify the expense of detailed laboratory validation. We first studied the VDR nuclear receptor, which is activated by the secosteroid hormone 1,25-dihydroxyvitamin-D. This receptor mediates the expression of regulators as ubiquitous as GnRH (Gonadatrophin hormone releasing hormone and the Parathyroid Hormone (PTH. Additionally we examined Peroxisome Proliferator-Activated Receptor Gamma (PPARgamma, which affects the function of phagocytic cells, and the C-CChemokine Receptor, type 2b, (CCR2b, which recruits monocytes to the site of inflammatory immune challenge. Results Telmisartan was predicted to strongly antagonize (Ki≈0.04nmol the VDR. The ARBs Olmesartan, Irbesartan and Valsartan (Ki≈10 nmol are likely to be useful VDR antagonists at typical in-vivo concentrations. Candesartan (Ki≈30 nmol and Losartan (Ki≈70 nmol may also usefully inhibit the VDR. Telmisartan is a strong modulator of PPARgamma (Ki≈0.3 nmol, while Losartan (Ki≈3 nmol, Irbesartan (Ki≈6 nmol, Olmesartan and Valsartan (Ki≈12 nmol also seem likely to have significant PPAR modulatory activity. Olmesartan andIrbesartan (Ki≈9 nmol additionally act as antagonists of a theoretical modelof CCR2b. Initial validation of this CCR2b model was performed, and a proposed model for the AngiotensinII Type1 receptor (AT2R1 has been presented. Conclusion Molecular modeling has proven valuable to generate testable hypotheses concerning receptor/ligand binding and is an important tool in drug design. ARBs were designed to act as antagonists for AT2R1, and it was not surprising to discover their affinity for the structurally similar CCR2b. However, this study also found evidence that ARBs modulate the

The MAPK-dependent regulation of the Jagged/Notch gene expression by VEGF, bFGF or PPAR gamma mediated angiogenesis in HUVEC

DEFF Research Database (Denmark)

Kiec-Wilk, B; Grzybowska-Galuszka, J; Polus, A

2010-01-01

The Jagged-Notch signalling, plays a crucial role in cell differentiation. Angiogenesis, is regulated by VEGF, bFGF as well as by the free fatty acid metabolites , which are regulators of transcription factors such as peroxisome proliferation activating receptors (PPARs). The study analyzed...... the signalling pathways involved in the regulation of Jagged-1/Notch-4 expression in endothelial cells (HUVECs) in response to VEGF, bFGF and PPAR-gamma exogenous activator - ciglitazone. HUVECs were incubated with investigated substances for 24 hours, with or without the presence of the MAP-kinases inhibitors...... were used. Jagged-1 and Notch-4 gene expression was determined using quantitative Real-Time PCR. The Jagged-1/Notch-4 protein expression was compared by flow cytometry, when the phosphorylation-dependent activation of kinases was estimated by Western-blot method. The opposite effect of VEGF, b...

Glucose-induced metabolic memory in Schwann cells: prevention by PPAR agonists.

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Kim, Esther S; Isoda, Fumiko; Kurland, Irwin; Mobbs, Charles V

2013-09-01

A major barrier in reversing diabetic complications is that molecular and pathologic effects of elevated glucose persist despite normalization of glucose, a phenomenon referred to as metabolic memory. In the present studies we have investigated the effects of elevated glucose on Schwann cells, which are implicated in diabetic neuropathy. Using quantitative PCR arrays for glucose and fatty acid metabolism, we have found that chronic (>8 wk) 25 mM high glucose induces a persistent increase in genes that promote glycolysis, while inhibiting those that oppose glycolysis and alternate metabolic pathways such as fatty acid metabolism, the pentose phosphate pathway, and trichloroacetic acid cycle. These sustained effects were associated with decreased peroxisome proliferator-activated receptor (PPAR)γ binding and persistently increased reactive oxygen species, cellular NADH, and altered DNA methylation. Agonists of PPARγ and PPARα prevented select effects of glucose-induced gene expression. These observations suggest that Schwann cells exhibit features of metabolic memory that may be regulated at the transcriptional level. Furthermore, targeting PPAR may prevent metabolic memory and the development of diabetic complications.

Citreoviridin induces triglyceride accumulation in hepatocytes through inhibiting PPAR-α in vivo and in vitro.

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Feng, Chang; Li, Dandan; Jiang, Liping; Liu, Xiaofang; Li, Qiujuan; Geng, Chengyan; Sun, Xiance; Yang, Guang; Yao, Xiaofeng; Chen, Min

2017-08-01

Citreoviridin (CIT) is a mycotoxin produced by Penicillum citreonigrum, Aspergillus terreus and Eupenicillium ochrosalmoneum. CIT occurs naturally in moldy rice and corn. CIT is associated with the development of atherosclerosis in the general population. Alteration in hepatic lipid metabolism is a pathogenic factor in atherosclerosis. However the effect and the underlying mechanism of CIT on hepatic lipid metabolism are largely unknown. In this study, we reported that CIT induced triglyceride accumulation in mice liver and human liver HepG2 cells as shown in oil red O staining. CIT (0.1 mg/kg-0.3 mg/kg) for 6 weeks elevated liver triglyceride contents in mice. CIT inhibited the transactivation activity of peroxisome proliferator-activated receptor-α (PPAR-α) in hepatocyte in vivo and in vitro, as shown by the reduced mRNA levels of PPAR-α target genes which play key roles in lipid metabolism in various aspects. PPAR-α agonist fenofibrate attenuated CIT-induced triglyceride accumulation in HepG2 cells. Furthermore, CIT increased serum total cholesterol/high-density lipoprotein cholesterol ratio, a strong risk factor for cardiovascular disease. In summary, we reported that CIT induced PPAR-α-dependent hepatic triglyceride accumulation and dyslipidemia. Our data will provide new mechanistic insights into CIT-induced lipid alterations. Copyright © 2017 Elsevier B.V. All rights reserved.

Telmisartan, a possible PPAR-δ agonist, reduces TNF-α-stimulated VEGF-C production by inhibiting the p38MAPK/HSP27 pathway in human proximal renal tubular cells

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Kimura, Hideki, E-mail: hkimura@u-fukui.ac.jp [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui (Japan); Mikami, Daisuke; Kamiyama, Kazuko [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Sugimoto, Hidehiro [Department of Clinical Laboratories and Nephrology, University of Fukui Hospital, Fukui (Japan); Kasuno, Kenji; Takahashi, Naoki [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Yoshida, Haruyoshi [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan); Division of Nephrology, Obama Municipal Hospital, Obama, Fukui (Japan); Iwano, Masayuki [Division of Nephrology, Department of General Medicine, School of Medicine, Faculty of Medical Sciences, University of Fukui, Fukui (Japan)

2014-11-14

Highlights: • TNF-α increased VEGF-C expression by enhancing phosphorylation of p38MAPK and HSP27. • Telmisartan decreased TNF-α-stimulated expression of VEGF-C. • Telmisartan suppressed TNF-α-induced phosphorylation of p38MAPK and HSP27. • Telmisartan activated endogenous PPAR-δ protein. • Telmisartan suppressed p38MAPK phosphorylation in a PPAR-δ-dependent manner. - Abstract: Vascular endothelial growth factor-C (VEGF-C) is a main inducer of inflammation-associated lymphangiogenesis in various inflammatory disorders including chronic progressive kidney diseases, for which angiotensin II receptor type 1 blockers (ARBs) are widely used as the main treatment. Although proximal renal tubular cells may affect the formation of lymphatic vessels in the interstitial area by producing VEGF-C, the molecular mechanisms of VEGF-C production and its manipulation by ARB have not yet been examined in human proximal renal tubular epithelial cells (HPTECs). In the present study, TNF-α dose-dependently induced the production of VEGF-C in HPTECs. The TNF-α-induced production of VEGF-C was mediated by the phosphorylation of p38MAPK and HSP27, but not by that of ERK or NFkB. Telmisartan, an ARB that can activate the peroxisome proliferator-activated receptor (PPAR), served as a PPAR-δ activator and reduced the TNF-α-stimulated production of VEGF-C. This reduction was partially attributed to a PPAR-δ-dependent decrease in p38MAPK phosphorylation. Our results indicate that TNF-α induced the production of VEGF-C in HPTECs by activating p38MAPK/HSP27, and this was partially inhibited by telmisartan in a PPAR-δ dependent manner. These results provide a novel insight into inflammation-associated lymphangiogenesis.

Genetic Manipulations of PPARs: Effects on Obesity and Metabolic Disease

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Yaacov Barak

2007-01-01

Full Text Available The interest in genetic manipulations of PPARs is as old as their discovery as receptors of ligands with beneficial clinical activities. Considering the effects of PPAR ligands on critical aspects of systemic physiology, including obesity, lipid metabolism, insulin resistance, and diabetes, gene knockout (KO in mice is the ideal platform for both hypothesis testing and discovery of new PPAR functions in vivo. With the fervent pursuit of the magic bullet to eradicate the obesity epidemic, special emphasis has been placed on the impacts of PPARs on obesity and its associated diseases. As detailed in this review, understanding how PPARs regulate gene expression and basic metabolic pathways is a necessary intermediate en route to deciphering their effects on obesity. Over a decade and dozens of genetic modifications of PPARs into this effort, valuable lessons have been learned, but we are left with more questions to be answered. These lessons and future prospects are the subject of this review.

Combination Therapy of PPAR Ligands and Inhibitors of Arachidonic Acid in Lung Cancer

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Jordi Tauler

2008-01-01

Full Text Available Lung cancer is the leading cause of cancer death in the United States and five-year survival remains low. Numerous studies have shown that chronic inflammation may lead to progression of carcinogenesis. As a result of inflammatory stimulation, arachidonic acid (AA metabolism produces proliferation mediators through complex and dynamic interactions of the products of the LOX/COX enzymes. One important mediator in the activation of the AA pathways is the nuclear protein PPAR. Targeting LOX/COX enzymes and inducing activation of PPAR have resulted in significant reduction of cell growth in lung cancer cell lines. However, specific COX-inhibitors have been correlated with an increased cardiovascular risk. Clinical applications are still being explored with a novel generation of dual LOX/COX inhibitors. PPAR activation through synthetic ligands (TZDs has revealed a great mechanistic complexity since effects are produced through PPAR-dependent and -independent mechanisms. Furthermore, PPAR could also be involved in regulation of COX-2. Overexpression of PPAR has reported to play a role in control of invasion and differentiation. Exploring the function of PPAR, in this new context, may provide a better mechanistic model of its role in cancer and give an opportunity to design a more efficient therapeutic approach in combination with LOX/COX inhibitors.

Neuron-specific deletion of peroxisome proliferator-activated receptor delta (PPARδ in mice leads to increased susceptibility to diet-induced obesity.

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Heidi E Kocalis

Full Text Available Central nervous system (CNS lipid accumulation, inflammation and resistance to adipo-regulatory hormones, such as insulin and leptin, are implicated in the pathogenesis of diet-induced obesity (DIO. Peroxisome proliferator-activated receptors (PPAR α, δ, γ are nuclear transcription factors that act as environmental fatty acid sensors and regulate genes involved in lipid metabolism and inflammation in response to dietary and endogenous fatty acid ligands. All three PPAR isoforms are expressed in the CNS at different levels. Recent evidence suggests that activation of CNS PPARα and/or PPARγ may contribute to weight gain and obesity. PPARδ is the most abundant isoform in the CNS and is enriched in the hypothalamus, a region of the brain involved in energy homeostasis regulation. Because in peripheral tissues, expression of PPARδ increases lipid oxidative genes and opposes inflammation, we hypothesized that CNS PPARδ protects against the development of DIO. Indeed, genetic neuronal deletion using Nes-Cre loxP technology led to elevated fat mass and decreased lean mass on low-fat diet (LFD, accompanied by leptin resistance and hypothalamic inflammation. Impaired regulation of neuropeptide expression, as well as uncoupling protein 2, and abnormal responses to a metabolic challenge, such as fasting, also occur in the absence of neuronal PPARδ. Consistent with our hypothesis, KO mice gain significantly more fat mass on a high-fat diet (HFD, yet are surprisingly resistant to diet-induced elevations in CNS inflammation and lipid accumulation. We detected evidence of upregulation of PPARγ and target genes of both PPARα and PPARγ, as well as genes of fatty acid oxidation. Thus, our data reveal a previously underappreciated role for neuronal PPARδ in the regulation of body composition, feeding responses, and in the regulation of hypothalamic gene expression.

Salvianolic acid B accelerated ABCA1-dependent cholesterol efflux by targeting PPAR-γ and LXRα

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Yue, Jianmei [Department of Endocrinology, Shandong Province Hospital Affiliated to Shandong University, 324# Jing 5 Road, Jinan 255021 (China); Department of Endocrinology, The First Hospital of Zibo, 4# E Mei Shan Dong Road, Zibo 255200 (China); Li, Bo, E-mail: libosubmit@163.com [Department of Cardiology, Central Hospital of Zibo, 54# Gong Qing Tuan Xi Road, Zibo, Shandong Province (China); Jing, Qingping [Department of Endocrinology, The First Hospital of Zibo, 4# E Mei Shan Dong Road, Zibo 255200 (China); Guan, Qingbo, E-mail: guanqingbosubmit@163.com [Department of Endocrinology, Shandong Province Hospital Affiliated to Shandong University, 324# Jing 5 Road, Jinan 255021 (China)

2015-07-03

Objectives: Cholesterol efflux has been thought to be the main and basic mechanism by which free cholesterol is transferred from extra hepatic cells to the liver or intestine for excretion. Salvianolic acid B (Sal B) has been widely used for the prevention and treatment of atherosclerotic diseases. Here, we sought to investigate the effects of Sal B on the cholesterol efflux in THP-1 macrophages. Methods: After PMA-stimulated THP-1 cells were exposed to 50 mg/L of oxLDL and [{sup 3}H] cholesterol (1.0 μCi/mL) for another 24 h, the effect of Sal B on cholesterol efflux was evaluated in the presence of apoA-1, HDL{sub 2} or HDL{sub 3}. The expression of ATP binding cassette transporter A1 (ABCA1), peroxisome proliferator-activated receptor-gamma (PPAR-γ), and liver X receptor-alpha (LXRα) was detected both at protein and mRNA levels in THP-1 cells after the stimulation of Sal B. Meanwhile, specific inhibition of PPAR-γ and LXRα were performed to investigate the mechanism. Results: The results showed that Sal B significantly accelerated apoA-I- and HDL-mediated cholesterol efflux in both dose- and time-dependent manners. Meanwhile, Sal B treatment also enhanced the expression of ABCA1 at both mRNA and protein levels. Then the data demonstrated that Sal B increased the expression of PPAR-γ and LXRα. And the application of specific agonists and inhibitors of further confirmed that Sal exert the function through PPAR-γ and LXRα. Conclusion: These results demonstrate that Sal B promotes cholesterol efflux in THP-1 macrophages through ABCA1/PPAR-γ/LXRα pathway. - Highlights: • Sal B promotes the expression of ABCA1. • Sal B promotes cholesterol efflux in macrophages. • Sal B promotes the expression of ABCA1 and cholesterol efflux through PPAR-γ/LXRα signaling pathway.

Activation of peroxisome proliferator-activated receptor-α (PPARα) suppresses postprandial lipidemia through fatty acid oxidation in enterocytes

International Nuclear Information System (INIS)

Kimura, Rino; Takahashi, Nobuyuki; Murota, Kaeko; Yamada, Yuko; Niiya, Saori; Kanzaki, Noriyuki; Murakami, Yoko; Moriyama, Tatsuya; Goto, Tsuyoshi; Kawada, Teruo

2011-01-01

Highlights: → PPARα activation increased mRNA expression levels of fatty acid oxidation-related genes in human intestinal epithelial Caco-2 cells. → PPARα activation also increased oxygen consumption rate and CO 2 production and decreased secretion of triglyceride and ApoB from Caco-2 cells. → Orally administration of bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and CO 2 production in small intestinal epithelial cells. → Treatment with bezafibrate decreased postprandial serum concentration of triglyceride after oral injection of olive oil in mice. → It suggested that intestinal lipid metabolism regulated by PPARα activation suppresses postprandial lipidemia. -- Abstract: Activation of peroxisome proliferator-activated receptor (PPAR)-α which regulates lipid metabolism in peripheral tissues such as the liver and skeletal muscle, decreases circulating lipid levels, thus improving hyperlipidemia under fasting conditions. Recently, postprandial serum lipid levels have been found to correlate more closely to cardiovascular diseases than fasting levels, although fasting hyperlipidemia is considered an important risk of cardiovascular diseases. However, the effect of PPARα activation on postprandial lipidemia has not been clarified. In this study, we examined the effects of PPARα activation in enterocytes on lipid secretion and postprandial lipidemia. In Caco-2 enterocytes, bezafibrate, a potent PPARα agonist, increased mRNA expression levels of fatty acid oxidation-related genes, such as acyl-CoA oxidase, carnitine palmitoyl transferase, and acyl-CoA synthase, and oxygen consumption rate (OCR) and suppressed secretion levels of both triglycerides and apolipoprotein B into the basolateral side. In vivo experiments revealed that feeding high-fat-diet containing bezafibrate increased mRNA expression levels of fatty acid oxidation-related genes and production of CO 2 and acid soluble metabolites in enterocytes. Moreover

Peroxisome proliferator-activated receptor α agonists modulate Th1 and Th2 chemokine secretion in normal thyrocytes and Graves' disease

International Nuclear Information System (INIS)

Antonelli, Alessandro; Ferrari, Silvia Martina; Frascerra, Silvia; Corrado, Alda; Pupilli, Cinzia; Bernini, Giampaolo; Benvenga, Salvatore; Ferrannini, Ele; Fallahi, Poupak

2011-01-01

Until now, no data are present about the effect of peroxisome proliferator-activated receptor (PPAR)α activation on the prototype Th1 [chemokine (C-X-C motif) ligand (CXCL)10] (CXCL10) and Th2 [chemokine (C-C motif) ligand 2] (CCL2) chemokines secretion in thyroid cells. The role of PPARα and PPARγ activation on CXCL10 and CCL2 secretion was tested in Graves' disease (GD) and control primary thyrocytes stimulated with interferon (IFN)γ and tumor necrosis factor (TNF)α. IFNγ stimulated both CXCL10 and CCL2 secretion in primary GD and control thyrocytes. TNFα alone stimulated CCL2 secretion, while had no effect on CXCL10. The combination of IFNγ and TNFα had a synergistic effect both on CXCL10 and CCL2 chemokines in GD thyrocytes at levels comparable to those of controls. PPARα activators inhibited the secretion of both chemokines (stimulated with IFNγ and TNFα) at a level higher (for CXCL10, about 60-72%) than PPARγ agonists (about 25-35%), which were confirmed to inhibit CXCL10, but not CCL2. Our data show that CCL2 is modulated by IFNγ and TNFα in GD and normal thyrocytes. Furthermore we first show that PPARα activators inhibit the secretion of CXCL10 and CCL2 in thyrocytes, suggesting that PPARα may be involved in the modulation of the immune response in the thyroid.

Elafibranor, an Agonist of the Peroxisome Proliferator-Activated Receptor-alpha and -delta, Induces Resolution of Nonalcoholic Steatohepatitis Without Fibrosis Worsening

NARCIS (Netherlands)

Ratziu, V.; Harrison, S.A.; Francque, S.; Bedossa, P.; Lehert, P.; Serfaty, L.; Romero-Gomez, M.; Boursier, J.; Abdelmalek, M.; Caldwell, S.; Drenth, J.P.; Anstee, Q.M.; Hum, D.; Hanf, R.; Roudot, A.; Megnien, S.; Staels, B.; Sanyal, A.

2016-01-01

BACKGROUND & AIMS: Elafibranor is an agonist of the peroxisome proliferator-activated receptor-alpha and peroxisome proliferator-activated receptor-delta. Elafibranor improves insulin sensitivity, glucose homeostasis, and lipid metabolism and reduces inflammation. We assessed the safety and efficacy

The PPAR alpha agonist gemfibrozil is an ineffective treatment for spinal cord injured mice.

Science.gov (United States)

Almad, Akshata; Lash, A Todd; Wei, Ping; Lovett-Racke, Amy E; McTigue, Dana M

2011-12-01

Peroxisome Proliferator Activated Receptor (PPAR)-α is a key regulator of lipid metabolism and recent studies reveal it also regulates inflammation in several different disease models. Gemfibrozil, an agonist of PPAR-α, is a FDA approved drug for hyperlipidemia and has been shown to inhibit clinical signs in a rodent model of multiple sclerosis. Since many studies have shown improved outcome from spinal cord injury (SCI) by anti-inflammatory and neuroprotective agents, we tested the efficacy of oral gemfibrozil given before or after SCI for promoting tissue preservation and behavioral recovery after spinal contusion injury in mice. Unfortunately, the results were contrary to our hypothesis; in our first attempt, gemfibrozil treatment exacerbated locomotor deficits and increased tissue pathology after SCI. In subsequent experiments, the behavioral effects were not replicated but histological outcomes again were worse. We also tested the efficacy of a different PPAR-α agonist, fenofibrate, which also modulates immune responses and is beneficial in several neurodegenerative disease models. Fenofibrate treatment did not improve recovery, although there was a slight trend for a modest increase in histological tissue sparing. Based on our results, we conclude that PPAR-α agonists yield either no effect or worsen recovery from spinal cord injury, at least at the doses and the time points of drug delivery tested here. Further, patients sustaining spinal cord injury while taking gemfibrozil might be prone to exacerbated tissue damage. Copyright © 2011 Elsevier Inc. All rights reserved.

Nicotinic Acid-Mediated Activation of Both Membrane and Nuclear Receptors towards Therapeutic Glucocorticoid Mimetics for Treating Multiple Sclerosis

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W. Todd Penberthy

2009-01-01

Full Text Available Acute attacks of multiple sclerosis (MS are most commonly treated with glucocorticoids, which can provide life-saving albeit only temporary symptomatic relief. The mechanism of action (MOA is now known to involve induction of indoleamine 2,3-dioxygenase (IDO and interleukin-10 (IL-10, where IL-10 requires subsequent heme oxygenase-1 (HMOX-1 induction. Ectopic expression studies reveal that even small changes in expression of IDO, HMOX-1, or mitochondrial superoxide dismutase (SOD2 can prevent demyelination in experimental autoimmune encephalomyelitis (EAE animal models of MS. An alternative to glucocorticoids is needed for a long-term treatment of MS. A distinctly short list of endogenous activators of both membrane G-protein-coupled receptors and nuclear peroxisome proliferating antigen receptors (PPARs demonstrably ameliorate EAE pathogenesis by MOAs resembling that of glucocorticoids. These dual activators and potential MS therapeutics include endocannabinoids and the prostaglandin 15-deoxy-Δ12,14-PGJ2. Nicotinamide profoundly ameliorates and prevents autoimmune-mediated demyelination in EAE via maintaining levels of nicotinamide adenine dinucleotide (NAD, without activating PPAR nor any G-protein-coupled receptor. By comparison, nicotinic acid provides even greater levels of NAD than nicotinamide in many tissues, while additionally activating the PPAR-dependent pathway already shown to provide relief in animal models of MS after activation of GPR109a/HM74a. Thus nicotinic acid is uniquely suited for providing therapeutic relief in MS. However nicotinic acid is unexamined in MS research. Nicotinic acid penetrates the blood brain barrier, cures pellagric dementia, has been used for over 50 years clinically without toxicity, and raises HDL concentrations to a greater degree than any pharmaceutical, thus providing unparalleled benefits against lipodystrophy. Summary analysis reveals that the expected therapeutic benefits of high-dose nicotinic

PPAR γ is highly expressed in F4/80hi adipose tissue macrophages and dampens adipose-tissue inflammation

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Bassaganya-Riera, Josep; Misyak, Sarah; Guri, Amir J.; Hontecillas, Raquel

2009-01-01

Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) γ agonist. Hence, we hypothesized that F4/80hi and F4/80lo ATM differentially express PPAR γ. This study phenotypically and functionally characterizes F4/80hi and F4/80lo ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80lo and F4/80hi ATM by quantitative real-time RT-PCR. We show that while F4/80lo macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80lo and F4/80hi ATM. Moreover, accumulation of F4/80hi ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80hi ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-α, MCP-1, and IL-10 than F4/80lo ATM. Gene expression analyses of the sorted populations revealed that only the F4/80lo population produced IL-4, whereas the F4/80hi ATM expressed greater amounts of PPAR γ, δ, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR γ in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR γ is differentially expressed in F4/80hi versus F4/80low ATM subsets and its deficiency favors a predominance of M1 markers in WAT. PMID:19423085

PPAR gamma is highly expressed in F4/80(hi) adipose tissue macrophages and dampens adipose-tissue inflammation.

Science.gov (United States)

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

2009-01-01

Macrophage infiltration into adipose tissue is a hallmark of obesity. We recently reported two phenotypically distinct subsets of adipose tissue macrophages (ATM) based on the surface expression of the glycoprotein F4/80 and responsiveness to treatment with a peroxisome proliferator-activated receptor (PPAR) gamma agonist. Hence, we hypothesized that F4/80(hi) and F4/80(lo) ATM differentially express PPAR gamma. This study phenotypically and functionally characterizes F4/80(hi) and F4/80(lo) ATM subsets during obesity. Changes in gene expression were also examined on sorted F4/80(lo) and F4/80(hi) ATM by quantitative real-time RT-PCR. We show that while F4/80(lo) macrophages predominate in adipose tissue of lean mice, obesity causes accumulation of both F4/80(lo) and F4/80(hi) ATM. Moreover, accumulation of F4/80(hi) ATM in adipose tissue is associated with impaired glucose tolerance. Phenotypically, F4/80(hi) ATM express greater amounts of CD11c, MHC II, CD49b, and CX3CR1 and produce more TNF-alpha, MCP-1, and IL-10 than F4/80(lo) ATM. Gene expression analyses of the sorted populations revealed that only the F4/80(lo) population produced IL-4, whereas the F4/80(hi) ATM expressed greater amounts of PPAR gamma, delta, CD36 and toll-like receptor-4. In addition, the deficiency of PPAR gamma in immune cells favors expression of M1 and impairs M2 macrophage marker expression in adipose tissue. Thus, PPAR gamma is differentially expressed in F4/80(hi) versus F4/80(low) ATM subsets and its deficiency favors a predominance of M1 markers in WAT.

Rosiglitazone Inhibits Adrenocortical Cancer Cell Proliferation by Interfering with the IGF-IR Intracellular Signaling

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Luconi Michaela

2008-07-01

Full Text Available Rosiglitazone (RGZ, a thiazolidinedione ligand of the peroxisome proliferator-activated receptor (PPAR-γ, has been recently described as possessing antitumoral properties. We investigated RGZ effect on cell proliferation in two cell line models (SW13 and H295R of human adrenocortical carcinoma (ACC and its interaction with the signaling pathways of the activated IGF-I receptor (IGF-IR. We demonstrate a high expression of IGF-IR in the two cell lines and in ACC. Cell proliferation is stimulated by IGF-I in a dose- and time-dependent manner and is inhibited by RGZ. The analysis of the main intracellular signaling pathways downstream of the activated IGF-IR, phosphatidyl inositol 3-kinase (PI3K-Akt, and extracellular signal-regulated kinase (ERK1/2 cascades reveals that RGZ rapidly interferes with the Akt and ERK1/2 phosphorylation/activation which mediates IGF-I stimulated proliferation. In conclusion, our results suggest that RGZ exerts an inhibitory effect on human ACC cell proliferation by interfering with the PI3K/Akt and ERK1/2 signaling pathways downstream of the activated IGF-IR.

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

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Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

2017-01-01

Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway

Apoptotic action of peroxisome proliferator-activated receptor-gamma activation in human non small-cell lung cancer is mediated via proline oxidase-induced reactive oxygen species formation.

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Kim, Ki Young; Ahn, Jin Hee; Cheon, Hyae Gyeong

2007-09-01

Peroxisome proliferator-activated receptor (PPAR)-gamma ligands have been shown to inhibit human lung cancers by inducing apoptosis and differentiation. In the present study, we elucidated the apoptotic mechanism of PPARgamma activation in human lung cancers by using a novel PPARgamma agonist, 1-(trans-methylimino-N-oxy)-6-(2-morpholinoethoxy)-3-phenyl-(1H-indene-2-carboxylic acid ethyl ester (KR-62980), and rosiglitazone. PPARgamma activation selectively inhibited cell viability of non-small-cell lung cancer with little effect on small-cell lung cancer and normal lung cells. The cell death induced by PPARgamma activation presented apoptotic features of oligonucleosomal DNA fragmentation in A549 human non-small-cell lung cancer cell line. Reactive oxygen species (ROS) production was accompanied by increased expression of proline oxidase (POX), a redox enzyme expressed in mitochondria, upon incubation with the agonists. POX RNA interference treatment blocked PPARgamma-induced ROS formation and cytotoxicity, suggesting that POX plays a functional role in apoptosis through ROS formation. The apoptotic effects by the agonists were antagonized by bisphenol A diglycidyl ether, a PPARgamma antagonist, and by knockdown of PPARgamma expression, indicating the involvement of PPARgamma in these actions. The results of the present study suggest that PPARgamma activation induces apoptotic cell death in non-small-cell lung carcinoma mainly through ROS formation via POX induction.

Structure-activity relationships of rosiglitazone for peroxisome proliferator-activated receptor gamma transrepression.

Science.gov (United States)

Toyota, Yosuke; Nomura, Sayaka; Makishima, Makoto; Hashimoto, Yuichi; Ishikawa, Minoru

2017-06-15

Anti-inflammatory effects of peroxisome proliferator-activated receptor gamma (PPRAγ) ligands are thought to be largely due to PPARγ-mediated transrepression. Thus, transrepression-selective PPARγ ligands without agonistic activity or with only partial agonistic activity should exhibit anti-inflammatory properties with reduced side effects. Here, we investigated the structure-activity relationships (SARs) of PPARγ agonist rosiglitazone, focusing on transrepression activity. Alkenic analogs showed slightly more potent transrepression with reduced efficacy of transactivating agonistic activity. Removal of the alkyl group on the nitrogen atom improved selectivity for transrepression over transactivation. Among the synthesized compounds, 3l exhibited stronger transrepressional activity (IC 50 : 14μM) and weaker agonistic efficacy (11%) than rosiglitazone or pioglitazone. Copyright © 2017 Elsevier Ltd. All rights reserved.

Mast cell tryptase stimulates myoblast proliferation; a mechanism relying on protease-activated receptor-2 and cyclooxygenase-2

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Côté Claude H

2011-10-01

Full Text Available Abstract Background Mast cells contribute to tissue repair in fibrous tissues by stimulating proliferation of fibroblasts through the release of tryptase which activates protease-activated receptor-2 (PAR-2. The possibility that a tryptase/PAR-2 signaling pathway exists in skeletal muscle cell has never been investigated. The aim of this study was to evaluate whether tryptase can stimulate myoblast proliferation and determine the downstream cascade. Methods Proliferation of L6 rat skeletal myoblasts stimulated with PAR-2 agonists (tryptase, trypsin and SLIGKV was assessed. The specificity of the tryptase effect was evaluated with a specific inhibitor, APC-366. Western blot analyses were used to evaluate the expression and functionality of PAR-2 receptor and to assess the expression of COX-2. COX-2 activity was evaluated with a commercial activity assay kit and by measurement of PGF2α production. Proliferation assays were also performed in presence of different prostaglandins (PGs. Results Tryptase increased L6 myoblast proliferation by 35% above control group and this effect was completely inhibited by APC-366. We confirmed the expression of PAR-2 receptor in vivo in skeletal muscle cells and in satellite cells and in vitro in L6 cells, where PAR-2 was found to be functional. Trypsin and SLIGKV increased L6 cells proliferation by 76% and 26% above control, respectively. COX-2 activity was increased following stimulation with PAR-2 agonist but its expression remained unchanged. Inhibition of COX-2 activity by NS-398 abolished the stimulation of cell proliferation induced by tryptase and trypsin. Finally, 15-deoxy-Δ-12,14-prostaglandin J2 (15Δ-PGJ2, a product of COX-2-derived prostaglandin D2, stimulated myoblast proliferation, but not PGE2 and PGF2α. Conclusions Taken together, our data show that tryptase can stimulate myoblast proliferation and this effect is part of a signaling cascade dependent on PAR-2 activation and on the downstream

Co-factors necessary for PPAR mediated transactivation of endogenous target genes

DEFF Research Database (Denmark)

Grøntved, Lars; Nielsen, Ronni; Stunnenberg, Henk

of endogenous target gene in different cell types are elusive. To mutually compare the ability of the PPAR subtypes to activate endogenous target genes in a given cell, PPARa, PPARb/d and PPARg2 were HA tagged and rapidly, equally and synchronously expressed using adenoviral delivery. Within a few hours after...... subtype specific activation of target genes. Accumulating evidence suggests that transcriptional co-factors can function as master regulators for nuclear receptors and impose promoter selectivity. To study co-factor necessity for PPAR mediated transactivation of endogenous target genes, specific co...

Portulaca Extract Attenuates Development of Dextran Sulfate Sodium Induced Colitis in Mice through Activation of PPARγ

OpenAIRE

Kong, Rui; Luo, Hui; Wang, Nan; Li, Jingjing; Xu, Shizan; Chen, Kan; Feng, Jiao; Wu, Liwei; Li, Sainan; Liu, Tong; Lu, Xiya; Xia, Yujing; Shi, Yanhong; Zhou, Yingqun; He, Weigang

2018-01-01

Portulaca oleracea L. is a traditional Chinese medicine, which has been used as adjuvant therapy for inflammatory bowel disease (IBD). However, the mechanism of its activity in IBD still remains unclear. Since previous studies have documented the anti-inflammatory effect of peroxisome proliferator activated receptors-γ (PPAR-γ), Portulaca regulation of PPAR-γ in inflammation was examined in current study. Ulcerative colitis (UC) was generated by 5% dextran sulfate sodium (DSS) in mice and fou...

Effect of PPAR-α and -γ agonist on the expression of visfatin, adiponectin, and TNF-α in visceral fat of OLETF rats

International Nuclear Information System (INIS)

Choi, K.C.; Ryu, O.H.; Lee, K.W.; Kim, H.Y.; Seo, J.A.; Kim, S.G.; Kim, N.H.; Choi, D.S.; Baik, S.H.; Choi, K.M.

2005-01-01

A variety of adipocytokines and peptides secreted from adipocytes have been considered to play a crucial role in obesity, insulin resistance, and type 2 diabetes. Recently, visfatin, a new adipocytokine, known as a pre-B cell colony-enhancing factor, has been isolated from visceral fat deposits. It has been shown to activate insulin receptors in a manner different from insulin. To understand the role of adipocytokines in improving insulin sensitivity via activation of the nuclear receptor peroxisome proliferator-activated receptor-α (PPAR-α) and -γ (PPAR-γ), we examined the expression of visfatin, adiponectin, and TNF-α in visceral fat depots of Otsuka Long-Evans Tokushima fatty (OLETF) rats from early to advanced diabetic stage (from 28 to 40 weeks of age). Serum glucose and insulin concentrations significantly (P < 0.05) decreased in rosiglitazone or fenofibrate-treated OLETF rats compared to untreated OLETF rats. Rosiglitazone significantly increased serum adiponectin concentration from 20 to 40 weeks of age (P < 0.05), whereas fenofibrate reduced TNF-α concentration. The expression of visfatin and adiponectin mRNA in visceral fat deposits was elevated by rosiglitazone or fenofibrate treatments when compared to untreated OLETF rats (P < 0.05), whereas, TNF-α mRNA was down-regulated by these drugs (P < 0.05). These results suggest that rosiglitazone and fenofibrate may prevent type 2 diabetes by regulating adipocytokines including visfatin, adiponectin, and TNF-α

Impact of diisobutyl phthalate and other PPAR agonists on steroidogenesis and plasma insulin and leptin levels in fetal rats

International Nuclear Information System (INIS)

Boberg, Julie; Metzdorff, Stine; Wortziger, Rasmus; Axelstad, Marta; Brokken, Leon; Vinggaard, Anne Marie; Dalgaard, Majken; Nellemann, Christine

2008-01-01

Endocrine disrupting chemicals can induce malformations and impairment of reproductive function in experimental animals and may have similar effects in humans. Recently, the environmental obesogen hypothesis was proposed, suggesting that environmental chemicals contribute to the development of obesity and insulin resistance. These effects could be related to chemical interaction with nuclear receptors such as the peroxisome proliferator activated receptors (PPARs). As several testosterone-reducing drugs are PPAR activators, we aimed to examine whether four PPAR agonists were able to affect fetal testosterone production and masculinization of rats. Additionally, we wished to examine whether these chemicals affected fetal plasma levels of insulin and leptin, which play important roles in the developmental programming of the metabolic system. Pregnant Wistar rats were exposed from gestation day (GD) 7-21 to diisobutyl phthalate (DiBP), butylparaben, perfluorooctanoate, or rosiglitazone (600, 100, 20, or 1 mg/kg bw/day, respectively). Endocrine endpoints were studied in offspring at GD 19 or 21. DiBP, butylparaben and rosiglitazone reduced plasma leptin levels in male and female offspring. DiBP and rosiglitazone additionally reduced fetal plasma insulin levels. In males, DiBP reduced anogenital distance, testosterone production and testicular expression of Insl-3 and genes related to steroidogenesis. PPARα mRNA levels were reduced by DiBP at GD 19 in testis and liver. In females, DiBP increased anogenital distance and increased ovarian aromatase mRNA levels. This study reveals new targets for phthalates and parabens in fetal male and female rats and contributes to the increasing concern about adverse effects of human exposure to these compounds

Double di oxygenation by mouse 8S-lipoxygenase: Specific formation of a potent peroxisome proliferator-activated receptor α agonist

International Nuclear Information System (INIS)

Jisaka, Mitsuo; Iwanaga, Chitose; Takahashi, Nobuyuki; Goto, Tsuyoshi; Kawada, Teruo; Yamamoto, Tatsuyuki; Ikeda, Izumi; Nishimura, Kohji; Nagaya, Tsutomu; Fushiki, Tohru; Yokota, Kazushige

2005-01-01

Mouse 8S-lipoxygenase (8-LOX) metabolizes arachidonic acid (AA) specifically to 8S-hydroperoxyeicosatetraenoic acid (8S-HPETE), which will be readily reduced under physiological circumstances to 8S-hydroxyeicosatetraenoic acid (8S-HETE), a natural agonist of peroxisome proliferator-activated receptor α (PPARα). Here, we investigated whether 8-LOX could further oxygenate AA and whether the products could activate PPARs. The purified recombinant 8-LOX converted AA exclusively to 8S-HPETE and then to (8S,15S)-dihydroperoxy-5Z,9E,11Z,13E-eicosatetraenoic acid (8S,15S-diHPETE). The k cat /K m values for 8S-HPETE and AA were 3.3 x 10 3 and 2.7 x 10 4 M -1 s -1 , respectively. 8-LOX also dioxygenated 8S-HETE and 15S-H(P)ETE specifically to the corresponding 8S,15S-disubstituted derivatives. By contrast, 15-LOX-2, a human homologue of 8-LOX, produced 8S,15S-diH(P)ETE from 8S-H(P)ETE but not from AA nor 15S-H(P)ETE. 8S,15S-diHETE activated PPARα more strongly than 8S-HETE did. The present results suggest that 8S,15S-diH(P)ETE as well as 8S-H(P)ETE would contribute to the physiological function of 8-LOX and also that 8-LOX can function as a potential 15-LOX

Hesperidin produces cardioprotective activity via PPAR-γ pathway in ischemic heart disease model in diabetic rats.

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Yogeeta O Agrawal

Full Text Available The present study investigated the effect of hesperidin, a natural flavonoid, in cardiac ischemia and reperfusion (I/R injury in diabetic rats. Male Wistar rats with diabetes were divided into five groups and were orally administered saline once daily (IR-sham and IR-control, Hesperidin (100 mg/kg/day; IR-Hesperidin, GW9962 (PPAR-γ receptor antagonist, or combination of both for 14 days. On the 15th day, in the IR-control and IR-treatment groups, rats were subjected to left anterior descending (LAD coronary artery occlusion for 45 minutes followed by a one-hour reperfusion. Haemodynamic parameters were recorded and rats were sacrificed; hearts were isolated for biochemical, histopathological, ultrastructural and immunohistochemistry. In the IR-control group, significant ventricular dysfunctions were observed along with enhanced expression of pro-apoptotic protein Bax. A decline in cardiac injury markers lactate dehydrogenase activity, CK-MB and increased content of thiobarbituric acid reactive substances, a marker of lipid peroxidation, and TNF-α were observed. Hesperidin pretreatment significantly improved mean arterial pressure, reduced left ventricular end-diastolic pressure, and improved both inotropic and lusitropic function of the heart (+LVdP/dt and -LVdP/dt as compared to IR-control. Furthermore, hesperidin treatment significantly decreased the level of thiobarbituric acid reactive substances and reversed the activity of lactate dehydrogenase towards normal value. Hesperidin showed anti-apoptotic effects by upregulating Bcl-2 protein and decreasing Bax protein expression. Additionally, histopathological and ultrastructural studies reconfirmed the protective action of hesperidin. On the other hand, GW9662, selective PPAR-γ receptor antagonist, produced opposite effects and attenuated the hesperidin induced improvements. The study for the first time evidence the involvement of PPAR-γ pathway in the cardioprotective activity of

Peroxisome proliferator-activated receptors (PPAR) agonists affect cell viability, apoptosis and expression of cell cycle related proteins in cell lines of glial brain tumors

Czech Academy of Sciences Publication Activity Database

Straková, N.; Ehrmann, J.; Bartoš, Jan; Malíková, J.; Doležel, Jaroslav; Kolář, Z.

2005-01-01

Roč. 52, - (2005), s. 126-136 ISSN 0028-2685 Institutional research plan: CEZ:AV0Z50380511; CEZ:AV0Z5038910 Keywords : PPAR * glioplasma * cell cycle Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 0.731, year: 2005

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...... in cells, and through use of chimeric proteins, we established that coactivation by Tip60 critically depends on the N-terminal activation function 1 of PPARgamma, a domain involved in isotype-specific gene expression and adipogenesis. Chromatin immunoprecipitation experiments showed that the endogenous Tip...... of proteins with which this nuclear receptor interacts under specific conditions. Here we identify the HIV-1 Tat-interacting protein 60 (Tip60) as a novel positive regulator of PPARgamma transcriptional activity. Using tandem mass spectrometry, we found that PPARgamma and the acetyltransferase Tip60 interact...

Food Components Modulate Obesity and Energy Metabolism via the Transcriptional Regulation of Lipid-Sensing Nuclear Receptors.

Science.gov (United States)

Goto, Tsuyoshi; Takahashi, Nobuyuki; Kawada, Teruo

2015-01-01

Obesity is a major risk factor for chronic diseases such as diabetes, cardiovascular diseases, and hypertension. Many modern people have a tendency to overeat owing to stress and loosening of self-control. Moreover, energy expenditure varies greatly among individuals. Scientific reduction of obesity is important under these circumstances. Furthermore, recent research on molecular levels has clarified the differentiation of adipocytes, the level of subsequent fat accumulation, and the secretion of the biologically active adipokines by adipocytes. Adipose tissues and obesity have become the most important target for the prevention and treatment of many chronic diseases. We have identified various food-derived compounds modulating nuclear receptors, especially peroxisome proliferators-activated receptor(PPAR), in the regulation of energy metabolism and obesity. In this review, we discuss the PPARs that are most important in obesity and energy metabolism.

A Mixture of Extracts of Kochia scoparia and Rosa multiflora with PPAR α/γ Dual Agonistic Effects Prevents Photoaging in Hairless Mice

Science.gov (United States)

Jeon, Hyerin; Kim, Dong Hye; Nho, Youn-Hwa; Park, Ji-Eun; Kim, Su-Nam; Choi, Eung Ho

2016-01-01

Activation of peroxisome proliferator-activated receptors (PPAR) α/γ is known to inhibit the increases in matrix metalloproteinase (MMP) and reactive oxygen species (ROS) induced by ultraviolet light (UV). Extracts of natural herbs, such as Kochia scoparia and Rosa multiflora, have a PPAR α/γ dual agonistic effect. Therefore, we investigated whether and how they have an antiaging effect on photoaging skin. Eighteen-week-old hairless mice were irradiated with UVA 14 J/cm2 and UVB 40 mJ/cm2 three times a week for 8 weeks. A mixture of extracts of Kochia scoparia and Rosa multiflora (KR) was topically applied on the dorsal skin of photoaging mice twice a day for 8 weeks. Tesaglitazar, a known PPAR α/γ agonist, and vehicle (propylene glycol:ethanol = 7:3, v/v) were applied as positive and negative controls, respectively. Dermal effects (including dermal thickness, collagen density, dermal expression of procollagen 1 and collagenase 13) and epidermal effects (including skin barrier function, epidermal proliferation, epidermal differentiation, and epidermal cytokines) were measured and compared. In photoaging murine skin, KR resulted in a significant recovery of dermal thickness as well as dermal fibroblasts, although it did not change dermal collagen density. KR increased the expression of dermal transforming growth factor (TGF)-β. The dermal effects of KR were explained by an increase in procollagen 1 expression, induced by TGF-β, and a decrease in MMP-13 expression. KR did not affect basal transepidermal water loss (TEWL) or stratum corneum (SC) integrity, but did decrease SC hydration. It also did not affect epidermal proliferation or epidermal differentiation. KR decreased the expression of epidermal interleukin (IL)-1α. Collectively, KR showed possible utility as a therapeutic agent for photoaging skin, with few epidermal side effects such as epidermal hyperplasia or poor differentiation. PMID:27854351

A Mixture of Extracts of Kochia scoparia and Rosa multiflora with PPAR α/γ Dual Agonistic Effects Prevents Photoaging in Hairless Mice

Directory of Open Access Journals (Sweden)

Hyerin Jeon

2016-11-01

Full Text Available Activation of peroxisome proliferator-activated receptors (PPAR α/γ is known to inhibit the increases in matrix metalloproteinase (MMP and reactive oxygen species (ROS induced by ultraviolet light (UV. Extracts of natural herbs, such as Kochia scoparia and Rosa multiflora, have a PPAR α/γ dual agonistic effect. Therefore, we investigated whether and how they have an antiaging effect on photoaging skin. Eighteen-week-old hairless mice were irradiated with UVA 14 J/cm2 and UVB 40 mJ/cm2 three times a week for 8 weeks. A mixture of extracts of Kochia scoparia and Rosa multiflora (KR was topically applied on the dorsal skin of photoaging mice twice a day for 8 weeks. Tesaglitazar, a known PPAR α/γ agonist, and vehicle (propylene glycol:ethanol = 7:3, v/v were applied as positive and negative controls, respectively. Dermal effects (including dermal thickness, collagen density, dermal expression of procollagen 1 and collagenase 13 and epidermal effects (including skin barrier function, epidermal proliferation, epidermal differentiation, and epidermal cytokines were measured and compared. In photoaging murine skin, KR resulted in a significant recovery of dermal thickness as well as dermal fibroblasts, although it did not change dermal collagen density. KR increased the expression of dermal transforming growth factor (TGF-β. The dermal effects of KR were explained by an increase in procollagen 1 expression, induced by TGF-β, and a decrease in MMP-13 expression. KR did not affect basal transepidermal water loss (TEWL or stratum corneum (SC integrity, but did decrease SC hydration. It also did not affect epidermal proliferation or epidermal differentiation. KR decreased the expression of epidermal interleukin (IL-1α. Collectively, KR showed possible utility as a therapeutic agent for photoaging skin, with few epidermal side effects such as epidermal hyperplasia or poor differentiation.

Cysteine dioxygenase type 1 promotes adipogenesis via interaction with peroxisome proliferator-activated receptor gamma

Energy Technology Data Exchange (ETDEWEB)

Deng, Peng; Chen, Yi; Ji, Ning; Lin, Yunfeng; Yuan, Quan; Ye, Ling; Chen, Qianming, E-mail: qmchen@scu.edu.cn

2015-02-27

Mammalian cysteine dioxygenase type 1 (CDO1) is an essential enzyme for taurine biosynthesis and the biodegradation of toxic cysteine. As previously suggested, Cdo1 may be a marker of liposarcoma progression and adipogenic differentiation, but the role of Cdo1 in adipogenesis has yet been reported. In this study, we found that the expression of Cdo1 is dramatically elevated during adipogenic differentiation of 3T3-L1 pre-adipocytes and mouse bone marrow-derived mesenchymal stem cells (mBMSCs). Conversely, knockdown of Cdo1 inhibited expression of adipogenic specific genes and lipid droplet formation in 3T3-L1 cells and mBMSCs. Mechanistically, we found Cdo1 interacted with Pparγ in response to adipogenic stimulus. Further, depletion of Cdo1 reduced the recruitment of Pparγ to the promoters of C/EBPα and Fabp4. Collectively, our finding indicates that Cdo1 may be a co-activator of Pparγ in adipogenesis, and may contribute to the development of disease associated with excessive adipose tissue. - Highlights: • Cdo1expression is highly up-regulated during adipogenic differentiation of 3T3-L1 and mBMSCs. • Depletion of Cdo1 inhibited expression of adipogenic specific genes and lipid droplet formation. • Cdo1interacts with Pparγ during adipogenesis. • Knockdown of Cdo1 inhibited Pparγ binding to the promoters of C/EBPα and Fabp4.

Association of Pro12Ala polymorphism of PPAR-γ2 Gene and diabetic retinopathy in type 2 diabetes

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Yong-Qing Liu

2013-06-01

Full Text Available AIM: To observe the relationship between Prol2Ala polymorphism of peroxisome proliferator activated receptor-γ2(PPAR-γ2gene and diabetic retinopathy(DRwith type 2 diabetic mellitus(T2DMof the Han nationality in Shanxi province. METHODS: Totally 90 patients with T2DM were selected into our research, who were at the age of 40 to 70 years old, diabetic duration from 10 to 20 years, blood pressure PPAR-γ2 gene were determined by polymerase chain reaction-restriction fragment length polymorphisms(PCR-RFLPassay in all the patients. RESULTS: PCR results showed that there were 2 alleles and 3 genotypes in the groups. The frequency of genotype PP, PA, AA were 40.0%, 53.3%, 6.7% in NDR group, 70.0%, 30.0%, 0.0% in BDR group, 76.7%, 23.3%, 0% in PDR group, respectively. The allele frequency(χ2=10.208and gene frequency(χ2=10.351were statistically significant(PCONCLUSION: The alanine variant of Prol2Ala polymorphism of PPAR-γ2 gene is associated with DR in type 2 diabetes among the Hans in Shanxi area, and the Ala allele might be a protective factor for the development of diabetic retinopathy.

Short-Chain Fatty Acids Stimulate Angiopoietin-Like 4 Synthesis in Human Colon Adenocarcinoma Cells by Activating Peroxisome Proliferator-Activated Receptor γ

DEFF Research Database (Denmark)

Alex, Sheril; Lange, Katja; Amolo, Tom

2013-01-01

with the notion that fermentation leads to PPAR activation in vivo, feeding mice a diet rich in inulin induced PPAR target genes and pathways in the colon. We conclude that (i) SCFA potently stimulate ANGPTL4 synthesis in human colon adenocarcinoma cells and (ii) SCFA transactivate and bind to PPARγ. Our data...

Hepatocellular proliferation in response to agonists of peroxisome proliferator-activated receptor alpha: a role for kupffer cells?

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Cunningham Michael

2006-01-01

Full Text Available Abstract Background It has been proposed that PPARα agonists stimulate Kupffer cells in rodents which in turn, release mitogenic factors leading to hepatic hyperplasia, and eventually cancer. However, Kupffer cells do not express PPARα receptors, and PPARα agonists stimulate hepatocellular proliferation in both TNFα- and TNFα receptor-null mice, casting doubt on the involvement of Kupffer cells in the mitogenic response to PPARα agonists. This study was therefore designed to investigate whether the PPARα agonist PFOA and the Kupffer cell inhibitor methylpalmitate produce opposing effects on hepatocellular proliferation and Kupffer cell activity in vivo, in a manner that would implicate these cells in the mitogenic effects of PPARα agonists. Methods Male Sprague-Dawley rats were treated intravenously via the tail vein with methylpalmitate 24 hrs prior to perfluorooctanoic acid (PFOA, and were sacrificed 24 hrs later, one hr after an intraperitoneal injection of bromodeoxyuridine (BrdU. Sera were analyzed for TNFα and IL-1β. Liver sections were stained immunohistochemically and quantified for BrdU incorporated into DNA. Results Data show that PFOA remarkably stimulated hepatocellular proliferation in the absence of significant changes in the serum levels of either TNFα or IL-1β. In addition, methylpalmitate did not alter the levels of these mitogens in PFOA-treated animals, despite the fact that it significantly blocked the hepatocellular proliferative effect of PFOA. Correlation between hepatocellular proliferation and serum levels of TNFα or IL-1β was extremely poor. Conclusion It is unlikely that mechanisms involving Kupffer cells play an eminent role in the hepatic hyperplasia, and consequently hepatocarcinogenicity attributed to PPARα agonists. This conclusion is based on the above mentioned published data and the current findings showing animals treated with PFOA alone or in combination with methylpalmitate to have similar

The nuclear receptor PPARγ as a therapeutic target for cerebrovascular and brain dysfunction in Alzheimer's disease

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Nektaria Nicolakakis

2010-05-01

Full Text Available Peroxisome proliferator-activated receptors (PPARs are ligand-activated nuclear transcription factors that regulate peripheral lipid and glucose metabolism. Three subtypes make up the PPAR family (α, γ, β/δ, and synthetic ligands for PPARα (fibrates and PPARγ (Thiazolidinediones, TZDs are currently prescribed for the respective management of dyslipidemia and type 2 diabetes. In contrast to the well characterized action of PPARs in the periphery, little was known about the presence or function of these receptors in the brain and cerebral vasculature, until fairly recently. Indeed, research in the last decade has uncovered these receptors in most brain cell types, and has shown that their activation, particularly that of PPARγ, is implicated in normal brain and cerebrovascular physiology, and confers protection under pathological conditions. Notably, accumulating evidence has highlighted the therapeutic potential of PPARγ ligands in the treatment of brain disorders such as Alzheimer’s disease (AD, leading to the testing of the TZDs pioglitazone and rosiglitazone in AD clinical trials. This review will focus on the benefits of PPARγ agonists for vascular, neuronal and glial networks, and assess the value of these compounds as future AD therapeutics in light of evidence from transgenic mouse models and recent clinical trials.

TLR4/MyD88/NF-κB signaling and PPAR-γ within the paraventricular nucleus are involved in the effects of telmisartan in hypertension

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Li, Hong-Bao; Li, Xiang; Huo, Chan-Juan; Su, Qing; Guo, Jing [Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an 710061 (China); Yuan, Zu-Yi [Department of Cardiovascular Medicine, First Affiliated Hospital of Medical College of Xi' an Jiaotong University, Xi' an 710061 (China); Zhu, Guo-Qing [Key Laboratory of Cardiovascular Disease and Molecular Intervention, Department of Physiology, Nanjing Medical University, Nanjing 210029 (China); Shi, Xiao-Lian, E-mail: shxl@mail.xjtu.edu.cn [Department of Pharmacology, School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Liu, Jin-Jun, E-mail: jupet@163.com [Department of Physiology and Pathophysiology, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an 710061 (China); Kang, Yu-Ming, E-mail: ykang@mail.xjtu.edu.cn [Department of Physiology and Pathophysiology, Key Laboratory of Environment and Genes Related to Diseases, Xi' an Jiaotong University School of Basic Medical Sciences, Xi' an Jiaotong University Health Science Center, Xi' an Jiaotong University Cardiovascular Research Center, Xi' an 710061 (China)

2016-08-15

Previous findings from our laboratory and others indicate that the main therapeutic effect of angiotensin II type 1 receptor (AT1-R) antagonists is to decrease blood pressure and exert anti-inflammatory effects in the cardiovascular system. In this study, we determined whether AT1-R antagonist telmisartan within the hypothalamic paraventricular nucleus (PVN) attenuates hypertension and hypothalamic inflammation via both the TLR4/MyD88/NF-κB signaling pathway and peroxisome proliferator-activated receptor-γ (PPAR-γ) in the PVN in hypertensive rats. Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto (WKY) rats were treated for 4 weeks through bilateral PVN infusion with the AT1-R antagonist telmisartan (TEL, 10 μg/h), or losartan (LOS, 20 μg/h), or the PPAR-γ antagonist GW9662 (GW, 100 μg/h), or vehicle via osmotic minipump. Mean arterial pressure (MAP) was recorded by a tail-cuff occlusion method. PVN tissue and blood were collected for the measurement of AT1-R, PPAR-γ, pro-inflammatory cytokines (tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6), inducible nitric oxide synthase (iNOS), TLR4, MyD88, nuclear factor-kappa B (NF-κB) activity and plasma norepinephrine (NE), respectively. Hypertensive rats exhibited significantly higher level of AT1-R and lower level of PPAR-γ in the PVN. PVN treatment with TEL attenuated MAP, improved cardiac hypertrophy, reduced TNF-α, IL-1β, IL-6, iNOS levels, and plasma NE in SHR but not in WKY rats. These results were associated with reduced TLR4, MyD88 and NF-κB levels and increased PPAR-γ level in the PVN of hypertensive rats. Our findings suggest that TLR4/MyD88/NF-κB signaling and PPAR-γ within the PVN are involved in the beneficial effects of telmisartan in hypertension. - Highlights: • PVN infusion of TEL in spontaneously hypertensive rats is reported. • PVN infusion of TEL attenuates hypertension and proinflammatory cytokines in PVN. • PVN blockade of AT1-R attenuates

Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children

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Stryjecki, Carolina; Peralta-Romero, Jesus; Alyass, Akram; Karam-Araujo, Roberto; Suarez, Fernando; Gomez-Zamudio, Jaime; Burguete-Garcia, Ana; Cruz, Miguel; Meyre, David

2016-01-01

The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10−4  ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia. PMID:27075119

Palmitic acid suppresses apolipoprotein M gene expression via the pathway of PPAR{sub β/δ} in HepG2 cells

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Luo, Guanghua; Shi, Yuanping; Zhang, Jun; Mu, Qinfeng; Qin, Li; Zheng, Lu; Feng, Yuehua [Comprehensive Laboratory, The Third Affiliated Hospital of Soochow University, Changzhou 213003 (China); Berggren-Söderlund, Maria; Nilsson-Ehle, Peter [Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund (Sweden); Zhang, Xiaoying, E-mail: zhangxy6689996@163.com [Department of Cardiothoracic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213003 (China); Xu, Ning, E-mail: ning.xu@med.lu.se [Division of Clinical Chemistry and Pharmacology, Department of Laboratory Medicine, Lund University, S-221 85 Lund (Sweden)

2014-02-28

Highlights: • Palmitic acid significantly inhibited APOM gene expression in HepG2 cells. • Palmitic acid could obviously increase PPARB/D mRNA levels in HepG2 cells. • PPAR{sub β/δ} antagonist, GSK3787, had no effect on APOM expression. • GSK3787 could reverse the palmitic acid-induced down-regulation of APOM expression. • Palmitic acid induced suppression of APOM expression is mediated via the PPAR{sub β/δ} pathway. - Abstract: It has been demonstrated that apolipoprotein M (APOM) is a vasculoprotective constituent of high density lipoprotein (HDL), which could be related to the anti-atherosclerotic property of HDL. Investigation of regulation of APOM expression is of important for further exploring its pathophysiological function in vivo. Our previous studies indicated that expression of APOM could be regulated by platelet activating factor (PAF), transforming growth factors (TGF), insulin-like growth factor (IGF), leptin, hyperglycemia and etc., in vivo and/or in vitro. In the present study, we demonstrated that palmitic acid could significantly inhibit APOM gene expression in HepG2 cells. Further study indicated neither PI-3 kinase (PI3K) inhibitor LY294002 nor protein kinase C (PKC) inhibitor GFX could abolish palmitic acid induced down-regulation of APOM expression. In contrast, the peroxisome proliferator-activated receptor beta/delta (PPAR{sub β/δ}) antagonist GSK3787 could totally reverse the palmitic acid-induced down-regulation of APOM expression, which clearly demonstrates that down-regulation of APOM expression induced by palmitic acid is mediated via the PPAR{sub β/δ} pathway.

Synergistic Effects of PPARγ Ligands and Retinoids in Cancer Treatment

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Masahito Shimizu

2008-01-01

Full Text Available Peroxisome proliferator-activated receptors (PPARs are members of the nuclear receptor superfamily. The activation of PPARs by their specific ligands is regarded as one of the promising strategies to inhibit cancer cell growth. However, recent clinical trials targeting several common cancers showed no beneficial effect when PPAR ligands are used as a monotherapy. Retinoid X receptors (RXRs, which play a critical role in normal cell proliferation as a master regulator for nuclear receptors, preferentially form heterodimers with PPARs. A malfunction of RXRα due to phosphorylation by the Ras/MAPK signaling pathway is associated with the development of certain types of human malignancies. The activation of PPARγ/RXR heterodimer by their respective ligands synergistically inhibits cell growth, while inducing apoptosis in human colon cancer cells when the phosphorylation of RXRα was inhibited. We herein review the synergistic antitumor effects produced by the combination of the PPAR, especially PPARγ, ligands plus other agents, especially retinoids, in a variety of human cancers. We also focus on the phosphorylation of RXRα because the inhibition of RXRα phosphorylation and the restoration of its physiological function may activate PPAR/RXR heterodimer and, therefore, be a potentially effective and critical strategy for the inhibition of cancer cell growth.

Structural Features and Transcriptional Activity of Chicken PPARs (α, β, and γ

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Ichiro Takada

2013-01-01

Full Text Available While an understanding of lipid metabolism in chickens is critical for a further improvement of food production, there are few studies concerning differences in lipid metabolism mechanisms between chickens and other species at a molecular level. Chickens have three PPAR gene subtypes (α, β, and γ that function differently from those present in humans and mice. The chicken PPAR-gamma (cPPARγ gene is shorter than that in humans and lacks a γ2 isoform. Moreover, in serum-free media, cPPARγ shows high transcriptional activity without exogenous ligands. Luciferase reporter assays were used to examine the effect of sera on cPPAR transcriptional activities and showed that adult bovine serum and chicken serum highly activate cPPARα and β functions. Moreover, we found that bezafibrate induces the transactivation function of cPPARβ, but not human PPARδ (human PPARβ ortholog. This ligand selectivity relies on one amino acid residue (chicken: Val419, human: Met444. These results show the possibilities for unique functions of cPPARs on chicken-specific lipid glucose metabolism. As such, a better understanding of the molecular mechanisms of lipid metabolism in chickens could result in higher productivity for the poultry industry.

Microglia P2Y13 Receptors Prevent Astrocyte Proliferation Mediated by P2Y1 Receptors

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Clara Quintas

2018-05-01

Full Text Available Cerebral inflammation is a common feature of several neurodegenerative diseases that requires a fine interplay between astrocytes and microglia to acquire appropriate phenotypes for an efficient response to neuronal damage. During brain inflammation, ATP is massively released into the extracellular medium and converted into ADP. Both nucleotides acting on P2 receptors, modulate astrogliosis through mechanisms involving microglia-astrocytes communication. In previous studies, primary cultures of astrocytes and co-cultures of astrocytes and microglia were used to investigate the influence of microglia on astroglial proliferation induced by ADPβS, a stable ADP analog. In astrocyte cultures, ADPβS increased cell proliferation through activation of P2Y1 and P2Y12 receptors, an effect abolished in co-cultures (of astrocytes with ∼12.5% microglia. The possibility that the loss of the ADPβS-mediated effect could have been caused by a microglia-induced degradation of ADPβS or by a preferential microglial localization of P2Y1 or P2Y12 receptors was excluded. Since ADPβS also activates P2Y13 receptors, the contribution of microglial P2Y13 receptors to prevent the proliferative effect of ADPβS in co-cultures was investigated. The results obtained indicate that P2Y13 receptors are low expressed in astrocytes and mainly expressed in microglia. Furthermore, in co-cultures, ADPβS induced astroglial proliferation in the presence of the selective P2Y13 antagonist MRS 2211 (3 μM and of the selective P2Y12 antagonist AR-C66096 (0.1 μM, suggesting that activation of microglial P2Y12 and P2Y13 receptors may induce the release of messengers that inhibit astroglial proliferation mediated by P2Y1,12 receptors. In this microglia-astrocyte paracrine communication, P2Y12 receptors exert opposite effects in astroglial proliferation as a result of its cellular localization: cooperating in astrocytes with P2Y1 receptors to directly stimulate proliferation and in

Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family.

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Schmidt, A; Vogel, R; Holloway, M K; Rutledge, S J; Friedman, O; Yang, Z; Rodan, G A; Friedman, E

1999-09-10

LXR and PPAR receptors belong to the nuclear receptor superfamily of transcriptional activating factors. Using ligand-dependent transcription assays, we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates chimeric receptors composed of the glucocorticoid receptor DNA binding domain and the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER) receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L-631,033) and LXRs (hydroxycholesterols) maintain their respective receptor selectivity. TOFA and hydroxycholesterols also stimulate transcription from a minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB transcription factor binding sites. In addition to their effects on transcription, these LXRbeta activators induce neuronal differentiation in rat pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)-hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells, respectively. No neurite outgrowth was induced by the related 22(S)-hydroxycholesterol, which does not activate the LXR family. These results suggest that the hydroxycholesterol signaling pathway has a complex effect on transcription that mediates the activity of TOFA and hydroxycholesterol on neuronal differentiation in pheochromocytoma cells.

The Effect of Resveratrol and Quercetin Treatment on PPAR Mediated Uncoupling Protein (UCP- 1, 2, and 3 Expression in Visceral White Adipose Tissue from Metabolic Syndrome Rats

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Vicente Castrejón-Tellez

2016-07-01

Full Text Available Uncoupling proteins (UCPs are members of the mitochondrial anion carrier superfamily involved in the control of body temperature and energy balance regulation. They are currently proposed as therapeutic targets for treating obesity and metabolic syndrome (MetS. We studied the gene expression regulation of UCP1, -2, and -3 in abdominal white adipose tissue (WAT from control and MetS rats treated with two doses of a commercial mixture of resveratrol (RSV and quercetin (QRC. We found that UCP2 was the predominantly expressed isoform, UCP3 was present at very low levels, and UCP1 was undetectable. The treatment with RSV + QRC did not modify UCP3 levels; however, it significantly increased UCP2 mRNA in control and MetS rats in association with an increase in oleic and linoleic fatty acids. WAT from MetS rats showed a significantly increased expression of peroxisome proliferator-activated receptor (PPAR-α and PPAR-γ when compared to the control group. Furthermore, PPAR-α protein levels were increased by the highest dose of RSV + QRC in the control and MetS groups. PPAR-γ expression was only increased in the control group. We conclude that the RSV + QRC treatment leads to overexpression of UCP2, which is associated with an increase in MUFA and PUFA, which might increase PPAR-α expression.

Peroxisome proliferator-activated receptor α agonist-induced down-regulation of hepatic glucocorticoid receptor expression in SD rats

International Nuclear Information System (INIS)

Chen Xiang; Li Ming; Sun Weiping; Bi Yan; Cai Mengyin; Liang Hua; Yu Qiuqiong; He Xiaoying; Weng Jianping

2008-01-01

It was reported that glucocorticoid production was inhibited by fenofibrate through suppression of type-1 11β-hydroxysteroid dehydrogenase gene expression in liver. The inhibition might be a negative-feedback regulation of glucocorticoid receptor (GR) activity by peroxisome proliferator-activated receptor alpha (PPARα), which is quickly induced by glucocorticoid in the liver. However, it is not clear if GR expression is changed by fenofibrate-induced PPARα activation. In this study, we tested this possibility in the liver of Sprague-Dawley rats. GR expression was reduced by fenofibrate in a time- and does-dependent manner. The inhibition was observed in liver, but not in fat and muscle. The corticosterone level in the blood was increased significantly by fenofibrate. These effects of fenofibrate were abolished by PPARα inhibitor MK886, suggesting that fenofibrate activated through PPARα. In conclusion, inhibition of GR expression may represent a new molecular mechanism for the negative feedback regulation of GR activity by PPARα

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

Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

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den Besten, Gijs; Gerding, Albert; van Dijk, Theo H; Ciapaite, Jolita; Bleeker, Aycha; van Eunen, Karen; Havinga, Rick; Groen, Albert K; Reijngoud, Dirk-Jan; Bakker, Barbara M

2015-01-01

The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs), have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR) γ repression and AMP-activated protein kinase (AMPK) activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

Protection against the Metabolic Syndrome by Guar Gum-Derived Short-Chain Fatty Acids Depends on Peroxisome Proliferator-Activated Receptor γ and Glucagon-Like Peptide-1.

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Gijs den Besten

Full Text Available The dietary fiber guar gum has beneficial effects on obesity, hyperglycemia and hypercholesterolemia in both humans and rodents. The major products of colonic fermentation of dietary fiber, the short-chain fatty acids (SCFAs, have been suggested to play an important role. Recently, we showed that SCFAs protect against the metabolic syndrome via a signaling cascade that involves peroxisome proliferator-activated receptor (PPAR γ repression and AMP-activated protein kinase (AMPK activation. In this study we investigated the molecular mechanism via which the dietary fiber guar gum protects against the metabolic syndrome. C57Bl/6J mice were fed a high-fat diet supplemented with 0% or 10% of the fiber guar gum for 12 weeks and effects on lipid and glucose metabolism were studied. We demonstrate that, like SCFAs, also guar gum protects against high-fat diet-induced metabolic abnormalities by PPARγ repression, subsequently increasing mitochondrial uncoupling protein 2 expression and AMP/ATP ratio, leading to the activation of AMPK and culminating in enhanced oxidative metabolism in both liver and adipose tissue. Moreover, guar gum markedly increased peripheral glucose clearance, possibly mediated by the SCFA-induced colonic hormone glucagon-like peptide-1. Overall, this study provides novel molecular insights into the beneficial effects of guar gum on the metabolic syndrome and strengthens the potential role of guar gum as a dietary-fiber intervention.

Effect of Persea americana (avocado) fruit extract on the level of expression of adiponectin and PPAR-γ in rats subjected to experimental hyperlipidemia and obesity.

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Padmanabhan, Monika; Arumugam, Geetha

2014-06-01

Persea americana, commonly known as avocado, is traditionally consumed fruit which possesses body fat lowering capacity. Adiponectin plays an important role in regulating obesity. In this study, the effect of hydro-alcoholic fruit extract of P. americana (HAEPA) on the level of blood lipids, glutathione, lipid peroxidation products, adiponectin and peroxisome proliferator activated receptor (PPAR)-γ expressions was investigated in rats fed a high-fat diet (HFD). Male Sprague Dawley rats were divided into four groups: groups 1 and 2 were fed normal rat chow (5% fat) and groups 3 and 4 were fed HFD (23% fat) for a period of 14 weeks. In addition, groups 2 and 4 rats were administered orally with 100 mg/kg body weight of HAEPA from third week. After 14 weeks, rats were sacrificed, and serum/plasma levels of total cholesterol, phospholipids, triglyceride, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and adiponectin were determined. The mRNA expression of adiponectin, PPAR-γ and protein expression of PPAR-γ were also evaluated. The body mass index (BMI), total fat pad mass and adiposity index were significantly decreased in HAEPA co-administered rats than in HFD-fed rats. The levels of LDL and lipid peroxides were significantly higher in HFD group than in HFD+HAEPA group. Levels of reduced glutathione, adiponectin, mRNA expression of adiponectin, PPAR-γ and protein expression of PPAR-γ were found to be increased in HFD+HAEPA group than in HFD group. The hypolipidemic effect of HAEPA is also evidenced by the histological observations in liver, heart and adipose tissue. The results indicate that HAEPA exhibits hypolipidemic activity probably by increasing the mRNA expression of adiponectin and PPAR-γ, which reduce the risk of hyperlipidemia and obesity.

Peroxisome Proliferator-Activated Receptors and Hepatitis C Virus-Induced Insulin Resistance

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Francesco Negro

2009-01-01

Full Text Available Insulin resistance and type 2 diabetes are associated with hepatitis C virus infection. A wealth of clinical and experimental data suggests that the virus is directly interfering with the insulin signalling in hepatocytes. In the case of at least one viral genotype (the type 3a, insulin resistance seems to be directly mediated by the downregulation of the peroxisome proliferator-activated receptor γ. Whether and how this interaction may be manipulated pharmacologically, in order to improve the responsiveness to antivirals of insulin resistant chronic hepatitis C, patients remain to be fully explored.

Overproduction of altered VLDL in an insulin-resistance rat model: Influence of SREBP-1c and PPAR-α.

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Lucero, Diego; Miksztowicz, Verónica; Macri, Vanesa; López, Gustavo H; Friedman, Silvia; Berg, Gabriela; Zago, Valeria; Schreier, Laura

2015-01-01

In insulin-resistance, VLDL presents alterations that increase its atherogenic potential. The mechanism by which insulin-resistance promotes the production of altered VLDL is still not completely understood. The aim of this study was to evaluate the relationship between the expression of sterol regulatory element binding protein 1c (SREBP-1c) and of peroxisome proliferator-activated receptor-α (PPAR-α), with the features of composition and size of VLDL in an insulin-resistance rat model induced by a sucrose rich diet (SRD). The study was conducted on 12 male Wistar rats (180g) receiving SRD (12 weeks) and 12 controls. Lipid profile, free fatty acids, glucose, and insulin were measured. Lipid content in liver and visceral fat were assessed. Isolated VLDL (d<1.006g/ml) was characterized by its chemical composition and size by HPLC. The respective hepatic expression of SREBP-1c and PPAR-α was determined (Western blot). As expected, SRD had elevated triglycerides (TG), free fatty acids and insulin levels, and decreased HDL-cholesterol (p<0.05), together with augmented hepatic and visceral fat (p<0.05). SRD showed higher VLDL total mass - with increased TG content - and predominance of large VLDL (p<0.05). SRD showed an increase in SREBP-1c (precursor and mature forms) and decreased PPAR-α expression (p<0.045). SREBP-1c forms were positively associated with VLDL total mass (p<0.04), VLDL-TG% (p<0.019), and large VLDL% (p<0.002). On the other hand, PPAR-α correlated negatively with VLDL total mass (p=0.05), VLDL-TG% (p=0.005), and large VLDL% (p=0.002). Insulin-resistance, by coordinated activation of SREBP-1c and reduction of PPAR-α, could promote the secretion of larger and TG over-enriched VLDL particles, with greater atherogenic capacity. Copyright © 2014 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

Vitamin D deficiency impairs glucose-stimulated insulin secretion and increases insulin resistance by reducing PPAR-γ expression in nonobese Type 2 diabetic rats.

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Park, Sunmin; Kim, Da Sol; Kang, Suna

2016-01-01

Human studies have provided relatively strong associations of poor vitamin D status with Type 2 diabetes but do not explain the nature of the association. Here, we explored the physiological pathways that may explain how vitamin D status modulates energy, lipid and glucose metabolisms in nonobese Type 2 diabetic rats. Goto-Kakizaki (GK) rats were fed high-fat diets containing 25 (VD-low), 1000 (VD-normal) or 10,000 (VD-high) cholecalciferol-IU/kg diet for 8 weeks. Energy expenditure, insulin resistance, insulin secretory capacity and lipid metabolism were measured. Serum 25-OH-D levels, an index of vitamin D status, increased dose dependently with dietary vitamin D. VD-low resulted in less fat oxidation without a significant difference in energy expenditure and less lean body mass in the abdomen and legs comparison to the VD-normal group. In comparison to VD-low, VD-normal had lower serum triglycerides and intracellular fat accumulation in the liver and skeletal muscles which was associated with down-regulation of the mRNA expressions of sterol regulatory element binding protein-1c and fatty acid synthase and up-regulation of gene expressions of peroxisome proliferator-activated receptors (PPAR)-α and carnitine palmitoyltransferase-1. In euglycemic hyperinsulinemic clamp, whole-body and hepatic insulin resistance was exacerbated in the VD-low group but not in the VD-normal group, possibly through decreasing hepatic insulin signaling and PPAR-γ expression in the adipocytes. In 3T3-L1 adipocytes 1,25-(OH)2-D (10 nM) increased triglyceride accumulation by elevating PPAR-γ expression and treatment with a PPAR-γ antagonist blocked the triglyceride deposition induced by 1,25-(OH)2-D treatment. VD-low impaired glucose-stimulated insulin secretion in hyperglycemic clamp and decreased β-cell mass by decreasing β-cell proliferation. In conclusion, vitamin D deficiency resulted in the dysregulation of glucose metabolism in GK rats by simultaneously increasing insulin

Journal of Chemical Sciences | Indian Academy of Sciences

Indian Academy of Sciences (India)

... peroxisome proliferator activated receptors ligands expected to exhibit PPAR and PPAR partial agonism in the management of hyperglycemia and hyperlipidemia for the treatment of type 2 diabetes is reported. Computational validation of the designed molecules through activity prediction and docking studies showed ...

Triptolide disrupts fatty acids and peroxisome proliferator-activated receptor (PPAR) levels in male mice testes followed by testicular injury: A GC–MS based metabolomics study

International Nuclear Information System (INIS)

Ma, Bo; Qi, Huanhuan; Li, Jing; Xu, Hong; Chi, Bo; Zhu, Jianwei; Yu, Lisha; An, Guohua; Zhang, Qi

2015-01-01

Graphical abstract: Heat map of hierarchical clustering of the testicular tissue samples (A) and serum samples (B) at the 2nd week. Red blocks indicate increased intensities whereas blue indicates decreased intensities. The above two columns represent model group and normal group. - Abstract: Triptolide is the major active ingredient of Tripterygium Glycosides (TG), a traditional Chinese medicine with very potent anti-inflammatory effects and has been used in China for the treatment of rheumatoid arthritis and many other inflammatory diseases. However, clinical application of triptolide is restricted due to its multiple side effects, especially male infertility. The mechanism of triptolide on reproduction toxicity remains unclear. In the present study, a GC–MS based metabolomic approach was employed to evaluate the mechanism of triptolide-induced reproductive toxicity as well as identify potential novel biomarkers for the early detection of spermatogenesis dysfunction. In brief, male mice were divided into two groups with or without triptolide intraperitoneal injection at 60 μg/kg/day for 2 weeks and toxic effect of triptolide on testicular tissues were examined by biochemical indicator analysis, testis histopathologic analysis, and sperm quantity analysis. Metabolomics technology was then performed to evaluate systematically the endogenous metabolites profiling. Our results demonstrated that triptolide suppressed the marker-enzymes of spermatogenesis and testosterone levels, decreased sperm counts, reduced the gonad index and destroyed the microstructure of testis. Multivariate data analysis revealed that mice with triptolide induced testicular toxicity could be distinctively differentiated from normal animals and 35 and 39 small molecule metabolites were changed significantly in testis and serum, respectively (Fold-changes >1.5, P < 0.05), in triptolide-treated mice. Abnormal level of fatty acids, an important energy source of sertoli cells with critical role

The effect of PPAR-γ agonist on 18F-FDG uptake in tumor and macrophages and tumor cells

International Nuclear Information System (INIS)

Kim, Se-Lim; Kim, Eun-Mi; Cheong, Su-Jin; Lee, Chang-Moon; Kim, Dong Wook; Jeong, Hwan-Jeong; Lim, Seok Tae; Sohn, Myung-Hee; Yim, Chang Yeol

2009-01-01

Purpose: The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a member of the nuclear receptor superfamily of ligand-dependent transcription factors, and its role in adipogenesis and glucose metabolism has been well established. PPAR-γ agonists have been shown to inhibit many cytokines and to have anti-inflammatory effects. In pathologic conditions, enhanced fluoro-2-deoxy-D-glucose (FDG) uptake is observed not only in malignant tumors but also in inflammatory lesions, and this uptake occurs through the glucose transporter in these cells. Thus, the present study was undertaken to investigate the potential of using PPAR-γ's glucose uptake ability as a diagnostic tool to differentiate between macrophage and tumor cells. Materials and Methods: Cellular uptake studies were carried out on macrophage and two tumor cell lines for comparison by using 18 F-FDG. Western blot analysis was performed to determine the expression levels of both the glucose transporter and hexokinase protein. To confirm the possibility of differentiation between tumor and inflammatory lesions using rosiglitazone based on in vitro studies, 18 F-FDG (3.7x10 6 Bq) uptake in A549 and RAW 264.7 xenograft mice was compared. Results: The cellular uptake study findings were quite different for macrophages and tumor cells. 18 F-FDG uptakes by macrophages decreased by about 60% but was increased twofold in tumor cells after rosiglitazone treatment. Moreover, the expressions of proteins related to glucose uptake correlated well with cellular glucose accumulation in both cell types. Higher tumor uptake was observed after the injection of rosiglitazone in A549 xenograft mice (1.58±0.55 to 4.66±1.16), but no significant change of 18 F-FDG uptake was shown in RAW 264.7 xenograft mice (4.04±1.16 to 4.00±0.14). Conclusion: The present study demonstrates the roles of PPAR-γ agonist on FDG uptake in macrophages and tumor cells in vitro and in vivo. Our findings suggest that rosiglitazone has the

DHEA attenuates PDGF-induced phenotypic proliferation of vascular smooth muscle A7r5 cells through redox regulation

Energy Technology Data Exchange (ETDEWEB)

Urata, Yoshishige; Goto, Shinji; Kawakatsu, Miho [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan); Yodoi, Junji [Department of Biological Responses, Institute for Viral Research, Graduate School of Medicine, Kyoto University, 53 Shogain, Kawahara-cho, Sakyo-ku, Kyoto 606-8397 (Japan); Eto, Masato [Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Akishita, Masahiro, E-mail: akishita-tky@umin.ac.jp [Department of Geriatric Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 (Japan); Kondo, Takahito [Department of Biochemistry and Molecular Biology in Disease, Atomic Bomb Disease Institute, Nagasaki University Graduate School of Medical Sciences, 1-12-4 Sakamoto, Nagasaki 852-8523 (Japan)

2010-05-28

It is known that dehydroepiandrosterone (DHEA) inhibits a phenotypic switch in vascular smooth muscle cells (VSMC) induced by platelet-derived growth factor (PDGF)-BB. However, the mechanism behind the effect of DHEA on VSMC is not clear. Previously we reported that low molecular weight-protein tyrosine phosphatase (LMW-PTP) dephosphorylates PDGF receptor (PDGFR)-{beta} via a redox-dependent mechanism involving glutathione (GSH)/glutaredoxin (GRX)1. Here we demonstrate that the redox regulation of PDGFR-{beta} is involved in the effect of DHEA on VSMC. DHEA suppressed the PDGF-BB-dependent phosphorylation of PDGFR-{beta}. As expected, DHEA increased the levels of GSH and GRX1, and the GSH/GRX1 system maintained the redox state of LMW-PTP. Down-regulation of the expression of LMW-PTP using siRNA restored the suppression of PDGFR-{beta}-phosphorylation by DHEA. A promoter analysis of GRX1 and {gamma}-glutamylcysteine synthetase ({gamma}-GCS), a rate-limiting enzyme of GSH synthesis, showed that DHEA up-regulated the transcriptional activity at the peroxisome proliferator-activated receptor (PPAR) response element, suggesting PPAR{alpha} plays a role in the induction of GRX1 and {gamma}-GCS expression by DHEA. In conclusion, the redox regulation of PDGFR-{beta} is involved in the suppressive effect of DHEA on VSMC proliferation through the up-regulation of GSH/GRX system.

PPAR Agonists: Potential as Therapeutics for Neovascular Retinopathies

Directory of Open Access Journals (Sweden)

Harrihar A. Pershadsingh

2008-01-01

Full Text Available The angiogenic, neovascular proliferative retinopathies, proliferative diabetic retinopathy (PDR, and age-dependent macular degeneration (AMD complicated by choroidal neovascularization (CNV, also termed exudative or “wet” AMD, are common causes of blindness. The antidiabetic thiazolidinediones (TZDs, rosiglitazone, and troglitazone are PPAR agonists with demonstrable antiproliferative, and anti-inflammatory effects, in vivo, were shown to ameliorate PDR and CNV in rodent models, implying the potential efficacy of TZDs for treating proliferative retinopathies in humans. Activation of the angiotensin II type 1 receptor (AT1-R propagates proinflammatory and proliferative pathogenic determinants underlying PDR and CNV. The antihypertensive dual AT1-R blocker (ARB, telmisartan, recently was shown to activate PPAR and improve glucose and lipid metabolism and to clinically improve PDR and CNV in rodent models. Therefore, the TZDs and telmisartan, clinically approved antidiabetic and antihypertensive drugs, respectively, may be efficacious for treating and attenuating PDR and CNV humans. Clinical trials are needed to test these possibilities.

Synthesis and biological evaluation of 2-heteroarylthioalkanoic acid analogues of clofibric acid as peroxisome proliferator-activated receptor alpha agonists.

Science.gov (United States)

Giampietro, Letizia; Ammazzalorso, Alessandra; Giancristofaro, Antonella; Lannutti, Fabio; Bettoni, Giancarlo; De Filippis, Barbara; Fantacuzzi, Marialuigia; Maccallini, Cristina; Petruzzelli, Michele; Morgano, Annalisa; Moschetta, Antonio; Amoroso, Rosa

2009-10-22

A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.

Catalpic acid decreases abdominal fat deposition, improves glucose homeostasis and upregulates PPAR alpha expression in adipose tissue.

Science.gov (United States)

Hontecillas, Raquel; Diguardo, Maggie; Duran, Elisa; Orpi, Marcel; Bassaganya-Riera, Josep

2008-10-01

Catalpic acid (CAT) is a conjugated linolenic acid (CLN) isomer containing trans-9, trans-11, cis-13 double bonds in an 18-carbon chain and it is found primarily in the seed oil of ornamental and medicinal trees and shrubs of the family Bignoniaceae. The objective of this study was to investigate whether CAT decreases obesity and ameliorates insulin sensitivity and glucose tolerance in mice fed high-fat diets. To test the efficacy of CAT in decreasing obesity and diabetes we used both a model of diet-induced obesity (DIO) and a genetic model of obesity (i.e., mice lacking the leptin receptor). Blood was collected on days 0, 7, 14, 21 and 28 for determining fasting glucose and insulin concentrations in plasma. In addition, a glucose tolerance test was administered on day 28. We found that dietary CAT (1g/100g) decreased fasting plasma glucose and insulin concentrations, ameliorated the glucose normalizing ability following glucose challenge and decreased abdominal white adipose tissue accumulation. In white adipose tissue (WAT), CAT upregulated peroxisome proliferator-activated receptor (PPAR) alpha and its responsive genes [i.e., stearoyl-coenzyme A desaturase (SCD1) and enoyl-coenzyme A hydratase (ECH)], increased concentrations of high-density lipoprotein (HDL) cholesterol and decreased plasma triglyceride (TG) levels. CAT decreased abdominal fat deposition, increased HDL cholesterol, decreased TG concentrations, decreased glucose and insulin homeostasis and modulated WAT gene expression in a manner reminiscent of the actions of the PPAR alpha-activating fibrate class of lipid-lowering drugs.

Does bilirubin prevent hepatic steatosis through activation of the PPARα nuclear receptor?

Science.gov (United States)

Hinds, Terry D; Adeosun, Samuel O; Alamodi, Abdulhadi A; Stec, David E

2016-10-01

Several large population studies have demonstrated a negative correlation between serum bilirubin levels and the development of obesity, hepatic steatosis, and cardiovascular disease. Despite the strong correlative data demonstrating the protective role of bilirubin, the mechanism by which bilirubin can protect against these pathologies remains unknown. Bilirubin has long been known as a powerful antioxidant and also has anti-inflammatory actions, each of which may contribute to the protection afforded by increased levels. We have recently described a novel function of bilirubin as a ligand for the peroxisome proliferator-activated receptor-alpha (PPARα), which we show specifically binds to the nuclear receptor. Bilirubin may function as a selective PPAR modulator (SPPARM) to control lipid accumulation and blood glucose. However, it is not known to what degree bilirubin activation of PPARα is responsible for the protection afforded to reduce hepatic steatosis. We hypothesize that bilirubin, acting as a novel SPPARM, increases hepatic fatty acid metabolism through a PPARα-dependent mechanism which reduces hepatic lipid accumulation and protects against hepatic steatosis and non-alcoholic fatty liver disease (NAFLD). Copyright © 2016 Elsevier Ltd. All rights reserved.

Enhancement of arachidonic acid signaling pathway by nicotinic acid receptor HM74A

Energy Technology Data Exchange (ETDEWEB)

Tang, Yuting [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Zhou, Lubing [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Gunnet, Joseph W [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Wines, Pamela G [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Cryan, Ellen V [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States); Demarest, Keith T [Endocrine Therapeutics and Metabolic Disorders, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., 1000 Rt. 202, Raritan, NJ 08869 (United States)

2006-06-23

HM74A is a G protein-coupled receptor for nicotinic acid (niacin), which has been used clinically to treat dyslipidemia for decades. The molecular mechanisms whereby niacin exerts its pleiotropic effects on lipid metabolism remain largely unknown. In addition, the most common side effect in niacin therapy is skin flushing that is caused by prostaglandin release, suggesting that the phospholipase A{sub 2} (PLA{sub 2})/arachidonic acid (AA) pathway is involved. Various eicosanoids have been shown to activate peroxisome-proliferator activated receptors (PPAR) that play a diverse array of roles in lipid metabolism. To further elucidate the potential roles of HM74A in mediating the therapeutic effects and/or side effects of niacin, we sought to explore the signaling events upon HM74A activation. Here we demonstrated that HM74A synergistically enhanced UTP- and bradykinin-mediated AA release in a pertussis toxin-sensitive manner in A431 cells. Activation of HM74A also led to Ca{sup 2+}-mobilization and enhanced bradykinin-promoted Ca{sup 2+}-mobilization through Gi protein. While HM74A increased ERK1/2 activation by the bradykinin receptor, it had no effects on UTP-promoted ERK1/2 activation.Furthermore, UTP- and bradykinin-mediated AA release was significantly decreased in the presence of both MAPK kinase inhibitor PD 098059 and PKC inhibitor GF 109203X. However, the synergistic effects of HM74A were not dramatically affected by co-treatment with both inhibitors, indicating the cross-talk occurred at the receptor level. Finally, stimulation of A431 cells transiently transfected with PPRE-luciferase with AA significantly induced luciferase activity, mimicking the effects of PPAR{gamma} agonist rosiglitazone, suggesting that alteration of AA signaling pathway can regulate gene expression via endogenous PPARs.

Mutation analysis of peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) and relationships of identified amino acid polymorphisms to Type II diabetes mellitus

DEFF Research Database (Denmark)

Ek, J; Andersen, G; Urhammer, S A

2001-01-01

This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus.......This study aimed to investigate if variability in the peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1) gene is associated with Type II (non-insulin-dependent) diabetes mellitus....

PPAR/RXR Regulation of Fatty Acid Metabolism and Fatty Acid -Hydroxylase (CYP4 Isozymes: Implications for Prevention of Lipotoxicity in Fatty Liver Disease

Directory of Open Access Journals (Sweden)

James P. Hardwick

2009-01-01

Full Text Available Fatty liver disease is a common lipid metabolism disorder influenced by the combination of individual genetic makeup, drug exposure, and life-style choices that are frequently associated with metabolic syndrome, which encompasses obesity, dyslipidemia, hypertension, hypertriglyceridemia, and insulin resistant diabetes. Common to obesity related dyslipidemia is the excessive storage of hepatic fatty acids (steatosis, due to a decrease in mitochondria -oxidation with an increase in both peroxisomal -oxidation, and microsomal -oxidation of fatty acids through peroxisome proliferator activated receptors (PPARs. How steatosis increases PPAR activated gene expression of fatty acid transport proteins, peroxisomal and mitochondrial fatty acid -oxidation and -oxidation of fatty acids genes regardless of whether dietary fatty acids are polyunsaturated (PUFA, monounsaturated (MUFA, or saturated (SFA may be determined by the interplay of PPARs and HNF4 with the fatty acid transport proteins L-FABP and ACBP. In hepatic steatosis and steatohepatitis, the -oxidation cytochrome P450 CYP4A gene expression is increased even with reduced hepatic levels of PPAR. Although numerous studies have suggested the role ethanol-inducible CYP2E1 in contributing to increased oxidative stress, Cyp2e1-null mice still develop steatohepatitis with a dramatic increase in CYP4A gene expression. This strongly implies that CYP4A fatty acid -hydroxylase P450s may play an important role in the development of steatohepatitis. In this review and tutorial, we briefly describe how fatty acids are partitioned by fatty acid transport proteins to either anabolic or catabolic pathways regulated by PPARs, and we explore how medium-chain fatty acid (MCFA CYP4A and long-chain fatty acid (LCFA CYP4F -hydroxylase genes are regulated in fatty liver. We finally propose a hypothesis that increased CYP4A expression with a decrease in CYP4F genes may promote the progression of steatosis to

The Peroxisome Proliferator-Activated Receptor α is dispensable for cold-induced adipose tissue browning in mice

NARCIS (Netherlands)

Defour, Merel; Dijk, Wieneke; Ruppert, Philip; Nascimento, Emmani B.M.; Schrauwen, Patrick; Kersten, Sander

2018-01-01

Objective: Chronic cold exposure causes white adipose tissue (WAT) to adopt features of brown adipose tissue (BAT), a process known as browning. Previous studies have hinted at a possible role for the transcription factor Peroxisome Proliferator-Activated Receptor alpha (PPARα) in cold-induced

Effects of the PPAR-β agonist GW501516 in an in vitro model of brain inflammation and antibody-induced demyelination

Directory of Open Access Journals (Sweden)

Honegger Paul

2009-05-01

Full Text Available Abstract Background Brain inflammation plays a central role in numerous brain pathologies, including multiple sclerosis (MS. Microglial cells and astrocytes are the effector cells of neuroinflammation. They can be activated also by agents such as interferon-γ (IFN-γ and lipopolysaccharide (LPS. Peroxisome proliferator-associated receptor (PPAR pathways are involved in the control of the inflammatory processes, and PPAR-β seems to play an important role in the regulation of central inflammation. In addition, PPAR-β agonists were shown to have trophic effects on oligodendrocytes in vitro, and to confer partial protection in experimental autoimmune encephalomyelitis (EAE, an animal model of MS. In the present work, a three-dimensional brain cell culture system was used as in vitro model to study antibody-induced demyelination and inflammatory responses. GW 501516, a specific PPAR-β agonist, was examined for its capacity to protect from antibody-mediated demyelination and to prevent inflammatory responses induced by IFN-γ and LPS. Methods Aggregating brain cells cultures were prepared from embryonal rat brain, and used to study the inflammatory responses triggered by IFN-γ and LPS and by antibody-mediated demyelination induced by antibodies directed against myelin-oligodendrocyte glycoprotein (MOG. The effects of GW 501516 on cellular responses were characterized by the quantification of the mRNA expression of tumor necrosis factor-α (TNF-α, interleukin-6 (IL-6, inducible NO synthase (i-NOS, PPAR-β, PPAR-γ, glial fibrillary acidic protein (GFAP, myelin basic protein (MBP, and high molecular weight neurofilament protein (NF-H. GFAP expression was also examined by immunocytochemistry, and microglial cells were visualized by isolectin B4 (IB4 and ED1 labeling. Results GW 501516 decreased the IFN-γ-induced up-regulation of TNF-α and iNOS in accord with the proposed anti-inflammatory effects of this PPAR-β agonist. However, it increased IL

The PPARα/p16INK4a Pathway inhibits Vascular Smooth Muscle Cell Proliferation by repressing Cell Cycle-dependent Telomerase Activation

Science.gov (United States)

Gizard, Florence; Nomiyama, Takashi; Zhao, Yue; Findeisen, Hannes M.; Heywood, Elizabeth B.; Jones, Karrie L.; Staels, Bart; Bruemmer, Dennis

2009-01-01

Peroxisome Proliferator-Activated Receptor (PPAR) α, the molecular target for fibrates used to treat dyslipidemia, exerts pleiotropic effects on vascular cells. In vascular smooth muscle cells (VSMCs), we have previously demonstrated that PPARα activation suppresses G1→S cell cycle progression by targeting the cyclin-dependent kinase inhibitor p16INK4a (p16). In the present study, we demonstrate that this inhibition of VSMC proliferation by PPARα is mediated through a p16-dependent suppression of telomerase activity, which has been implicated in key cellular functions including proliferation. PPARα activation inhibited mitogen-induced telomerase activity by repressing the catalytic subunit telomerase reverse transcriptase (TERT) through negative cross-talk with an E2F-1-dependent trans-activation of the TERT promoter. This trans-repression involved the recruitment of the retinoblastoma (RB) family proteins p107 and p130 to the TERT promoter resulting in impaired E2F-1 binding, an effect which was dependent on p16. The inhibition of cell proliferation by PPARα activation was lost in VSMC following TERT overexpression or knock-down, pointing to a key role of telomerase as a target for the antiproliferative effects of PPARα. Finally, we demonstrate that PPARα agonists suppress telomerase activation during the proliferative response following vascular injury indicating that these findings are applicable in vivo. In concert, these results demonstrate that the anti-proliferative effects of PPARα in VSMCs depend on the suppression of telomerase activity by targeting the p16/RB/E2F transcriptional cascade. PMID:18818403

ANGIOTENSIN RECEPTOR BLOCKERS WITH PLEIOTROPIC PROPERTIES: A NEW STANDARD IN CARDIOVASCULAR RISK MANAGEMENT AND TREATMENT OF HYPERTENSION

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V. I. Podzolkov

2017-01-01

Full Text Available An increase in the activity of the renin-angiotensin-aldosterone system is one of the most important mechanisms for the realization of the cardiovascular continuum. The role that angiotensin receptor blockers play in achieving target figures of blood pressure and reducing cardiovascular risk is discussed. The importance of pleiotropic properties of angiotensin receptor blockers (in particular, activation of peroxisome proliferator-activated receptors gamma – PPAR-γ in the management of patients with insulin resistance, obesity, dyslipidemia is also covered. The evidence base for the use of telmisartan as a drug with pleiotropic effect in patients with arterial hypertension and associated diseases (diabetes mellitus, obesity, renal dysfunction is discussed. 

Atorvastatin Inhibits the HIF1α-PPAR Axis, Which Is Essential for Maintaining the Function of Human Induced Pluripotent Stem Cells.

Science.gov (United States)

Nakashima, Yoshiki; Miyagi-Shiohira, Chika; Noguchi, Hirofumi; Omasa, Takeshi

2018-06-19

We herein report a novel mechanism of action of statin preparations using a new drug discovery method. Milk fat globule-EGF factor 8 protein (MFG-E8) was identified from the secretory component of mouse embryonic fibroblast (MEF) as a cell adhesion-promoting factor effective for screening active cellular agents of human induced pluripotent stem cells (hiPSCs) in vitro using electrochemical impedance. Our analyses showed that atorvastatin did not cause death in myocardial cells differentiated from hiPSCs but reduced the pluripotent cell survival in vitro when using serum- and albumin-free media, and inhibited the ability to form teratomas in mice. This result could have been already the cytopathic effect of atorvastatin, and complete elimination of hiPSCs was confirmed in the xenotransplantation assay. The administration of atorvastatin to hiPSCs caused the expression of hypoxia inducible factor (HIF)1α mRNA to be unchanged at 6 hr and downregulated at 24 hr. In addition, the inhibition of the survival of hiPSCs was confirmed by HIF1α-peroxisome proliferator-activated receptor (PPAR) axis inhibition. These results suggest that the addition of atorvastatin to hiPSC cultures reduces the survival of pluripotent cells by suppressing the HIF1α-PPAR axis. In summary, the HIF1α-PPAR axis has an important role in maintaining the survival of pluripotent hiPSCs. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Inhibitors of Fatty Acid Synthesis Induce PPAR α -Regulated Fatty Acid β -Oxidative Genes: Synergistic Roles of L-FABP and Glucose.

Science.gov (United States)

Huang, Huan; McIntosh, Avery L; Martin, Gregory G; Petrescu, Anca D; Landrock, Kerstin K; Landrock, Danilo; Kier, Ann B; Schroeder, Friedhelm

2013-01-01

While TOFA (acetyl CoA carboxylase inhibitor) and C75 (fatty acid synthase inhibitor) prevent lipid accumulation by inhibiting fatty acid synthesis, the mechanism of action is not simply accounted for by inhibition of the enzymes alone. Liver fatty acid binding protein (L-FABP), a mediator of long chain fatty acid signaling to peroxisome proliferator-activated receptor- α (PPAR α ) in the nucleus, was found to bind TOFA and its activated CoA thioester, TOFyl-CoA, with high affinity while binding C75 and C75-CoA with lower affinity. Binding of TOFA and C75-CoA significantly altered L-FABP secondary structure. High (20 mM) but not physiological (6 mM) glucose conferred on both TOFA and C75 the ability to induce PPAR α transcription of the fatty acid β -oxidative enzymes CPT1A, CPT2, and ACOX1 in cultured primary hepatocytes from wild-type (WT) mice. However, L-FABP gene ablation abolished the effects of TOFA and C75 in the context of high glucose. These effects were not associated with an increased cellular level of unesterified fatty acids but rather by increased intracellular glucose. These findings suggested that L-FABP may function as an intracellular fatty acid synthesis inhibitor binding protein facilitating TOFA and C75-mediated induction of PPAR α in the context of high glucose at levels similar to those in uncontrolled diabetes.

Genotyping of PPAR-γ gene polymorphism in Egyptian neonates affected with sepsis disease and its severity

Directory of Open Access Journals (Sweden)

Rabah M. Shawky

2018-07-01

Full Text Available Background: Peroxisome Proliferator-Activated Receptor gamma (PPARγ is a ligand-dependent transcription factor involved in inflammatory process. PPAR-γ gene was mentioned as having a modulating role in the pathological status of sepsis.The present study aimed to make a correlation between The Pro12Ala polymorphism in PPAR-γ gene and occurrence of neonatal sepsis and its severity among a sample of Egyptian neonates suffering sepsis. Subjects and methods: This case-control study included 30 neonates (11 females and19 males newly admitted with neonatal sepsis at the intensive care unit (NICU (mean age 10.3 days ± 6.23. The control group included 50 age and sex matched neonates (23 females and 27 males (mean age 10.20 days ± 5.36 days. All the neonates (preterm and full term included were with clinical signs and laboratory data consistent with neonatal sepsis. Genotyping for PPARγ gene region harboring the Pro12Ala variant locus were carried out using Tetra ARMS technique. Results: About 56.7% of the patients group was homozygote (GG for polymorphic locus (coding for Alanine/Alanine while 30% was heterozygote for polymorphic locus (CG (coding for Proline/Alanine and up to 13.3% was homozygote for the polymorphic locus (CC (coding for Proline/Proline. Compared to the control group where homozygotes for CC were the most prevalent (90% and the CG were 10% with absence of GG genotypes. There was a strong statistical significant difference between patients and the normal control group as regards prevalence of PPAR-γ gene polymorphism in occurrence of neonatal sepsis and its severity. Also, there were strong relation between genotype GG and low birth weight, neonatal fever, prematurity and depressed neonatal reflexes. Conclusion: PPAR-γ gene has been suggested to be a candidate gene for neonatal sepsis. Therefore, Pro12Ala polymorphism might be useful in predicting the risk factor of neonatal sepsis and its severity. Keywords: Sepsis, PPAR

Xingshentongqiao Decoction Mediates Proliferation, Apoptosis, Orexin-A Receptor and Orexin-B Receptor Messenger Ribonucleic Acid Expression and Represses Mitogen-activated Protein Kinase Signaling

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Yuanli Dong

2015-01-01

Full Text Available Background: Hypocretin (HCRT signaling plays an important role in the pathogenesis of narcolepsy and can be significantly influenced by Chinese herbal therapy. Our previous study showed that xingshentongqiao decoction (XSTQ is clinically effective for the treatment of narcolepsy. To determine whether XSTQ improves narcolepsy by modulating HCRT signaling, we investigated its effects on SH-SY5Y cell proliferation, apoptosis, and HCRT receptor 1/2 (orexin receptor 1 [OX1R] and orexin receptor 2 [OX2R] expression. The signaling pathways involved in these processes were also assessed. Methods: The effects of XSTQ on proliferation and apoptosis in SH-SY5Y cells were assessed using cell counting kit-8 and annexin V-fluorescein isothiocyanate assays. OX1R and OX2R expression was assessed by quantitative real-time polymerase chain reaction analysis. Western blotting for mitogen-activated protein kinase (MAPK pathway activation was performed to further assess the signaling mechanism of XSTQ. Results: XSTQ reduced the proliferation and induced apoptosis of SH-SY5Y cells. This effect was accompanied by the upregulation of OX1R and OX2R expression and the reduced phosphorylation of extracellular signal-regulated kinase (Erk 1/2, p38 MAPK and c-Jun N-terminal kinase (JNK. Conclusions: XSTQ inhibits proliferation and induces apoptosis in SH-SY5Y cells. XSTQ also promotes OX1R and OX2R expression. These effects are associated with the repression of the Erk1/2, p38 MAPK, and JNK signaling pathways. These results define a molecular mechanism for XSTQ in regulating HCRT and MAPK activation, which may explain its ability to treat narcolepsy.

PPAR-γ and CYP46A1 genes polymorphism is associated with ...

African Journals Online (AJOL)

Syed Tasleem Raza

2016-04-30

Apr 30, 2016 ... Abstract Background: Involvement of genetic factors like gene polymorphisms was found to con- ... PPAR-c is a type II nuclear receptor which is encoded by the PPAR-c ... nificantly associated with diabetic retinopathy [10,11].

[Coactivators in energy metabolism: peroxisome proliferator-activated receptor-gamma coactivator 1 family].

Science.gov (United States)

Wang, Rui; Chang, Yong-sheng; Fang, Fu-de

2009-12-01

Peroxisome proliferator-activated receptor gamma coactivator 1 (PGC1) family is highly expressed in tissues with high energy metabolism. They coactivate transcription factors in regulating genes engaged in processes such as gluconeogenesis, adipose beta-oxydation, lipoprotein synthesis and secretion, mitochondrial biogenesis, and oxidative metabolism. Protein conformation studies demonstrated that they lack DNA binding domains and act as coactivators through physical interaction with transcription factors. PGC1 activity is regulated at transcription level or by multiple covalent chemical modifications such as phosphorylation, methylation and acetylation/deacetylation. Abnormal expression of PGC1 coactivators usually is closely correlated with diseases such as diabetes, obesity, hyperglycemia, hyperlipemia, and arterial and brain neuron necrosis diseases.

Expression of peroxisome proliferator-activated receptor-gamma in key neuronal subsets regulating glucose metabolism and energy homeostasis.

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Sarruf, David A; Yu, Fang; Nguyen, Hong T; Williams, Diana L; Printz, Richard L; Niswender, Kevin D; Schwartz, Michael W

2009-02-01

In addition to increasing insulin sensitivity and adipogenesis, peroxisome proliferator-activated receptor (PPAR)-gamma agonists cause weight gain and hyperphagia. Given the central role of the brain in the control of energy homeostasis, we sought to determine whether PPARgamma is expressed in key brain areas involved in metabolic regulation. Using immunohistochemistry, PPARgamma distribution and its colocalization with neuron-specific protein markers were investigated in rat and mouse brain sections spanning the hypothalamus, the ventral tegmental area, and the nucleus tractus solitarius. In several brain areas, nuclear PPARgamma immunoreactivity was detected in cells that costained for neuronal nuclei, a neuronal marker. In the hypothalamus, PPARgamma immunoreactivity was observed in a majority of neurons in the arcuate (including both agouti related protein and alpha-MSH containing cells) and ventromedial hypothalamic nuclei and was also present in the hypothalamic paraventricular nucleus, the lateral hypothalamic area, and tyrosine hydroxylase-containing neurons in the ventral tegmental area but was not expressed in the nucleus tractus solitarius. To validate and extend these histochemical findings, we generated mice with neuron-specific PPARgamma deletion using nestin cre-LoxP technology. Compared with littermate controls, neuron-specific PPARgamma knockout mice exhibited dramatic reductions of both hypothalamic PPARgamma mRNA levels and PPARgamma immunoreactivity but showed no differences in food intake or body weight over a 4-wk study period. We conclude that: 1) PPARgamma mRNA and protein are expressed in the hypothalamus, 2) neurons are the predominant source of PPARgamma in the central nervous system, although it is likely expressed by nonneuronal cell types as well, and 3) arcuate nucleus neurons that control energy homeostasis and glucose metabolism are among those in which PPARgamma is expressed.

Peroxisome proliferator-activated receptors-alpha and gamma are targets to treat offspring from maternal diet-induced obesity in mice.

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D'Angelo Carlo Magliano

Full Text Available AIM: The aim of the present study was to evaluate whether activation of peroxisome proliferator-activated receptor (PPARalpha and PPARgamma by Bezafibrate (BZ could attenuate hepatic and white adipose tissue (WAT abnormalities in male offspring from diet-induced obese dams. MATERIALS AND METHODS: C57BL/6 female mice were fed a standard chow (SC; 10% lipids diet or a high-fat (HF; 49% lipids diet for 8 weeks before mating and during gestation and lactation periods. Male offspring received SC diet at weaning and were subdivided into four groups: SC, SC/BZ, HF and HF/BZ. Treatment with BZ (100 mg/Kg diet started at 12 weeks of age and was maintained for three weeks. RESULTS: The HF diet resulted in an overweight phenotype and an increase in oral glucose intolerance and fasting glucose of dams. The HF offspring showed increased body mass, higher levels of plasmatic and hepatic triglycerides, higher levels of pro-inflammatory and lower levels of anti-inflammatory adipokines, impairment of glucose metabolism, abnormal fat pad mass distribution, higher number of larger adipocytes, hepatic steatosis, higher expression of lipogenic proteins concomitant to decreased expression of PPARalpha and carnitine palmitoyltransferase I (CPT-1 in liver, and diminished expression of PPARgamma and adiponectin in WAT. Treatment with BZ ameliorated the hepatic and WAT abnormalities generated by diet-induced maternal obesity, with improvements observed in the structural, biochemical and molecular characteristics of the animals' livers and epididymal fat. CONCLUSION: Diet-induced maternal obesity lead to alterations in metabolism, hepatic lipotoxicity and adverse liver and WAT remodeling in the offspring. Targeting PPAR with Bezafibrate has beneficial effects reducing the alterations, mainly through reduction of WAT inflammatory state through PPARgamma activation and enhanced hepatic beta-oxidation due to increased PPARalpha/PPARgamma ratio in liver.

Synthesis and antidiabetic activity of β-acetamido ketones

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Xing-hua Zhang

2011-08-01

Full Text Available This paper reports the use of trifluoroacetic acid as a catalyst in the Dakin–West reaction for the synthesis of β-acetamido ketones. The method has several advantages such as requiring only mild conditions and a low concentration of catalyst. Screening of 19 β-acetamido ketones for antidiabetic activity in vitro showed that their activity as peroxisome proliferator-activated receptor (PPAR agonists and as dipeptidyl peptidase 4 (DPP-IV inhibitors was fairly weak.

Energy Balance, Myostatin, and GILZ: Factors Regulating Adipocyte Differentiation in Belly and Bone

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Xingming Shi

2007-01-01

Full Text Available Peroxisome proliferator-activated receptor gamma (PPAR-γ belongs to the nuclear hormone receptor subfamily of transcription factors. PPARs are expressed in key target tissues such as liver, fat, and muscle and thus they play a major role in the regulation of energy balance. Because of PPAR-γ's role in energy balance, signals originating from the gut (e.g., GIP, fat (e.g., leptin, muscle (e.g., myostatin, or bone (e.g., GILZ can in turn modulate PPAR expression and/or function. Of the two PPAR-γ isoforms, PPAR-γ2 is the key regulator of adipogenesis and also plays a role in bone development. Activation of this receptor favors adipocyte differentiation of mesenchymal stem cells, while inhibition of PPAR-γ2 expression shifts the commitment towards the osteoblastogenic pathway. Clinically, activation of this receptor by antidiabetic agents of the thiazolidinedione class results in lower bone mass and increased fracture rates. We propose that inhibition of PPAR-γ2 expression in mesenchymal stem cells by use of some of the hormones/factors mentioned above may be a useful therapeutic strategy to favor bone formation.

Metabolic adaptation to intermittent fasting is independent of peroxisome proliferator-activated receptor alpha

OpenAIRE

Li, Guolin; Brocker, Chad N.; Yan, Tingting; Xie, Cen; Krausz, Kristopher W.; Xiang, Rong; Gonzalez, Frank J.

2017-01-01

Background: Peroxisome proliferator-activated receptor alpha (PPARA) is a major regulator of fatty acid oxidation and severe hepatic steatosis occurs during acute fasting in Ppara-null mice. Thus, PPARA is considered an important mediator of the fasting response; however, its role in other fasting regiments such as every-other-day fasting (EODF) has not been investigated. Methods: Mice were pre-conditioned using either a diet containing the potent PPARA agonist Wy-14643 or an EODF regimen ...

Expression and Localization of Peroxisome Proliferator-Activated Receptors and Nuclear Factor κB in Normal and Lesional Psoriatic Skin

DEFF Research Database (Denmark)

Westergaard, Majken; Henningsen, Jeanette; Johansen, Claus

2003-01-01

Abnormal epidermal proliferation and differentiation characterize the inflammatory skin disease psoriasis. Here we demonstrate that expression of PPARdelta mRNA and protein is markedly upregulated in psoriatic lesions and that lipoxygenase products accumulating in psoriatic lesions are potent...... activators of PPARdelta. The expression levels of NF-kappaB p50 and p65 were not significantly altered in lesional compared with nonlesional psoriatic skin. In the basal layer of normal epidermis both p50 and p65 were sequestered in the cytoplasm, whereas p50, but not p65, localized to nuclei...... in the suprabasal layers, and this distribution was maintained in lesional psoriatic skin. In normal human keratinocytes PPAR agonists neither impaired IL-1beta-induced translocation of p65 nor IL-1beta-induced NF-kappaB DNA binding. We show that PPARdelta physically interacts with the N-terminal Rel homology...

Fruit extracts of Momordica charantia potentiate glucose uptake and up-regulate Glut-4, PPAR gamma and PI3K.

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Kumar, Ramadhar; Balaji, S; Uma, T S; Sehgal, P K

2009-12-10

Momordica charantia fruit is a widely used traditional medicinal herb as, anti-diabetic, anti-HIV, anti-ulcer, anti-inflammatory, anti-leukemic, anti-microbial, and anti-tumor. The present study is undertaken to investigate the possible mode of action of fruit extracts derived from Momordica charantia (MC) and study its pharmacological effects for controlling diabetic mellitus. Effects of aqueous and chloroform extracts of Momordica charantia fruit on glucose uptake and up-regulation of glucose transporter (Glut-4), peroxisome proliferator activator receptor gamma (PPAR gamma) and phosphatidylinositol-3 kinase (PI3K), were investigated to show its efficacy as a hypoglycaemic agent. Dose dependent glucose uptake assay was performed on L6 myotubes using 2-deoxy-D-[1-(3)H] glucose. Up-regulatory effects of the extracts on the mRNA expression level of Glut-4, PPAR gamma and PI3K have been studied. The association of Momordica charantia with the aqueous and chloroform extracts of Momordica charantia fruit at 6 microg/ml has shown significant up-regulatory effect, respectively, by 3.6-, 2.8- and 3.8-fold on the battery of targets Glut-4, PPAR gamma and PI3K involved in glucose transport. The up-regulation of glucose uptake was comparable with insulin and rosiglitazone which was approximately 2-fold over the control. Moreover, the inhibitory effect of the cyclohexamide on Momordica charantia fruit extract mediated glucose uptake suggested the requirement of new protein synthesis for the enhanced glucose uptake. This study demonstrated the significance of Glut-4, PPAR gamma and PI3K up-regulation by Momordica charantia in augmenting the glucose uptake and homeostasis.

Glial cell line-derived neurotrophic factor protects against high-fat diet-induced hepatic steatosis by suppressing hepatic PPAR-γ expression.

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Mwangi, Simon Musyoka; Peng, Sophia; Nezami, Behtash Ghazi; Thorn, Natalie; Farris, Alton B; Jain, Sanjay; Laroui, Hamed; Merlin, Didier; Anania, Frank; Srinivasan, Shanthi

2016-01-15

Glial cell line-derived neurotrophic factor (GDNF) protects against high-fat diet (HFD)-induced hepatic steatosis in mice, however, the mechanisms involved are not known. In this study we investigated the effects of GDNF overexpression and nanoparticle delivery of GDNF in mice on hepatic steatosis and fibrosis and the expression of genes involved in the regulation of hepatic lipid uptake and de novo lipogenesis. Transgenic overexpression of GDNF in liver and other metabolically active tissues was protective against HFD-induced hepatic steatosis. Mice overexpressing GDNF had significantly reduced P62/sequestosome 1 protein levels suggestive of accelerated autophagic clearance. They also had significantly reduced peroxisome proliferator-activated receptor-γ (PPAR-γ) and CD36 gene expression and protein levels, and lower expression of mRNA coding for enzymes involved in de novo lipogenesis. GDNF-loaded nanoparticles were protective against short-term HFD-induced hepatic steatosis and attenuated liver fibrosis in mice with long-standing HFD-induced hepatic steatosis. They also suppressed the liver expression of steatosis-associated genes. In vitro, GDNF suppressed triglyceride accumulation in Hep G2 cells through enhanced p38 mitogen-activated protein kinase-dependent signaling and inhibition of PPAR-γ gene promoter activity. These results show that GDNF acts directly in the liver to protect against HFD-induced cellular stress and that GDNF may have a role in the treatment of nonalcoholic fatty liver disease.

Lack of association between the Pro12Ala polymorphism of the PPAR-gamma 2 gene and type 2 diabetes mellitus in the Qatari consanguineous population.

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Badii, Ramin; Bener, Abdulbari; Zirie, Mahmoud; Al-Rikabi, Ammar; Simsek, Mehmet; Al-Hamaq, Abdulla O A A; Ghoussaini, Maya; Froguel, Philippe; Wareham, Nick J

2008-03-01

Peroxisome proliferators-activated receptor gamma (PPAR gamma) is a nuclear hormone receptor that serves as a master regulator for adipocytes-specific genes contributing to adipocytes differentiation, insulin sensitivity and lipid metabolism. The substitution of proline to alanine at codon 12 of the PPAR gamma 2 gene (Pro12Ala polymorphism) is most widely studied, and the associations with diabetes, obesity, and other clinical parameters have been reported and discussed in several ethnic groups. Among native Qatar ethnicity, however, there is no report about this polymorphism. The aim of this study was to estimate the allele frequency of the Pro12Ala polymorphism of PPAR gamma 2 gene among Qatari population and investigate the association between this polymorphism and obesity or type 2 diabetes. This is a matched case-control study. It was carried out among diabetic patients and healthy subjects at the Primary Healthcare Clinics, and the survey was conducted from February 2003 to March 2006 in Qatari male and female nationals aged 35 to 60 years. The study was based on matched age, sex, and ethnicity of 400 cases (with diabetes) and 450 controls (without diabetes). Face-to-face interviews were based on a questionnaire that included variables such as age, sex, sociodemographic status, body mass index (BMI), and obesity. Their health status was assessed by medical conditions, family history, and blood pressure measurements. The allele frequency of Pro12Ala polymorphism in PPAR gamma 2 gene among Qataris is lower than that in many Caucasian ethnic groups. No association is seen between the Pro12Ala and type 2 Diabetes (0.055 vs 0.059, OR = 1.1311, P = 0.669). Nearly half of the diabetic type 2 patients (48.5%) were obese (BMI > 30) compared to nondiabetic subjects (29.8%) (P Qatar.

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