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Sample records for regulate liver triglyceride

  1. Lipasin, a novel nutritionally-regulated liver-enriched factor that regulates serum triglyceride levels.

    Science.gov (United States)

    Zhang, Ren

    2012-08-10

    The metabolic syndrome, a common disorder including glucose intolerance and dyslipidemia, poses a major public health issue. Patients with high blood lipids, such as triglycerides, are at high risk in developing atherosclerotic cardiovascular diseases. To identify genes involved in metabolism, we performed RNA-seq experiments on the liver and fat in mice treated with a high-fat diet or fasting, and identified Gm6484 (named Lipasin) as a novel nutritionally regulated gene. Human LIPASIN is liver specific, while the mouse one is enriched in the liver and fat, including both brown and white adipose tissues. Obesity increases liver Lipasin, whereas fasting reduces its expression in fat. ANGPTL3 (Angiopoietin-like 3) and ANGPTL4 are critical regulators of blood lipids. LIPASIN shares homology with ANGPTL3's N-terminal domain that is needed for lipid regulation, and with ANGPTL4's N-terminal segment that mediates lipoprotein lipase (LPL) binding. Lipasin overexpression by adenoviruses in mice increases serum triglyceride levels, and a recombinant Lipasin inhibits LPL activity. Therefore, a potential mechanism for Lipasin-mediated triglyceride elevation is through reduced triglyceride clearance by LPL inhibition. Lipasin is thus a novel nutritionally-regulated liver-enriched factor that plays a role in lipid metabolism. Copyright © 2012 Elsevier Inc. All rights reserved.

  2. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR.

    Science.gov (United States)

    Sun, Chuanzheng; Huang, Feizhou; Liu, Xunyang; Xiao, Xuefei; Yang, Mingshi; Hu, Gui; Liu, Huaizheng; Liao, Liangkan

    2015-03-01

    Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health issue with a prevalence of 15-30% in Western populations and 6-25% in Asian populations. Certain studies have revealed the alteration of microRNA (miRNA or miR) profiles in NAFLD and it has been suggested that miR-21 is associated with NAFLD. In the present study, we measured the serum levels of miR-21 in patients with NAFLD and also performed in vitro experiments using a cellular model of NAFLD to further investigate the effects of miR-21 on triglyceride and cholesterol metabolism. Furthermore, a novel target through which miR-21 exerts its effects on NAFLD was identified. The results revealed that the serum levels of miR-21 were lower in patients with NAFLD compared with the healthy controls. In addition, 3-hydroxy-3-methylglutaryl-co-enzyme A reductase (HMGCR) expression was increased in the serum of patients with NAFLD both at the mRNA and protein level. To mimic the NAFLD condition in vitro, HepG2 cells were treated with palmitic acid (PA) and oleic acid (OA). Consistent with the results obtained in the in vivo experiments, the expression levels of miR-21 were decreased and those of HMGCR were increased in the in vitro model of NAFLD. Luciferase reporter assay revealed that HMGCR was a direct target of miR-21 and that miR-21 exerted an effect on both HMGCR transcript degradation and protein translation. Furthermore, the results from the in vitro experiments revealed that miR-21 decreased the levels of triglycerides (TG), free cholesterol (FC) and total cholesterol (TC) in the PA/OA-treated HepG2 cells and that this effect was attenuated by HMGCR overexpression. Taken together, to the best of our knowledge, the present study is the first to report that miR-21 regulates triglyceride and cholesterol metabolism in an in vitro model of NAFLD, and that this effect is achieved by the inhibition of HMGCR expression. We speculate that miR-21 may be a useful biomarker for the diagnosis and

  3. The Mammalian "Obesogen" Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish.

    Directory of Open Access Journals (Sweden)

    Angeliki Lyssimachou

    Full Text Available Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT, which causes imposex in gastropod snails, induces an "obesogenic" phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR and peroxisome proliferator-activated receptor gamma (PPARγ. In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound.

  4. The Mammalian “Obesogen” Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish

    Science.gov (United States)

    Lyssimachou, Angeliki; Santos, Joana G.; André, Ana; Soares, Joana; Lima, Daniela; Guimarães, Laura; Almeida, C. Marisa R.; Teixeira, Catarina; Castro, L. Filipe C.; Santos, Miguel M.

    2015-01-01

    Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs) interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT), which causes imposex in gastropod snails, induces an “obesogenic” phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARγ). In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn) from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound. PMID:26633012

  5. The Mammalian "Obesogen" Tributyltin Targets Hepatic Triglyceride Accumulation and the Transcriptional Regulation of Lipid Metabolism in the Liver and Brain of Zebrafish.

    Science.gov (United States)

    Lyssimachou, Angeliki; Santos, Joana G; André, Ana; Soares, Joana; Lima, Daniela; Guimarães, Laura; Almeida, C Marisa R; Teixeira, Catarina; Castro, L Filipe C; Santos, Miguel M

    2015-01-01

    Recent findings indicate that different Endocrine Disrupting Chemicals (EDCs) interfere with lipid metabolic pathways in mammals and promote fat accumulation, a previously unknown site of action for these compounds. The antifoulant and environmental pollutant tributyltin (TBT), which causes imposex in gastropod snails, induces an "obesogenic" phenotype in mammals, through the activation of the nuclear receptors retinoid X receptor (RXR) and peroxisome proliferator-activated receptor gamma (PPARγ). In teleosts, the effects of TBT on the lipid metabolism are poorly understood, particularly following exposure to low, environmental concentrations. In this context, the present work shows that exposure of zebrafish to 10 and 50 ng/L of TBT (as Sn) from pre-hatch to 9 months of age alters the body weight, condition factor, hepatosomatic index and hepatic triglycerides in a gender and dose related manner. Furthermore, TBT modulated the transcription of key lipid regulating factors and enzymes involved in adipogenesis, lipogenesis, glucocorticoid metabolism, growth and development in the brain and liver of exposed fish, revealing sexual dimorphic effects in the latter. Overall, the present study shows that the model mammalian obesogen TBT interferes with triglyceride accumulation and the transcriptional regulation of lipid metabolism in zebrafish and indentifies the brain lipogenic transcription profile of fish as a new target of this compound.

  6. Polyiodinated triglycerides for CT of the liver

    International Nuclear Information System (INIS)

    Weichert, J.P.; Longino, M.A.; Ullrich, K.A.; Schwendner, S.W.; Glazer, G.M.; Counsell, R.E.

    1989-01-01

    Several polyiodinated aryl triglyceride analogs have been synthesized, radioiodinated, emulsified, and administered to rats and normal or tumor-bearing rabbits in tracer or radiologic doses for tissue distribution (TD) and CT studies. The authors present preliminary TD results in rats with three of these analogs: glyceryl 1,3-diiopanoyl 2-palmitate; glyceryl 1,3-diiopanoyl 2-oleate; and glyceryl 1,3-di-7-(3-amino-2,4,6-triiodophenyl) heptanoyl 2-oleate. Respectively, 74%, 28%, and 55% of the injected radioactivity was present in the liver 1/2 hours after administration. Chemical structure and method of formulation bad a pronounced effect on the uptake, metabolism, and clearance properties of the agent. Initial CT studies with analog 1 (32 mg I/kg) in rabbits bearing hepatic VX2 tumors revealed tumors ranging in diameter from 0.3 to 3 cm

  7. Muscle and liver glycogen, protein, and triglyceride in the rat

    DEFF Research Database (Denmark)

    Richter, Erik; Sonne, Bente; Joensen Mikines, Kari

    1984-01-01

    in skeletal muscle was accompanied by increased breakdown of triglyceride and/or protein. Thus, the effect of exhausting swimming and of running on concentrations of glycogen, protein, and triglyceride in skeletal muscle and liver were studied in rats with and without deficiencies of the sympatho......-adrenal system. In control rats, both swimming and running decreased the concentration of glycogen in fast-twitch red and slow-twitch red muscle whereas concentrations of protein and triglyceride did not decrease. In the liver, swimming depleted glycogen stores but protein and triglyceride concentrations did...... not decrease. In exercising rats, muscle glycogen breakdown was impaired by adrenodemedullation and restored by infusion of epinephrine. However, impaired glycogen breakdown during exercise was not accompanied by a significant net breakdown of protein or triglyceride. Surgical sympathectomy of the muscles did...

  8. Rapamycin up-regulates triglycerides in hepatocytes by down-regulating Prox1.

    Science.gov (United States)

    Kwon, Sora; Jeon, Ji-Sook; Kim, Su Bin; Hong, Young-Kwon; Ahn, Curie; Sung, Jung-Suk; Choi, Inho

    2016-02-27

    Although the prolonged use of rapamycin may cause unwanted side effects such as hyperlipidemia, the underlying mechanism remains unknown. Prox1 is a transcription factor responsible for the development of several tissues including lymphatics and liver. There is growing evidences that Prox1 participates in metabolism in addition to embryogenesis. However, whether Prox1 is directly related to lipid metabolism is currently unknown. HepG2 human hepatoma cells were treated with rapamycin and total lipids were analyzed by thin layer chromatography. The effect of rapamycin on the expression of Prox1 was determined by western blotting. To investigate the role of Prox1 in triglycerides regulation, siRNA and overexpression system were employed. Rapamycin was injected into mice for 2 weeks and total lipids and proteins in liver were measured by thin layer chromatography and western blot analysis, respectively. Rapamycin up-regulated the amount of triglyceride and down-regulated the expression of Prox1 in HepG2 cells by reducing protein half-life but did not affect its transcript. The loss-of-function of Prox1 was coincident with the increase of triglycerides in HepG2 cells treated with rapamycin. The up-regulation of triglycerides by rapamycin in HepG2 cells reverted to normal levels by the compensation of Prox1 using the overexpression system. Rapamycin also down-regulated Prox1 expression but increased triglycerides in mouse liver. This study suggests that rapamycin can increase the amount of triglycerides by down-regulating Prox1 expression in hepatocytes, which means that the mammalian target of rapamycin (mTOR) signaling is important for the regulation of triglycerides by maintaining Prox1 expression.

  9. Kinesin-dependent mechanism for controlling triglyceride secretion from the liver.

    Science.gov (United States)

    Rai, Priyanka; Kumar, Mukesh; Sharma, Geetika; Barak, Pradeep; Das, Saumitra; Kamat, Siddhesh S; Mallik, Roop

    2017-12-05

    Despite massive fluctuations in its internal triglyceride content, the liver secretes triglyceride under tight homeostatic control. This buffering function is most visible after fasting, when liver triglyceride increases manyfold but circulating serum triglyceride barely fluctuates. How the liver controls triglyceride secretion is unknown, but is fundamentally important for lipid and energy homeostasis in animals. Here we find an unexpected cellular and molecular mechanism behind such control. We show that kinesin motors are recruited to triglyceride-rich lipid droplets (LDs) in the liver by the GTPase ARF1, which is a key activator of lipolysis. This recruitment is activated by an insulin-dependent pathway and therefore responds to fed/fasted states of the animal. In fed state, ARF1 and kinesin appear on LDs, consequently transporting LDs to the periphery of hepatocytes where the smooth endoplasmic reticulum (sER) is present. Because the lipases that catabolize LDs in hepatocytes reside on the sER, LDs can now be catabolized efficiently to provide triglyceride for lipoprotein assembly and secretion from the sER. Upon fasting, insulin is lowered to remove ARF1 and kinesin from LDs, thus down-regulating LD transport and sER-LD contacts. This tempers triglyceride availabiity for very low density lipoprotein assembly and allows homeostatic control of serum triglyceride in a fasted state. We further show that kinesin knockdown inhibits hepatitis-C virus replication in hepatocytes, likely because translated viral proteins are unable to transfer from the ER to LDs. Copyright © 2017 the Author(s). Published by PNAS.

  10. Decreased liver triglyceride content in adult rats exposed to protein restriction during gestation and lactation: role of hepatic triglyceride utilization.

    Science.gov (United States)

    Qasem, Rani J; Li, Jing; Tang, Hee Man; Browne, Veron; Mendez-Garcia, Claudia; Yablonski, Elizabeth; Pontiggia, Laura; D'Mello, Anil P

    2015-04-01

    We have previously demonstrated that protein restriction throughout gestation and lactation reduces liver triglyceride content in adult rat offspring. However, the mechanisms mediating the decrease in liver triglyceride content are not understood. The aim of the current study was to use a new group of pregnant animals and their offspring and determine the contribution of increased triglyceride utilization via the hepatic fatty-acid oxidation and triglyceride secretory pathways to the reduction in liver triglyceride content. Pregnant Sprague-Dawley rats received either a control or a low protein diet throughout pregnancy and lactation. Pups were weaned onto laboratory chow on day 28 and killed on day 65. Liver triglyceride content was reduced in male, but not female, low-protein offspring, both in the fed and fasted states. The reduction was accompanied by a trend towards higher liver carnitine palmitoyltransferase-1a activity, suggesting increased fatty-acid transport into the mitochondrial matrix. However, medium-chain acyl coenzyme A dehydrogenase activity within the mitochondrial matrix, expression of nuclear peroxisome proliferator activated receptor-α, and plasma levels of β-hydroxybutyrate were similar between low protein and control offspring, indicating a lack of change in fatty-acid oxidation. Hepatic triglyceride secretion, assessed by blocking peripheral triglyceride utilization and measuring serum triglyceride accumulation rate, and the activity of microsomal transfer protein, were similar between low protein and control offspring. Because enhanced triglyceride utilization is not a significant contributor, the decrease in liver triglyceride content in male low-protein offspring is likely due to alterations in liver fatty-acid transport or triglyceride biosynthesis. © 2015 Wiley Publishing Asia Pty Ltd.

  11. Triglycerides

    Science.gov (United States)

    What are triglycerides? Triglycerides are a type of fat. They are the most common type of fat in your body. They come from ... especially butter, oils, and other fats you eat. Triglycerides also come from extra calories. These are the ...

  12. Regulation of triglyceride metabolism by angiopoietin-like proteins

    NARCIS (Netherlands)

    Mattijssen, F.B.J.; Kersten, A.H.

    2012-01-01

    asma triglyceride concentrations are determined by the balance between production of the triglyceride-rich lipoproteins VLDL and chylomicrons in liver and intestine, and their lipoprotein lipase-mediated clearance in peripheral tissues. In the last decade, the group of Angiopoietin-like proteins has

  13. Liver protein expression in dairy cows with high liver triglycerides in early lactation

    DEFF Research Database (Denmark)

    Sejersen, Henrik; Sørensen, Martin Tang; Larsen, Torben

    2012-01-01

    Fatty liver is a frequent subclinical health disorder in dairy cows that may lead to disorders related to the liver function. However, the effect of triglyceride (TG) accumulation on liver metabolic pathways is still unclear. The objective was, therefore, to characterize quantitative differences...... in the liver proteome between early lactation dairy cows with a low or high liver TG content. The liver proteome analysis indicated that a high liver TG content in early lactation dairy cows is associated with increased oxidation of saturated fatty acids, oxidative stress, and urea synthesis...... and decreasedoxidation of unsaturated fatty acids. Furthermore, liver gluconeogenesis is apparently not impaired by an increased liver TG content. Based on correlations between liver proteins and plasma components, we suggest that future studies investigate the sensitivity and specificity of plasma aspartate...

  14. Ultrasonographic diagnosis of fatty liver and relations with body index, serum lipid, and serum triglyceride

    International Nuclear Information System (INIS)

    Jang, Young Deog; Lee, S. H.; Lee, H. K.; Kim, D. H.; Kwon, K. H.; Kim, K. C.

    1989-01-01

    Hepatic fatty infiltration appears as an area of increased echogenicity. And many factors concerned to fatty infiltration. With 65 cases of fatty liver and 42 cases of normal group, we analyzed fatty liver with grading and attempt to find relations between grade of fatty liver and levels of body index, serum triglyceride, and serum lipid. And compared fatty liver with normal control group. Patients with fatty liver are higher percentage of supra-normal value in body index, serum lipid, and serum triglyceride than normal control group. As fatty infiltration progressed, serum lipid, serum trig-lyceride and body index are also increased. Conclusively ultrasonographic examination of liver with serum triglyceride, serum lipid, and body index are simple method, useful follow-up examination of fatty liver, and preventive routine check-up of chronic liver disease

  15. Chlamydia pneumoniae acute liver infection affects hepatic cholesterol and triglyceride metabolism in mice.

    Science.gov (United States)

    Marangoni, Antonella; Fiorino, Erika; Gilardi, Federica; Aldini, Rita; Scotti, Elena; Nardini, Paola; Foschi, Claudio; Donati, Manuela; Montagnani, Marco; Cevenini, Monica; Franco, Placido; Roda, Aldo; Crestani, Maurizio; Cevenini, Roberto

    2015-08-01

    Chlamydia pneumoniae has been linked to atherosclerosis, strictly associated with hyperlipidemia. The liver plays a central role in the regulation of lipid metabolism. Since in animal models C. pneumoniae can be found at hepatic level, this study aims to elucidate whether C. pneumoniae infection accelerates atherosclerosis by affecting lipid metabolism. Thirty Balb/c mice were challenged intra-peritoneally with C. pneumoniae elementary bodies and thirty with Chlamydia trachomatis, serovar D. Thirty mice were injected with sucrose-phosphate-glutamate buffer, as negative controls. Seven days after infection, liver samples were examined both for presence of chlamydia and expression of genes involved in inflammation and lipid metabolism. C. pneumoniae was isolated from 26 liver homogenates, whereas C. trachomatis was never re-cultivated (P triglycerides levels compared both with negative controls (P metabolism. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  16. The g0/g1 switch gene 2 is an important regulator of hepatic triglyceride metabolism.

    Science.gov (United States)

    Wang, Yinfang; Zhang, Yahui; Qian, Hang; Lu, Juan; Zhang, Zhifeng; Min, Xinwen; Lang, Mingjian; Yang, Handong; Wang, Nanping; Zhang, Peng

    2013-01-01

    Nonalcoholic fatty liver disease is associated with obesity and insulin resistance. Factors that regulate the disposal of hepatic triglycerides contribute to the development of hepatic steatosis. G0/G1 switch gene 2 (G0S2) is a target of peroxisome proliferator-activated receptors and plays an important role in regulating lipolysis in adipocytes. Therefore, we investigated whether G0S2 plays a role in hepatic lipid metabolism. Adenovirus-mediated expression of G0S2 (Ad-G0S2) potently induced fatty liver in mice. The liver mass of Ad-G0S2-infected mice was markedly increased with excess triglyceride content compared to the control mice. G0S2 did not change cellular cholesterol levels in hepatocytes. G0S2 was found to be co-localized with adipose triglyceride lipase at the surface of lipid droplets. Hepatic G0S2 overexpression resulted in an increase in plasma Low-density lipoprotein (LDL)/Very-Low-density (VLDL) lipoprotein cholesterol level. Plasma High-density lipoprotein (HDL) cholesterol and ketone body levels were slightly decreased in Ad-G0S2 injected mice. G0S2 also increased the accumulation of neutral lipids in cultured HepG2 and L02 cells. However, G0S2 overexpression in the liver significantly improved glucose tolerance in mice. Livers expressing G0S2 exhibited increased 6-(N-(7-nitrobenz-2-oxa-1-3-diazol-4-yl) amino)-6-deoxyglucose uptake compared with livers transfected with control adenovirus. Taken together, our results provide evidence supporting an important role for G0S2 as a regulator of triglyceride content in the liver and suggest that G0S2 may be a molecular target for the treatment of insulin resistance and other obesity-related metabolic disorders.

  17. CTRP3 attenuates diet-induced hepatic steatosis by regulating triglyceride metabolism.

    Science.gov (United States)

    Peterson, Jonathan M; Seldin, Marcus M; Wei, Zhikui; Aja, Susan; Wong, G William

    2013-08-01

    CTRP3 is a secreted plasma protein of the C1q family that helps regulate hepatic gluconeogenesis and is downregulated in a diet-induced obese state. However, the role of CTRP3 in regulating lipid metabolism has not been established. Here, we used a transgenic mouse model to address the potential function of CTRP3 in ameliorating high-fat diet-induced metabolic stress. Both transgenic and wild-type mice fed a high-fat diet showed similar body weight gain, food intake, and energy expenditure. Despite similar adiposity to wild-type mice upon diet-induced obesity (DIO), CTRP3 transgenic mice were strikingly resistant to the development of hepatic steatosis, had reduced serum TNF-α levels, and demonstrated a modest improvement in systemic insulin sensitivity. Additionally, reduced hepatic triglyceride levels were due to decreased expression of enzymes (GPAT, AGPAT, and DGAT) involved in triglyceride synthesis. Importantly, short-term daily administration of recombinant CTRP3 to DIO mice for 5 days was sufficient to improve the fatty liver phenotype, evident as reduced hepatic triglyceride content and expression of triglyceride synthesis genes. Consistent with a direct effect on liver cells, recombinant CTRP3 treatment reduced fatty acid synthesis and neutral lipid accumulation in cultured rat H4IIE hepatocytes. Together, these results establish a novel role for CTRP3 hormone in regulating hepatic lipid metabolism and highlight its protective function and therapeutic potential in attenuating hepatic steatosis.

  18. Meta-Analysis of Structured Triglyceride versus Physical Mixture Medium- and Long-Chain Triglycerides for PN in Liver Resection Patients

    OpenAIRE

    Zhao, Yajie; Wang, Chengfeng

    2017-01-01

    Background. The use of total parenteral nutrition can affect liver function, causing a series of problems such as cholestasis. The aim of this meta-analysis was to compare structured triglyceride- (STG-) based lipid emulsions with physical medium-chain triglyceride (MCT)/long-chain triglyceride (LCT) mixtures in patients who had undergone liver surgery to identify any differences between these two types of parenteral nutrition. Methods. We searched the databases of PubMed, the Cochrane Librar...

  19. Metabolic Circuit Involving Free Fatty Acids, microRNA 122, and Triglyceride Synthesis in Liver and Muscle Tissues.

    Science.gov (United States)

    Chai, Chofit; Rivkin, Mila; Berkovits, Liav; Simerzin, Alina; Zorde-Khvalevsky, Elina; Rosenberg, Nofar; Klein, Shiri; Yaish, Dayana; Durst, Ronen; Shpitzen, Shoshana; Udi, Shiran; Tam, Joseph; Heeren, Joerg; Worthmann, Anna; Schramm, Christoph; Kluwe, Johannes; Ravid, Revital; Hornstein, Eran; Giladi, Hilla; Galun, Eithan

    2017-11-01

    Effective treatments are needed for hepatic steatosis characterized by accumulation of triglycerides in hepatocytes, which leads to hepatocellular carcinoma. MicroRNA 122 (MIR122) is expressed only in the liver, where it regulates lipid metabolism. We investigated the mechanism by which free fatty acids (FFAs) regulate MIR122 expression and the effect of MIR122 on triglyceride synthesis. We analyzed MIR122 promoter activity and validated its target mRNAs by transfection of Luciferase reporter plasmids into Huh7, BNL-1ME, and HEK293 cultured cell lines. We measured levels of microRNAs and mRNAs by quantitative real-time PCR analysis of RNA extracted from plasma, liver, muscle, and adipose tissues of C57BL/6 mice given the FFA-inducer CL316243. MIR122 was inhibited using an inhibitor of MIR122. Metabolic profiles of mice were determined using metabolic chambers and by histologic analyses of liver tissues. We performed RNA sequence analyses to identify metabolic pathways involving MIR122. We validated human Agpat1 and Dgat1 mRNAs, involved in triglyceride synthesis, as targets of MIR122. FFAs increased MIR122 expression in livers of mice by activating the retinoic acid-related orphan receptor alpha, and induced secretion of MIR122 from liver to blood. Circulating MIR122 entered muscle and adipose tissues of mice, reducing mRNA levels of genes involved in triglyceride synthesis. Mice injected with an inhibitor of MIR122 and then given CL316243, accumulated triglycerides in liver and muscle tissues, and had reduced rates of β-oxidation. There was a positive correlation between level of FFAs and level of MIR122 in plasma samples from 6 healthy individuals, collected before and during fasting. In biochemical and histologic studies of plasma, liver, muscle, and adipose tissues from mice, we found that FFAs increase hepatic expression and secretion of MIR122, which regulates energy storage vs expenditure in liver and peripheral tissues. Strategies to reduce

  20. [Methods for enzymatic determination of triglycerides in liver homogenates].

    Science.gov (United States)

    Höhn, H; Gartzke, J; Burck, D

    1987-10-01

    An enzymatic method is described for the determination of triacylglycerols in liver homogenate. In contrast to usual methods, higher reliability and selectivity are achieved by omitting the extraction step.

  1. GCN2 in the Brain Programs PPARγ2 and Triglyceride Storage in the Liver during Perinatal Development in Response to Maternal Dietary Fat

    Science.gov (United States)

    Xu, Xu; Hu, Jingjie; McGrath, Barbara C.; Cavener, Douglas R.

    2013-01-01

    The liver plays a central role in regulating lipid metabolism and facilitates efficient lipid utilization and storage. We discovered that a modest increase in maternal dietary fat in mice programs triglyceride storage in the liver of their developing offspring. The activation of this programming is not apparent, however, until several months later at the adult stage. We found that the perinatal programming of adult hepatic triglyceride storage was controlled by the eIF2α kinase GCN2 (EIF2AK4) in the brain of the offspring, which stimulates epigenetic modification of the Pparγ2 gene in the neonatal liver. Genetic ablation of Gcn2 in the offspring exhibited reduced hepatic triglyceride storage and repressed expression of the peroxisome proliferator-activated receptor gamma 2 (Pparγ2) and two lipid droplet protein genes, Fsp27 and Cidea. Brain-specific, but not liver-specific, Gcn2 KO mice exhibit these same defects demonstrating that GCN2 in the developing brain programs hepatic triglyceride storage. GCN2 and nutrition-dependent programming of Pparγ2 is correlated with trimethylation of lysine 4 of histone 3 (H3K4me3) in the Pparγ2 promoter region during neonatal development. In addition to regulating hepatic triglyceride in response to modest changes in dietary fat, Gcn2 deficiency profoundly impacts the severity of the obese-diabetic phenotype of the leptin receptor mutant (db/db) mouse, by reducing hepatic steatosis and obesity but exacerbating the diabetic phenotype. We suggest that GCN2-dependent perinatal programming of hepatic triglyceride storage is an adaptation to couple early nutrition to anticipated needs for hepatic triglyceride storage in adults. However, increasing the hepatic triglyceride set point during perinatal development may predispose individuals to hepatosteatosis, while reducing circulating fatty acid levels that promote insulin resistance. PMID:24130751

  2. Meta-Analysis of Structured Triglyceride versus Physical Mixture Medium- and Long-Chain Triglycerides for PN in Liver Resection Patients.

    Science.gov (United States)

    Zhao, Yajie; Wang, Chengfeng

    2017-01-01

    The use of total parenteral nutrition can affect liver function, causing a series of problems such as cholestasis. The aim of this meta-analysis was to compare structured triglyceride- (STG-) based lipid emulsions with physical medium-chain triglyceride (MCT)/long-chain triglyceride (LCT) mixtures in patients who had undergone liver surgery to identify any differences between these two types of parenteral nutrition. We searched the databases of PubMed, the Cochrane Library, Web of Science, EMBASE, and Chinese Biomedicine Database from January 2007 to March 2017 and included studies that compared STG-based lipid emulsions with physical MCT/LCT mixtures for surgical patients with liver disease. The STG was more beneficial than physical MCT/LCT on recovery of liver function and immune function. Therefore, STGs may represent a promising alternative to other types of lipid emulsions for hepatic surgery patients.

  3. Meta-Analysis of Structured Triglyceride versus Physical Mixture Medium- and Long-Chain Triglycerides for PN in Liver Resection Patients

    Directory of Open Access Journals (Sweden)

    Yajie Zhao

    2017-01-01

    Full Text Available Background. The use of total parenteral nutrition can affect liver function, causing a series of problems such as cholestasis. The aim of this meta-analysis was to compare structured triglyceride- (STG- based lipid emulsions with physical medium-chain triglyceride (MCT/long-chain triglyceride (LCT mixtures in patients who had undergone liver surgery to identify any differences between these two types of parenteral nutrition. Methods. We searched the databases of PubMed, the Cochrane Library, Web of Science, EMBASE, and Chinese Biomedicine Database from January 2007 to March 2017 and included studies that compared STG-based lipid emulsions with physical MCT/LCT mixtures for surgical patients with liver disease. Conclusion. The STG was more beneficial than physical MCT/LCT on recovery of liver function and immune function. Therefore, STGs may represent a promising alternative to other types of lipid emulsions for hepatic surgery patients.

  4. Kisspeptin-10 Enhanced Egg Production in Quails Associated with the Increase of Triglyceride Synthesis in Liver

    Directory of Open Access Journals (Sweden)

    J. Wu

    2013-08-01

    Full Text Available Our previous results showed that kisspeptin-10 (Kp-10 injections via intraperitoneal (i.p. once daily for three weeks notably promoted the egg laying rate in quails. In order to investigate the mechanism behind the effects of Kp-10 on enhancing the egg laying rate in birds, this study focused on the alternations of lipids synthesis in liver after Kp-10 injections. 75 female quails (22 d of age were allocated to three groups randomly, and subjected to 0 (control, Con, 10 nmol (low dosage, L and 100 nmol (high dosage, H Kp-10 injections via i.p. once daily for three weeks, respectively. At d 52, quails were sacrificed and sampled for further analyses. Serum E2 concentration was increased by Kp-10 injections, and reached statistical significance in H group. Serum triglyceride (TG concentrations were increased by 46.7% in L group and 36.8% in H group, respectively, but did not reach statistical significance, and TG contents in liver were significantly elevated by Kp-10 injections in a dose-dependent manner. Serum total cholesterol (Tch concentrations significantly decreased in H group, while in H group the hepatic Tch content was markedly increased. The level of non-esterified fatty acid (NEFA, apolipoprotein A1 and B (apoA1 and apoB were not altered by Kp-10 injections. The genes expression of sterol regulatory element binding protein-1 (SREBP-1, fatty acid synthetase (FAS, apolipoprotein VLDL-II (apoVLDL-II, cholesterol 7α-hydroxylase (CYP7A1 and vitellogenin II (VTG-II were significantly up-regulated by high but not low dosage of Kp-10 injection compared to the control group. However, the expression of SREBP-2, acetyl-CoA carboxylase (ACCα, malic enzyme (ME, stearoyl-CoA (Δ9 desaturase 1 (SCD1, apolipoprotein A1 (apoA1, fatty acid binding protein 2 (FABP2, 3-hydroxyl-3-methyl glutaryl-coenzyme A reductases (HMGCR, estrogen receptor α, β (ERα and β mRNA were not affected by Kp-10 treatment. In line with hepatic mRNA abundance, hepatic SREBP

  5. The fatty liver dystrophy (fld) mutation: Developmentally related alterations in hepatic triglyceride metabolism and protein expression

    Energy Technology Data Exchange (ETDEWEB)

    Reue, K.; Rehnmark, S.; Cohen, R.D.; Leete, T.H.; Doolittle, M.H. [West Los Angeles VA Medical Center, CA (United States). Lipid Research Lab.]|[Univ. of California, Los Angeles, CA (United States). Dept. of Medicine; Giometti, C.S.; Mishler, K. [Argonne National Lab., IL (United States); Slavin, B.G. [Univ. of Southern California, Los Angeles, CA (United States)

    1997-07-01

    Fatty liver dystrophy (fld) is an autosomal recessive mutation in mice characterized by hypertriglyceridemia and development of a fatty liver in the early neonatal period. Also associated with the fld phenotype is a tissue-specific deficiency in the expression of lipoprotein lipase and hepatic lipase, as well as elevations in hepatic apolipoprotein A-IV and apolipoprotein C-II mRNA levels. Although these lipid abnormalities resolve at the age of weaning, adult mutant mice exhibit a peripheral neuropathy associated with abnormal myelin formation. The fatty liver in fld/fld neonates is characterized by the accumulation of large triglyceride droplets within the parenchymal cells, and these droplets persist within isolated hepatocytes maintained in culture for several days. To identify the metabolic defect that leads to lipid accumulation, the authors investigated several aspects of cellular triglyceride metabolism. The mutant mice exhibited normal activity of acid triacylglycerol lipase, an enzyme thought to be responsible for hydrolysis of dietary triglycerides in the liver. Metabolic labeling studies performed with oleic acid revealed that free fatty acids accumulate in the liver of 3 day old fld/fld mice, but not in adults. This accumulation in liver was mirrored by elevated free fatty acid levels in plasma of fld/fld neonates, with levels highest in very young mice and returning to normal by the age of one month. Quantitation of fatty acid oxidation in cells isolated from fld/fld neonates revealed that oxidation rate is reduced 60% in hepatocytes and 40% in fibroblasts; hepatocytes from adult fld/fld mice exhibited an oxidation rate similar to those from wild-type mice.

  6. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis

    Science.gov (United States)

    Jiao, Yang; Lu, Yan; Li, Xiao-ying

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia. PMID:25500875

  7. Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

    Science.gov (United States)

    Scherer, Thomas; Lindtner, Claudia; O'Hare, James; Hackl, Martina; Zielinski, Elizabeth; Freudenthaler, Angelika; Baumgartner-Parzer, Sabina; Tödter, Klaus; Heeren, Joerg; Krššák, Martin; Scheja, Ludger; Fürnsinn, Clemens; Buettner, Christoph

    2016-06-01

    Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  8. Interactions between fatty acid synthesis, oxidation, and esterification in the production of triglyceride-rich lipoproteins by the liver.

    Science.gov (United States)

    Fukuda, N; Ontko, J A

    1984-08-01

    In a series of experiments with male rat livers perfused with or without 5-tetradecyloxy-2-furoic acid (TOFA) in the presence and absence of oleate, the relationships between fatty acid synthesis, oxidation, and esterification from newly synthesized and exogenous fatty acid substrates have been examined. When livers from fed rats were perfused without exogenous fatty acid substrate, 20% of the triglyceride secreted was derived from de novo fatty acid synthesis. Addition of TOFA caused immediate and nearly complete inhibition of fatty acid synthesis, measured by incorporation of 3H2O into fatty acids. Concurrently, ketone body production increased 140% and triglyceride secretion decreased 84%. These marked reciprocal alterations in fatty acid synthesis and oxidation in the liver almost completely abolished the production of very low density lipoproteins (VLDL). Cholesterol synthesis was also depressed by TOFA, suggesting that this drug also inhibited lipid synthesis at a site other than acetyl-CoA carboxylase. When livers from fed rats were supplied with a continuous infusion of [1-14C]oleate as exogenous substrate, similar proportions, about 45-47%, of both ketone bodies and triglyceride in the perfusate were derived from the infused [1-14C]oleate. The production of ketone bodies was markedly increased by TOFA; the secretion of triglyceride and cholesterol were decreased. Altered conversion of [1-14C]oleate into these products occurred in parallel. While TOFA decreased esterification of oleate into triglyceride, incorporation of [1-14C]oleate into liver phospholipid was increased, indicating that TOFA also affected glycerolipid synthesis at the stage of diglyceride processing. The decreased secretion of triglyceride and cholesterol following TOFA treatment was localized almost exclusively in VLDL. The specific activities of 3H and of 14C fatty acids in triglyceride of the perfusate were greater than those of liver triglyceride, indicating preferential secretion of

  9. Micro RNA-124a Regulates Lipolysis via Adipose Triglyceride Lipase and Comparative Gene Identification 58

    Directory of Open Access Journals (Sweden)

    Suman K. Das

    2015-04-01

    Full Text Available Lipolysis is the biochemical pathway responsible for the catabolism of cellular triacylglycerol (TG. Lipolytic TG breakdown is a central metabolic process leading to the generation of free fatty acids (FA and glycerol, thereby regulating lipid, as well as energy homeostasis. The precise tuning of lipolysis is imperative to prevent lipotoxicity, obesity, diabetes and other related metabolic disorders. Here, we present our finding that miR-124a attenuates RNA and protein expression of the major TG hydrolase, adipose triglyceride lipase (ATGL/PNPLA2 and its co-activator comparative gene identification 58 (CGI-58/ABHD5. Ectopic expression of miR-124a in adipocytes leads to reduced lipolysis and increased cellular TG accumulation. This phenotype, however, can be rescued by overexpression of truncated Atgl lacking its 3'UTR, which harbors the identified miR-124a target site. In addition, we observe a strong negative correlation between miR-124a and Atgl expression in various murine tissues. Moreover, miR-124a regulates the expression of Atgl and Cgi-58 in murine white adipose tissue during fasting as well as the expression of Atgl in murine liver, during fasting and re-feeding. Together, these results point to an instrumental role of miR-124a in the regulation of TG catabolism. Therefore, we suggest that miR-124a may be involved in the regulation of several cellular and organismal metabolic parameters, including lipid storage and plasma FA concentration.

  10. Impaired Insulin Suppression of VLDL-Triglyceride Kinetics in Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Poulsen, Marianne K; Nellemann, Birgitte; Stødkilde-Jørgensen, Hans; Pedersen, Steen B; Grønbæk, Henning; Nielsen, Søren

    2016-04-01

    Nonalcoholic fatty liver disease (NAFLD) is associated with glucose and lipid metabolic abnormalities. However, insulin suppression of very low-density lipoprotein-triglyceride (VLDL-TG) kinetics is not fully understood. The objective of the study was to determine VLDL-TG, glucose, and palmitate kinetics during fasting and hyperinsulinemia in men with (NAFLD+) and without NAFLD (NAFLD−). Twenty-seven nondiabetic, upper-body obese (waist to hip ratio > 0.9, body mass index > 28 kg/m2) men, 18 NAFLD+, and nine NAFLD− determined by magnetic resonance spectroscopy were enrolled.14C-labeled VLDL-TG and 3H-labeled glucose and palmitate tracers were applied in combination with indirect calorimetry and breath samples to assess kinetics and substrate oxidations postabsorptively and during a hyperinsulinemic-euglycemic clamp. Dual-X-ray absorptiometry and magnetic resonance imaging assessed body composition. Liver fat content was greater in NAFLD+ than NAFLD− men (21.0% vs 3.7%), even though body composition, metabolites (except triglycerides), and insulin were similar in the groups. Insulin suppression of VLDL-TG secretion (P = .0001), oxidation (P = .0003), and concentration (P= .008) as well as percentage decreases were lower in NAFLD+ than NAFLD− men (secretion: 31.9% ± 17.2% vs 64.7% ± 19.9%; oxidation: −9.0% ± 24.7% vs 46.5% ± 36.6%; concentration: 11.9% ± 20.7% vs 56.2% ± 22.9%, all P glucose production was similar in the groups. Compared with endogenous glucose production, the inability of NAFLD+ men to suppress VLDL-TG kinetics to compensate for the increased liver fat content seems to be an early pathophysiological manifestation of male NAFLD+. These data suggest therapeutic targets reducing liver fat content may ameliorate metabolic abnormalities associated with NAFLD and presumably diabetes.

  11. Triglyceride kinetics, tissue lipoprotein lipase, and liver lipogenesis in septic rats

    International Nuclear Information System (INIS)

    Lanza-Jacoby, S.; Tabares, A.

    1990-01-01

    The mechanism for the development of hypertriglyceridemia during gram-negative sepsis was studied by examining liver production and clearance of very-low-density lipoprotein (VLDL) triglyceride (TG). To assess liver output and peripheral clearance the kinetics of VLDL-TG were determined by a constant iv infusion of [2-3H]glycerol-labeled VLDL. Clearance of VLDL-TG was also evaluated by measuring activities of lipoprotein lipase (LPL) in heart, soleus muscle, and adipose tissue from fasted control, fasted E. coli-treated, fed control, and fed E. coli-treated rats. Lewis inbred rats, 275-300 g, were made septic with 8 x 10(7) live E. coli colonies per 100 g body wt. Twenty-four hours after E. coli injection, serum TG, free fatty acids (FFA), and cholesterol of fasted E. coli-treated rats were elevated by 170, 76, and 16%, respectively. The elevation of serum TG may be attributed to the 67% decrease in clearance rate of VLDL-TG in fasted E. coli-treated rats compared with their fasted controls. The suppressed activities of LPL in adipose tissue, skeletal muscle, and heart were consistent with reduced clearance of TG. Secretion of VLDL-TG declined by 31% in livers of fasted E. coli-treated rats, which was accompanied by a twofold increase in the composition of liver TG. Rates of in vivo TG synthesis in livers of the fasted E. coli-treated rats were twofold higher than in those of fasted control rats. Decreased rate of TG appearance along with the increase in liver synthesis of TG contributed to the elevation of liver lipids in the fasted E. coli-treated rats

  12. Triglycerides produced in the livers of fasting rabbits are predominantly stored as opposed to secreted into the plasma

    Science.gov (United States)

    Tuvdendorj, Demidmaa; Zhang, Xiao-jun; Chinkes, David L.; Wang, Lijian; Wu, Zhanpin; Rodriguez, Noe A.; Herndon, David N.; Wolfe, Robert R.

    2015-01-01

    Objective The liver plays a central role in regulating fat metabolism; however, it is not clear how the liver distributes the synthesized triglycerides (TGs) to storage and to the plasma. Materials and Methods We have measured the relative distribution of TGs produced in the liver to storage and the plasma by means of U-13C16-palmitate infusion in anesthetized rabbits after an overnight fast. Results The fractional synthesis rates of TGs stored in the liver and secreted into the plasma were not significantly different (Stored vs. Secreted: 31.9 ± 0.8 vs. 27.7 ± 2.6 %•h−1, p > 0.05. However, the absolute synthesis rates of hepatic stored and secreted TGs were 543 ± 158 and 27 ± 7 nmol·kg−1·min−1 respectively, indicating that in fasting rabbits the TGs produced in the liver were predominately stored (92±3%) rather than secreted (8±3%) into the plasma. This large difference was mainly due to the larger pool size of the hepatic TGs which was 21±9-fold that of plasma TGs. Plasma free fatty acids (FFAs) contributed 47±1% of the FA precursor for hepatic TG synthesis, and the remaining 53±1% was derived from hepatic lipid breakdown and possibly plasma TGs depending on the activity of hepatic lipase. Plasma palmitate concentration significantly correlated with hepatic palmitoyl-CoA and TG synthesis. Conclusion In rabbits, after an overnight fast, the absolute synthesis rate of hepatic stored TGs was significantly higher than that of secreted due to the larger pool size of hepatic TGs. The net synthesis rate of TG was approximately half the absolute rate. Plasma FFA is a major determinant of hepatic TG synthesis, and therefore hepatic TG storage. PMID:25682063

  13. Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice[S

    Science.gov (United States)

    Palmisano, Brian T.; Le, Thao D.; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M.

    2016-01-01

    Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism. PMID:27354419

  14. Cholesteryl ester transfer protein alters liver and plasma triglyceride metabolism through two liver networks in female mice.

    Science.gov (United States)

    Palmisano, Brian T; Le, Thao D; Zhu, Lin; Lee, Yoon Kwang; Stafford, John M

    2016-08-01

    Elevated plasma TGs increase risk of cardiovascular disease in women. Estrogen treatment raises plasma TGs in women, but molecular mechanisms remain poorly understood. Here we explore the role of cholesteryl ester transfer protein (CETP) in the regulation of TG metabolism in female mice, which naturally lack CETP. In transgenic CETP females, acute estrogen treatment raised plasma TGs 50%, increased TG production, and increased expression of genes involved in VLDL synthesis, but not in nontransgenic littermate females. In CETP females, estrogen enhanced expression of small heterodimer partner (SHP), a nuclear receptor regulating VLDL production. Deletion of liver SHP prevented increases in TG production and expression of genes involved in VLDL synthesis in CETP mice with estrogen treatment. We also examined whether CETP expression had effects on TG metabolism independent of estrogen treatment. CETP increased liver β-oxidation and reduced liver TG content by 60%. Liver estrogen receptor α (ERα) was required for CETP expression to enhance β-oxidation and reduce liver TG content. Thus, CETP alters at least two networks governing TG metabolism, one involving SHP to increase VLDL-TG production in response to estrogen, and another involving ERα to enhance β-oxidation and lower liver TG content. These findings demonstrate a novel role for CETP in estrogen-mediated increases in TG production and a broader role for CETP in TG metabolism. Copyright © 2016 by the American Society for Biochemistry and Molecular Biology, Inc.

  15. Unacylated ghrelin does not alter mitochondrial function, redox state and triglyceride content in rat liver in vivo

    Directory of Open Access Journals (Sweden)

    Gianluca Gortan Cappellari

    2015-12-01

    Full Text Available Changes in liver mitochondrial function with more oxidized redox state and enhanced inflammation may contribute to the onset of obesity- and insulin resistance-associated hepatic complications, including non-alcoholic fatty liver disease and steato-hepatitis. Unacylated ghrelin (UnAG is a gastric hormone reported to be associated with lower oxidative stress in different cell types, but its potential effects on liver mitochondrial function, redox state and inflammation in vivo remains undetermined. We investigated the impact of chronic UnAG overexpression (Tg Myh6/Ghrl leading to systemic upregulation of circulating hormone on mitochondrial ATP production, redox state (oxidized-to-total glutathione and inflammation markers in lean mice. Compared to wild-type animals (wt, Tg Myh6/Ghrl had superimposable liver weight, triglyceride content and plasma lipid profile. Liver mitochondrial enzyme activities and ATP production as well as oxidized-to-total glutathione were also similar in the two groups. In addition, no differences were observed in tissue inflammation marker TNF-alpha between wild-type and Tg Myh6/Ghrl animals. Thus, chronic systemic UnAG upregulation does not alter liver triglyceride content, mitochondrial function, redox state and inflammation markers in lean mice. These findings do not support a major role of UnAG as a physiological modulator of in vivo liver oxidative-lipid metabolism and inflammation.

  16. The Effect of 10 Weeks Resistance Training on Cholesterol and Blood Triglyceride Levels of Patients with Fatty Liver Disease.

    Science.gov (United States)

    Valizadeh, Rohollah; Hosseini Askarabadi, Siroos; Karampour, Sedigheh; Abdolhamid Tehrani, Mona

    2014-01-01

    The present study aims to consider the effect of 10 weeks resistance trainings on cholesterol and blood triglyceride (TG) levels of patients with having fatty liver, aged 50 to 60 in National Iranian South Oil Company (NISOC). This research is practical and its plan has been done experimentally with pretest and post-test on experimental and control groups. In this study, 20 samples from 100 patients who referred to sonography clinic in NISOC with distinction of fatty liver were selected randomly and divided into two groups of control (n = 10) and experimental (n = 10). Cholesterol and blood trigly-ceride were measured as pretest. Test of normality for TG was (p = 0/200) by Kolmogorov-Smirnov and (p = 0/070) for cholesterol by Shapiro-Wilk test. After 10 weeks resistance trainings, the analysis and resolution of data were done by computer and SPSS (16) software as well as the descriptive and statistical methods (t-test). Comparison between these two groups showed that 8 weeks resistance trainings with a ≤ 0.05 causes significant decrease in the amount of TG but did not any significant effect on cholesterol of fatty liver patients. How to cite this article: Valizadeh R, Askarabadi SH, Karampour S, Tehrani MA. The Effect of 10 Weeks Resistance Training on Cholesterol and Blood Triglyceride Levels of Patients with Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2014;4(1):64-65.

  17. Pluronic L-81 ameliorates diabetic symptoms in db/db mice through transcriptional regulation of microsomal triglyceride transfer protein

    Science.gov (United States)

    Au, Wo-Shing; Lu, Li-Wei; Tam, Sidney; Ko, Otis King Hung; Chow, Billy KC; He, Ming-Liang; Ng, Samuel S; Yeung, Chung-Man; Liu, Ching-Chiu; Kung, Hsiang-Fu; Lin, Marie C

    2009-01-01

    AIM: To test whether oral L-81 treatment could improve the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver. METHODS: Genetically diabetic (db/db) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mechanism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B (apoB) secretion and mRNA level of the MTP gene were assessed. RESULTS: Treatment of db/db mice with L-81 significantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also significantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter. CONCLUSION: L-81 represents a promising candidate in the development of a selective insulin-mimetic molecule and an anti-diabetic agent. PMID:19554651

  18. Alpha-lipoic acid reduces body weight and regulates triglycerides in obese patients with diabetes mellitus.

    Science.gov (United States)

    Okanović, Azra; Prnjavorac, Besim; Jusufović, Edin; Sejdinović, Rifat

    2015-08-01

    To determine an influence of alpha-lipoic acid to reduction of body weight and regulation of total cholesterol concentration, triglycerides and glucose serum levels in obese patients with diabetes mellitus type 2. A prospective study includes two groups of obese patients with diabetes mellitus and signs of peripheral polyneuropathia: examined group (30 patients; 15 females and 15 males), and control group (30 patients; 12 females and 18 males). All were treated with metformin (850-1700 mg/day). Examined patients were additionally treated with alpha-lipoic acid 600 mg/day during 20 weeks. Body mass index and concentrations of total cholesterol, triglycerides and glucose in serum were compared before and after the treatment. The group treated with 600 mg alpha-lipoic acid lost significantly more weight, and had lower triglyceride level than the control group. There were no significant differences in total cholesterol and glucose serum levels between the groups. Alpha-lipoic acid of 600 mg/day treatment have influenced weight and triglycerides loss in obese patients with diabetes mellitus type 2. It should be considered as an important additive therapy in obese patients with diabetes mellitus type 2. Copyright© by the Medical Assotiation of Zenica-Doboj Canton.

  19. The liver in regulation of iron homeostasis.

    Science.gov (United States)

    Rishi, Gautam; Subramaniam, V Nathan

    2017-09-01

    The liver is one of the largest and most functionally diverse organs in the human body. In addition to roles in detoxification of xenobiotics, digestion, synthesis of important plasma proteins, gluconeogenesis, lipid metabolism, and storage, the liver also plays a significant role in iron homeostasis. Apart from being the storage site for excess body iron, it also plays a vital role in regulating the amount of iron released into the blood by enterocytes and macrophages. Since iron is essential for many important physiological and molecular processes, it increases the importance of liver in the proper functioning of the body's metabolism. This hepatic iron-regulatory function can be attributed to the expression of many liver-specific or liver-enriched proteins, all of which play an important role in the regulation of iron homeostasis. This review focuses on these proteins and their known roles in the regulation of body iron metabolism. Copyright © 2017 the American Physiological Society.

  20. G0/G1 switch gene-2 regulates human adipocyte lipolysis by affecting activity and localization of adipose triglyceride lipase

    NARCIS (Netherlands)

    Schweiger, M.; Paar, M.; Eder, C.; Brandis, J.; Moser, E.; Gorkiewisz, G.; Grond, S.; Radner, F.P.W.; Cerk, I.; Cornaciu, I.; Oberer, M.; Kersten, A.H.; Zechner, R.; Zimmermann, M.B.; Lass, A.

    2012-01-01

    The hydrolysis of triglycerides in adipocytes, termed lipolysis, provides free fatty acids as energy fuel. Murine lipolysis largely depends on the activity of adipose triglyceride lipase (ATGL)5, which is regulated by two proteins annotated as comparative gene identification-58 (CGI-58) and G0/G1

  1. Lipid regulation in lipodystrophy versus the obesity-associated metabolic syndrome: the dissociation of HDL-C and triglycerides.

    Science.gov (United States)

    Joseph, Jalaja; Shamburek, Robert D; Cochran, Elaine K; Gorden, Phillip; Brown, Rebecca J

    2014-09-01

    There is an inverse relationship between triglycerides and high-density lipoprotein cholesterol (HDL-C) in insulin resistance, such that improvement in insulin resistance decreases triglycerides and increases HDL-C. Patients with lipodystrophy have extreme insulin resistance with high triglycerides and low HDL-C. Leptin replacement in lipodystrophy leads to a marked decrease in triglycerides (∼60%). Our objective was to study the effects of metreleptin on triglycerides and HDL-C in lipodystrophy in contrast to changes in triglycerides and HDL-C in interventions for the obesity-associated metabolic syndrome. This open-label nonrandomized study at the National Institutes of Health included 82 patients with various forms of lipodystrophy. Metreleptin (0.06-0.24 mg/kg/d) was administered for 24 months in lipodystrophy. Serum triglycerides and HDL-C were measured. At baseline, lipodystrophy patients had low HDL-C (30 ± 1 mg/dL) and high triglycerides (961 ± 220 mg/dL) with an inverse relationship between the two (R = -0.37, P = .0006). There was no change in HDL-C with metreleptin despite major improvement in triglycerides, and individual changes in triglycerides only weakly predicted HDL-C change. On linear regression, in obesity, a decrease of 0.1 mg/dL in log(triglycerides) was associated with a 4.2 mg/dL rise in HDL-C, whereas in lipodystrophy, a decrease of 0.1 mg/dL in log(triglycerides) was associated with only a 0.6 mg/dL rise in HDL-C. The normal reciprocal relationship between triglyceride and HDL-C change seen in response to interventions for the obesity-associated metabolic syndrome is quantitatively different from that seen in lipodystrophy in response to metreleptin. Further work is needed to understand HDL-C regulation in this condition.

  2. Dietary fructans, but not cellulose, decrease triglyceride accumulation in the liver of obese Zucker fa/fa rats.

    Science.gov (United States)

    Daubioul, Catherine; Rousseau, Nicolas; Demeure, Roger; Gallez, Bernard; Taper, Henryk; Declerck, Barbara; Delzenne, Nathalie

    2002-05-01

    This study was designed to compare the effects of dietary supplementation with nondigestible carbohydrates, differing in fermentability by colonic bacteria, on hepatic steatosis in growing obese Zucker rats. Male Zucker fa/fa rats were divided into three groups: a control group that received the basal diet, a fructan group that received 10 g highly fermented Synergy 1/100 g diet and a cellulose group that received 10 g poorly fermented Vivapur Microcrystalline cellulose/100 g diet. Rats consuming fructan had a lower energy intake, a lower body weight and less triacylglycerol accumulation in the liver as assessed in vivo by nuclear magnetic resonance (NMR) spectroscopy, and ex vivo by biochemical and histochemical analysis compared with the control and/or cellulose groups. The high fermentation of fructans compared with cellulose was reflected by greater cecal contents and by a twofold greater propionate concentration in the portal vein of rats fed fructan compared with those fed cellulose. By measuring the capacity of hepatocytes isolated from liver of Zucker rats to synthesize triglycerides or total lipids from different precursors, we showed that propionate, at the concentrations measured in the portal vein of rats treated with fructan, selectively decreased the incorporation of acetate into total lipids, a phenomenon that could contribute, along with the lower energy intake, to less triglyceride accumulation in the liver of obese Zucker rats fed dietary fructans.

  3. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of nonalcoholic fatty liver disease

    Science.gov (United States)

    Obesity is often associated with a cluster of increased health risks collectively known as "Metabolic Syndrome" (MS). MS is often accompanied by development of fatty liver. Sometimes fatty liver results in damage leading to reduced liver function, and need for a transplant. This condition is known...

  4. Triglyceride glucose-body mass index is effective in identifying nonalcoholic fatty liver disease in nonobese subjects.

    Science.gov (United States)

    Zhang, Shujun; Du, Tingting; Li, Mengni; Jia, Jing; Lu, Huiming; Lin, Xuan; Yu, Xuefeng

    2017-06-01

    Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition that is highly correlated with obesity; however, it is not uncommon among nonobese individuals. Triglyceride (TG) and glucose index combined with body mass index (TyG-BMI) has been proposed as a favorable marker of insulin resistance. We sought to investigate the effectiveness of TyG-BMI in identifying NAFLD in nonobese subjects.We conducted a cross-sectional study in a nonobese (BMI glucose, for identifying nonobese subjects at risk for NAFLD.In this study, the prevalence of NAFLD was over one-fifth in the nonobese population. TyG-BMI was an effective marker to detect NAFLD in nonobese subjects.

  5. Apolipoprotein B synthesis in rat small intestine: regulation by dietary triglyceride and biliary lipid

    International Nuclear Information System (INIS)

    Davidson, N.O.; Kollmer, M.E.; Glickman, R.M.

    1986-01-01

    Apolipoprotein B (apoB) synthesis rates have been determined, in vivo, in rat enterocytes. Following intralumenal administration of a pulse of [ 3 H]leucine, newly synthesized apoB was quantitated by specific immunoprecipitation and compared to [ 3 H]leucine incorporation into total, trichloroacetic acid-insoluble protein. ApoB synthesis rates were determined after acute administration of either 0.1 or 1 g of triglyceride to fasting animals. No differences were found at any time from 90 min to 6 hr after challenge and values were not different from the basal values established in fasted controls. Animals rechallenged with triglyceride after 8 days' intake of fat-free chow also failed to demonstrate a change in intestinal apoB synthesis rate. By contrast, enterocyte content of apoB appeared to fall, temporarily, with the onset of active triglyceride flux. Groups of animals were then subjected to external bile diversion for 48 hr, a maneuver designed to remove all lumenal sources of lipid. Jejunal apoB synthesis rates fell by 43% (from 0.76% +/- 0.14 to 0.43% +/- 0.12, P less than 0.001), a change that was completely prevented by continuous replacement with 10 mM Na taurocholate. The suppression of jejunal apoB synthesis, induced by prolonged bile diversion, was reversed after 14 hr, but not 8 hr, of intralumenal perfusion with 10 mM Na taurocholate. The addition of micellar fatty acid-monoolein to the perfusate for 4 hr produced no further change in apoB synthesis. Ileal apoB synthesis rates fell by 70% (from 0.61% +/- 0.15 to 0.18% +/- 0.10, P less than 0.001) following 48 hr external bile diversion, a change that was only partially prevented by continuous bile salt replacement. These results suggest that jejunal apoB synthesis demonstrates bile salt dependence but not regulation by acute triglyceride flux

  6. Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

    Science.gov (United States)

    Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

  7. Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy

    International Nuclear Information System (INIS)

    Hirano, Ken-ichi; Tanaka, Tatsuya; Ikeda, Yoshihiko; Yamaguchi, Satoshi; Zaima, Nobuhiro; Kobayashi, Kazuhiro; Suzuki, Akira; Sakata, Yasuhiko

    2014-01-01

    Highlights: •Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare severe heart disease. •PPARγ is up-regulated in myocardium in patients with TGCV. •Possible vicious cycle for fatty acid may be involved in pathophysiology of TGCV. -- Abstract: Adipose triglyceride lipase (ATGL, also known as PNPLA2) is an essential molecule for hydrolysis of intracellular triglyceride (TG). Genetic ATGL deficiency is a rare multi-systemic neutral lipid storage disease. Information regarding its clinical profile and pathophysiology, particularly for cardiac involvement, is still very limited. A previous middle-aged ATGL-deficient patient in our institute (Case 1) with severe heart failure required cardiac transplantation (CTx) and exhibited a novel phenotype, “Triglyceride deposit cardiomyovasculopathy (TGCV)”. Here, we tried to elucidate molecular mechanism underlying TGCV. The subjects were two cases with TGCV, including our second case who was a 33-year-old male patient (Case 2) with congestive heart failure requiring CTx. Case 2 was homozygous for a point mutation in the 5′ splice donor site of intron 5 in the ATGL, which results in at least two types of mRNAs due to splicing defects. The myocardium of both patients (Cases 1 and 2) showed up-regulation of peroxisome proliferated activated receptors (PPARs), key transcription factors for metabolism of long chain fatty acids (LCFAs), which was in contrast to these molecules’ lower expression in ATGL-targeted mice. We investigated the intracellular metabolism of LCFAs under human ATGL-deficient conditions using patients’ passaged skin fibroblasts as a model. ATGL-deficient cells showed higher uptake and abnormal intracellular transport of LCFA, resulting in massive TG accumulation. We used these findings from cardiac specimens and cell-biological experiments to construct a hypothetical model to clarify the pathophysiology of the human disorder. In patients with TGCV, even when hydrolysis of intracellular TG

  8. Genetic mutations in adipose triglyceride lipase and myocardial up-regulation of peroxisome proliferated activated receptor-γ in patients with triglyceride deposit cardiomyovasculopathy

    Energy Technology Data Exchange (ETDEWEB)

    Hirano, Ken-ichi, E-mail: khirano@cnt-osaka.com [Laboratory of Cardiovascular Disease, Novel, Non-Invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874 (Japan); Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871 (Japan); Tanaka, Tatsuya [Center for Medical Research and Education, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871 (Japan); Ikeda, Yoshihiko [Department of Pathology, National Cerebral and Cardiovascular Center, 5-7-1 Fujishirodai, Suita 565-8565 (Japan); Yamaguchi, Satoshi [Laboratory of Cardiovascular Disease, Novel, Non-Invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874 (Japan); Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871 (Japan); Zaima, Nobuhiro [Department of Applied Biochemistry, Kinki University, 3327-204, Nakamachi, Nara 631-8505 (Japan); Kobayashi, Kazuhiro [Division of Neurology/Molecular Brain Science, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, Hyogo 650-0017 (Japan); Suzuki, Akira [Laboratory of Cardiovascular Disease, Novel, Non-Invasive, and Nutritional Therapeutics (CNT), Graduate School of Medicine, Osaka University, 6-2-3, Furuedai, Suita, Osaka 565-0874 (Japan); Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871 (Japan); Sakata, Yasuhiko [Department of Cardiovascular Medicine, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita, Osaka 565-0871 (Japan); Department of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, 1-1, Seiryo-cho, Aoba-ku, Sendai 980-8574 (Japan); and others

    2014-01-10

    Highlights: •Triglyceride deposit cardiomyovasculopathy (TGCV) is a rare severe heart disease. •PPARγ is up-regulated in myocardium in patients with TGCV. •Possible vicious cycle for fatty acid may be involved in pathophysiology of TGCV. -- Abstract: Adipose triglyceride lipase (ATGL, also known as PNPLA2) is an essential molecule for hydrolysis of intracellular triglyceride (TG). Genetic ATGL deficiency is a rare multi-systemic neutral lipid storage disease. Information regarding its clinical profile and pathophysiology, particularly for cardiac involvement, is still very limited. A previous middle-aged ATGL-deficient patient in our institute (Case 1) with severe heart failure required cardiac transplantation (CTx) and exhibited a novel phenotype, “Triglyceride deposit cardiomyovasculopathy (TGCV)”. Here, we tried to elucidate molecular mechanism underlying TGCV. The subjects were two cases with TGCV, including our second case who was a 33-year-old male patient (Case 2) with congestive heart failure requiring CTx. Case 2 was homozygous for a point mutation in the 5′ splice donor site of intron 5 in the ATGL, which results in at least two types of mRNAs due to splicing defects. The myocardium of both patients (Cases 1 and 2) showed up-regulation of peroxisome proliferated activated receptors (PPARs), key transcription factors for metabolism of long chain fatty acids (LCFAs), which was in contrast to these molecules’ lower expression in ATGL-targeted mice. We investigated the intracellular metabolism of LCFAs under human ATGL-deficient conditions using patients’ passaged skin fibroblasts as a model. ATGL-deficient cells showed higher uptake and abnormal intracellular transport of LCFA, resulting in massive TG accumulation. We used these findings from cardiac specimens and cell-biological experiments to construct a hypothetical model to clarify the pathophysiology of the human disorder. In patients with TGCV, even when hydrolysis of intracellular TG

  9. Non-invasive quantification of triglyceride content in steatotic rat livers by (1)H-MRS: when water meets (too much) fat

    NARCIS (Netherlands)

    Heger, Michal; Marsman, Hendrik A.; Bezemer, Rick; Cloos, Martijn A.; van Golen, Rowan F.; van Gulik, Thomas M.

    2011-01-01

    The aims of this study were to explore the relationship between triglyceride (TG) and water in steatotic rat livers and to accordingly test the validity of the currently used steatosis calculation methods from magnetic resonance spectra. The approximations commonly used to derive steatosis degrees

  10. Atorvastatin and fenofibrate increase apolipoprotein AV and decrease triglycerides by up-regulating peroxisome proliferator-activated receptor-α

    Science.gov (United States)

    Huang, Xian-sheng; Zhao, Shui-ping; Bai, Lin; Hu, Min; Zhao, Wang; Zhang, Qian

    2009-01-01

    Background and purpose: Combining statin and fibrate in clinical practice provides a greater reduction of triglycerides than either drug given alone, but the mechanism for this effect is poorly understood. Apolipoprotein AV (apoAV) has been implicated in triglyceride metabolism. This study was designed to investigate the effect of the combination of statin and fibrate on apoAV and the underlying mechanism(s). Experimental approach: Hypertriglyceridaemia was induced in rats by giving them 10% fructose in drinking water for 2 weeks. They were then treated with atorvastatin, fenofibrate or the two agents combined for 4 weeks, and plasma triglyceride and apoAV measured. We also tested the effects of these two agents on triglycerides and apoAV in HepG2 cells in culture. Western blot and reverse transcription polymerase chain reaction was used to measure apoAV and peroxisome proliferator-activated receptor-α (PPARα) expression. Key results: The combination of atorvastatin and fenofibrate resulted in a greater decrease in plasma triglycerides and a greater increase in plasma and hepatic apoAV than either agent given alone. Hepatic expression of the PPARα was also more extensively up-regulated in rats treated with the combination. A similar, greater increase in apoAV and a greater decrease in triglycerides were observed following treatment of HepG2 cells pre-exposed to fructose), with the combination. Adding an inhibitor of PPARα (MK886) abolished the effects of atorvastatin on HepG2 cells. Conclusions and implications: A combination of atorvastatin and fenofibrate increased apoAV and decreased triglycerides through up-regulation of PPARα. PMID:19694729

  11. Association of decrease in liver triglyceride content with increase in plasma adiponectin levels after pioglitazone treatment in Japanese patients with type 2 diabetes

    International Nuclear Information System (INIS)

    Nagasawa, Kan; Kaneko, Yoshihito; Taneichi, Haruhito

    2010-01-01

    Pioglitazone, an insulin-sensitizing thiazolidinedione, has multiple clinical effects including improvement of insulin sensitivity, blood glucose levels and serum lipid profiles, decrease in liver triglyceride (TG) content, and increase in serum adiponectin. However, the correlation and causal relationship between these effects are not fully understood clinically. Therefore, we analyzed these relationships in patients with type 2 diabetes treated with pioglitazone, focusing on changes in liver TG content and serum adiponectin. Thirteen Japanese patients with type 2 diabetes were treated with pioglitazone (15 mg/day) for more than 3 months. Before and after the pioglitazone treatment, liver TG content was measured by magnetic resonance spectroscopy and various clinical variables were also measured. The pioglitazone treatment significantly decreased the liver TG content (-12.9±8.1%, p 2 =0.53, p=0.017), implying increased serum adiponectin may have decreased liver fat content. (author)

  12. mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

    DEFF Research Database (Denmark)

    Kleinert, Maximilian; Parker, Benjamin L; Chaudhuri, Rima

    2016-01-01

    culture. RESULTS: Ric mKO mice exhibited a greater reliance on fat as an energy substrate, a re-partitioning of lean to fat mass and an increase in intramyocellular triglyceride (IMTG) content, along with increases in several lipid metabolites in muscle. Unbiased proteomics revealed an increase......OBJECTIVE: We have recently shown that acute inhibition of both mTOR complexes (mTORC1 and mTORC2) increases whole-body lipid utilization, while mTORC1 inhibition had no effect. Therefore, we tested the hypothesis that mTORC2 regulates lipid metabolism in skeletal muscle. METHODS: Body composition...... in the expression of the lipid droplet binding protein Perilipin 3 (PLIN3) in muscle from Ric mKO mice. This was associated with increased AMPK activity in Ric mKO muscle. Reducing AMPK kinase activity decreased muscle PLIN3 expression and IMTG content. AMPK agonism, in turn, increased PLIN3 expression in a FoxO1...

  13. Etiology of fatty liver in dairy cattle: effects of nutritional and hormonal status on hepatic microsomal triglyceride transfer protein.

    Science.gov (United States)

    Bremmer, D R; Trower, S L; Bertics, S J; Besong, S A; Bernabucci, U; Grummer, R R

    2000-10-01

    We conducted three experiments to determine the effects of nutritional and hormonal status on microsomal triglyceride transfer protein (MTP) activity and mass. In experiment 1, 18 nonlactating Holstein cows, 75 d before expected calving date, in their second gestation or greater were monitored from d 75 to 55 prepartum. Cows were fed a control diet from d 75 to 62 prepartum for covariable measurements. From d 61 to 55 prepartum, six cows continued to receive the control diet, six cows were restricted to 2.3 kg of grass hay/d, and six cows were fed the control diet plus 1.8 kg of concentrate/d and 500 ml of propylene glycol given 2 times/d as an oral drench. Plasma glucose and serum insulin concentrations were highest in cows that received propylene glycol and lowest in feed restricted cows. Plasma nonesterified fatty acids (NEFA) and liver triglyceride (TG) concentrations were highest in feed restricted cows and not different between cows that received the control diet and cows that received propylene glycol. Hepatic MTP activity and mass were not affected by treatment in experiment 1. In experiment 2, bovine hepatocytes isolated from the caudate process of five preruminating Holstein bull calves were incubated with either 0, 0.5, 1.0, or 2.0 mM NEFA for 48 h. Intracellular TG increased linearly as NEFA concentration in the media increased. Concentration of NEFA in the incubation media had no effect on MTP activity or mass. There was a quadratic effect of concentration of NEFA in the incubation media on MTP mRNA. In experiment 3, bovine hepatocytes isolated from the caudate process of five preruminating Holstein bull calves were incubated with 2 mM [1-14C]oleate for 24 h to accumulate TG, followed by a 36-h period of TG depletion, during which hepatocytes were incubated with no hormone, 10 nM insulin, or 10 nM glucagon. There was no effect of insulin or glucagon on intracellular TG, MTP activity or mass. Cells incubated with no hormone had higher levels of MTP m

  14. Regulation of triglyceride metabolism. I. Eukaryotic neutral lipid synthesis: "Many ways to skin ACAT or a DGAT".

    Science.gov (United States)

    Turkish, Aaron; Sturley, Stephen L

    2007-04-01

    Esterification of sterols, fatty acids and other alcohols into biologically inert forms conserves lipid resources for many cellular functions. Paradoxically, the accumulation of neutral lipids such as cholesteryl ester or triglyceride, is linked to several major disease pathologies. In a remarkable example of genetic expansion, there are at least eleven acyltransferase reactions that lead to neutral lipid production. In this review, we speculate that the complexity and apparent redundancy of neutral lipid synthesis may actually hasten rather than impede the development of novel, isoform-specific, therapeutic interventions for acne, type 2 diabetes, obesity, hyperlipidemia, fatty liver disease, and atherosclerosis.

  15. Effects of Artemisia dracunculus Aqueous Extract on Blood Sugar, Serum Insulin, Triglyceride and Liver Enzymes in Fructose Drinking Water Male Rats

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Shahraki

    2017-02-01

    Full Text Available Background Artemisia are various groups of plants which are used as an herbal medicine in all countries; the present study was designed to evaluate the effects of Artemisia dracunculus (AD leaves aqueous extract on blood sugar, serum insulin, and triglyceride and liver enzymes in Fructose Drinking water (FDW male rats. Methods At the beginning of experiment, 48 Wistar-albino male rats, weighing 200 - 250g were divided into control (C and FDW groups (n = 24. FDW group received FDW (10%, w/v for a month but control group did not receive any agents during the trial period. A half of control and FDW groups received AD L aqueous extract daily during trial period. At the end, animals were anesthetized, sacrificed and blood samples were collected from cervical vessels. Serum insulin, Blood glucose, insulin resistance index, triglyceride and liver enzymes were measured by ordinary methods. Obtained data were analyzed using SPSS-17 via one way ANOVA and Tukey tests. Results Our results showed that serum insulin, blood sugar, insulin resistance index, triglyceride, Aspartate amino transferase (AST and Alanine amino transferase (ALT values in FDW group significantly increased compared to C and C + E groups but these values in group FDW + E were significantly decreases compared to group FDW (P < 0.001. Conclusions Our findings demonstrated that AD L aqueous extract improves blood sugar, serum insulin, insulin resistance index and liver enzymes in rat model.

  16. Foxa1 reduces lipid accumulation in human hepatocytes and is down-regulated in nonalcoholic fatty liver.

    Directory of Open Access Journals (Sweden)

    Marta Moya

    Full Text Available Triglyceride accumulation in nonalcoholic fatty liver (NAFL results from unbalanced lipid metabolism which, in the liver, is controlled by several transcription factors. The Foxa subfamily of winged helix/forkhead box (Fox transcription factors comprises three members which play important roles in controlling both metabolism and homeostasis through the regulation of multiple target genes in the liver, pancreas and adipose tissue. In the mouse liver, Foxa2 is repressed by insulin and mediates fasting responses. Unlike Foxa2 however, the role of Foxa1 in the liver has not yet been investigated in detail. In this study, we evaluate the role of Foxa1 in two human liver cell models, primary cultured hepatocytes and HepG2 cells, by adenoviral infection. Moreover, human and rat livers were analyzed to determine Foxa1 regulation in NAFL. Results demonstrate that Foxa1 is a potent inhibitor of hepatic triglyceride synthesis, accumulation and secretion by repressing the expression of multiple target genes of these pathways (e.g., GPAM, DGAT2, MTP, APOB. Moreover, Foxa1 represses the fatty acid transporter protein FATP2 and lowers fatty acid uptake. Foxa1 also increases the breakdown of fatty acids by inducing peroxisomal fatty acid β-oxidation and ketone body synthesis. Finally, Foxa1 is able to largely up-regulate UCP1, thereby dissipating energy and consistently decreasing the mitochondria membrane potential. We also report that human and rat NAFL have a reduced Foxa1 expression, possibly through a protein kinase C-dependent pathway. We conclude that Foxa1 is an antisteatotic factor that coordinately tunes several lipid metabolic pathways to block triglyceride accumulation in hepatocytes. However, Foxa1 is down-regulated in human and rat NAFL and, therefore, increasing Foxa1 levels could protect from steatosis. Altogether, we suggest that Foxa1 could be a novel therapeutic target for NAFL disease and insulin resistance.

  17. PCSK9 Induces CD36 Degradation and Affects Long-Chain Fatty Acid Uptake and Triglyceride Metabolism in Adipocytes and in Mouse Liver.

    Science.gov (United States)

    Demers, Annie; Samami, Samaneh; Lauzier, Benjamin; Des Rosiers, Christine; Ngo Sock, Emilienne Tudor; Ong, Huy; Mayer, Gaetan

    2015-12-01

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) promotes the degradation of the low-density lipoprotein receptor thereby elevating plasma low-density lipoprotein cholesterol levels and the risk of coronary heart disease. Thus, the use of PCSK9 inhibitors holds great promise to prevent heart disease. Previous work found that PCSK9 is involved in triglyceride metabolism, independently of its action on low-density lipoprotein receptor, and that other yet unidentified receptors could mediate this effect. Therefore, we assessed whether PCSK9 enhances the degradation of CD36, a major receptor involved in transport of long-chain fatty acids and triglyceride storage. Overexpressed or recombinant PCSK9 induced CD36 degradation in cell lines and primary adipocytes and reduced the uptake of the palmitate analog Bodipy FL C16 and oxidized low-density lipoprotein in 3T3-L1 adipocytes and hepatic HepG2 cells, respectively. Surface plasmon resonance, coimmunoprecipitation, confocal immunofluorescence microscopy, and protein degradation pathway inhibitors revealed that PCSK9 directly interacts with CD36 and targets the receptor to lysosomes through a mechanism involving the proteasome. Importantly, the level of CD36 protein was increased by >3-fold upon small interfering RNA knockdown of endogenous PCSK9 in hepatic cells and similarly increased in the liver and visceral adipose tissue of Pcsk9(-/-) mice. In Pcsk9(-/-) mice, increased hepatic CD36 was correlated with an amplified uptake of fatty acid and accumulation of triglycerides and lipid droplets. Our results demonstrate an important role of PCSK9 in modulating the function of CD36 and triglyceride metabolism. PCSK9-mediated CD36 degradation may serve to limit fatty acid uptake and triglyceride accumulation in tissues, such as the liver. © 2015 American Heart Association, Inc.

  18. The triglyceride and glucose index (TyG) is an effective biomarker to identify nonalcoholic fatty liver disease.

    Science.gov (United States)

    Zhang, Shujun; Du, Tingting; Zhang, Jianhua; Lu, Huiming; Lin, Xuan; Xie, Junhui; Yang, Yan; Yu, Xuefeng

    2017-01-19

    The triglyceride and glucose index (TyG) has been proposed as a marker of insulin resistance. We aimed to investigate the ability of TyG, through comparing with the predictive value of alanine aminotransferase (ALT), to identify individuals at risk for nonalcoholic fatty liver disease (NAFLD). A cross-sectional study was conducted in a Chinese health examination cohort of 10 761 people aged above 20 years. NAFLD was diagnosed by ultrasonography. Compared with the participants in the lowest quartile of TyG, the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for NAFLD were 1.8 (1.5-2.1), 3.0 (2.5-3.5), and 6.3 (5.3-7.5) for those in the second, the third, and the fourth quartile of TyG, whereas the corresponding ORs (95% CI) for NAFLD were 1.5 (1.3-1.7), 1.9 (1.6-2.2), and 3.1 (2.6-3.7) for the upper three quartiles of ALT. These results suggested that TyG was superior to ALT in association with NAFLD risk. According to the ROC analysis, the optimal cut-off point of TyG for NAFLD was 8.5 and the area under the ROC curve (AUC) was 0.782 (95% CI 0.773-0.790), with 72.2 and 70.5% sensitivity and specificity, respectively. The AUC of TyG was larger than that of ALT (0.715 (95% CI 0.705-0.725), P for difference <0.0001), whereas the largest AUC was obtained when adding TyG to ALT (0.804 (95% CI 0.795-0.812), P for difference <0.0001). TyG is effective to identify individuals at risk for NAFLD. A TyG threshold of 8.5 was highly sensitive for detecting NAFLD subjects and may be suitable as a diagnostic criterion for NAFLD in Chinese adults.

  19. Triglyceride level

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/article/003493.htm Triglyceride level To use the sharing features on this page, please enable JavaScript. The triglyceride level is a blood test to measure the amount ...

  20. AMP-Activated Kinase Regulates Lipid Droplet Localization and Stability of Adipose Triglyceride Lipase in C. elegans Dauer Larvae.

    Directory of Open Access Journals (Sweden)

    Meng Xie

    Full Text Available Animals have developed diverse mechanisms to adapt to their changing environment. Like many organisms the free-living nematode C. elegans can alternate between a reproductive mode or a diapause-like "dauer" stage during larval development to circumvent harsh environmental conditions. The master metabolic regulator AMP-activated protein kinase (AMPK is critical for survival during the dauer stage, where it phosphorylates adipose triglyceride lipase (ATGL-1 at multiple sites to block lipid hydrolysis and ultimately protect the cellular triglyceride-based energy depot from rapid depletion. However, how the AMPK-mediated phosphorylation affects the function of ATGL-1 has not been characterised at the molecular level. Here we show that AMPK phosphorylation leads to the generation of 14-3-3 binding sites on ATGL-1, which are recognized by the C. elegans 14-3-3 protein orthologue PAR-5. Physical interaction of ATGL-1 with PAR-5 results in sequestration of ATGL-1 away from the lipid droplets and eventual proteasome-mediated degradation. In addition, we also show that the major AMPK phosphorylation site on ATGL-1, Ser 303, is required for both modification of its lipid droplet localization and its degradation. Our data provide mechanistic insight as to how AMPK functions to enhance survival through its ability to protect the accumulated triglyceride deposits from rapid hydrolysis to preserve the energy stores during periods of extended environmental duress.

  1. The genetic regulation of the terminating phase of liver regeneration

    DEFF Research Database (Denmark)

    Nygård, Ingvild E.; Mortensen, Kim E.; Hedegaard, Jakob

    2012-01-01

    Background After partial hepatectomy (PHx), the liver regeneration process terminates when the normal liver-mass/body-weight ratio of 2.5% has been re-established. To investigate the genetic regulation of the terminating phase of liver regeneration, we performed a 60% PHx in a porcine model. Liver...... biopsies were taken at the time of resection, after three weeks and upon termination the sixth week. Gene expression profiles were obtained using porcine oligonucleotide microarrays. Our study reveals the interactions between genes regulating the cell cycle, apoptosis and angiogenesis, and the role...... of Transforming Growth Factor-β (TGF-β) signalling towards the end of liver regeneration. Results Microarray analysis revealed a dominance of genes regulating apoptosis towards the end of regeneration. Caspase Recruitment Domain-Containing Protein 11 (CARD11) was up-regulated six weeks after PHx, suggesting...

  2. Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation

    NARCIS (Netherlands)

    Rojas, Jennifer M; Bruinstroop, E.; Printz, Richard L; Alijagic-Boers, Aldijana; Foppen, E.; Turney, Maxine K; George, Leena; Beck-Sickinger, Annette G; Kalsbeek, A.; Niswender, Kevin D

    OBJECTIVE: Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous

  3. Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation

    NARCIS (Netherlands)

    Rojas, Jennifer M.; Bruinstroop, Eveline; Printz, Richard L.; Alijagic-Boers, Aldijana; Foppen, Ewout; Turney, Maxine K.; George, Leena; Beck-Sickinger, Annette G.; Kalsbeek, Andries; Niswender, Kevin D.

    2015-01-01

    Objective: Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous

  4. Rexinoid Bexarotene Modulates Triglyceride but not Cholesterol Metabolism via Gene-Specific Permissivity of the RXR/LXR Heterodimer in the Liver

    DEFF Research Database (Denmark)

    Lalloyer, Fanny; Pedersen, Thomas Åskov; Gross, Barbara

    2009-01-01

    OBJECTIVE: Bexarotene (Targretin) is a clinically used antitumoral agent which exerts its action through binding to and activation of the retinoid-X-receptor (RXR). The most frequent side-effect of bexarotene administration is an increase in plasma triglycerides, an independent risk factor...... controlling cholesterol homeostasis. CONCLUSIONS: These findings demonstrate that the hypertriglyceridemic action of bexarotene occurs via the RXR/LXR heterodimer and show that RXR heterodimers can act with a selective permissivity on target genes of specific metabolic pathways in the liver....

  5. Hormonal regulation of gluconeogenic gene transcription in the liver

    Indian Academy of Sciences (India)

    Prakash

    and in various nutritional states such as high protein diets and fasting ... Glucose levels in the circulation are regulated by the liver, the metabolic centre which produces glucose ..... AMP-activated kinase (AMPK) under energy stress blocks.

  6. Regulation of organic anion transport in the liver

    NARCIS (Netherlands)

    Roelofsen, H; Jansen, PLM

    1997-01-01

    In several liver diseases the biliary transport is disturbed, resulting in, for example, jaundice and cholestasis. Many of these symptoms can be attributed to altered regulation of hepatic transporters. Organic anion transport, mediated by the canalicular multispecific organic anion transporter

  7. Kaempferol ameliorates symptoms of metabolic syndrome by regulating activities of liver X receptor-β.

    Science.gov (United States)

    Hoang, Minh-Hien; Jia, Yaoyao; Mok, Boram; Jun, Hee-jin; Hwang, Kwang-Yeon; Lee, Sung-Joon

    2015-08-01

    Kaempferol is a dietary flavonol previously shown to regulate cellular lipid and glucose metabolism. However, its molecular mechanisms of action and target proteins have remained elusive, probably due to the involvement of multiple proteins. This study investigated the molecular targets of kaempferol. Ligand binding of kaempferol to liver X receptors (LXRs) was quantified by time-resolved fluorescence resonance energy transfer and surface plasmon resonance analyses. Kaempferol directly binds to and induces the transactivation of LXRs, with stronger specificity for the β-subtype (EC50 = 0.33 μM). The oral administration of kaempferol in apolipoprotein-E-deficient mice (150 mg/day/kg body weight) significantly reduced plasma glucose and increased high-density lipoprotein cholesterol levels and insulin sensitivity compared with the vehicle-fed control. Kaempferol also reduced plasma triglyceride concentrations and did not cause liver steatosis, a common side effect of potent LXR activation. In immunoblotting analysis, kaempferol reduced the nuclear accumulation of sterol regulatory element-binding protein-1 (SREBP-1). Our results show that the suppression of SREBP-1 activity and the selectivity for LXR-β over LXR-α by kaempferol contribute to the reductions of plasma and hepatic triglyceride concentrations in mice fed kaempferol. They also suggest that kaempferol activates LXR-β and suppresses SREBP-1 to enhance symptoms in metabolic syndrome. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. mTORC2 and AMPK differentially regulate muscle triglyceride content via Perilipin 3

    Directory of Open Access Journals (Sweden)

    Maximilian Kleinert

    2016-08-01

    Conclusions: We identified a novel link between mTORC2 and PLIN3, which regulates lipid storage in muscle. While mTORC2 is a negative regulator, we further identified AMPK as a positive regulator of PLIN3, which impacts whole-body substrate utilization and nutrient partitioning.

  9. JTP-103237, a monoacylglycerol acyltransferase inhibitor, prevents fatty liver and suppresses both triglyceride synthesis and de novo lipogenesis

    Directory of Open Access Journals (Sweden)

    Chihiro Okuma

    2015-07-01

    Conclusion: In the present study, JTP-103237 prevented carbohydrate-induced fatty liver and suppressed both TG synthesis and de novo lipogenesis, suggesting MGAT inhibitor may prevent carbohydrate-induced metabolic disorders, including NAFLD, obesity and diabetes.

  10. Short term exposure to perluoroalkyl acids causes increase of hepatic lipid and triglyceride in conjunction with liver hypertrophy

    Science.gov (United States)

    ABSTRACT BODY: Persistent presence of perfluoroalkyl acids (PFAAs) in the environment is due to extensive use of industrial and consumer products. These chemicals activate peroxisome proliferatoractivated receptor-alpha (PPARa) in liver and after lipid metabolism. The current stu...

  11. Neurohumoral fluid regulation in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens Henrik

    1998-01-01

    and lungs. It is still an enigma why patients with chronic liver disease are at the same time overloaded and functional hypovolaemic with a hyperdynamic, hyporeactive circulation. Further research is needed to find the solution to this apparent haemodynamic conflict concerning the abnormal neurohumoral...

  12. Effect of functional sympathetic nervous system impairment of the liver and abdominal visceral adipose tissue on circulating triglyceride-rich lipoproteins.

    Science.gov (United States)

    La Fountaine, Michael F; Cirnigliaro, Christopher M; Kirshblum, Steven C; McKenna, Cristin; Bauman, William A

    2017-01-01

    Interruption of sympathetic innervation to the liver and visceral adipose tissue (VAT) in animal models has been reported to reduce VAT lipolysis and hepatic secretion of very low density lipoprotein (VLDL) and concentrations of triglyceride-rich lipoprotein particles. Whether functional impairment of sympathetic nervous system (SNS) innervation to tissues of the abdominal cavity reduce circulating concentrations of triglyceride (TG) and VLDL particles (VLDL-P) was tested in men with spinal cord injury (SCI). One hundred-three non-ambulatory men with SCI [55 subjects with neurologic injury at or proximal to the 4th thoracic vertebrae (↑T4); 48 subjects with SCI at or distal to the 5th thoracic vertebrae (↓T5)] and 53 able-bodied (AB) subjects were studied. Fasting blood samples were obtained for determination of TG, VLDL-P concentration by NMR spectroscopy, serum glucose by autoanalyzer, and plasma insulin by radioimmunoassay. VAT volume was determined by dual energy x-ray absorptiometry imaging with calculation by a validated proprietary software package. Significant group main effects for TG and VLDL-P were present; post-hoc tests revealed that serum TG concentrations were significantly higher in ↓T5 group compared to AB and ↑T4 groups [150±9 vs. 101±8 (plipoproteins (i.e., TG or Large VLDL-P) and VAT volume or HOMA-IR was significant only in the ↓T5 group. Despite a similar VAT volume and insulin resistance in both SCI groups, the ↓T5 group had significantly higher serum TG and VLDL-P values than that observed in the ↑T4 and the AB control groups. Thus, level of injury is an important determinate of the concentration of circulating triglyceride rich lipoproteins, which may play a role in the genesis of cardiometabolic dysfunction.

  13. Dual regulation of adipose triglyceride lipase by pigment epithelium-derived factor: a novel mechanistic insight into progressive obesity.

    Science.gov (United States)

    Dai, Zhiyu; Qi, Weiwei; Li, Cen; Lu, Juling; Mao, Yuling; Yao, Yachao; Li, Lei; Zhang, Ting; Hong, Honghai; Li, Shuai; Zhou, Ti; Yang, Zhonghan; Yang, Xia; Gao, Guoquan; Cai, Weibin

    2013-09-05

    Both elevated plasma free fatty acids (FFA) and accumulating triglyceride in adipose tissue are observed in the process of obesity and insulin resistance. This contradictory phenomenon and its underlying mechanisms have not been thoroughly elucidated. Recent studies have demonstrated that pigment epithelium-derived factor (PEDF) contributes to elevated plasma FFA and insulin resistance in obese mice via the activation of adipose triglyceride lipase (ATGL). However, we found that PEDF downregulated adipose ATGL protein expression despite of enhancing lipolysis. Plasma PEDF and FFA were increased in associated with a progressive high-fat-diet, and those outcomes were also accompanied by fat accumulation and a reduction in adipose ATGL. Exogenous PEDF injection downregulated adipose ATGL protein expression and elevated plasma FFA, while endogenous PEDF neutralization significantly rescued the adipose ATGL reduction and also reduced plasma FFA in obese mice. PEDF reduced ATGL protein expression in a time- and dose-dependent manner in differentiated 3T3-L1 cells. Small interfering RNA-mediated PEDF knockdown and antibody-mediated PEDF blockage increased endogenous ATGL expression, and PEDF overexpression downregulated ATGL. PEDF resulted in a decreased half-life of ATGL and regulated ATGL degradation via ubiquitin-dependent proteasomal degradation pathway. PEDF stimulated lipolysis via ATGL using ATGL inhibitor bromoenol lactone, and PEDF also downregulated G0/G1 switch gene 2 (G0S2) expression, which is an endogenous inhibitor of ATGL activation. Overall, PEDF attenuated ATGL protein accumulation via proteasome-mediated degradation in adipocytes, and PEDF also promoted lipolysis by activating ATGL. Elevated PEDF may contribute to progressive obesity and insulin resistance via its dual regulation of ATGL. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  14. Influence of thermally-oxidized vegetable oils and animal fats on growth performance, liver gene expression, and liver and serum cholesterol and triglycerides in young pigs

    Science.gov (United States)

    To evaluate the effect of feeding thermally-oxidized vegetable oils and animal fats on growth performance, liver gene expression, and liver and serum fatty acid and cholesterol concentration in young pigs, 102 barrows (6.67 ± 0.03 kg BW) were divided into 3 groups and randomly assigned to dietary tr...

  15. Triglyceride-rich lipoprotein modulates endothelial vascular cell adhesion molecule (VCAM-1 expression via differential regulation of endoplasmic reticulum stress.

    Directory of Open Access Journals (Sweden)

    Ying I Wang

    Full Text Available Circulating triglyceride-rich lipoproteins (TGRL from hypertriglyceridemic subjects exacerbate endothelial inflammation and promote monocyte infiltration into the arterial wall. We have recently reported that TGRL isolated from human blood after a high-fat meal can elicit a pro- or anti-atherogenic state in human aortic endothelial cells (HAEC, defined as up- or down-regulation of VCAM-1 expression in response to tumor necrosis factor alpha (TNFα stimulation, respectively. A direct correlation was found between subjects categorized at higher risk for cardiovascular disease based upon serum triglycerides and postprandial production of TGRL particles that increased VCAM-1-dependent monocyte adhesion to inflamed endothelium. To establish how TGRL metabolism is linked to VCAM-1 regulation, we examined endoplasmic reticulum (ER stress and the unfolded protein response (UPR pathways. Regardless of its atherogenicity, the rate and extent of TGRL internalization and lipid droplet formation by HAEC were uniform. However, pro-atherogenic TGRL exacerbated ER membrane expansion and stress following TNFα stimulation, whereas anti-atherogenic TGRL ameliorated such effects. Inhibition of ER stress with a chemical chaperone 4-phenylbutyric acid decreased TNFα-induced VCAM-1 expression and abrogated TGRL's atherogenic effect. Activation of ER stress sensors PKR-like ER-regulated kinase (PERK and inositol requiring protein 1α (IRE1α, and downstream effectors including eukaryotic initiation factor-2α (eIF2α, spliced X-box-binding protein 1 (sXBP1 and C/EBP homologous protein (CHOP, directly correlated with the atherogenic activity of an individual's TGRL. Modulation of ER stress sensors also correlated with changes in expression of interferon regulatory factor 1 (IRF-1, a transcription factor of Vcam-1 responsible for regulation of its expression. Moreover, knockdown studies using siRNA defined a causal relationship between the PERK/eIF2α/CHOP pathway and

  16. Liver physiological polyploidization: MicroRNA-122 a key regulator.

    Science.gov (United States)

    Celton-Morizur, Séverine; Desdouets, Chantal

    2017-03-01

    Polyploidy is defined as an increase in genome DNA content and is observed in all mammalian species. Polyploidy is a common characteristic of hepatocytes. Polyploidization occurs mainly during liver development, but also in adults with increasing age or due to cellular stress. During liver development, hepatocytes polyploidization occurs through cytokinesis failure leading to the genesis of binucleate hepatocytes. Recently, Hsu et al. demonstrated that miR-122 is a key regulator of hepatic binucleation. In fact, during liver development, miR-122 directly antagonizes procytokinesis targets and thus induces cytokinesis failure leading to the genesis of binucleate hepatocytes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

  17. Triglycerides Test

    Science.gov (United States)

    ... K. Brunner & Suddarth's Handbook of Laboratory and Diagnostic Tests. 2 nd Ed, Kindle. Philadelphia: Wolters Kluwer Health, Lippincott Williams & Wilkins; c2014. Triglycerides; 491–2 p. Lab Tests ...

  18. Effect of functional sympathetic nervous system impairment of the liver and abdominal visceral adipose tissue on circulating triglyceride-rich lipoproteins.

    Directory of Open Access Journals (Sweden)

    Michael F La Fountaine

    Full Text Available Interruption of sympathetic innervation to the liver and visceral adipose tissue (VAT in animal models has been reported to reduce VAT lipolysis and hepatic secretion of very low density lipoprotein (VLDL and concentrations of triglyceride-rich lipoprotein particles. Whether functional impairment of sympathetic nervous system (SNS innervation to tissues of the abdominal cavity reduce circulating concentrations of triglyceride (TG and VLDL particles (VLDL-P was tested in men with spinal cord injury (SCI.One hundred-three non-ambulatory men with SCI [55 subjects with neurologic injury at or proximal to the 4th thoracic vertebrae (↑T4; 48 subjects with SCI at or distal to the 5th thoracic vertebrae (↓T5] and 53 able-bodied (AB subjects were studied. Fasting blood samples were obtained for determination of TG, VLDL-P concentration by NMR spectroscopy, serum glucose by autoanalyzer, and plasma insulin by radioimmunoassay. VAT volume was determined by dual energy x-ray absorptiometry imaging with calculation by a validated proprietary software package.Significant group main effects for TG and VLDL-P were present; post-hoc tests revealed that serum TG concentrations were significantly higher in ↓T5 group compared to AB and ↑T4 groups [150±9 vs. 101±8 (p<0.01 and 112±8 mg/dl (p<0.05, respectively]. VLDL-P concentration was significantly elevated in ↓T5 group compared to AB and ↑T4 groups [74±4 vs. 58±4 (p<0.05 and 55±4 μmol/l (p<0.05]. VAT volume was significantly higher in both SCI groups than in the AB group, and HOMA-IR was higher and approached significance in the SCI groups compared to the AB group. A linear relationship between triglyceride rich lipoproteins (i.e., TG or Large VLDL-P and VAT volume or HOMA-IR was significant only in the ↓T5 group.Despite a similar VAT volume and insulin resistance in both SCI groups, the ↓T5 group had significantly higher serum TG and VLDL-P values than that observed in the ↑T4 and the AB

  19. Neurohumoral fluid regulation in chronic liver disease

    DEFF Research Database (Denmark)

    Møller, Søren; Henriksen, Jens Henrik Sahl

    1998-01-01

    oxide and vasodilating peptides seem to play an important role. The development of central hypovolaemia and activation of potent vasoconstricting systems such as the renin-angiotensin-aldosterone system and the sympathetic nervous system lead to a hyperdynamic circulation with increased heart rate...... and lungs. It is still an enigma why patients with chronic liver disease are at the same time overloaded and functional hypovolaemic with a hyperdynamic, hyporeactive circulation. Further research is needed to find the solution to this apparent haemodynamic conflict concerning the abnormal neurohumoral...

  20. Regulation of Cholesterol Metabolism in Liver: Link to NAFLD and Impact of n-3 PUFAs

    OpenAIRE

    Bae, Jin-Sik; Oh, Ah-Reum; Cha, Ji-Young

    2013-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most common causes of chronic liver disease that affects one-third of adults in westernized countries. NAFLD represents a wide spectrum of hepatic alterations, ranging from simple triglyceride accumulation in the liver to steatohepatitis. Several pharmaceutical approaches to NAFLD management have been examined, but no particular treatment has been considered both safe and highly effective. Growing evidence reveal that supplemental fish o...

  1. Sex Hormones and Their Receptors Regulate Liver Energy Homeostasis

    Directory of Open Access Journals (Sweden)

    Minqian Shen

    2015-01-01

    Full Text Available The liver is one of the most essential organs involved in the regulation of energy homeostasis. Hepatic steatosis, a major manifestation of metabolic syndrome, is associated with imbalance between lipid formation and breakdown, glucose production and catabolism, and cholesterol synthesis and secretion. Epidemiological studies show sex difference in the prevalence in fatty liver disease and suggest that sex hormones may play vital roles in regulating hepatic steatosis. In this review, we summarize current literature and discuss the role of estrogens and androgens and the mechanisms through which estrogen receptors and androgen receptors regulate lipid and glucose metabolism in the liver. In females, estradiol regulates liver metabolism via estrogen receptors by decreasing lipogenesis, gluconeogenesis, and fatty acid uptake, while enhancing lipolysis, cholesterol secretion, and glucose catabolism. In males, testosterone works via androgen receptors to increase insulin receptor expression and glycogen synthesis, decrease glucose uptake and lipogenesis, and promote cholesterol storage in the liver. These recent integrated concepts suggest that sex hormone receptors could be potential promising targets for the prevention of hepatic steatosis.

  2. Postprandial triglyceride-rich lipoproteins regulate perilipin-2 and perilipin-3 lipid-droplet-associated proteins in macrophages.

    Science.gov (United States)

    Varela, Lourdes M; López, Sergio; Ortega-Gómez, Almudena; Bermúdez, Beatriz; Buers, Insa; Robenek, Horst; Muriana, Francisco J G; Abia, Rocío

    2015-04-01

    Lipid accumulation in macrophages contributes to atherosclerosis. Within macrophages, lipids are stored in lipid droplets (LDs); perilipin-2 and perilipin-3 are the main LD-associated proteins. Postprandial triglyceride (TG)-rich lipoproteins induce LD accumulation in macrophages. The role of postprandial lipoproteins in perilipin-2 and perilipin-3 regulation was studied. TG-rich lipoproteins (TRLs) induced the levels of intracellular TGs, LDs and perilipin-2 protein expression in THP-1 macrophages and in Apoe(-/-) mice bone-marrow-derived macrophages with low and high basal levels of TGs. Perilipin-3 was only synthesized in mice macrophages with low basal levels of TGs. The regulation was dependent on the fatty acid composition of the lipoproteins; monounsaturated and polyunsaturated fatty acids (PUFAs) more strongly attenuated these effects compared with saturated fatty acids. In THP-1 macrophages, immunofluorescence microscopy and freeze-fracture immunogold labeling indicated that the lipoproteins translocated perilipin-3 from the cytoplasm to the LD surface; only the lipoproteins that were rich in PUFAs suppressed this effect. Chemical inhibition showed that lipoproteins induced perilipin-2 protein expression through the peroxisome proliferator-activated nuclear receptor (PPAR) PPARα and PPARγ pathways. Overall, our data indicate that postprandial TRLs may be involved in atherosclerotic plaque formation through the regulation of perilipin-2 and perilipin-3 proteins in macrophages. Because the fatty acid composition of the lipoproteins is dependent on the type of fat consumed, the ingestion of olive oil, which is rich in monounsaturated fatty acids, and fish oil, which is rich in omega-3 fatty acids, can be considered a good nutritional strategy to reduce the risk of atherosclerosis by LD-associated proteins decrease. Copyright © 2015 Elsevier Inc. All rights reserved.

  3. Dendritic cells regulate angiogenesis associated with liver fibrogenesis.

    Science.gov (United States)

    Blois, Sandra M; Piccioni, Flavia; Freitag, Nancy; Tirado-González, Irene; Moschansky, Petra; Lloyd, Rodrigo; Hensel-Wiegel, Karin; Rose, Matthias; Garcia, Mariana G; Alaniz, Laura D; Mazzolini, Guillermo

    2014-01-01

    During liver fibrogenesis the immune response and angiogenesis process are fine-tuned resulting in activation of hepatic stellate cells that produce an excess of extracellular matrix proteins. Dendritic cells (DC) play a central role modulating the liver immunity and have recently been implicated to favour fibrosis regression; although their ability to influence the development of fibrogenesis is unknown. Therefore, we explored whether the depletion of DC during early stages of liver injury has an impact in the development of fibrogenesis. Using the CD11c.DTR transgenic mice, DC were depleted in two experimental models of fibrosis in vivo. The effect of anti-angiogenic therapy was tested during early stages of liver fibrogenesis. DC depletion accelerates the development of fibrosis and as a consequence, the angiogenesis process is boosted. We observed up-regulation of pro-angiogenic factors together with an enhanced vascular endothelial growth factor (VEGF) bioavailability, mainly evidenced by the decrease of anti-angiogenic VEGF receptor 1 (also known as sFlt-1) levels. Interestingly, fibrogenesis process enhanced the expression of Flt-1 on hepatic DC and administration of sFlt-1 was sufficient to abrogate the acceleration of fibrogenesis upon DC depletion. Thus, DC emerge as novel players during the development of liver fibrosis regulating the angiogenesis process and thereby influencing fibrogenesis.

  4. Hepatic diseases related to triglyceride metabolism.

    Science.gov (United States)

    Aguilera-Méndez, Asdrubal; Álvarez-Delgado, Carolina; Hernández-Godinez, Daniel; Fernandez-Mejia, Cristina

    2013-10-01

    Triglycerides participate in key metabolic functions such as energy storage, thermal insulation and as deposit for essential and non-essential fatty acids that can be used as precursors for the synthesis of structural and functional phospholipids. The liver is a central organ in the regulation of triglyceride metabolism, and it participates in triglyceride synthesis, export, uptake and oxidation. The metabolic syndrome and associated diseases are among the main concerns of public health worldwide. One of the metabolic syndrome components is impaired triglyceride metabolism. Diseases associated with the metabolic syndrome promote the appearance of hepatic alterations e.g., non-alcoholic steatosis, steatohepatitis, fibrosis, cirrhosis and cancer. In this article, we review the molecular actions involved in impaired triglyceride metabolism and its association with hepatic diseases. We discuss mechanisms that reconcile the chronic inflammation and insulin resistance, and new concepts on the role of intestinal micro-flora permeability and proliferation in fatty liver etiology. We also describe the participation of oxidative stress in the progression of events leading from steatosis to steatohepatitis and fibrosis. Finally, we provide information regarding the mechanisms that link fatty acid accumulation during steatosis with changes in growth factors and cytokines that lead to the development of neoplastic cells. One of the main medical concerns vis-a-vis hepatic diseases is the lack of symptoms at the onset of the illness and, as result, its late diagnosis. The understandings of the molecular mechanisms that underlie hepatic diseases could help design strategies towards establishing markers for their accurate and timely diagnosis.

  5. Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.

    Science.gov (United States)

    Xu, Jiesi; Xu, Yang; Li, Yuanyuan; Jadhav, Kavita; You, Min; Yin, Liya; Zhang, Yanqiao

    2016-04-14

    The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.

  6. MicroRNA-122 regulates polyploidization in the murine liver.

    Science.gov (United States)

    Hsu, Shu-Hao; Delgado, Evan R; Otero, P Anthony; Teng, Kun-Yu; Kutay, Huban; Meehan, Kolin M; Moroney, Justin B; Monga, Jappmann K; Hand, Nicholas J; Friedman, Joshua R; Ghoshal, Kalpana; Duncan, Andrew W

    2016-08-01

    A defining feature of the mammalian liver is polyploidy, a numerical change in the entire complement of chromosomes. The first step of polyploidization involves cell division with failed cytokinesis. Although polyploidy is common, affecting ∼90% of hepatocytes in mice and 50% in humans, the specialized role played by polyploid cells in liver homeostasis and disease remains poorly understood. The goal of this study was to identify novel signals that regulate polyploidization, and we focused on microRNAs (miRNAs). First, to test whether miRNAs could regulate hepatic polyploidy, we examined livers from Dicer1 liver-specific knockout mice, which are devoid of mature miRNAs. Loss of miRNAs resulted in a 3-fold reduction in binucleate hepatocytes, indicating that miRNAs regulate polyploidization. Second, we surveyed age-dependent expression of miRNAs in wild-type mice and identified a subset of miRNAs, including miR-122, that is differentially expressed at 2-3 weeks, a period when extensive polyploidization occurs. Next, we examined Mir122 knockout mice and observed profound, lifelong depletion of polyploid hepatocytes, proving that miR-122 is required for complete hepatic polyploidization. Moreover, the polyploidy defect in Mir122 knockout mice was ameliorated by adenovirus-mediated overexpression of miR-122, underscoring the critical role miR-122 plays in polyploidization. Finally, we identified direct targets of miR-122 (Cux1, Rhoa, Iqgap1, Mapre1, Nedd4l, and Slc25a34) that regulate cytokinesis. Inhibition of each target induced cytokinesis failure and promoted hepatic binucleation. Among the different signals that have been associated with hepatic polyploidy, miR-122 is the first liver-specific signal identified; our data demonstrate that miR-122 is both necessary and sufficient in liver polyploidization, and these studies will serve as the foundation for future work investigating miR-122 in liver maturation, homeostasis, and disease. (Hepatology 2016

  7. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

    Energy Technology Data Exchange (ETDEWEB)

    Yao, Jiayin; Zhi, Min; Gao, Xiang; Hu, Pinjin; Li, Chujun; Yang, Xiaobo [Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong Province (China)

    2013-03-15

    Our previous study has shown that reduced insulin resistance (IR) was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD) in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks) and an HFD + silibinin group (high-fat diet + 0.5 mg kg{sup -1}·day{sup -1} silibinin, starting at the beginning of the protocol). Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR), intraperitoneal glucose tolerance test and insulin tolerance test (ITT) were performed. The expression of adipose triglyceride lipase (ATGL) and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms.

  8. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

    International Nuclear Information System (INIS)

    Yao, Jiayin; Zhi, Min; Gao, Xiang; Hu, Pinjin; Li, Chujun; Yang, Xiaobo

    2013-01-01

    Our previous study has shown that reduced insulin resistance (IR) was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD) in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks) and an HFD + silibinin group (high-fat diet + 0.5 mg kg -1 ·day -1 silibinin, starting at the beginning of the protocol). Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR), intraperitoneal glucose tolerance test and insulin tolerance test (ITT) were performed. The expression of adipose triglyceride lipase (ATGL) and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms

  9. Effect and the probable mechanisms of silibinin in regulating insulin resistance in the liver of rats with non-alcoholic fatty liver

    Directory of Open Access Journals (Sweden)

    Jiayin Yao

    Full Text Available Our previous study has shown that reduced insulin resistance (IR was one of the possible mechanisms for the therapeutic effect of silibinin on non-alcoholic fatty liver disease (NAFLD in rats. In the present study, we investigated the pathways of silibinin in regulating hepatic glucose production and IR amelioration. Forty-five 4- to 6-week-old male Sprague Dawley rats were divided into a control group, an HFD group (high-fat diet for 6 weeks and an HFD + silibinin group (high-fat diet + 0.5 mg kg-1·day-1 silibinin, starting at the beginning of the protocol. Both subcutaneous and visceral fat was measured. Homeostasis model assessment-IR index (HOMA-IR, intraperitoneal glucose tolerance test and insulin tolerance test (ITT were performed. The expression of adipose triglyceride lipase (ATGL and of genes associated with hepatic gluconeogenesis was evaluated. Silibinin intervention significantly protected liver function, down-regulated serum fat, and improved IR, as shown by decreased HOMA-IR and increased ITT slope. Silibinin markedly prevented visceral obesity by reducing visceral fat, enhanced lipolysis by up-regulating ATGL expression and inhibited gluconeogenesis by down-regulating associated genes such as Forkhead box O1, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. Silibinin was effective in ameliorating IR in NAFLD rats. Reduction of visceral obesity, enhancement of lipolysis and inhibition of gluconeogenesis might be the underlying mechanisms.

  10. Fatty Acid–Regulated Transcription Factors in the Liver

    Science.gov (United States)

    Jump, Donald B.; Tripathy, Sasmita; Depner, Christopher M.

    2014-01-01

    Fatty acid regulation of hepatic gene transcription was first reported in the early 1990s. Several transcription factors have been identified as targets of fatty acid regulation. This regulation is achieved by direct fatty acid binding to the transcription factor or by indirect mechanisms where fatty acids regulate signaling pathways controlling the expression of transcription factors or the phosphorylation, ubiquitination, or proteolytic cleavage of the transcription factor. Although dietary fatty acids are well-established regulators of hepatic transcription factors, emerging evidence indicates that endogenously generated fatty acids are equally important in controlling transcription factors in the context of glucose and lipid homeostasis. Our first goal in this review is to provide an up-to-date examination of the molecular and metabolic bases of fatty acid regulation of key transcription factors controlling hepatic metabolism. Our second goal is to link these mechanisms to nonalcoholic fatty liver disease (NAFLD), a growing health concern in the obese population. PMID:23528177

  11. Urokinase-type plasminogen activator (uPA) stimulates triglyceride synthesis in Huh7 hepatoma cells via p38-dependent upregulation of DGAT2.

    Science.gov (United States)

    Paland, Nicole; Gamliel-Lazarovich, Aviva; Coleman, Raymond; Fuhrman, Bianca

    2014-11-01

    The liver is the central organ of fatty acid and triglyceride metabolism. Oxidation and synthesis of fatty acids and triglycerides is under the control of peroxisome-proliferator-activated receptors (PPAR) α. Impairment of these receptors' function contributes to the accumulation of triglycerides in the liver resulting in non-alcoholic fatty liver disease. Urokinase-type plasminogen activator (uPA) was shown to regulate gene expression in the liver involving PPARγ transcriptional activity. In this study we questioned whether uPA modulates triglyceride metabolism in the liver, and investigated the mechanisms involved in the observed processes. Huh7 hepatoma cells were incubated with increasing concentrations of uPA for 24 h uPA dose-dependently increased the cellular triglyceride mass, and this effect resulted from increased de novo triglyceride synthesis mediated by the enzyme diglyceride acyltransferase 2 (DGAT2). Also, the amount of free fatty acids was highly up regulated by uPA through activation of the transcription factor SREBP-1. Chemical activation of PPARα further increased uPA-stimulated triglyceride synthesis, whereas inhibition of p38, an upstream activator of PPARα, completely abolished the stimulatory effect of uPA on both triglyceride synthesis and DGAT2 upregulation. The effect of uPA on triglyceride synthesis in Huh7 cells was mediated via binding to its receptor, the uPAR. In vivo studies in uPAR(-/-) mice demonstrated that no lipid droplets were observed in their livers compared to C57BL/6 mice and the triglyceride levels were significantly lower. This study presents a new biological function of the uPA/uPAR system in the metabolism of triglycerides and might present a new target for an early therapeutic intervention for NAFLD. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  12. NK Cell Subtypes as Regulators of Autoimmune Liver Disease

    Directory of Open Access Journals (Sweden)

    Guohui Jiao

    2016-01-01

    Full Text Available As major components of innate immunity, NK cells not only exert cell-mediated cytotoxicity to destroy tumors or infected cells, but also act to regulate the functions of other cells in the immune system by secreting cytokines and chemokines. Thus, NK cells provide surveillance in the early defense against viruses, intracellular bacteria, and cancer cells. However, the effecter function of NK cells must be exquisitely controlled to prevent inadvertent attack against normal “self” cells. In an organ such as the liver, where the distinction between immunotolerance and immune defense against routinely processed pathogens is critical, the plethora of NK cells has a unique role in the maintenance of homeostasis. Once self-tolerance is broken, autoimmune liver disease resulted. NK cells act as a “two-edged weapon” and even play opposite roles with both regulatory and inducer activities in the hepatic environment. That is, NK cells act not only to produce inflammatory cytokines and chemokines, but also to alter the proliferation and activation of associated lymphocytes. However, the precise regulatory mechanisms at work in autoimmune liver diseases remain to be identified. In this review, we focus on recent research with NK cells and their potential role in the development of autoimmune liver disease.

  13. Sox17 regulates liver lipid metabolism and adaptation to fasting.

    Directory of Open Access Journals (Sweden)

    Samuel Rommelaere

    Full Text Available Liver is a major regulator of lipid metabolism and adaptation to fasting, a process involving PPARalpha activation. We recently showed that the Vnn1 gene is a PPARalpha target gene in liver and that release of the Vanin-1 pantetheinase in serum is a biomarker of PPARalpha activation. Here we set up a screen to identify new regulators of adaptation to fasting using the serum Vanin-1 as a marker of PPARalpha activation. Mutagenized mice were screened for low serum Vanin-1 expression. Functional interactions with PPARalpha were investigated by combining transcriptomic, biochemical and metabolic approaches. We characterized a new mutant mouse in which hepatic and serum expression of Vanin-1 is depressed. This mouse carries a mutation in the HMG domain of the Sox17 transcription factor. Mutant mice display a metabolic phenotype featuring lipid abnormalities and inefficient adaptation to fasting. Upon fasting, a fraction of the PPARα-driven transcriptional program is no longer induced and associated with impaired fatty acid oxidation. The transcriptional phenotype is partially observed in heterozygous Sox17+/- mice. In mutant mice, the fasting phenotype but not all transcriptomic signature is rescued by the administration of the PPARalpha agonist fenofibrate. These results identify a novel role for Sox17 in adult liver as a modulator of the metabolic adaptation to fasting.

  14. The cholesterol, fatty acid and triglyceride synthesis pathways regulated by site 1 protease (S1P) are required for efficient replication of severe fever with thrombocytopenia syndrome virus.

    Science.gov (United States)

    Urata, Shuzo; Uno, Yukiko; Kurosaki, Yohei; Yasuda, Jiro

    2018-06-12

    Severe fever with thrombocytopenia syndrome (SFTS) is an emerging infectious disease caused by the SFTS virus (SFTSV), which has a high mortality rate. Currently, no licensed vaccines or therapeutic agents have been approved for use against SFTSV infection. Here, we report that the cholesterol, fatty acid, and triglyceride synthesis pathways regulated by S1P is involved in SFTSV replication, using CHO-K1 cell line (SRD-12B) that is deficient in site 1 protease (S1P) enzymatic activity, PF-429242, a small compound targeting S1P enzymatic activity, and Fenofibrate and Lovastatin, which inhibit triglyceride and cholesterol synthesis, respectively. These results enhance our understanding of the SFTSV replication mechanism and may contribute to the development of novel therapies for SFTSV infection. Copyright © 2018. Published by Elsevier Inc.

  15. Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation

    Science.gov (United States)

    Rojas, Jennifer M.; Bruinstroop, Eveline; Printz, Richard L.; Alijagic-Boers, Aldijana; Foppen, Ewout; Turney, Maxine K.; George, Leena; Beck-Sickinger, Annette G.; Kalsbeek, Andries; Niswender, Kevin D.

    2015-01-01

    Objective Elevated very low-density lipoprotein (VLDL)-triglyceride (TG) secretion from the liver contributes to an atherogenic dyslipidemia that is associated with obesity, diabetes and the metabolic syndrome. Numerous models of obesity and diabetes are characterized by increased central nervous system (CNS) neuropeptide Y (NPY); in fact, a single intracerebroventricular (icv) administration of NPY in lean fasted rats elevates hepatic VLDL-TG secretion and does so, in large part, via signaling through the CNS NPY Y1 receptor. Thus, our overarching hypothesis is that elevated CNS NPY action contributes to dyslipidemia by activating central circuits that modulate liver lipid metabolism. Methods Chow-fed Zucker fatty (ZF) rats were pair-fed by matching their caloric intake to that of lean controls and effects on body weight, plasma TG, and liver content of TG and phospholipid (PL) were compared to ad-libitum (ad-lib) fed ZF rats. Additionally, lean 4-h fasted rats with intact or disrupted hepatic sympathetic innervation were treated with icv NPY or NPY Y1 receptor agonist to identify novel hepatic mechanisms by which NPY promotes VLDL particle maturation and secretion. Results Manipulation of plasma TG levels in obese ZF rats, through pair-feeding had no effect on liver TG content; however, hepatic PL content was substantially reduced and was tightly correlated with plasma TG levels. Treatment with icv NPY or a selective NPY Y1 receptor agonist in lean fasted rats robustly activated key hepatic regulatory proteins, stearoyl-CoA desaturase-1 (SCD-1), ADP-ribosylation factor-1 (ARF-1), and lipin-1, known to be involved in remodeling liver PL into TG for VLDL maturation and secretion. Lastly, we show that the effects of CNS NPY on key liporegulatory proteins are attenuated by hepatic sympathetic denervation. Conclusions These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is

  16. ECR-MAPK regulation in liver early development.

    Science.gov (United States)

    Zhao, Xiu-Ju; Zhuo, Hexian

    2014-01-01

    Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region)-socs2 (-SH2-containing signals/receptor tyrosine kinases)-ppp2r2a/pik3c3 (MAPK signaling)-hsd3b5/cav2 (metabolism/organization) plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

  17. ECR-MAPK Regulation in Liver Early Development

    Directory of Open Access Journals (Sweden)

    Xiu-Ju Zhao

    2014-01-01

    Full Text Available Early growth is connected to a key link between embryonic development and aging. In this paper, liver gene expression profiles were assayed at postnatal day 22 and week 16 of age. Meanwhile another independent animal experiment and cell culture were carried out for validation. Significance analysis of microarrays, qPCR verification, drug induction/inhibition assays, and metabonomics indicated that alpha-2u globulin (extracellular region-socs2 (-SH2-containing signals/receptor tyrosine kinases-ppp2r2a/pik3c3 (MAPK signaling-hsd3b5/cav2 (metabolism/organization plays a vital role in early development. Taken together, early development of male rats is ECR and MAPK-mediated coordination of cancer-like growth and negative regulations. Our data represent the first comprehensive description of early individual development, which could be a valuable basis for understanding the functioning of the gene interaction network of infant development.

  18. The Liver X Receptor Ligand T0901317 Down-regulates APOA5 GeneExpression through Activation of SREBP-1c

    Energy Technology Data Exchange (ETDEWEB)

    Jakel, Heidelinde; Nowak, Maxime; Moitrot, Emanuelle; Dehondt, Helene; Hum, Dean W.; Pennacchio, Len A.; Fruchart-Najib, Jamila; Fruchart,Jean-Charles

    2004-07-23

    Alterations in the expression of the recently discovered apolipoprotein A5 gene strongly affect plasma triglyceride levels. In this study, we investigated the contribution of APOA5 to the liver X-receptor (LXR) ligand mediated effect on plasma triglyceride levels.Following treatment with the LXR ligand T0901317, we found that APOA5mRNA levels were decreased in hepatoma cell lines. The observation that no down-regulation of APOA5 promoter activity was obtained by LXR-retinoid X receptor (RXR) co-transfection prompted us to explore the possible involvement of the known LXR target gene SREBP-1c (sterol regulatory element-binding protein 1c). In fact, we found that co-transfection with the active form of SREBP-1c down-regulated APOA5promoter activity in a dose-dependent manner. We then scanned the human APOA5 promoter sequence and identified two putative E-box elements that were able to bind specifically SREBP-1c in gel-shift assays and were shown to be functional by mutation analysis. Subsequent suppression of SREBP-1 mRNA through small interfering RNA interference abolished the decrease of APOA5 mRNA in response to T0901317. Finally, administration of T0901317 to hAPOA5 transgenic mice revealed a significant decrease OF APOA5 mRNA in liver tissue and circulating apolipoprotein AV protein in plasma, confirming that the described down-regulation also occurs in vivo. Taken together, our results demonstrate that APOA5 gene expression is regulated by the LXR ligand T0901317 in a negative manner through SREBP-1c. These findings may provide a new mechanism responsible for the elevation of plasma triglyceride levels by LXR ligands and support the development of selective LXR agonists, not affecting SREBP-1c, as beneficial modulators of lipid metabolism.

  19. Triglycerides and Heart Disease, Still a Hypothesis?

    Science.gov (United States)

    Goldberg, Ira J.; Eckel, Robert H.; McPherson, Ruth

    2011-01-01

    The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport and tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride rich lipoproteins, their influence on HDL and LDL, or the underlying diseases leading to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate VLDL and their remnants, and chylomicron remnants in atherosclerosis development; but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population, and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease. PMID:21527746

  20. Tim-3/galectin-9 regulate the homeostasis of hepatic NKT cells in a murine model of nonalcoholic fatty liver disease.

    Science.gov (United States)

    Tang, Zhao-Hui; Liang, Shuwen; Potter, James; Jiang, Xuan; Mao, Hai-Quan; Li, Zhiping

    2013-02-15

    T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti-IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl(2)MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3(+) NKT cells are in an activated state, and Gal-9 directly induces Tim-3(+) NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3-expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9-signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD.

  1. Tim-3/Galectin-9 Regulate the Homeostasis of Hepatic NKT Cells in a Murine Model of Nonalcoholic Fatty Liver Disease

    Science.gov (United States)

    Liang, Shuwen; Potter, James; Jiang, Xuan; Mao, Hai-Quan

    2013-01-01

    T cell Ig and mucin domain (Tim)-3 is well known to interact with its natural ligand, Galectin-9 (Gal-9), to regulate T cell function. However, little is known about the function of Tim-3/Gal-9 signaling in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) mediated by hepatic NKT cells that also express Tim-3. In the current study, we define the role and the mechanism of Tim-3/Gal-9 signaling in hepatic NKT cell regulation in a mouse model of diet-induced NAFLD. Adult male wild-type or CD1d knockout C57BL/6 mice were fed a high-fat diet to induce steatosis. Some of the mice also received one or a combination of Gal-9, anti–IL-15R/IL-15 mAb, rIL-15, α-galactosylceramide, and multilamellar liposomes containing Cl2MDP. The expression of Tim-3 and various markers reflecting cell proliferation, activation, cytokine production, and apoptosis was analyzed. Liver histology, steatosis grade, and hepatic triglyceride content were also evaluated. In the liver, Tim-3+ NKT cells are in an activated state, and Gal-9 directly induces Tim-3+ NKT cell apoptosis and contributes to the depletion of NKT cells in diet-induced steatosis. However, Gal-9 also interacts with Tim-3–expressing Kupffer cells to induce secretion of IL-15, thus promoting NKT cell proliferation. Exogenous administration of Gal-9 significantly ameliorates diet-induced steatosis by modulating hepatic NKT cell function. In summary, the Tim-3/Gal-9–signaling pathway plays a critical role in the homeostasis of hepatic NKT cells through activation-induced apoptosis and secondary proliferation and, thus, contributes to the pathogenesis of NAFLD. PMID:23296703

  2. Analyzing the temporal regulation of translation efficiency in mouse liver

    Directory of Open Access Journals (Sweden)

    Peggy Janich

    2016-06-01

    Full Text Available Mammalian physiology and behavior follow daily rhythms that are orchestrated by endogenous timekeepers known as circadian clocks. Rhythms in transcription are considered the main mechanism to engender rhythmic gene expression, but important roles for posttranscriptional mechanisms have recently emerged as well (reviewed in Lim and Allada (2013 [1]. We have recently reported on the use of ribosome profiling (RPF-seq, a method based on the high-throughput sequencing of ribosome protected mRNA fragments, to explore the temporal regulation of translation efficiency (Janich et al., 2015 [2]. Through the comparison of around-the-clock RPF-seq and matching RNA-seq data we were able to identify 150 genes, involved in ribosome biogenesis, iron metabolism and other pathways, whose rhythmicity is generated entirely at the level of protein synthesis. The temporal transcriptome and translatome data sets from this study have been deposited in NCBI's Gene Expression Omnibus under the accession number GSE67305. Here we provide additional information on the experimental setup and on important optimization steps pertaining to the ribosome profiling technique in mouse liver and to data analysis.

  3. Osteopontin regulates the cross-talk between phosphatidylcholine and cholesterol metabolism in mouse liver.

    Science.gov (United States)

    Nuñez-Garcia, Maitane; Gomez-Santos, Beatriz; Buqué, Xabier; García-Rodriguez, Juan L; Romero, Marta R; Marin, Jose J G; Arteta, Beatriz; García-Monzón, Carmelo; Castaño, Luis; Syn, Wing-Kin; Fresnedo, Olatz; Aspichueta, Patricia

    2017-09-01

    Osteopontin (OPN) is involved in different liver pathologies in which metabolic dysregulation is a hallmark. Here, we investigated whether OPN could alter liver, and more specifically hepatocyte, lipid metabolism and the mechanism involved. In mice, lack of OPN enhanced cholesterol 7α-hydroxylase (CYP7A1) levels and promoted loss of phosphatidylcholine (PC) content in liver; in vivo treatment with recombinant (r)OPN caused opposite effects. rOPN directly decreased CYP7A1 levels through activation of focal adhesion kinase-AKT signaling in hepatocytes. PC content was also decreased in OPN-deficient (OPN-KO) hepatocytes in which de novo FA and PC synthesis was lower, whereas cholesterol (CHOL) synthesis was higher, than in WT hepatocytes. In vivo inhibition of cholesterogenesis normalized liver PC content in OPN-KO mice, demonstrating that OPN regulates the cross-talk between liver CHOL and PC metabolism. Matched liver and serum samples showed a positive correlation between serum OPN levels and liver PC and CHOL concentration in nonobese patients with nonalcoholic fatty liver. In conclusion, OPN regulates CYP7A1 levels and the metabolic fate of liver acetyl-CoA as a result of CHOL and PC metabolism interplay. The results suggest that CYP7A1 is a main axis and that serum OPN could disrupt liver PC and CHOL metabolism, contributing to nonalcoholic fatty liver disease progression in nonobese patients.

  4. Silymarin attenuated hepatic steatosis through regulation of lipid metabolism and oxidative stress in a mouse model of nonalcoholic fatty liver disease (NAFLD).

    Science.gov (United States)

    Ni, Xunjun; Wang, Haiyan

    2016-01-01

    Silymarin, which derived from the milk thistle plant (silybum marianum), has been used for centuries as a natural remedy for diseases of the liver and biliary tract. Considering the therapeutic potential to liver disease, we tested efficacy of silymarin on hepatic steatosis with a high fat diet (HFD)-induced mouse model of non-alcoholic fatty liver disease (NAFLD), and investigated possible effects on lipid metabolic pathways. In our study, silymarin could attenuate the hepatic steatosis, which was proved by both Oil Red O staining and hepatic triglyceride (TG) level determination. Furthermore, compared with INT-747, a potent and selective FXR agonist, silymarin could preserve plasmatic high-density lipoprotein cholesterol (HDL-C) to a higher level and low-density lipoprotein cholesterol (LDL-C) to a lower level, which benefited more to the circulation system. Through real-time PCR analysis, we clarified a vital protective role of silymarin in mRNA regulation of genes involved in lipid metabolism and oxidative stress. It was also shown that silymarin had no effects on body weight, food intake, and liver transaminase. Taken together, silymarin could attenuate hepatic steatosis in a mouse model of NAFLD through regulation of lipid metabolism and oxidative stress, and benefit to the circulation system. All these findings shed new light on NAFLD treatment.

  5. LIVER AND BONE MARROW STEM/PROGENITOR CELLS AS REGULATORS OF REPARATIVE REGENERATION OF DAMAGED LIVER

    Directory of Open Access Journals (Sweden)

    А. V. Lundup

    2010-01-01

    Full Text Available In this review the modern information about effectiveness of liver insufficiency treatment by stem/ progenitor cells of liver (oval cells and bone marrow (hemopoietic cells and mesenchymal cells was presented. It is shown that medical action of these cells is referred on normalization of liver cell interaction and reorganization of processes of a reparative regeneration in damaged liver. It is believed that application of mesenchymal stromal cells from an autological bone marrow is the most perspective strategy. However, for definitive judgement about regenerative possibilities of the autological bone marrow cells it is necessary to carry out large-scale double blind clinical researches. 

  6. Mechanisms of intrahepatic triglyceride accumulation

    Science.gov (United States)

    Ress, Claudia; Kaser, Susanne

    2016-01-01

    Hepatic steatosis defined as lipid accumulation in hepatocytes is very frequently found in adults and obese adolescents in the Western World. Etiologically, obesity and associated insulin resistance or excess alcohol intake are the most frequent causes of hepatic steatosis. However, steatosis also often occurs with chronic hepatitis C virus (HCV) infection and is also found in rare but potentially life-threatening liver diseases of pregnancy. Clinical significance and outcome of hepatic triglyceride accumulation are highly dependent on etiology and histological pattern of steatosis. This review summarizes current concepts of pathophysiology of common causes of hepatic steatosis, including non-alcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease, chronic HCV infections, drug-induced forms of hepatic steatosis, and acute fatty liver of pregnancy. Regarding the pathophysiology of NAFLD, this work focuses on the close correlation between insulin resistance and hepatic triglyceride accumulation, highlighting the potential harmful effects of systemic insulin resistance on hepatic metabolism of fatty acids on the one side and the role of lipid intermediates on insulin signalling on the other side. Current studies on lipid droplet morphogenesis have identified novel candidate proteins and enzymes in NAFLD. PMID:26819531

  7. Hepatic ABC transporters and triglyceride metabolism.

    Science.gov (United States)

    Parks, John S; Chung, Soonkyu; Shelness, Gregory S

    2012-06-01

    Elevated plasma triglyceride and reduced HDL concentrations are prominent features of metabolic syndrome and type 2 diabetes. Individuals with Tangier disease also have elevated plasma triglyceride concentrations and very low HDL, resulting from mutations in ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein that facilitates nascent HDL particle assembly. Past studies attributed the inverse relationship between plasma HDL and triglyceride to intravascular lipid exchange and catabolic events. However, recent studies also suggest that hepatic signaling and lipid mobilization and secretion may explain how HDL affects plasma triglyceride concentrations. Hepatocyte-specific ABCA1 knockout mice have markedly reduced plasma HDL and a two-fold increase in triglyceride due to failure to assemble nascent HDL particles by hepatocytes, causing increased catabolism of HDL apolipoprotein A-I and increased hepatic production of triglyceride-enriched VLDL. In-vitro studies suggest that nascent HDL particles may induce signaling to decrease triglyceride secretion. Inhibition of microRNA 33 expression in nonhuman primates augments hepatic ABCA1, genes involved in fatty acid oxidation, and decreases expression of lipogenic genes, causing increased plasma HDL and decreased triglyceride levels. New evidence suggests potential mechanisms by which hepatic ABCA1-mediated nascent HDL formation regulates VLDL-triglyceride production and contributes to the inverse relationship between plasma HDL and triglyceride.

  8. Bone morphogenetic protein 9 as a key regulator of liver progenitor cells in DDC-induced cholestatic liver injury.

    Science.gov (United States)

    Addante, Annalisa; Roncero, Cesáreo; Almalé, Laura; Lazcanoiturburu, Nerea; García-Álvaro, María; Fernández, Margarita; Sanz, Julián; Hammad, Seddik; Nwosu, Zeribe C; Lee, Se-Jin; Fabregat, Isabel; Dooley, Steven; Ten Dijke, Peter; Herrera, Blanca; Sánchez, Aránzazu

    2018-05-11

    Bone morphogenetic protein 9 (BMP9) interferes with liver regeneration upon acute injury, while promoting fibrosis upon carbon tetrachloride-induced chronic injury. We have now addressed the role of BMP9 in 3,5 diethoxicarbonyl-1,4 dihydrocollidine (DDC)-induced cholestatic liver injury, a model of liver regeneration mediated by hepatic progenitor cell (known as oval cell), exemplified as ductular reaction and oval cell expansion. WT and BMP9KO mice were submitted to DDC diet. Livers were examined for liver injury, fibrosis, inflammation and oval cell expansion by serum biochemistry, histology, RT-qPCR and western blot. BMP9 signalling and effects in oval cells were studied in vitro using western blot and transcriptional assays, plus functional assays of DNA synthesis, cell viability and apoptosis. Crosslinking assays and short hairpin RNA approaches were used to identify the receptors mediating BMP9 effects. Deletion of BMP9 reduces liver damage and fibrosis, but enhances inflammation upon DDC feeding. Molecularly, absence of BMP9 results in overactivation of PI3K/AKT, ERK-MAPKs and c-Met signalling pathways, which together with an enhanced ductular reaction and oval cell expansion evidence an improved regenerative response and decreased damage in response to DDC feeding. Importantly, BMP9 directly targets oval cells, it activates SMAD1,5,8, decreases cell growth and promotes apoptosis, effects that are mediated by Activin Receptor-Like Kinase 2 (ALK2) type I receptor. We identify BMP9 as a negative regulator of oval cell expansion in cholestatic injury, its deletion enhancing liver regeneration. Likewise, our work further supports BMP9 as an attractive therapeutic target for chronic liver diseases. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  9. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles

    NARCIS (Netherlands)

    Grefhorst, A.; Elzinga, B.M.; Voshol, P.J.; Plösch, T.; Kok, T.; Bloks, V.W.; Sluijs, F.H. van der; Havekes, L.M.; Romijn, J.A.; Verkade, H.J.; Kuipers, F.

    2002-01-01

    The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist

  10. Exercise-induced regulation of key factors in substrate choice and gluconeogenesis in mouse liver

    DEFF Research Database (Denmark)

    Knudsen, Jakob Grunnet; Biensø, Rasmus Sjørup; Hassing, Helle Adser

    2015-01-01

    As the demand for hepatic glucose production increases during exercise, regulation of liver substrate choice and gluconeogenic activity becomes essential. The aim of the present study was to investigate the effect of a single exercise bout on gluconeogenic protein content and regulation of enzymes...... involved in substrate utilization in the liver. Mice were subjected to 1 h of treadmill exercise, and livers were removed immediately, 4 or 10 h after exercise. Glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxylase (PEPCK) mRNA contents in the liver increased immediately after exercise, while...... phosphorylation decreased immediately after exercise may indicate that carbohydrates rather than fatty acids are utilized for oxidation in the liver during non-exhaustive exercise....

  11. Triglyceride-rich lipoprotein regulates APOB48 receptor gene expression in human THP-1 monocytes and macrophages.

    Science.gov (United States)

    Bermudez, Beatriz; Lopez, Sergio; Varela, Lourdes M; Ortega, Almudena; Pacheco, Yolanda M; Moreda, Wenceslao; Moreno-Luna, Rafael; Abia, Rocio; Muriana, Francisco J G

    2012-02-01

    The postprandial metabolism of dietary fats implies that the production of TG-rich lipoproteins (TRL) contributes to the progression of plaque development. TRL and their remnants cause rapid receptor-mediated monocyte/macrophage lipid engorgement via the cell surface apoB48 receptor (apoB48R). However, the mechanistic basis for apoB48 receptor (APOB48R) regulation by postprandial TRL in monocytes and macrophages is not well established. In this study, we investigated the effects of postprandial TRL from healthy volunteers on the expression of APOB48R mRNA and lipid uptake in human THP-1 monocytes and THP-1-derived macrophages. The expression of APOB48R mRNA was upregulated in THP-1 monocytes, but downregulated in THP-1-derived macrophages when treated with postprandial TRL (P < 0.05), in a dose- and time-dependent manner. TG and free cholesterol were dramatically increased in THP-1-derived macrophages (140 and 50%, respectively; P < 0.05) and in THP-1 monocytes (160 and 95%, respectively; P < 0.05). This lipid accumulation was severely decreased (~50%; P < 0.05) in THP-1-derived macrophages by small interfering RNA (siRNA) targeting of APOB48R. Using PPAR and retinoid X receptor (RXR) agonists, antagonists, and siRNA, our data indicate that PPARα, PPARγ, and RXRα are involved in postprandial TRL-induced APOB48R transcriptional regulation. Co-incubation with acyl-CoA synthetase or acyl-CoA:cholesterol acyltransferase inhibitors potentiated the effects of postprandial TRL on the expression of APOB48R mRNA in THP-1 monocytes and THP-1-derived macrophages. Our findings collectively suggest that APOB48R represents a molecular target of postprandial TRL via PPAR-dependent pathways in human THP-1 monocytes and macrophages and advance a potentially important link between postprandial metabolism of dietary fats and atherogenesis.

  12. The regulation of cytoskeletal and liver-specific gene expression during liver regeneration and primary hepatocyte culture

    International Nuclear Information System (INIS)

    Robinson, G.S.

    1989-01-01

    The focus of this dissertation is to determine what role(s) the extracellular matrix and expression of certain cytoskeletal genes play in the regulation of hepatocyte growth and the maintenance of a differential state. The expression of several cytoskeletal and liver-specific genes was examined during liver regeneration and in hepatocyte cultures maintained in a hormonally-defined, serum-free medium and plated on two different matrices: rat tail collagen and the EHS matrix. During liver regeneration and in hepatocytes cultured on rat tail collagen, there was a dramatic increase in tubulin mRNA levels coincident with but not linked to DNA synthesis. The message levels for other cytoskeletal genes similarly increased, while a decrease was observed in the mRNA levels of the liver-specific genes, serum albumin and alpha 1 inhibitor III. Hepatocytes cultured on the EHS matrix resulted in the maintenance of low levels of cytoskeletal gene expression and high levels of liver-specific gene expression, similar to that observed in the normal liver. Results from subcellar fractionation and two-dimensional gel electrophoresis of 35 S-labelled proteins paralleled the results seen at the mRNA level. Preliminary work suggests that microtubule organization may play a role in the expression of the liver-specific genes which encode secreted proteins. These studies, which compare hepatocytes cultured on collagen or the EHS matrix gel, reveal that both cell-cell and cell-matrix interactions play a major role in the maintenance of the differential phenotype in hepatocytes

  13. A brain-liver circuit regulates glucose homeostasis.

    Science.gov (United States)

    Pocai, Alessandro; Obici, Silvana; Schwartz, Gary J; Rossetti, Luciano

    2005-01-01

    Increased glucose production (GP) is the major determinant of fasting hyperglycemia in diabetes mellitus. Previous studies suggested that lipid metabolism within specific hypothalamic nuclei is a biochemical sensor for nutrient availability that exerts negative feedback on GP. Here we show that central inhibition of fat oxidation leads to selective activation of brainstem neurons within the nucleus of the solitary tract and the dorsal motor nucleus of the vagus and markedly decreases liver gluconeogenesis, expression of gluconeogenic enzymes, and GP. These effects require central activation of ATP-dependent potassium channels (K(ATP)) and descending fibers within the hepatic branch of the vagus nerve. Thus, hypothalamic lipid sensing potently modulates glucose metabolism via neural circuitry that requires the activation of K(ATP) and selective brainstem neurons and intact vagal input to the liver. This crosstalk between brain and liver couples central nutrient sensing to peripheral nutrient production and its disruption may lead to hyperglycemia.

  14. Triglycerides and cardiovascular disease

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Varbo, Anette

    2014-01-01

    cholesterol might not cause cardiovascular disease as originally thought has now generated renewed interest in raised concentrations of triglycerides. This renewed interest has also been driven by epidemiological and genetic evidence supporting raised triglycerides, remnant cholesterol, or triglyceride......-rich lipoproteins as an additional cause of cardiovascular disease and all-cause mortality. Triglycerides can be measured in the non-fasting or fasting states, with concentrations of 2-10 mmol/L conferring increased risk of cardiovascular disease, and concentrations greater than 10 mmol/L conferring increased risk...... of acute pancreatitis and possibly cardiovascular disease. Although randomised trials showing cardiovascular benefit of triglyceride reduction are scarce, new triglyceride-lowering drugs are being developed, and large-scale trials have been initiated that will hopefully provide conclusive evidence...

  15. The effect of isotretinoin on triglycerides and liver aminotransferases Influência da isotretinoína nas transaminases hepáticas e triglicerídeos

    Directory of Open Access Journals (Sweden)

    Andreia Salezze Vieira

    2012-06-01

    Full Text Available BACKGROUND: Isotretinoin has been used to treat the most severe cases of acne; however, it may provoke adverse events in mucocutaneous and hepatic tissues, lead to alterations in lipid levels and cause teratogenicity. OBJECTIVE: The objective of this study was to evaluate the profile of changes in alanine aminotransferase (ALT, aspartate aminotransferase (AST and triglyceride levels in patients who had been treated with oral isotretinoin dispensed by the São Mateus/ES pharmacy for special drugs. METHODS: A retrospective, observational, longitudinal study was conducted by carrying out a secondary analysis of each patient's data. RESULTS: Of the 130 patients who received isotretinoin between January and December 2009, only 70 were actually treated for 3 months or more and handed in the results of their laboratory tests. Of these 70 patients, 39 (55.7% were female. The mean age of the women (23.9 years was higher than the mean age of the men (20.1 years. There was a statistically significant increase in the levels of triglycerides (87.01 ± 48.25 versus 105.32 ± 48.76 mg/dL, AST (20.44 ± 6.26 versus 24.38 ± 11.92 U/L and ALT (18.24 ± 8.31 versus 23.34 ± 20.03 U/L performed prior to and 3 months or more after oral isotretinoin treatment. After treatment with oral isotretinoin, triglyceride levels had increased beyond the normal range in 11% of the patients, while 8.6% had elevated AST levels and 7.3% had increased ALT levels. CONCLUSION: The results in this population show that the use of oral isotretinoin for the treatment of acne may result in altered triglyceride, AST and ALT levels. These findings are in accordance with data published previously in the scientific literature, confirming the need to monitor these patients.FUNDAMENTOS: A isotretinoína tem sido usada no tratamento dos casos mais graves de acne, embora possa induzir reações adversas nos tecidos mucocutâneos e hepáticos, alterações nos níveis lipídicos e

  16. Structured triglyceride emulsions in parenteral nutrition.

    Science.gov (United States)

    Chambrier, C; Lauverjat, M; Bouletreau, P

    2006-08-01

    Over the past 3 decades, various concepts for IV fat emulsions (IVFE) have been developed. A randomized, structured-lipid emulsion based on an old technology has recently become available. This structured-lipid emulsion is produced by mixing medium-chain triglycerides and long-chain triglycerides, then allowing hydrolysis to form free fatty acids, followed by random transesterification of the fatty acids into mixed triglyceride molecules. Studies in animals have shown an improvement in nitrogen balance with the use of these lipid emulsions. Only 8 human clinical studies with these products have been performed. The results of these human clinical studies have been less promising than the animal studies; however, an improvement in nitrogen balance and lipid metabolism exceeds results associated with infusion of long-chain triglycerides (LCT) or a physical mixture of long-chain triglycerides and medium-chain triglycerides (LCT-MCT). Structured-lipid emulsion seems to induce less elevation in serum liver function values compared with standard IVFEs. In addition, structured-lipid emulsions have no detrimental effect on the reticuloendothelial system. Further studies are necessary in order to recommend the use of structured-lipid emulsions. The clinical community hopes that chemically defined structured triglycerides will make it possible to determine the distribution of specific fatty acids on a specific position on the glycerol core and therefore obtain specific activity for a specific clinical situation.

  17. ApoB-100 secretion by HepG2 cells is regulated by the rate of triglyceride biosynthesis but not by intracellular lipid pools.

    Science.gov (United States)

    Benoist, F; Grand-Perret, T

    1996-10-01

    Triglycerides (TGs), cholesteryl esters (CEs), cholesterol, and phosphatidylcholine have been independently proposed as playing regulatory roles in apoB-100 secretion; the results depended on the cellular model used. In this study, we reinvestigate the role of lipids in apoB-100 production in HepG2 cells and in particular, we clarify the respective roles of intracellular mass and the biosynthesis of lipids in the regulation of apoB-100 production. In a first set of experiments, the pool size of cholesterol, CEs, and TGs was modulated by a 3-day treatment with either lipid precursors or inhibitors of enzymes involved in lipid synthesis. We used simvastatin (a hydroxymethylglutaryl coenzyme A reductase inhibitor), 58-035 (an acyl coenzyme A cholesterol acyltransferase inhibitor), 5-tetradecyloxy-2-furancarboxylic acid (TOFA, an inhibitor of fatty acid synthesis), and oleic acid. The secretion rate of apoB-100 was not affected by the large modulation of lipid mass induced by these various pre-treatments. In a second set of experiments, the same lipid modulators were added during a 4-hour labeling period. Simvastatin and 58-035 inhibited cholesterol and CE synthesis without affecting apoB-100 secretion. By contrast, treatment of HepG2 cells with TOFA resulted in the inhibition of TG synthesis and apoB-100 secretion. This effect was highly specific for apoB-100 and was reversed by adding oleic acid, which stimulated both TG synthesis and apoB-100 secretion. Moreover, a combination of oleic acid and 58-035 inhibited CE biosynthesis and increased both TG synthesis and apoB-100 secretion. These results show that in HepG2 cells TG biosynthesis regulates apoB-100 secretion, whereas the rate of cholesterol or CE biosynthesis has no effect.

  18. Liver X receptor β controls thyroid hormone feedback in the brain and regulates browning of subcutaneous white adipose tissue.

    Science.gov (United States)

    Miao, Yifei; Wu, Wanfu; Dai, Yubing; Maneix, Laure; Huang, Bo; Warner, Margaret; Gustafsson, Jan-Åke

    2015-11-10

    The recent discovery of browning of white adipose tissue (WAT) has raised great research interest because of its significant potential in counteracting obesity and type 2 diabetes. Browning is the result of the induction in WAT of a newly discovered type of adipocyte, the beige cell. When mice are exposed to cold or several kinds of hormones or treatments with chemicals, specific depots of WAT undergo a browning process, characterized by highly activated mitochondria and increased heat production and energy expenditure. However, the mechanisms underlying browning are still poorly understood. Liver X receptors (LXRs) are one class of nuclear receptors, which play a vital role in regulating cholesterol, triglyceride, and glucose metabolism. Following our previous finding that LXRs serve as repressors of uncoupling protein-1 (UCP1) in classic brown adipose tissue in female mice, we found that LXRs, especially LXRβ, also repress the browning process of subcutaneous adipose tissue (SAT) in male rodents fed a normal diet. Depletion of LXRs activated thyroid-stimulating hormone (TSH)-releasing hormone (TRH)-positive neurons in the paraventricular nucleus area of the hypothalamus and thus stimulated secretion of TSH from the pituitary. Consequently, production of thyroid hormones in the thyroid gland and circulating thyroid hormone level were increased. Moreover, the activity of thyroid signaling in SAT was markedly increased. Together, our findings have uncovered the basis of increased energy expenditure in male LXR knockout mice and provided support for targeting LXRs in treatment of obesity.

  19. Aspects of the regulation of long-chain fatty acid oxidation in bovine liver

    International Nuclear Information System (INIS)

    Jesse, B.W.; Emery, R.S.; Thomas, J.W.

    1986-01-01

    Factors involved in regulation of bovine hepatic fatty acid oxidation were examined using liver slices. Fatty acid oxidation was measured as the conversion of l-[ 14 C] palmitate to 14 CO 2 and total [ 14 C] acid-soluble metabolites. Extended (5 to 7 d) fasting of Holstein cows had relatively little effect on palmitate oxidation to acid-soluble metabolites by liver slices, although oxidation to CO 2 was decreased. Feeding a restricted roughage, high concentrate ration to lactating cows resulted in inhibition of palmitate oxidation. Insulin, glucose, and acetate inhibited palmitate oxidation by bovine liver slices. The authors suggest the regulation of bovine hepatic fatty acid oxidation may be less dependent on hormonally induced alterations in enzyme activity as observed in rat liver and more dependent upon action of rumen fermentation products or their metabolites on enzyme systems involved in fatty acid oxidation

  20. Intake of Mung Bean Protein Isolate Reduces Plasma Triglyceride Level in Rats

    Directory of Open Access Journals (Sweden)

    Nobuhiko Tachibana

    2013-09-01

    Full Text Available ABSTRACTBackground: Mung bean is well known as a starch source, but the physiological effects of mung bean protein have received little attention. In this study, we isolated mung bean protein from de-starched mung bean solutions, and investigated its influence on lipid metabolism. Objective: The aim of this study is to clarify the influence of the lipid metabolism by consumption of mung bean protein isolate (MPIMethods: Diets containing either mung bean protein isolate (MPI or casein were fed to normal rats for 28 days.Results: Both groups ate the same amount of food, but the plasma triglyceride level, relative liver weight and liver lipid contents (cholesterol and triglyceride pool in the MPI group were significantly lower than in the casein group. In the MPI group, the expression of sterol regulatory-element binding factor 1 (SREBF1 mRNA in the liver was significantly different when compared with the casein group. The significantly lower levels of insulin and free fatty acids in the MPI-fed rats may be due to the regulation of genes related to lipid metabolism in the liver.Conclusions: These results suggest that MPI may improve the plasma lipid profile by normalizing insulin sensitivity.Keywords: mung bean, Vigna radiata L., 8S globulin, triglyceride, β-conglycinin, 7S globulin, insulin sensitivity, SREBF1

  1. Triglyceride-mediated pathways and coronary disease: collaborative analysis of 101 studies

    DEFF Research Database (Denmark)

    Sarwar, Nadeem; Sandhu, Manjinder S; Ricketts, Sally L

    2010-01-01

    Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality.......Whether triglyceride-mediated pathways are causally relevant to coronary heart disease is uncertain. We studied a genetic variant that regulates triglyceride concentration to help judge likelihood of causality....

  2. Triglycerides: A reappraisal.

    Science.gov (United States)

    Wiesner, Philipp; Watson, Karol E

    2017-08-01

    Elevated cholesterol levels are clearly independently associated with adverse cardiovascular events. Another class of lipid particles, triglycerides, is also abundant in the human body and has been found in atherosclerotic plaques. Recent observational studies have demonstrated an association between elevated triglyceride levels and increased risk for future cardiovascular events. With this knowledge and the discovery of effective agents to lower triglyceride levels, the management of triglycerides is currently undergoing a renaissance. Unfortunately, no randomized, controlled clinical trials have been completed to date, proving that lowering triglycerides will reduce cardiovascular events. In this review we highlight some of the evidence that led to this stage and discuss the current data on pharmacologic intervention of triglyceride levels and the effect on clinical outcomes. Lastly, we want to give the reader insight on what the most recent lipid guidelines state about clinical triglyceride management, mention new pharmacological agents, and highlight the clinical evidence for safe and effective lowering of triglycerides levels with life style modification. Copyright © 2017. Published by Elsevier Inc.

  3. Dynamic regulation of canonical TGFβ signalling by endothelial transcription factor ERG protects from liver fibrogenesis.

    Science.gov (United States)

    Dufton, Neil P; Peghaire, Claire R; Osuna-Almagro, Lourdes; Raimondi, Claudio; Kalna, Viktoria; Chuahan, Abhishek; Webb, Gwilym; Yang, Youwen; Birdsey, Graeme M; Lalor, Patricia; Mason, Justin C; Adams, David H; Randi, Anna M

    2017-10-12

    The role of the endothelium in protecting from chronic liver disease and TGFβ-mediated fibrosis remains unclear. Here we describe how the endothelial transcription factor ETS-related gene (ERG) promotes liver homoeostasis by controlling canonical TGFβ-SMAD signalling, driving the SMAD1 pathway while repressing SMAD3 activity. Molecular analysis shows that ERG binds to SMAD3, restricting its access to DNA. Ablation of ERG expression results in endothelial-to-mesenchymal transition (EndMT) and spontaneous liver fibrogenesis in EC-specific constitutive hemi-deficient (Erg cEC-Het ) and inducible homozygous deficient mice (Erg iEC-KO ), in a SMAD3-dependent manner. Acute administration of the TNF-α inhibitor etanercept inhibits carbon tetrachloride (CCL 4 )-induced fibrogenesis in an ERG-dependent manner in mice. Decreased ERG expression also correlates with EndMT in tissues from patients with end-stage liver fibrosis. These studies identify a pathogenic mechanism where loss of ERG causes endothelial-dependent liver fibrogenesis via regulation of SMAD2/3. Moreover, ERG represents a promising candidate biomarker for assessing EndMT in liver disease.The transcription factor ERG is key to endothelial lineage specification and vascular homeostasis. Here the authors show that ERG balances TGFβ signalling through the SMAD1 and SMAD3 pathways, protecting the endothelium from endothelial-to-mesenchymal transition and consequent liver fibrosis in mice via a SMAD3-dependent mechanism.

  4. Physiologic and genetic evidence links hemopexin to triglycerides in mice and humans.

    Science.gov (United States)

    Lawson, H A; Zayed, M; Wayhart, J P; Fabbrini, E; Love-Gregory, L; Klein, S; Semenkovich, C F

    2017-04-01

    Elevated triglycerides predict insulin resistance and vascular disease in obesity, but how the inert triglyceride molecule is related to development of metabolic disease is unknown. To pursue novel potential mediators of triglyceride-associated metabolic disease, we used a forward genetics approach involving inbred mice and translated our findings to human subjects. Hemopexin (HPX) was identified as a differentially expressed gene within a quantitative trait locus associated with serum triglycerides in an F 16 advanced intercross between the LG/J and SM/J strains of mice. Hpx expression was evaluated in both the reproductive fat pads and livers of mice representing three strains, LG/J (n=25), SM/J (n=27) and C57Bl/6J (n=19), on high- and low-fat diets. The effect of altered Hpx expression on adipogenesis was studied in 3T3-L1 cells. Circulating HPX protein along with HPX expression were characterized in subcutaneous white adipose tissue samples obtained from a cohort of metabolically abnormal (n=18) and of metabolically normal (n=24) obese human subjects. We further examined the relationship between HPX and triglycerides in human atherosclerotic plaques (n=18). HPX expression in mouse adipose tissue, but not in liver, was regulated by dietary fat regardless of genetic background. HPX increased in concert with adipogenesis in 3T3-L1 cells, and disruption of its expression impaired adipocyte differentiation. RNAseq data from the adipose tissue of obese humans showed differential expression of HPX based on metabolic disease status (Ptriglycerides in these subjects (r=0.33; P=0.03). HPX was also found in an unbiased proteomic screen of human atherosclerotic plaques and shown to display differential abundance based on the extent of disease and triglyceride content (Ptriglycerides and provide a framework for understanding mechanisms underlying lipid metabolism and metabolic disease.

  5. Triglycerides: Why Do They Matter?

    Science.gov (United States)

    ... high level of triglycerides, a type of fat (lipid) in your blood, can increase your risk of ... triglycerides, too. Triglycerides are a type of fat (lipid) found in your blood. When you eat, your ...

  6. Prostaglandin E2 Regulates Liver versus Pancreas Cell Fate Decisions and Endodermal Outgrowth

    Science.gov (United States)

    Nissim, Sahar; Sherwood, Richard I.; Wucherpfennig, Julia; Saunders, Diane; Harris, James M.; Esain, Virginie; Carroll, Kelli J.; Frechette, Gregory M.; Kim, Andrew J.; Hwang, Katie L.; Cutting, Claire C.; Elledge, Susanna; North, Trista E.; Goessling, Wolfram

    2014-01-01

    SUMMARY The liver and pancreas arise from common endodermal progenitors. How these distinct cell fates are specified is poorly understood. Here, we describe prostaglandin E2 (PGE2) as a regulator of endodermal fate specification during development. Modulating PGE2 activity has opposing effects on liver-versus-pancreas specification in zebrafish embryos as well as mouse endodermal progenitors. The PGE2 synthetic enzyme cox2a and receptor ep2a are patterned such that cells closest to PGE2 synthesis acquire a liver fate whereas more distant cells acquire a pancreas fate. PGE2 interacts with the bmp2b pathway to regulate fate specification. At later stages of development, PGE2 acting via the ep4a receptor promotes outgrowth of both the liver and pancreas. PGE2 remains important for adult organ growth, as it modulates liver regeneration. This work provides in vivo evidence that PGE2 may act as a morphogen to regulate cell fate decisions and outgrowth of the embryonic endodermal anlagen. PMID:24530296

  7. Lipid Emulsion Administered Intravenously or Orally Attenuates Triglyceride Accumulation and Expression of Inflammatory Markers in the Liver of Nonobese Mice Fed Parenteral Nutrition Formula123

    Science.gov (United States)

    Ito, Kyoko; Hao, Lei; Wray, Amanda E.; Ross, A. Catharine

    2013-01-01

    The accumulation of hepatic TG and development of hepatic steatosis (HS) is a serious complication of the use of parenteral nutrition (PN) formulas containing a high percentage of dextrose. But whether fat emulsions or other nutrients can ameliorate the induction of HS by high-carbohydrate diets is still uncertain. We hypothesized that administration of a lipid emulsion (LE; Intralipid) and/or the vitamin A metabolite retinal (RAL) will reduce hepatic TG accumulation and attenuate indicators of inflammation. C57BL/6 male mice were fed PN formula as their only source of hydration and nutrition for 4–5 wk. In Expt. 1, mice were fed PN only or PN plus treatment with RAL (1 μg/g orally), LE (200 μL i.v.), or both LE and RAL. In Expt. 2, LE was orally administered at 4 and 13.5% of energy to PN-fed mice. All PN mice developed HS compared with mice fed normal chow (NC) and HS was reduced by LE. The liver TG mass was lower in the PN+LE and PN+RAL+LE groups compared with the PN and PN+RAL groups (P < 0.01) and in the 4% and 13.5% PN+LE groups compared with PN alone. Hepatic total retinol was higher in the RAL-fed mice (P < 0.0001), but RAL did not alter TG mass. mRNA transcripts for fatty acid synthase (Fasn) and sterol regulatory element-binding protein-1c (Srebpf1) were higher in the PN compared with the NC mice, but FAS protein and Srebpf1 mRNA were lower in the PN+LE groups compared with PN alone. The inflammation marker serum amyloid P component was also reduced. In summary, LE given either i.v. or orally may be sufficient to reduce the steatotic potential of orally fed high-dextrose formulas and may suppress the early development of HS during PN therapy. PMID:23325918

  8. The role of the daily feeding rhythm in the regulation of the day/night rhythm in triglyceride secretion in rats

    NARCIS (Netherlands)

    Su, Yan; Foppen, Ewout; Mansur Machado, Frederico Sander; Fliers, Eric; Kalsbeek, A.

    2018-01-01

    Plasma triglyceride (TG) levels show a clear daily rhythm, however, thus far it is still unknown whether this rhythm results from a daily rhythm in TG production, TG uptake or both. Previous studies have shown that feeding activity affects plasma TG concentrations, but it is not clear how the daily

  9. Investigations with tritium-labelled glycerol of the triglyceride metabolism in patients

    International Nuclear Information System (INIS)

    Leonhardt, W.; Julius, U.; Koch, R.; Schulze, J.

    1980-01-01

    Triglycerides, being components of lipoproteins, are secreted by the liver into the blood and climinated from the blood by adipose and muscle tissue. The kinetics of this metabolic pathway were studied after injection of tritium-labelled glycerol which is incorporated into triglycerides by the liver. The serum triglyceride radioactivity-time curve was analysed with a computer. 99 examinations showed a decrease of the fractional turnover rate and an increase of the turnover rate with the triglyceride level. The test enables to decide whether an increased triglyceride concentration is caued by overproduction or by disturbed climination. (author)

  10. Liver

    International Nuclear Information System (INIS)

    Bernardino, M.E.; Sones, P.J. Jr.; Barton Price, R.; Berkman, W.A.

    1984-01-01

    Evaluation of the liver for focal lesions is extremely important because the liver is one of the most common sites for metastatic disease. Most patients with metastatic deposits to the liver have a survival rate of about 6 months. Thus, metastatic disease to the liver has an extremely grave prognosis. In the past patients with hepatic lesions had no therapeutic recourse. However, with recent aggressive surgical advances (such as partial hepatectomies) and hepatic artery embolization, survival of patients with hepatic metastases has increased. Thus it is important for noninvasive imaging not only to detect lesions early in their course, but also to give their true hepatic involvement and the extent of the neoplastic process elsewhere in the body. Recent advances in imaging have been rapidly changing over the past 5 years. These changes have been more rapid in computed tomography (CT) and ultrasound than in radionuclide imaging. Thus, the question addressed in this chapter is: What is the relationship of hepatic ultrasound to the other current diagnostic modalities in detecting metastatic liver disease and other focal liver lesions? Also, what is its possible future relationship to nuclear magnetic resonance?

  11. High-fructose corn syrup-55 consumption alters hepatic lipid metabolism and promotes triglyceride accumulation.

    Science.gov (United States)

    Mock, Kaitlin; Lateef, Sundus; Benedito, Vagner A; Tou, Janet C

    2017-01-01

    High-fructose corn syrup-55 (HFCS-55) has been suggested to be more lipogenic than sucrose, which increases the risk for nonalcoholic fatty liver disease (NAFLD) and dyslipidemia. The study objectives were to determine the effects of drinking different sugar-sweetened solutions on hepatic gene expression in relation to liver fatty acid composition and risk of NAFLD. Female rats were randomly assigned (n=7 rats/group) to drink water or water sweetened with 13% (w/v) HFCS-55, sucrose or fructose for 8 weeks. Rats drinking HFCS-55 solution had the highest (P=.03) hepatic total lipid and triglyceride content and histological evidence of fat infiltration. Rats drinking HFCS-55 solution had the highest hepatic de novo lipogenesis indicated by the up-regulation of stearoyl-CoA desaturase-1 and the highest (Ptriglyceride-rich lipoprotein from the liver was increased as shown by up-regulation of gene expression of microsomal triglyceride transfer protein in rats drinking sucrose, but not HFCS-55 solution. The observed lipogenic effects were attributed to the slightly higher fructose content of HFCS-55 solution in the absence of differences in macronutrient and total caloric intake between rats drinking HFCS-55 and sucrose solution. Results from gene expression and fatty acid composition analysis showed that, in a hypercaloric state, some types of sugars are more detrimental to the liver. Based on these preclinical study results, excess consumption of caloric sweetened beverage, particularly HFCS-sweetened beverages, should be limited. Published by Elsevier Inc.

  12. MicroRNA-mediated regulation of glutathione and methionine metabolism and its relevance for liver disease.

    Science.gov (United States)

    Lu, Shelly C; Mato, José M; Espinosa-Diez, Cristina; Lamas, Santiago

    2016-11-01

    The discovery of the microRNA (miRNA) family of small RNAs as fundamental regulators of post-transcriptional gene expression has fostered research on their importance in every area of biology and clinical medicine. In the particular area of liver metabolism and disease, miRNAs are gaining increasing importance. By focusing on two fundamental hepatic biosynthetic pathways, glutathione and methionine, we review recent advances on the comprehension of the role of miRNAs in liver pathophysiology and more specifically of models of hepatic cholestasis/fibrosis and hepatocellular carcinoma. Copyright © 2016 Elsevier Inc. All rights reserved.

  13. The regulation of non-coding RNA expression in the liver of mice fed DDC.

    Science.gov (United States)

    Oliva, Joan; Bardag-Gorce, Fawzia; French, Barbara A; Li, Jun; French, Samuel W

    2009-08-01

    Mallory-Denk bodies (MDBs) are found in the liver of patients with alcoholic and chronic nonalcoholic liver disease, and hepatocellular carcinoma (HCC). Diethyl 1,4-dihydro-2,4,6,-trimethyl-3,5-pyridinedicarboxylate (DDC) is used as a model to induce the formation of MDBs in mouse liver. Previous studies in this laboratory showed that DDC induced epigenetic modifications in DNA and histones. The combination of these modifications changes the phenotype of the MDB forming hepatocytes, as indicated by the marker FAT10. These epigenetic modifications are partially prevented by adding to the diet S-adenosylmethionine (SAMe) or betaine, both methyl donors. The expression of three imprinted ncRNA genes was found to change in MDB forming hepatocytes, which is the subject of this report. NcRNA expression was quantitated by real-time PCR and RNA FISH in liver sections. Microarray analysis showed that the expression of three ncRNAs was regulated by DDC: up regulation of H19, antisense Igf2r (AIR), and down regulation of GTL2 (also called MEG3). S-adenosylmethionine (SAMe) feeding prevented these changes. Betaine, another methyl group donor, prevented only H19 and AIR up regulation induced by DDC, on microarrays. The results of the SAMe and betaine groups were confirmed by real-time PCR, except for AIR expression. After 1 month of drug withdrawal, the expression of the three ncRNAs tended toward control levels of expression. Liver tumors that developed also showed up regulation of H19 and AIR. The RNA FISH approach showed that the MDB forming cells' phenotype changed the level of expression of AIR, H19 and GTL2, compared to the surrounding cells. Furthermore, over expression of H19 and AIR was demonstrated in tumors formed in mice withdrawn for 9 months. The dysregulation of ncRNA in MDB forming liver cells has been observed for the first time in drug-primed mice associated with liver preneoplastic foci and tumors.

  14. Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting.

    Science.gov (United States)

    Fu, Suneng; Fan, Jason; Blanco, Joshua; Gimenez-Cassina, Alfredo; Danial, Nika N; Watkins, Steve M; Hotamisligil, Gökhan S

    2012-08-01

    Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER)-associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity.

  15. Polysome profiling in liver identifies dynamic regulation of endoplasmic reticulum translatome by obesity and fasting.

    Directory of Open Access Journals (Sweden)

    Suneng Fu

    2012-08-01

    Full Text Available Obesity-associated metabolic complications are generally considered to emerge from abnormalities in carbohydrate and lipid metabolism, whereas the status of protein metabolism is not well studied. Here, we performed comparative polysome and associated transcriptional profiling analyses to study the dynamics and functional implications of endoplasmic reticulum (ER-associated protein synthesis in the mouse liver under conditions of obesity and nutrient deprivation. We discovered that ER from livers of obese mice exhibits a general reduction in protein synthesis, and comprehensive analysis of polysome-bound transcripts revealed extensive down-regulation of protein synthesis machinery, mitochondrial components, and bile acid metabolism in the obese translatome. Nutrient availability also plays an important but distinct role in remodeling the hepatic ER translatome in lean and obese mice. Fasting in obese mice partially reversed the overall translatomic differences between lean and obese nonfasted controls, whereas fasting of the lean mice mimicked many of the translatomic changes induced by the development of obesity. The strongest examples of such regulations were the reduction in Cyp7b1 and Slco1a1, molecules involved in bile acid metabolism. Exogenous expression of either gene significantly lowered plasma glucose levels, improved hepatic steatosis, but also caused cholestasis, indicating the fine balance bile acids play in regulating metabolism and health. Together, our work defines dynamic regulation of the liver translatome by obesity and nutrient availability, and it identifies a novel role for bile acid metabolism in the pathogenesis of metabolic abnormalities associated with obesity.

  16. Gal-3 regulates the capacity of dendritic cells to promote NKT-cell-induced liver injury.

    Science.gov (United States)

    Volarevic, Vladislav; Markovic, Bojana Simovic; Bojic, Sanja; Stojanovic, Maja; Nilsson, Ulf; Leffler, Hakon; Besra, Gurdyal S; Arsenijevic, Nebojsa; Paunovic, Verica; Trajkovic, Vladimir; Lukic, Miodrag L

    2015-02-01

    Galectin-3 (Gal-3), an endogenous lectin, exhibits pro- and anti-inflammatory effects in various disease conditions. In order to explore the role of Gal-3 in NKT-cell-dependent pathology, we induced hepatitis in C57BL/6 WT and Gal-3-deficient mice by using specific ligand for NKT cells: α-galactosylceramide, glycolipid Ag presented by CD1d. The injection of α-galactosylceramide significantly enhanced expression of Gal-3 in liver NKT and dendritic cells (DCs). Genetic deletion or selective inhibition of Gal-3 (induced by Gal-3-inhibitor TD139) abrogated the susceptibility to NKT-cell-dependent hepatitis. Blood levels of pro-inflammatory cytokines (TNF-α, IFN-γ, IL-12) and their production by liver DCs and NKT cells were also downregulated. Genetic deletion or selective inhibition of Gal-3 alleviated influx of inflammatory CD11c(+) CD11b(+) DCs in the liver and favored tolerogenic phenotype and IL-10 production of liver NKT and DCs. Deletion of Gal-3 attenuated the capacity of DCs to support liver damage in the passive transfer experiments and to produce pro-inflammatory cytokines in vitro. Gal-3-deficient DCs failed to optimally stimulate production of pro-inflammatory cytokines in NKT cells, in vitro and in vivo. In conclusion, Gal-3 regulates the capacity of DCs to support NKT-cell-mediated liver injury, playing an important pro-inflammatory role in acute liver injury. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  17. Regulation of retinoid X receptor gamma expression by fed state in mouse liver

    International Nuclear Information System (INIS)

    Park, Sangkyu; Lee, Yoo Jeong; Ko, Eun Hee; Kim, Jae-woo

    2015-01-01

    Glucose metabolism is balanced by glycolysis and gluconeogenesis with precise control in the liver. The expression of genes related to glucose metabolism is regulated primarily by glucose and insulin at transcriptional level. Nuclear receptors play important roles in regulating the gene expression of glucose metabolism at transcriptional level. Some of these nuclear receptors form heterodimers with RXRs to bind to their specific regulatory elements on the target promoters. To date, three isotypes of RXRs have been identified; RXRα, RXRβ and RXRγ. However, their involvement in the interactions with other nuclear receptors in the liver remains unclear. In this study, we found RXRγ is rapidly induced after feeding in the mouse liver, indicating a potential role of RXRγ in controlling glucose or lipid metabolism in the fasting–feeding cycle. In addition, RXRγ expression was upregulated by glucose in primary hepatocytes. This implies that glucose metabolism governed by RXRγ in conjunction with other nuclear receptors. The luciferase reporter assay showed that RXRγ as well as RXRα increased SREBP-1c promoter activity in hepatocytes. These results suggest that RXRγ may play an important role in tight control of glucose metabolism in the fasting–feeding cycle. - Highlights: • Refeeding increases the RXRγ expression level in mouse liver. • RXRγ expression is induced by high glucose condition in primary hepatocytes. • RXRγ and LXRα have synergistic effect on SREBP-1c promoter activity. • RXRγ binds to LXRE(-299/-280) located within SREBP-1c promoter region and interacts with LXRα

  18. Regulation of retinoid X receptor gamma expression by fed state in mouse liver

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sangkyu, E-mail: 49park@cku.ac.kr [Department of Biochemistry, College of Medicine, Catholic Kwandong University, Gangneung 210-701 (Korea, Republic of); Lee, Yoo Jeong [Division of Metabolic Disease, Center for Biomedical Sciences, National Institute of Health Korea, Osong 361-709 (Korea, Republic of); Ko, Eun Hee [Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Kim, Jae-woo [Department of Biochemistry and Molecular Biology, Integrated Genomic Research Center for Metabolic Regulation, Institute of Genetic Science, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of); Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul 120-752 (Korea, Republic of)

    2015-02-27

    Glucose metabolism is balanced by glycolysis and gluconeogenesis with precise control in the liver. The expression of genes related to glucose metabolism is regulated primarily by glucose and insulin at transcriptional level. Nuclear receptors play important roles in regulating the gene expression of glucose metabolism at transcriptional level. Some of these nuclear receptors form heterodimers with RXRs to bind to their specific regulatory elements on the target promoters. To date, three isotypes of RXRs have been identified; RXRα, RXRβ and RXRγ. However, their involvement in the interactions with other nuclear receptors in the liver remains unclear. In this study, we found RXRγ is rapidly induced after feeding in the mouse liver, indicating a potential role of RXRγ in controlling glucose or lipid metabolism in the fasting–feeding cycle. In addition, RXRγ expression was upregulated by glucose in primary hepatocytes. This implies that glucose metabolism governed by RXRγ in conjunction with other nuclear receptors. The luciferase reporter assay showed that RXRγ as well as RXRα increased SREBP-1c promoter activity in hepatocytes. These results suggest that RXRγ may play an important role in tight control of glucose metabolism in the fasting–feeding cycle. - Highlights: • Refeeding increases the RXRγ expression level in mouse liver. • RXRγ expression is induced by high glucose condition in primary hepatocytes. • RXRγ and LXRα have synergistic effect on SREBP-1c promoter activity. • RXRγ binds to LXRE(-299/-280) located within SREBP-1c promoter region and interacts with LXRα.

  19. Dendrobium nobile Lindl. alkaloids regulate metabolism gene expression in livers of mice.

    Science.gov (United States)

    Xu, Yun-Yan; Xu, Ya-Sha; Wang, Yuan; Wu, Qin; Lu, Yuan-Fu; Liu, Jie; Shi, Jing-Shan

    2017-10-01

    In our previous studies, Dendrobium nobile Lindl. alkaloids (DNLA) has been shown to have glucose-lowering and antihyperlipidaemia effects in diabetic rats, in rats fed with high-fat diets, and in mice challenged with adrenaline. This study aimed to examine the effects of DNLA on the expression of glucose and lipid metabolism genes in livers of mice. Mice were given DNLA at doses of 10-80 mg/kg, po for 8 days, and livers were removed for total RNA and protein isolation to perform real-time RT-PCR and Western blot analysis. Dendrobium nobile Lindl. alkaloids increased PGC1α at mRNA and protein levels and increased glucose metabolism gene Glut2 and FoxO1 expression. DNLA also increased the expression of fatty acid β-oxidation genes Acox1 and Cpt1a. The lipid synthesis regulator Srebp1 (sterol regulatory element-binding protein-1) was decreased, while the lipolysis gene ATGL was increased. Interestingly, DNLA increased the expression of antioxidant gene metallothionein-1 and NADPH quinone oxidoreductase-1 (Nqo1) in livers of mice. Western blot on selected proteins confirmed these changes including the increased expression of GLUT4 and PPARα. DNLA has beneficial effects on liver glucose and lipid metabolism gene expressions, and enhances the Nrf2-antioxidant pathway gene expressions, which could play integrated roles in regulating metabolic disorders. © 2017 Royal Pharmaceutical Society.

  20. The let-7/Lin28 axis regulates activation of hepatic stellate cells in alcoholic liver injury.

    Science.gov (United States)

    McDaniel, Kelly; Huang, Li; Sato, Keisaku; Wu, Nan; Annable, Tami; Zhou, Tianhao; Ramos-Lorenzo, Sugeily; Wan, Ying; Huang, Qiaobing; Francis, Heather; Glaser, Shannon; Tsukamoto, Hidekazu; Alpini, Gianfranco; Meng, Fanyin

    2017-07-07

    The let-7/Lin28 axis is associated with the regulation of key cellular regulatory genes known as microRNAs in various human disorders and cancer development. This study evaluated the role of the let-7/Lin28 axis in regulating a mesenchymal phenotype of hepatic stellate cells in alcoholic liver injury. We identified that ethanol feeding significantly down-regulated several members of the let-7 family in mouse liver, including let-7a and let-7b. Similarly, the treatment of human hepatic stellate cells (HSCs) with lipopolysaccharide (LPS) and transforming growth factor-β (TGF-β) significantly decreased the expressions of let-7a and let-7b. Conversely, overexpression of let-7a and let-7b suppressed the myofibroblastic activation of cultured human HSCs induced by LPS and TGF-β, as evidenced by repressed ACTA2 (α-actin 2), COL1A1 (collagen 1A1), TIMP1 (TIMP metallopeptidase inhibitor 1), and FN1 (fibronectin 1); this supports the notion that HSC activation is controlled by let-7. A combination of bioinformatics, dual-luciferase reporter assay, and Western blot analysis revealed that Lin28B and high-mobility group AT-hook (HMGA2) were the direct targets of let-7a and let-7b. Furthermore, Lin28B deficiency increased the expression of let-7a/let-7b as well as reduced HSC activation and liver fibrosis in mice with alcoholic liver injury. This feedback regulation of let-7 by Lin28B is verified in hepatic stellate cells isolated by laser capture microdissection from the model. The identification of the let-7/Lin28 axis as an important regulator of HSC activation as well as its upstream modulators and down-stream targets will provide insights into the involvement of altered microRNA expression in contributing to the pathogenesis of alcoholic liver fibrosis and novel therapeutic approaches for human alcoholic liver diseases. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  1. Polymerized and functionalized triglycerides

    Science.gov (United States)

    Plant oils are useful sustainable raw materials for the development of new chemical products. As part of our research emphasis in sustainability and green polymer chemistry, we have explored a new method for polymerizing epoxidized triglycerides with the use of fluorosulfonic acid. Depending on the ...

  2. Triglyceride Metabolism under Attack

    NARCIS (Netherlands)

    Kersten, Sander

    2017-01-01

    Hydrolysis of circulating triglycerides is carried out by the enzyme lipoprotein lipase, which is transported and anchored to the capillary wall by the protein GPIHBP1. Recent evidence indicates that certain individuals develop autoantibodies against GPIHBP1, impairing lipoprotein lipase function

  3. Central nervous system neuropeptide Y regulates mediators of hepatic phospholipid remodeling and very low-density lipoprotein triglyceride secretion via sympathetic innervation

    Directory of Open Access Journals (Sweden)

    Jennifer M. Rojas

    2015-03-01

    Conclusions: These data support a model in which CNS NPY modulates mediators of hepatic PL remodeling and VLDL maturation to stimulate VLDL-TG secretion that is dependent on the Y1 receptor and sympathetic signaling to the liver.

  4. Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.

    Science.gov (United States)

    Calabro, Sarah R; Maczurek, Annette E; Morgan, Alison J; Tu, Thomas; Wen, Victoria W; Yee, Christine; Mridha, Auvro; Lee, Maggie; d'Avigdor, William; Locarnini, Stephen A; McCaughan, Geoffrey W; Warner, Fiona J; McLennan, Susan V; Shackel, Nicholas A

    2014-01-01

    The classical paradigm of liver injury asserts that hepatic stellate cells (HSC) produce, remodel and turnover the abnormal extracellular matrix (ECM) of fibrosis via matrix metalloproteinases (MMPs). In extrahepatic tissues MMP production is regulated by a number of mechanisms including expression of the glycoprotein CD147. Previously, we have shown that CD147 is expressed on hepatocytes but not within the fibrotic septa in cirrhosis [1]. Therefore, we investigated if hepatocytes produce MMPs, regulated by CD147, which are capable of remodelling fibrotic ECM independent of the HSC. Non-diseased, fibrotic and cirrhotic livers were examined for MMP activity and markers of fibrosis in humans and mice. CD147 expression and MMP activity were co-localised by in-situ zymography. The role of CD147 was studied in-vitro with siRNA to CD147 in hepatocytes and in-vivo in mice with CCl4 induced liver injury using ãCD147 antibody intervention. In liver fibrosis in both human and mouse tissue MMP expression and activity (MMP-2, -9, -13 and -14) increased with progressive injury and localised to hepatocytes. Additionally, as expected, MMPs were abundantly expressed by activated HSC. Further, with progressive fibrosis there was expression of CD147, which localised to hepatocytes but not to HSC. Functionally significant in-vitro regulation of hepatocyte MMP production by CD147 was demonstrated using siRNA to CD147 that decreased hepatocyte MMP-2 and -9 expression/activity. Further, in-vivo α-CD147 antibody intervention decreased liver MMP-2, -9, -13, -14, TGF-β and α-SMA expression in CCl4 treated mice compared to controls. We have shown that hepatocytes produce active MMPs and that the glycoprotein CD147 regulates hepatocyte MMP expression. Targeting CD147 regulates hepatocyte MMP production both in-vitro and in-vivo, with the net result being reduced fibrotic matrix turnover in-vivo. Therefore, CD147 regulation of hepatocyte MMP is a novel pathway that could be targeted by

  5. Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.

    Directory of Open Access Journals (Sweden)

    Sarah R Calabro

    Full Text Available The classical paradigm of liver injury asserts that hepatic stellate cells (HSC produce, remodel and turnover the abnormal extracellular matrix (ECM of fibrosis via matrix metalloproteinases (MMPs. In extrahepatic tissues MMP production is regulated by a number of mechanisms including expression of the glycoprotein CD147. Previously, we have shown that CD147 is expressed on hepatocytes but not within the fibrotic septa in cirrhosis [1]. Therefore, we investigated if hepatocytes produce MMPs, regulated by CD147, which are capable of remodelling fibrotic ECM independent of the HSC.Non-diseased, fibrotic and cirrhotic livers were examined for MMP activity and markers of fibrosis in humans and mice. CD147 expression and MMP activity were co-localised by in-situ zymography. The role of CD147 was studied in-vitro with siRNA to CD147 in hepatocytes and in-vivo in mice with CCl4 induced liver injury using ãCD147 antibody intervention.In liver fibrosis in both human and mouse tissue MMP expression and activity (MMP-2, -9, -13 and -14 increased with progressive injury and localised to hepatocytes. Additionally, as expected, MMPs were abundantly expressed by activated HSC. Further, with progressive fibrosis there was expression of CD147, which localised to hepatocytes but not to HSC. Functionally significant in-vitro regulation of hepatocyte MMP production by CD147 was demonstrated using siRNA to CD147 that decreased hepatocyte MMP-2 and -9 expression/activity. Further, in-vivo α-CD147 antibody intervention decreased liver MMP-2, -9, -13, -14, TGF-β and α-SMA expression in CCl4 treated mice compared to controls.We have shown that hepatocytes produce active MMPs and that the glycoprotein CD147 regulates hepatocyte MMP expression. Targeting CD147 regulates hepatocyte MMP production both in-vitro and in-vivo, with the net result being reduced fibrotic matrix turnover in-vivo. Therefore, CD147 regulation of hepatocyte MMP is a novel pathway that could be

  6. An HDAC3-PROX1 corepressor module acts on HNF4α to control hepatic triglycerides.

    Science.gov (United States)

    Armour, Sean M; Remsberg, Jarrett R; Damle, Manashree; Sidoli, Simone; Ho, Wesley Y; Li, Zhenghui; Garcia, Benjamin A; Lazar, Mitchell A

    2017-09-15

    The histone deacetylase HDAC3 is a critical mediator of hepatic lipid metabolism, and liver-specific deletion of HDAC3 leads to fatty liver. To elucidate the underlying mechanism, here we report a method of cross-linking followed by mass spectrometry to define a high-confidence HDAC3 interactome in vivo that includes the canonical NCoR-HDAC3 complex as well as Prospero-related homeobox 1 protein (PROX1). HDAC3 and PROX1 co-localize extensively on the mouse liver genome, and are co-recruited by hepatocyte nuclear factor 4α (HNF4α). The HDAC3-PROX1 module controls the expression of a gene program regulating lipid homeostasis, and hepatic-specific ablation of either component increases triglyceride content in liver. These findings underscore the importance of specific combinations of transcription factors and coregulators in the fine tuning of organismal metabolism.HDAC3 is a critical mediator of hepatic lipid metabolism and its loss leads to fatty liver. Here, the authors characterize the liver HDAC3 interactome in vivo, provide evidence that HDAC3 interacts with PROX1, and show that HDAC3 and PROX1 control expression of genes regulating lipid homeostasis.

  7. IL-4 Receptor Alpha Signaling through Macrophages Differentially Regulates Liver Fibrosis Progression and Reversal

    Directory of Open Access Journals (Sweden)

    Shih-Yen Weng

    2018-03-01

    Full Text Available Chronic hepatitis leads to liver fibrosis and cirrhosis. Cirrhosis is a major cause of worldwide morbidity and mortality. Macrophages play a key role in fibrosis progression and reversal. However, the signals that determine fibrogenic vs fibrolytic macrophage function remain ill defined. We studied the role of interleukin-4 receptor α (IL-4Rα, a potential central switch of macrophage polarization, in liver fibrosis progression and reversal. We demonstrate that inflammatory monocyte infiltration and liver fibrogenesis were suppressed in general IL-4Rα−/− as well as in macrophage-specific IL-4Rα−/− (IL-4RαΔLysM mice. However, with deletion of IL-4RαΔLysM spontaneous fibrosis reversal was retarded. Results were replicated by pharmacological intervention using IL-4Rα-specific antisense oligonucleotides. Retarded resolution was linked to the loss of M2-type resident macrophages, which secreted MMP-12 through IL-4 and IL-13-mediated phospho-STAT6 activation. We conclude that IL-4Rα signaling regulates macrophage functional polarization in a context-dependent manner. Pharmacological targeting of macrophage polarization therefore requires disease stage-specific treatment strategies. Research in Context: Alternative (M2-type macrophage activation through IL-4Rα promotes liver inflammation and fibrosis progression but speeds up fibrosis reversal. This demonstrates context dependent, opposing roles of M2-type macrophages. During reversal IL-4Rα induces fibrolytic MMPs, especially MMP-12, through STAT6. Liver-specific antisense oligonucleotides efficiently block IL-4Rα expression and attenuate fibrosis progression. Keywords: Fibrosis, IL-4 receptor alpha, Liver, Macrophage, MMP12, Progression, Reversal

  8. Regulation of glutamate dehydrogenase expression in the developing rat liver: control at different levels in the prenatal period

    NARCIS (Netherlands)

    Das, A. T.; Salvadó, J.; Boon, L.; Biharie, G.; Moorman, A. F.; Lamers, W. H.

    1996-01-01

    To study the regulation of the expression of glutamate dehydrogenase (Glu-DH) in rat liver during development, the Glu-DH mRNA concentration in the liver of rats ranging in age from 14 days prenatal development to 3 months after birth was determined. This concentration increased up to two days

  9. Disruption of STAT5b-Regulated Sexual Dimorphism of the Liver Transcriptome by Diverse Factors Is a Common Event

    Science.gov (United States)

    Signal transducer and activator of transcription 5b (STAT5b) is a growth hormone (GH)-activated transcription factor and a master regulator of sexually dimorphic gene expression in the liver. Disruption ofthe GH hypothalamo-pituitary-liver axis controlling STAT5b activation can ...

  10. Expression and Regulation of the Bile Acid Transporter, OST alpha-OST beta in Rat and Human Intestine and Liver

    NARCIS (Netherlands)

    Khan, Ansar A.; Chow, Edwin C. Y.; Porte, Robert J.; Pang, K. Sandy; Groothuis, Geny M. M.

    The regulation of the OST alpha and OST beta expression was studied in the rat jejunum, ileum, colon and liver and in human ileum and liver by ligands for the farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR) and glucocorticoid receptor (GR) using precision cut tissue

  11. Central effects of humanin on hepatic triglyceride secretion.

    Science.gov (United States)

    Gong, Zhenwei; Su, Kai; Cui, Lingguang; Tas, Emir; Zhang, Ting; Dong, H Henry; Yakar, Shoshana; Muzumdar, Radhika H

    2015-08-01

    Humanin (HN) is an endogenous mitochondria-associated peptide that has been shown to protect against various Alzheimer's disease-associated insults, myocardial ischemia-reperfusion injury, and reactive oxygen species-induced cell death. We have shown previously that HN improves whole body glucose homeostasis by improving insulin sensitivity and increasing glucose-stimulated insulin secretion (GSIS) from the β-cells. Here, we report that intraperitoneal treatment with one of HN analogs, HNG, decreases body weight gain, visceral fat, and hepatic triglyceride (TG) accumulation in high-fat diet-fed mice. The decrease in hepatic TG accumulation is due to increased activity of hepatic microsomal triglyceride transfer protein (MTTP) and increased hepatic TG secretion. Both intravenous (iv) and intracerebroventricular (icv) infusion of HNG acutely increase TG secretion from the liver. Vagotomy blocks the effect on both iv and icv HNG on TG secretion, suggesting that the effects of HNG on hepatic TG flux are centrally mediated. Our data suggest that HN is a new player in central regulation of peripheral lipid metabolism. Copyright © 2015 the American Physiological Society.

  12. Central nervous system control of triglyceride metabolism

    NARCIS (Netherlands)

    Geerling, Johanna Janetta (Janine)

    2013-01-01

    This thesis describes the role of the brain in the regulation of peripheral triglyceride metabolism, in the context of the metabolic syndrome. Based on various pharmacological studies we described the role of two hormones, insulin and glucagon-like peptide-1, in the production and clearance of

  13. SENP1 attenuates the liver fibrosis through down-regulating the expression of SMAD2.

    Science.gov (United States)

    Wu, Linshi; Qiu, Weiqing; Sun, Jianhua; Wang, Jian

    2018-01-01

    To investigate whether SENP1 could play a regulating role in the liver fibrosis process, the Sprague-Dawley (SD) rats were used to establish the liver fibrosis rat models by intraperitoneally injecting with 1 ml/kg of 10% CCl 4 , while the control normal rats were injected with olive oil. Then confirmation experiments to verify the successful establishment of these models were conducted by detecting the cellular and lobular architecture, and liver function indexes using hematoxylin-eosin staining, Masson's trichrome staining and microplate method, respectively. In addition, the expression levels of fibrosis markers including collagen I, collagen III, α-SMA and TGF-β1 were inspected using quantitative real-time PCR (qRT-PCR), as well as SMAD2. Subsequently, the relative mRNA and protein level of SENP1 was also determined via qRT-PCR and western blot analysis. Next, the HSC-T6 cells of SENP1 knock-down were constructed and used to test the relative protein expression levels of α-SMA and SMAD2 in these cells. The results of hematoxylin-eosin staining, Masson's trichrome staining and microplate method turned out that the rat liver fibrosis models were constructed successfully, which was further confirmed by the increased expression of collagen I, collagen III, α-SMA and TGF-β1 in mRNA and protein level, as well as SMAD2. Then the expression of SENP1 was overexpressed in the rat liver fibrosis models induced by CCl 4 and the TGF-β1 treatment could increase the protein expression level of collagen I, collagen III and α-SMA. Lastly, the SENP1 knockdown HSC-T6 cells were successfully constructed, while the silence of SENP1 down-regulated the protein expression of α-SMA and SMAD2. In conclusion, this study provided a new regulation mechanism about the liver fibrosis process. Copyright © 2017 Elsevier Inc. All rights reserved.

  14. Lipopolysaccharide significantly influences the hepatic triglyceride metabolism in growing pigs.

    Science.gov (United States)

    Liu, Zhiqing; Liu, Weifeng; Huang, Yanping; Guo, Jun; Zhao, Ruqian; Yang, Xiaojing

    2015-06-30

    In the practical commercial pig farms, inflammation is a perennial problem, yet most of studies on inflammation are focused on immune response. Actually, inflammation can induce body metabolism disorder which will finally influence animals' growth. In this study, we investigated the effect of acute inflammation on the triglyceride (TG) metabolism in the liver of growing pigs and the possible underlying mechanisms. Twelve male growing pigs were randomly divided into two groups, a control group (received saline) and a LPS group (intramuscular injected with 15 μg/kg LPS). Six hours after LPS injection, the pigs were euthanized and sampled. Biochemical indexes, inflammation factors, lipid metabolism related parameters and mitochondrial function were evaluated. The relationship between glucocorticoid receptor (GR) and the key enzymes of de novo lipogenesis were also investigated by chromatin immunoprecipitation assay (ChIP). LPS induced a serious inflammation in the liver of growing pigs proved by liver morphologic changes, the up-regulated plasma cortisol, tumor necrosis factor-α (TNF-α) content and gene expression of inflammation related genes in liver. For de novo lipogenesis, LPS significantly decreased the gene expression of fatty acid synthase (FAS), Acetyl-CoA carboxylase-1 (ACC-1) and Stearoyl-CoA desaturase-1 (SCD-1), and the protein expression of ACC-1 and SCD-1. For lipolysis, only the gene expression of adipose triglyceride lipase (ATGL) was decreased. LPS did nothing to the gene expression of hormone-sensitive lipase (HSL) and the lipolytic enzymes activities. For β-oxidation, LPS significantly increased the protein expression of CPT-1α, but the gene expression of mitochondrial DNA-encoded genes and the activities of mitochondrial complex IV and V demonstrated no obviously changes. Furthermore, ChIP results showed that LPS significantly decreased the level of GR binding to ACC-1 promoter. LPS infection has a profound impact on hepatic TG metabolism

  15. BIOCHEMICAL MARKERS OF BONE RESORPTION AND HORMONAL REGULATION OF BONE METABOLISM FOLLOWING LIVER TRANSPLANTATION

    Directory of Open Access Journals (Sweden)

    V. P. Buzulina

    2013-01-01

    Full Text Available Aim. Comparative evaluation of two biochemical markers of bone resorption and hormonal regulation of bone metabolism in liver recipients. Methods and results. Bоne densitometry of L2–L4 and neck of femur, serum level of some hormones (PTH, vitamin D3, estradiol, testosterone regulating osteoclastogenesis as well as com- parative analyses of two bone resorption markers β-crosslaps and tartrate-resistant acid phosphatase type 5b (TRAP-5b were fulfilled in patients after orthotopic liver transplantation (OLT. In 1 month after OLT bone density reduction of L2–L4 and neck of femur; decrease of vitamin D3, estradiol in women, testosterone in men and increase levels of bone resorption markers were observed. In 1 and 2 years after OLT the rise of bone density, increased levels of PTH, estradiol, testosterone and decreased β-crosslaps levels were revealed, while vitamin D3 and TRAP-5b levels remained stable. Conclusion. TRAP-5b was found to be a more speciffic marker of bone resorption, independent from collagen metabolism in liver. Osteoporosis defined in long-term period after OLT was associated with higher TRAP-5b and revialed in women with low estradiol level. 

  16. Lipopolysaccharide derived from the rumen down-regulates stearoyl-CoA desaturase 1 expression and alters fatty acid composition in the liver of dairy cows fed a high-concentrate diet.

    Science.gov (United States)

    Xu, Tianle; Tao, Hui; Chang, Guangjun; Zhang, Kai; Xu, Lei; Shen, Xiangzhen

    2015-03-07

    Dairy cows are often fed a high-concentrate diet to meet lactating demands, yet long-term concentrate feeding induces subacute ruminal acidosis (SARA) and leads to a decrease in milk fat. Stearoyl-CoA desaturase1 (SCD1) participates in fatty acid biosynthesis in the liver of lactating ruminants. Here, we conducted this study to investigate the impact of lipopolysaccharide derived from the rumen on SCD1 expression and on fatty acid composition in the liver of dairy cows fed a high-concentrate diet. Eight multiparous mid-lactating Holstein cows (455 ± 28 kg) were randomly assigned into two groups in the experiment and were fed a low-concentrate diet (LC) or high-concentrate diet (HC) for 18 weeks. The results showed that the total volatile fatty acids and lactic acid accumulated in the rumen, leading to a decreased rumen pH and elevated lipopolysaccharides (LPSs) in the HC group. The long chain fatty acid profile in the rumen and hepatic vein was remarkably altered in the animals fed the HC diet. The triglyceride (TG), non-esterified fatty acid (NEFA) and total cholesterol (TCH) content in the plasma was significantly decreased, whereas plasma glucose and insulin levels were increased. The expression of SCD1 in the liver was significantly down-regulated in the HC group. In regards to transcriptional regulators, the expression of sterol regulatory element binding transcription factors (SREBF1c, SREBF2) and SREBP cleavage activating protein (SCAP) was down-regulated, while peroxisome proliferator-activated receptor α (PPARα) was up-regulated. These data indicate that lipopolysaccharide derived from the rumen down-regulates stearoyl-CoA desaturase 1 expression and alters fatty acid composition in the liver of dairy cows fed a high-concentrate diet.

  17. PGC-1α in aging and lifelong exercise training-mediated regulation of UPR in mouse liver

    DEFF Research Database (Denmark)

    Maag Kristensen, Caroline; Brandt, Christina Tingbjerg; Jørgensen, Stine Ringholm

    2017-01-01

    of specific UPR pathways and increased activity of the ATF6 pathway in the liver with aging. Lifelong exercise training prevented the age-associated change in BiP and IRE1α protein, but not cleaved ATF6 protein and resulted in further decreased PERK protein. Taken together, the present study provides evidence...... that the capacity and activity of the three UPR pathways are differentially regulated in the liver with aging and lifelong exercise training. In addition, PGC-1α does not seem to regulate the activity of hepatic UPR in response to exercise training, but to influence the capacity of the liver to induce UPR......Aging is associated with changes in several metabolic pathways affecting liver function including the adaptive unfolded protein response (UPR). On the other hand, exercise training has been shown to exert beneficial effects on metabolism in the liver and exercise training has been reported...

  18. Regulation of coagulation factor XI expression by microRNAs in the human liver.

    Directory of Open Access Journals (Sweden)

    Salam Salloum-Asfar

    Full Text Available High levels of factor XI (FXI increase the risk of thromboembolic disease. However, the genetic and environmental factors regulating FXI expression are still largely unknown. The aim of our study was to evaluate the regulation of FXI by microRNAs (miRNAs in the human liver. In silico prediction yielded four miRNA candidates that might regulate FXI expression. HepG2 cells were transfected with miR-181a-5p, miR-23a-3p, miR-16-5p and miR-195-5p. We used mir-494, which was not predicted to bind to F11, as a negative control. Only miR-181a-5p caused a significant decrease both in FXI protein and F11 mRNA levels. In addition, transfection with a miR-181a-5p inhibitor in PLC/PRF/5 hepatic cells increased both the levels of F11 mRNA and extracellular FXI. Luciferase assays in human colon cancer cells deficient for Dicer (HCT-DK demonstrated a direct interaction between miR-181a-5p and 3'untranslated region of F11. Additionally, F11 mRNA levels were inversely and significantly correlated with miR-181a-5p levels in 114 healthy livers, but not with miR-494. This study demonstrates that FXI expression is directly regulated by a specific miRNA, miR-181a-5p, in the human liver. Future studies are necessary to further investigate the potential consequences of miRNA dysregulation in pathologies involving FXI.

  19. Cobalt-chromium-molybdenum alloy causes metal accumulation and metallothionein up-regulation in rat liver and kidney

    DEFF Research Database (Denmark)

    Jakobsen, Stig Storgaard; Danscher, Gorm; Stoltenberg, Meredin

    2007-01-01

    in liver and kidney. We found that metal ions are liberated from CoCrMo alloys and suggest that they are released by dissolucytosis, a process where macrophages causes the metallic surface to release metal ions. Animals with intramuscular implants accumulated metal in liver and kidney and metallohionein I....../II were elevated in liver tissue. The present data do not tell whether kidney and liver are the primary target organs or what possible toxicological effect the different metal ions might have, but they show that metal ions are liberated from CoCrMo alloys that are not subjected to mechanical wear...... and that they accumulate in liver and kidney tissue. That the liberated metal ions affect the tissues is supported by an up-regulation of the detoxifying/pacifying metalloprotein I/II in the liver. Udgivelsesdato: 2007-Dec...

  20. The PNPLA3 rs738409 G-allele associates with reduced fasting serum triglyceride and serum cholesterol in Danes with impaired glucose regulation

    DEFF Research Database (Denmark)

    Krarup, Nikolaj Thure; Grarup, Niels; Banasik, Karina

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a common condition, associated with hepatic insulin resistance and the metabolic syndrome including hyperglycaemia and dyslipidemia. We aimed at studying the potential impact of the NAFLD-associated PNPLA3 rs738409 G-allele on NAFLD-related metabolic...

  1. Identification of protective components that prevent the exacerbation of goose fatty liver: Characterization, expression and regulation of adiponectin receptors.

    Science.gov (United States)

    Geng, Tuoyu; Yang, Biao; Li, Fuyuan; Xia, Lili; Wang, Qianqian; Zhao, Xing; Gong, Daoqing

    2016-01-01

    Fat accumulation in the liver is a natural process in goose, which prepares goose for long-distance migration. In contrast to mammalian fatty liver that usually progresses into an irreversible status, steatohepatitis, goose fatty liver can return to normal without obvious pathological damage, suggesting a protective system exists in goose liver. This study was to identify the components of this system. We first focused on goose adiponectin receptor 1 and 2 (Adipor1/2) as they have ceramidase activity, and can cleave ceramide, a group of proinflammatory signaling lipid species. Quantitative analysis indicated that tumor necrosis factor alpha (Tnfα), a key proinflammatory cytokine, was down-regulated in goose fatty liver by overfeeding. This inhibition of Tnfα was accompanied with reduced adiponectin and increased Adipor1/2 in the adipose tissues and in the livers of the overfed geese, respectively. To investigate the regulation of goose Adipor2 in the context of fatty liver, we treated goose primary hepatocytes with fatty liver associated factors. Data indicated that Adipor2 was upregulated by glucose and oleate but not palmitate. Its expression was even suppressed by high level of insulin. The regulation of Adipor1 by these factors was quite similar to that of Adipor2 except that glucose did not induce Adipor1. Together, these findings suggest the upregulation of Adipor1/2 may, at least partially, contribute to the inhibition of inflammation in goose fatty liver, and the expression of Adipor1/2 can be regulated by fatty liver-associated factors. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Regulation of N-nitrosodimethylamine demethylase in rat liver and kidney.

    Science.gov (United States)

    Hong, J Y; Pan, J M; Dong, Z G; Ning, S M; Yang, C S

    1987-11-15

    In previous work, the low Km form of N-nitrosodimethylamine (NDMA) demethylase has been demonstrated to be due to a specific form of cytochrome P-450 (designated as P-450ac) and to be the enzyme required for the metabolic activation of NDMA. The present work deals with the regulation of P-450ac in rat liver during development as well as the mechanism of induction of P-450ac in rat liver and kidney by inducers. NDMA demethylase activity was almost undetectable in the liver of newborn rats, increased after day 4, and remained elevated throughout the first 17 days of the neonatal period. The enhancement of NDMA demethylase activity during development was accompanied by corresponding increases of P-450ac content and P-450ac mRNA levels as determined by Western and slot blot analyses, respectively. No sex differences with respect to this enzyme were observed in the developing rats. Acetone treatment on late-term pregnant rats for 2 days resulted in transplacental inductions of P-450ac and P-450ac mRNA in the newborn rats. Pretreatment of young male rats and adult female rats with acetone or isopropyl alcohol caused increases of NDMA demethylase activity and P-450ac content in the liver but no significant change in the P-450ac mRNA level. These facts suggest the possible existence of a posttranscription regulatory mechanism under these induction conditions. The presence of P-450ac in rat kidney was demonstrated by Western and Northern blot analyses. The renal form of P-450ac seemed to be regulated in a fashion similar to the hepatic P-450ac regarding its response to inducing factors such as fasting and acetone treatment.

  3. Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1 (SR-BI expression in liver and association with lipid levels in a population-based study

    Directory of Open Access Journals (Sweden)

    Barrett-Connor Elizabeth

    2010-01-01

    Full Text Available Abstract Background Several studies have noted that genetic variants of SCARB1, a lipoprotein receptor involved in reverse cholesterol transport, are associated with serum lipid levels in a sex-dependent fashion. However, the mechanism underlying this gene by sex interaction has not been explored. Methods We utilized both epidemiological and molecular methods to study how estrogen and gene variants interact to influence SCARB1 expression and lipid levels. Interaction between 35 SCARB1 haplotype-tagged polymorphisms and endogenous estradiol levels was assessed in 498 postmenopausal Caucasian women from the population-based Rancho Bernardo Study. We further examined associated variants with overall and SCARB1 splice variant (SR-BI and SR-BII expression in 91 human liver tissues using quantitative real-time PCR. Results Several variants on a haplotype block spanning intron 11 to intron 12 of SCARB1 showed significant gene by estradiol interaction affecting serum lipid levels, the strongest for rs838895 with HDL-cholesterol (p = 9.2 × 10-4 and triglycerides (p = 1.3 × 10-3 and the triglyceride:HDL cholesterol ratio (p = 2.7 × 10-4. These same variants were associated with expression of the SR-BI isoform in a sex-specific fashion, with the strongest association found among liver tissue from 52 young women Conclusions Estrogen and SCARB1 genotype may act synergistically to regulate expression of SCARB1 isoforms and impact serum levels of HDL cholesterol and triglycerides. This work highlights the importance of considering sex-dependent effects of gene variants on serum lipid levels.

  4. Coagulopathy following major liver resection: the effect of rBPI21 and the role of decreased synthesis of regulating proteins by the liver

    NARCIS (Netherlands)

    Meijer, C.; Wiezer, M. J.; Hack, C. E.; Boelens, P. G.; Wedel, N. I.; Meijer, S.; Nijveldt, R. J.; Statius Muller, M. G.; Wiggers, T.; Zoetmulder, F. A.; Borel Rinkes, I. H.; Cuesta, M. A.; Gouma, D. J.; van de Velde, C. J.; Tilanus, H. W.; Scotté, M.; Thijs, L. G.; van Leeuwen, P. A.

    2001-01-01

    This prospective study investigated the role of reduced hepatic synthesis of regulating proteins in coagulopathy after partial hepatectomy (PH) compared with major abdominal surgery (MAS) without involvement of the liver. Furthermore, we studied the effect of rBPI21, an endotoxin-neutralizing agent,

  5. Inhibitory activity of diacylglycerol acyltransferase (DGAT) and microsomal triglyceride transfer protein (MTP) by the flavonoid, taxifolin, in HepG2 cells: potential role in the regulation of apolipoprotein B secretion.

    Science.gov (United States)

    Casaschi, Adele; Rubio, Brent K; Maiyoh, Geoffrey K; Theriault, Andre G

    2004-10-01

    The purpose of the present study was to examine the role of taxifolin, a plant flavonoid, on several aspects involving apolipoprotein B (apoB) secretion and triglyceride (TG) availability in HepG2 cells. Taxifolin was shown by ELISA to markedly reduce apoB secretion under basal and lipid-rich conditions up to 63% at 200 micromol/L. As to the mechanism underlying this effect, we examined whether taxifolin exerted its effect by limiting TG availability in the microsomal lumen essential for lipoprotein assembly. Taxifolin was shown to inhibit microsomal TG synthesis by 37% and its subsequent transfer into the lumen (-26%). The reduction in synthesis was due to a decrease in diacylglycerol acyltransferase (DGAT) activity (-35%). The effect on DGAT activity was found to be non-competitive and non-transcriptional in nature. Both DGAT-1 and DGAT-2 mRNA expression remained essentially unchanged suggesting the point of regulation may be at the post-transcriptional level. Evidence is accumulating that microsomal triglyceride transfer protein (MTP) is also involved in determining the amount of lumenal TG available for lipoprotein assembly and secretion. Taxifolin was shown to inhibit this enzyme by 41%. Whether the reduction in TG accumulation in the microsomal lumen is predominantly due to DGAT and/or MTP activity remains to be addressed. In summary, taxifolin reduced apoB secretion by limiting TG availability via DGAT and MTP activity.

  6. The effects of space flight on some rat liver enzymes regulating carbohydrate and lipid metabolism

    Science.gov (United States)

    Abraham, S.; Lin, C. Y.; Klein, H. P.; Volkmann, C.

    1981-01-01

    The effects of space flight conditions on the activities of certain enzymes regulating carbohydrate and lipid metabolism in rat liver are investigated in an attempt to account for the losses in body weight observed during space flight despite preflight caloric consumption. Liver samples were analyzed for the activities of 32 cytosolic and microsomal enzymes as well as hepatic glycogen and individual fatty acid levels for ground control rats and rats flown on board the Cosmos 936 biosatellite under normal space flight conditions and in centrifuges which were sacrificed upon recovery or 25 days after recovery. Significant decreases in the activities of glycogen phosphorylase, alpha-glycerol phosphate acyl transferase, diglyceride acyl transferase, aconitase and 6-phosphogluconate dehydrogenase and an increase in palmitoyl CoA desaturase are found in the flight stationary relative to the flight contrifuged rats upon recovery, with all enzymes showing alterations returning to normal values 25 days postflight. The flight stationary group is also observed to be characterized by more than twice the amount of liver glycogen of the flight centrifuged group as well as a significant increase in the ratio of palmitic to palmitoleic acid. Results thus indicate metabolic changes which may be involved in the mechanism of weight loss during weightlessness, and demonstrate the equivalence of centrifugation during space flight to terrestrial gravity.

  7. The role of the daily feeding rhythm in the regulation of the day/night rhythm in triglyceride secretion in rats.

    Science.gov (United States)

    Su, Yan; Foppen, Ewout; Mansur Machado, Frederico Sander; Fliers, Eric; Kalsbeek, Andries

    2018-02-15

    Plasma triglyceride (TG) levels show a clear daily rhythm, however, thus far it is still unknown whether this rhythm results from a daily rhythm in TG production, TG uptake or both. Previous studies have shown that feeding activity affects plasma TG concentrations, but it is not clear how the daily rhythm in feeding activity affects plasma TG concentrations. In the present study, we measured plasma TG concentrations and TG secretion rates in rats at 6 Zeitgeber times to investigate whether plasma TG concentrations and TG secretion show a daily rhythm. We found that plasma TG concentrations and TG secretion show a significant day/night rhythm. Next, we removed the daily rhythm in feeding behavior by introducing a 6-meals-a-day (6M) feeding schedule to investigate whether the daily rhythm in feeding behavior is necessary to maintain the daily rhythm in TG secretion. We found that the day/night rhythm in TG secretion was abolished under 6M feeding conditions. Hepatic apolipoprotein B (ApoB) and microsomal TG transfer protein (Mttp), which are both involved in TG secretion, also lost their daily rhythmicity under 6M feeding conditions. Together, these results indicate that: (1) the daily rhythm in TG secretion contributes to the formation of a day/night rhythm in plasma TG levels and (2) a daily feeding rhythm is essential for maintaining the daily rhythm in TG secretion.

  8. Aryl hydrocarbon receptor nuclear translocator in human liver is regulated by miR-24

    Energy Technology Data Exchange (ETDEWEB)

    Oda, Yuki; Nakajima, Miki; Mohri, Takuya [Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Takamiya, Masataka; Aoki, Yasuhiro [Department of Legal Medicine, Iwate Medical University School of Medicine, 19-1 Uchimaru, Morioka 020-8505 (Japan); Fukami, Tatsuki [Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@kenroku.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Division of Pharmaceutical Sciences, Graduate School of Medical Science, Kanazawa University, Kakuma-machi, Kanazawa 920-1192 (Japan)

    2012-05-01

    Aryl hydrocarbon receptor nuclear translocator (ARNT) forms a heterodimer with aryl hydrocarbon receptor or hypoxia inducible factor 1α to mediate biological responses to xenobiotic exposure and hypoxia. Although the regulation mechanism of the ARNT expression is largely unknown, earlier studies reported that the human ARNT protein level was decreased by hydrogen peroxide or reactive oxygen species. These stimuli increase the miR-24 level in various human cell lines. In silico analysis predicts that some microRNAs including miR-16 and miR-23b may bind to ARNT mRNA. This background prompted us to investigate whether human ARNT is regulated by microRNAs. Overexpression of miR-24 into HuH-7 and HepG2 cells significantly decreased the ARNT protein level, but not the ARNT mRNA level, indicating translational repression. However, overexpression of miR-16 or miR-23b caused no change in the ARNT expression. The miR-24-dependent down-regulation of ARNT decreased the expression of its downstream genes such as CYP1A1 and carbonic anhydrase IX. Luciferase assay was performed to determine the element on the ARNT mRNA to which miR-24 binds. Finally, it was demonstrated that the miR-24 levels in a panel of 26 human livers were inversely correlated with the protein levels or the translational efficiency of ARNT. Taken together, we found that miR-24 negatively regulates ARNT expression in human liver, affecting the expression of its downstream genes. miR-24 would be one of the factors underlying the mechanisms by which ARNT protein is decreased by reactive oxygen species. -- Highlights: ► Overexpression of miR-24 into human cell lines decreased the ARNT protein level. ► miR-24-dependent down-regulation of ARNT affected the expression of CYP1A1 and CA IX. ► Luciferase assay was performed to identify functional MREs for miR-24 in ARNT mRNA. ► The miR-24 levels inversely correlated with the ARNT protein levels in human liver.

  9. Studies on the mechanism of quinone action on hormonal regulation of metabolism in the rat liver

    International Nuclear Information System (INIS)

    Cheng, E.Y.

    1989-01-01

    The mechanism of quinone actions in liver cell metabolism had been investigated using menadione as a model compound. Previous reports suggested that quinones and free radicals could produce perturbations in cellular calcium homeostasis. Since calcium plays an important role in the regulation of cellular metabolic processes, then regulation of cytosolic calcium concentrations, and thus of cellular metabolism, by calcium-mobilizing hormones such as phenylephrine and vasopressin could possibly be modified by quinones such as menadione. Methods used to approach this hypothesis included the assay for activation of glycogen phosphorylase, an indirect index of calcium mobilization; the determination of calcium mobilization with 45 Ca efflux exchange and with fluorescent calcium indicator fura-2; and the measurement of phosphatidylinositides, an important link in the membrane-associated receptor-mediated signal transduction mechanism

  10. Liver-Derived Insulin-Like Growth Factor-I is Involved in the Regulation of Blood Pressure in Mice

    DEFF Research Database (Denmark)

    Tivesten, Asa; Bollano, Entela; Andersson, Irene

    2002-01-01

    IGF-I has been suggested to be of importance for cardiovascular structure and function, but the relative role of locally produced and liver-derived endocrine IGF-I remains unclear. Using the Cre-LoxP recombination system, we have previously created transgenic mice with a liver-specific, inducible...... IGF-I knockout (LI-IGF-I-/-). To examine the role of liver-derived IGF-I in cardiovascular physiology, liver-derived IGF-I was inactivated at 4 wk of age, resulting in a 79% reduction of serum IGF-I levels. At 4 months of age, systolic blood pressure (BP) was increased in LI-IGF-I-/- mice...... to endothelial dysfunction associated with increased expression of endothelin-1 and impaired vasorelaxation of resistance vessels. In conclusion, our findings suggest that liver-derived IGF-I is involved in the regulation of BP in mice....

  11. MicroRNA regulation in Ames dwarf mouse liver may contribute to delayed aging.

    Science.gov (United States)

    Bates, David J; Li, Na; Liang, Ruqiang; Sarojini, Harshini; An, Jin; Masternak, Michal M; Bartke, Andrzej; Wang, Eugenia

    2010-02-01

    The Ames dwarf mouse is well known for its remarkable propensity to delay the onset of aging. Although significant advances have been made demonstrating that this aging phenotype results primarily from an endocrine imbalance, the post-transcriptional regulation of gene expression and its impact on longevity remains to be explored. Towards this end, we present the first comprehensive study by microRNA (miRNA) microarray screening to identify dwarf-specific lead miRNAs, and investigate their roles as pivotal molecular regulators directing the long-lived phenotype. Mapping the signature miRNAs to the inversely expressed putative target genes, followed by in situ immunohistochemical staining and in vitro correlation assays, reveals that dwarf mice post-transcriptionally regulate key proteins of intermediate metabolism, most importantly the biosynthetic pathway involving ornithine decarboxylase and spermidine synthase. Functional assays using 3'-untranslated region reporter constructs in co-transfection experiments confirm that miRNA-27a indeed suppresses the expression of both of these proteins, marking them as probable targets of this miRNA in vivo. Moreover, the putative repressed action of this miRNA on ornithine decarboxylase is identified in dwarf mouse liver as early as 2 months of age. Taken together, our results show that among the altered aspects of intermediate metabolism detected in the dwarf mouse liver--glutathione metabolism, the urea cycle and polyamine biosynthesis--miRNA-27a is a key post-transcriptional control. Furthermore, compared to its normal siblings, the dwarf mouse exhibits a head start in regulating these pathways to control their normality, which may ultimately contribute to its extended health-span and longevity.

  12. DEPTOR in POMC neurons affects liver metabolism but is dispensable for the regulation of energy balance.

    Science.gov (United States)

    Caron, Alexandre; Labbé, Sébastien M; Mouchiroud, Mathilde; Huard, Renaud; Lanfray, Damien; Richard, Denis; Laplante, Mathieu

    2016-06-01

    We have recently demonstrated that specific overexpression of DEP-domain containing mTOR-interacting protein (DEPTOR) in the mediobasal hypothalamus (MBH) protects mice against high-fat diet-induced obesity, revealing DEPTOR as a significant contributor to energy balance regulation. On the basis of evidence that DEPTOR is expressed in the proopiomelanocortin (POMC) neurons of the MBH, the present study aimed to investigate whether these neurons mediate the metabolic effects of DEPTOR. Here, we report that specific DEPTOR overexpression in POMC neurons does not recapitulate any of the phenotypes observed when the protein was overexpressed in the MBH. Unlike the previous model, mice overexpressing DEPTOR only in POMC neurons 1) did not show differences in feeding behavior, 2) did not exhibit changes in locomotion activity and oxygen consumption, 3) did not show an improvement in systemic glucose metabolism, and 4) were not resistant to high-fat diet-induced obesity. These results support the idea that other neuronal populations are responsible for these phenotypes. Nonetheless, we observed a mild elevation in fasting blood glucose, insulin resistance, and alterations in liver glucose and lipid homeostasis in mice overexpressing DEPTOR in POMC neurons. Taken together, these results show that DEPTOR overexpression in POMC neurons does not affect energy balance regulation but could modulate metabolism through a brain-liver connection. Copyright © 2016 the American Physiological Society.

  13. Laser Capture and Deep Sequencing Reveals the Transcriptomic Programmes Regulating the Onset of Pancreas and Liver Differentiation in Human Embryos

    Directory of Open Access Journals (Sweden)

    Rachel E. Jennings

    2017-11-01

    Full Text Available To interrogate the alternative fates of pancreas and liver in the earliest stages of human organogenesis, we developed laser capture, RNA amplification, and computational analysis of deep sequencing. Pancreas-enriched gene expression was less conserved between human and mouse than for liver. The dorsal pancreatic bud was enriched for components of Notch, Wnt, BMP, and FGF signaling, almost all genes known to cause pancreatic agenesis or hypoplasia, and over 30 unexplored transcription factors. SOX9 and RORA were imputed as key regulators in pancreas compared with EP300, HNF4A, and FOXA family members in liver. Analyses implied that current in vitro human stem cell differentiation follows a dorsal rather than a ventral pancreatic program and pointed to additional factors for hepatic differentiation. In summary, we provide the transcriptional codes regulating the start of human liver and pancreas development to facilitate stem cell research and clinical interpretation without inter-species extrapolation.

  14. ADAM12 in human liver cancers: TGF-beta-regulated expression in stellate cells is associated with matrix remodeling

    DEFF Research Database (Denmark)

    Le Pabic, Hélène; Bonnier, Dominique; Wewer, Ulla M

    2003-01-01

    "A disintegrin and metalloproteinases" (ADAMs) form a family of cell-surface glycoproteins with potential protease and cell-adhesion activities. We have investigated ADAM expression in human liver cancers and their regulation by several cytokines involved in liver injury. Using degenerative RT...... carcinomas (up to 3- and 6-fold, respectively) and liver metastases from colonic carcinomas (up to 40- and 60-fold, respectively). The up-regulation of both ADAM9 and ADAM12 was correlated with an increase in matrix metalloproteinase 2 expression and activity. In conclusion, in liver cancers ADAM9 and ADAM12......-PCR, cDNA encoding sequences for ADAM9 and ADAM12 were identified in human activated hepatic stellate cells (HSCs). Northern blot analyses showed that HSCs, but not hepatocytes, expressed transcripts for ADAM9 messenger RNA (mRNA) and both the long and short forms of ADAM12. This expression...

  15. The role of glucose, insulin and NEFA in regulating tissue triglyceride accumulation: Substrate cooperation in adipose tissue versus substrate competition in skeletal muscle.

    Science.gov (United States)

    Guzzardi, M A; Hodson, L; Guiducci, L; La Rosa, F; Salvadori, P A; Burchielli, S; Iozzo, P

    2017-11-01

    Metabolic factors initiating adipose tissue expansion and ectopic triglyceride accumulation are not completely understood. We aimed to investigate the independent role of circulating glucose, NEFA and insulin on glucose and NEFA uptake, and lipogenesis in skeletal muscle and subcutaneous adipose tissue (SCAT). Twenty-two pigs were stratified according to four protocols: 1) and 2) low NEFA + high insulin ± high glucose (hyperinsulinaemia-hyperglycaemia or hyperinsulinaemia-euglycaemia), 3) high NEFA + low insulin (fasting), 4) low NEFA + low insulin (nicotinic acid). Positron emission tomography with [ 18 F]fluoro-2-deoxyglucose and [ 11 C]acetate, was combined with [ 14 C]acetate and [U- 13 C]palmitate enrichment techniques to assess glucose and lipid metabolism. Hyperinsulinaemia increased glucose extraction, whilst hyperglycaemia enhanced glucose uptake in skeletal muscle and SCAT. In SCAT, during hyperglycaemia, elevated glucose uptake was accompanied by greater [U- 13 C]palmitate-TG enrichment compared to the other groups, and by a 39% increase in de novo lipogenesis (DNL) compared to baseline, consistent with a 70% increment in plasma lipogenic index. Conversely, in skeletal muscle, [U- 13 C]palmitate-TG enrichment was higher after prolonged fasting. Our data show the necessary role of hyperglycaemia-hyperinsulinaemia vs euglycaemia-hyperinsulinaemia in promoting expansion of TG stores in SCAT, by the consensual elevation in plasma NEFA and glucose uptake and DNL. In contrast, skeletal muscle NEFA uptake for TG synthesis is primarily driven by circulating NEFA levels. These results suggest that a) prolonged fasting or dietary regimens enhancing lipolysis might promote muscle steatosis, and b) the control of glucose levels, in association with adequate energy balance, might contribute to weight loss. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and

  16. CAR-mediated repression of Foxo1 transcriptional activity regulates the cell cycle inhibitor p21 in mouse livers

    International Nuclear Information System (INIS)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Pustylnyak, Vladimir O.

    2014-01-01

    Highlights: • CAR activation decreased the level of Foxo1 in mouse livers. • CAR activation decreased the level of p21 in mouse livers. • CAR activation inhibited Foxo1 transcriptional activity in mouse livers. - Abstract: 1,4-Bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), an agonist of constitutive androstane receptor (CAR), is a well-known strong primary chemical mitogen for the mouse liver. Despite extensive investigation of the role of CAR in the regulation of cell proliferation, our knowledge of the intricate mediating mechanism is incomplete. In this study, we demonstrated that long-term CAR activation by TCPOBOP increased liver-to-body weight ratio and decreased tumour suppressor Foxo1 expression and transcriptional activity, which were correlated with reduced expression of genes regulated by Foxo1, including the cell-cycle inhibitor Cdkn1a(p21), and upregulation of the cell-cycle regulator Cyclin D1. Moreover, we demonstrated the negative regulatory effect of TCPOBOP-activated CAR on the association of Foxo1 with the target Foxo1 itself and Cdkn1a(p21) promoters. Thus, we identified CAR-mediated repression of cell cycle inhibitor p21, as mediated by repression of FOXO1 expression and transcriptional activity. CAR-FOXO1 cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments

  17. Remote ischemic preconditioning protects liver ischemia-reperfusion injury by regulating eNOS-NO pathway and liver microRNA expressions in fatty liver rats.

    Science.gov (United States)

    Duan, Yun-Fei; An, Yong; Zhu, Feng; Jiang, Yong

    2017-08-15

    Ischemic preconditioning (IPC) is a strategy to reduce ischemia-reperfusion (I/R) injury. The protective effect of remote ischemic preconditioning (RIPC) on liver I/R injury is not clear. This study aimed to investigate the roles of RIPC in liver I/R in fatty liver rats and the involvement of endothelial nitric oxide synthase-nitric oxide (eNOS-NO) pathway and microRNA expressions in this process. A total of 32 fatty rats were randomly divided into the sham group, I/R group, RIPC group and RIPC+I/R group. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) and nitric oxide (NO) were measured. Hematoxylin-eosin staining was used to observe histological changes of liver tissues, TUNEL to detect hepatocyte apoptosis, and immunohistochemistry assay to detect heat shock protein 70 (HSP70) expression. Western blotting was used to detect liver inducible NOS (iNOS) and eNOS protein levels and real-time quantitative polymerase chain reaction to detect miR-34a, miR-122 and miR-27b expressions. Compared with the sham and RIPC groups, serum ALT, AST and iNOS in liver tissue were significantly higher in other two groups, while serum NO and eNOS in liver tissue were lower, and varying degrees of edema, degeneration and inflammatory cell infiltration were found. Cell apoptosis number was slightly lower in the RIPC+I/R group than that in I/R group. Compared with the sham group, HSP70 expressions were significantly increased in other three groups (all Pfatty liver I/R injury by affecting the eNOS-NO pathway and liver microRNA expressions. Copyright © 2017 The Editorial Board of Hepatobiliary & Pancreatic Diseases International. Published by Elsevier B.V. All rights reserved.

  18. MiR-181b regulates steatosis in nonalcoholic fatty liver disease via targeting SIRT1.

    Science.gov (United States)

    Wang, Yunxia; Zhu, Kongxi; Yu, Weihua; Wang, Hongjuan; Liu, Lan; Wu, Qiong; Li, Shuai; Guo, Jianqiang

    2017-11-04

    Non-alcoholic fatty liver diseases (NAFLD) is one of the leading cause of chronic liver diseases in the world. However, the pathogenesis of NAFLD is still unclear. Emerging studies have demonstrated that microRNAs (miRs) are profoundly involved in NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-181b influences NAFLD via direct targeting SIRT1. The expression of miR181b was up-regulated while SIRT1 was down-regulated in both human NAFLD patients and high fat diet (HFD) induced NAFDL mice model. And palmitic acid (PA) treatment increased the miR-181b expression while decreased SIRT1 expression in HepG2 cells. Further, we identified that SIRT1 is a direct downstream target of miR-181b. Ectopic expression of miR-181b significantly repressed the 3'-UTR reporter activities of SIRT1 in a dose-dependent manner, while the effect of miR-181b was interrupted when the binding site of miR-181b within the SIRT1 3'-UTR was mutated. And overexpression of miR-181b reduced both the mRNA and protein levels of SIRT1 in HepG2 cells. We also found that inhibition of miR-181b expression alleviates hepatic steatosis both in vitro and in vivo. And the effect of miR-181b on steatosis was blocked by SIRT1 overexpression. Taken together, our data indicated that increased expression of miR-181b potentially contributes to altered lipid metabolism in NAFLD. Downregulation of miR-34a may be a therapeutic strategy against NAFLD by regulating its target SIRT1. Copyright © 2017 Elsevier Inc. All rights reserved.

  19. Profile Triglycerides Japanese Quail (Coturnix coturnix japonica After Giving Turmeric (Curcuma longa Powder

    Directory of Open Access Journals (Sweden)

    Sukarman Hadi jaya Putra

    2014-12-01

    Full Text Available The purpose of this study was to determine the triglyceride profile of Japanese quail (Coturnix coturnix japonica after being given the parameters of turmeric (Curcuma longa powder; feed intake, profiles of liver triglycerides, profiles of serum triglycerides and profiles of meat triglycerides. This study uses an experimental method with A Completely Randomized Design Pattern. Test animals used were 45 female Japanese quails were divided into 3 groups, namely; P0: quail were not given turmeric powder, P1: quail were given turmeric powder a dose of 54 mg/quail/day, P3: quail were given turmeric powder a dose of 108 mg/quail/day. Each group with 5 replications. Each repeat consists of 3 Japanese quails. Provision of treatment every day for 30 days starting from the age of 14 days. Data were analyzed using analysis of variance (ANOVA followed by Duncan's test with 95% confidence interval (α = 0.05 level. Analysis of the data used is software Minitab software 16. Results showed that the levels of turmeric powder are given in Japanese quail significant (P˂0.05 on liver triglyceride levels, serum and Japanese quail meat but had no significant effect (P˃0.05 on consumption feed. The results showed that the optimal dose of turmeric powder to lower triglyceride levels of Japanese quail is 108 mg/quail/day as evidenced by the highest decrease in liver triglyceride profiles, profiles of serum triglycerides and triglyceride profiles of Japanese quail meat compared with other treatments.

  20. Sympathetic nervous system control of triglyceride metabolism: novel concepts derived from recent studies

    NARCIS (Netherlands)

    Geerling, Janine J.; Boon, Mariëtte R.; Kooijman, Sander; Parlevliet, Edwin T.; Havekes, Louis M.; Romijn, Johannes A.; Meurs, Illiana M.; Rensen, Patrick C. N.

    2014-01-01

    Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels.

  1. Evidence for an indirect transcriptional regulation of glucose-6-phosphatase gene expression by liver X receptors

    International Nuclear Information System (INIS)

    Grempler, Rolf; Guenther, Susanne; Steffensen, Knut R.; Nilsson, Maria; Barthel, Andreas; Schmoll, Dieter; Walther, Reinhard

    2005-01-01

    Liver X receptor (LXR) paralogues α and β (LXRα and LXRβ) are members of the nuclear hormone receptor family and have oxysterols as endogenous ligands. LXR activation reduces hepatic glucose production in vivo through the inhibition of transcription of the key gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6-phosphatase (G6Pase). In the present study, we investigated the molecular mechanisms involved in the regulation of G6Pase gene expression by LXR. Both T0901317, a synthetic LXR agonist, and the adenoviral overexpression of either LXRα or LXRβ suppressed G6Pase gene expression in H4IIE hepatoma cells. However, compared to the suppression of G6Pase expression seen by insulin, the decrease of G6Pase mRNA by LXR activation was delayed and was blocked by cycloheximide, an inhibitor of protein synthesis. These observations, together with the absence of a conserved LXR-binding element within the G6Pase promoter, suggest an indirect inhibition of G6Pase gene expression by liver X receptors

  2. The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism.

    Science.gov (United States)

    Arrieta-Cruz, Isabel; Gutiérrez-Juárez, Roger

    2016-07-01

    A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes. © 2016 American Society for Nutrition.

  3. The Role of Circulating Amino Acids in the Hypothalamic Regulation of Liver Glucose Metabolism123

    Science.gov (United States)

    Arrieta-Cruz, Isabel; Gutiérrez-Juárez, Roger

    2016-01-01

    A pandemic of diabetes and obesity has been developing worldwide in close association with excessive nutrient intake and a sedentary lifestyle. Variations in the protein content of the diet have a direct impact on glucose homeostasis because amino acids (AAs) are powerful modulators of insulin action. In this work we review our recent findings on how elevations in the concentration of the circulating AAs leucine and proline activate a metabolic mechanism located in the mediobasal hypothalamus of the brain that sends a signal to the liver via the vagus nerve, which curtails glucose output. This neurogenic signal is strictly dependent on the metabolism of leucine and proline to acetyl-coenzyme A (CoA) and the subsequent production of malonyl-CoA; the signal also requires functional neuronal ATP-sensitive potassium channels. The liver then responds by lowering the rate of gluconeogenesis and glycogenolysis, ultimately leading to a net decrease in glucose production and in concentrations of circulating glucose. Furthermore, we review here how our work with proline suggests a new role of astrocytes in the central regulation of glycemia. Last, we outline how factors such as the consumption of fat-rich diets can interfere with glucoregulatory mechanisms and, in the long term, may contribute to the development of hyperglycemia, a hallmark of type 2 diabetes. PMID:27422516

  4. Fasting and nonfasting triglycerides in cardiovascular and other diseases.

    Science.gov (United States)

    Piťha, J; Kovář, J; Blahová, T

    2015-01-01

    Moderately elevated plasma/serum triglycerides (2-10 mmol/l) signalize increased risk for cardiovascular disease or presence of non-alcoholic steatohepatitis. Extremely elevated triglycerides (more than 10 mmol/l) signalize increased risk for pancreatitis and lipemia retinalis. The concentration of triglycerides is regulated by many genetic and nongenetic factors. Extremely elevated triglycerides not provoked by nutritional factors, especially inappropriate alcohol intake are more likely to have a monogenic cause. On the contrary, mildly to moderately elevated triglycerides are often caused by polygenic disorders; these could be also associated with central obesity, insulin resistance, and diabetes mellitus. Concentration of triglycerides is also closely interconnected with presence of atherogenic remnant lipoproteins, impaired reverse cholesterol transport and more atherogenic small LDL particles. In general, there is tight association between triglycerides and many other metabolic factors including intermediate products of lipoprotein metabolism which are frequently atherogenic. Therefore, reliable evaluation of the independent role of triglycerides especially in atherosclerosis and cardiovascular disease is difficult. In individual cases values of HDL cholesterol, non-HDL cholesterol (total minus HDL cholesterol), non-HDL/nonLDL cholesterol (total minus HDL minus LDL cholesterol, especially in nonfasting status), atherogenic index of plasma and/or apolipoprotein B could help in decisions regarding aggressiveness of treatment.

  5. CE: Triglycerides: Do They Matter?

    Science.gov (United States)

    Scordo, Kristine; Pickett, Kim Anne

    2017-01-01

    : Since the introduction of HMG-CoA reductase inhibitors, also known as statins, as an adjunct to diet in the treatment of hyperlipidemia and the greater emphasis placed on reducing low-density lipoprotein (LDL) cholesterol levels in the prevention of atherosclerosis and cardiovascular disease (CVD), there has been less focus on the value of lowering serum triglyceride levels. Many patients are aware of their "good" and "bad" cholesterol levels, but they may not be aware of their triglyceride level or of the association between high triglycerides and the development of CVD. In recent years, however, in light of the increasing incidences of obesity, insulin resistance, and type 2 diabetes, lowering triglyceride levels has gained renewed interest. In addition to the focus on lowering LDL cholesterol levels in CVD prevention, clinicians need to be aware of the role of triglycerides-their contribution to CVD, and the causes and treatment of hypertriglyceridemia.

  6. Silent information regulator 1 (SIRT1) ameliorates liver fibrosis via promoting activated stellate cell apoptosis and reversion

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Yuting, E-mail: wuyuting1302@sina.com; Liu, Xuejiao; Zhou, Qun; Huang, Cheng; Meng, Xiaoming; Xu, Fengyun; Li, Jun, E-mail: lj@ahmu.edu.cn

    2015-12-01

    SIRT1 (silent information regulator 1), a conserved NAD +-dependent histone deacetylase, is closely related with various biological processes. Moreover, the important role of SIRT1 in alcoholic liver disease, nonalcoholic fatty liver and HCC had been widely reported. Recently, a novel role of SIRT1 was uncovered in organ fibrosis diseases. Here, we investigated the inhibitory effect of SIRT1 in liver fibrogenesis. SIRT1 protein was dramatically decreased in CCl4-treated mice livers. Stimulation of LX-2 cells with TGF-β1 also resulted in a significant suppression of SIRT1 protein. Nevertheless, TGF-β1-induced LX-2 cell activation was inhibited by SIRT1 plasmid, and this was accompanied by up-regulation of cell apoptosis-related proteins. Overexpression of SIRT1 also attenuated TGF-β1-induced expression of myofibroblast markers α-SMA and COL1a. However, the important characteristic of the recovery of liver fibrosis is not only the apoptosis of activated stellate cells but also the reversal of the myofibroblast-like phenotype to a quiescent-like phenotype. Restoration of SIRT1 protein was observed in the in vivo spontaneously liver fibrosis reversion model and in vitro MDI (isobutylmethylxanthine, dexamethasone, and insulin)-induced reversed stellate cells, and forced expression of SIRT1 also promoted the reversal of activated stellate cells. Furthermore, lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) was increased in liver fibrosis. RNAi-mediated suppression of MALAT1 resulted in a decrease of myofibroblast markers and restoration of SIRT1 protein. These observations suggested that SIRT1 contributed to apoptosis and reversion of activated LX-2 cells and SIRT1 might be regulated by MALAT1 in liver fibrosis. Therefore, SIRT1 could be considered as a valuable therapeutic target for translational studies of liver fibrosis. - Highlights: • This is the first report of SIRT1 expression and function in liver fibrogenesis and reversion.

  7. Functional proteomic analysis of corticosteroid pharmacodynamics in rat liver: Relationship to hepatic stress, signaling, energy regulation, and drug metabolism.

    Science.gov (United States)

    Ayyar, Vivaswath S; Almon, Richard R; DuBois, Debra C; Sukumaran, Siddharth; Qu, Jun; Jusko, William J

    2017-05-08

    Corticosteroids (CS) are anti-inflammatory agents that cause extensive pharmacogenomic and proteomic changes in multiple tissues. An understanding of the proteome-wide effects of CS in liver and its relationships to altered hepatic and systemic physiology remains incomplete. Here, we report the application of a functional pharmacoproteomic approach to gain integrated insight into the complex nature of CS responses in liver in vivo. An in-depth functional analysis was performed using rich pharmacodynamic (temporal-based) proteomic data measured over 66h in rat liver following a single dose of methylprednisolone (MPL). Data mining identified 451 differentially regulated proteins. These proteins were analyzed on the basis of temporal regulation, cellular localization, and literature-mined functional information. Of the 451 proteins, 378 were clustered into six functional groups based on major clinically-relevant effects of CS in liver. MPL-responsive proteins were highly localized in the mitochondria (20%) and cytosol (24%). Interestingly, several proteins were related to hepatic stress and signaling processes, which appear to be involved in secondary signaling cascades and in protecting the liver from CS-induced oxidative damage. Consistent with known adverse metabolic effects of CS, several rate-controlling enzymes involved in amino acid metabolism, gluconeogenesis, and fatty-acid metabolism were altered by MPL. In addition, proteins involved in the metabolism of endogenous compounds, xenobiotics, and therapeutic drugs including cytochrome P450 and Phase-II enzymes were differentially regulated. Proteins related to the inflammatory acute-phase response were up-regulated in response to MPL. Functionally-similar proteins showed large diversity in their temporal profiles, indicating complex mechanisms of regulation by CS. Clinical use of corticosteroid (CS) therapy is frequent and chronic. However, current knowledge on the proteome-level effects of CS in liver and

  8. Iterative use of nuclear receptor Nr5a2 regulates multiple stages of liver and pancreas development

    Science.gov (United States)

    Nissim, Sahar; Weeks, Olivia; Talbot, Jared C.; Hedgepeth, John W.; Wucherpfennig, Julia; Schatzman-Bone, Stephanie; Swinburne, Ian; Cortes, Mauricio; Alexa, Kristen; Megason, Sean; North, Trista E.; Amacher, Sharon L.; Goessling, Wolfram

    2016-01-01

    The stepwise progression of common endoderm progenitors into differentiated liver and pancreas organs is regulated by a dynamic array of signals that are not well understood. The nuclear receptor subfamily 5, group A, member 2 gene nr5a2, also known as Liver receptor homolog-1 (Lrh-1) is expressed in several tissues including the developing liver and pancreas. Here, we interrogate the role of Nr5a2 at multiple developmental stages using genetic and chemical approaches and uncover novel pleiotropic requirements during zebrafish liver and pancreas development. Zygotic loss of nr5a2 in a targeted genetic null mutant disrupted the development of the exocrine pancreas and liver, while leaving the endocrine pancreas intact. Loss of nr5a2 abrogated exocrine pancreas markers such as trypsin, while pancreas progenitors marked by ptf1a or pdx1 remained unaffected, suggesting a role for Nr5a2 in regulating pancreatic acinar cell differentiation. In the developing liver, Nr5a2 regulates hepatic progenitor outgrowth and differentiation, as nr5a2 mutants exhibited reduced hepatoblast markers hnf4α and prox1 as well as differentiated hepatocyte marker fabp10a. Through the first in vivo use of Nr5a2 chemical antagonist Cpd3, the iterative requirement for Nr5a2 for exocrine pancreas and liver differentiation was temporally elucidated: chemical inhibition of Nr5a2 function during hepatopancreas progenitor specification was sufficient to disrupt exocrine pancreas formation and enhance the size of the embryonic liver, suggesting that Nr5a2 regulates hepatic versus pancreatic progenitor fate choice. Chemical inhibition of Nr5a2 at a later time during pancreas and liver differentiation was sufficient to block the formation of mature acinar cells and hepatocytes. These findings define critical iterative and pleiotropic roles for Nr5a2 at distinct stages of pancreas and liver organogenesis, and provide novel perspectives for interpreting the role of Nr5a2 in disease. PMID:27474396

  9. Med1 subunit of the mediator complex in nuclear receptor-regulated energy metabolism, liver regeneration, and hepatocarcinogenesis.

    Science.gov (United States)

    Jia, Yuzhi; Viswakarma, Navin; Reddy, Janardan K

    2014-01-01

    Several nuclear receptors regulate diverse metabolic functions that impact on critical biological processes, such as development, differentiation, cellular regeneration, and neoplastic conversion. In the liver, some members of the nuclear receptor family, such as peroxisome proliferator-activated receptors (PPARs), constitutive androstane receptor (CAR), farnesoid X receptor (FXR), liver X receptor (LXR), pregnane X receptor (PXR), glucocorticoid receptor (GR), and others, regulate energy homeostasis, the formation and excretion of bile acids, and detoxification of xenobiotics. Excess energy burning resulting from increases in fatty acid oxidation systems in liver generates reactive oxygen species, and the resulting oxidative damage influences liver regeneration and liver tumor development. These nuclear receptors are important sensors of exogenous activators as well as receptor-specific endogenous ligands. In this regard, gene knockout mouse models revealed that some lipid-metabolizing enzymes generate PPARα-activating ligands, while others such as ACOX1 (fatty acyl-CoA oxidase1) inactivate these endogenous PPARα activators. In the absence of ACOX1, the unmetabolized ACOX1 substrates cause sustained activation of PPARα, and the resulting increase in energy burning leads to hepatocarcinogenesis. Ligand-activated nuclear receptors recruit the multisubunit Mediator complex for RNA polymerase II-dependent gene transcription. Evidence indicates that the Med1 subunit of the Mediator is essential for PPARα, PPARγ, CAR, and GR signaling in liver. Med1 null hepatocytes fail to respond to PPARα activators in that these cells do not show induction of peroxisome proliferation and increases in fatty acid oxidation enzymes. Med1-deficient hepatocytes show no increase in cell proliferation and do not give rise to liver tumors. Identification of nuclear receptor-specific coactivators and Mediator subunits should further our understanding of the complexities of metabolic

  10. Increased Tim-3 expression alleviates liver injury by regulating macrophage activation in MCD-induced NASH mice.

    Science.gov (United States)

    Du, Xianhong; Wu, Zhuanchang; Xu, Yong; Liu, Yuan; Liu, Wen; Wang, Tixiao; Li, Chunyang; Zhang, Cuijuan; Yi, Fan; Gao, Lifen; Liang, Xiaohong; Ma, Chunhong

    2018-05-07

    As an immune checkpoint, Tim-3 plays roles in the regulation of both adaptive and innate immune cells including macrophages and is greatly involved in chronic liver diseases. However, the precise roles of Tim-3 in nonalcoholic steatohepatitis (NASH) remain unstated. In the current study, we analyzed Tim-3 expression on different subpopulations of liver macrophages and further investigated the potential roles of Tim-3 on hepatic macrophages in methionine and choline-deficient diet (MCD)-induced NASH mice. The results of flow cytometry demonstrated the significantly increased expression of Tim-3 on all detected liver macrophage subsets in MCD mice, including F4/80 + CD11b + , F4/80 + CD68 + , and F4/80 + CD169 + macrophages. Remarkably, Tim-3 knockout (KO) significantly accelerated MCD-induced liver steatosis, displaying higher serum ALT, larger hepatic vacuolation, more liver lipid deposition, and more severe liver fibrosis. Moreover, compared with wild-type C57BL/6 mice, Tim-3 KO MCD mice demonstrated an enhanced expression of NOX2, NLRP3, and caspase-1 p20 together with increased generation of IL-1β and IL-18 in livers. In vitro studies demonstrated that Tim-3 negatively regulated the production of reactive oxygen species (ROS) and related downstream pro-inflammatory cytokine secretion of IL-1β and IL-18 in macrophages. Exogenous administration of N-Acetyl-L-cysteine (NAC), a small molecular inhibitor of ROS, remarkably suppressed caspase-1 p20 expression and IL-1β and IL-18 production in livers of Tim-3 KO mice, thus significantly reducing the severity of steatohepatitis induced by MCD. In conclusion, Tim-3 is a promising protector in MCD-induced steatohepatitis by controlling ROS and the associated pro-inflammatory cytokine production in macrophages.

  11. Lipoprotein lipase: genetics, lipid uptake, and regulation.

    Science.gov (United States)

    Merkel, Martin; Eckel, Robert H; Goldberg, Ira J

    2002-12-01

    Lipoprotein lipase (LPL) regulates the plasma levels of triglyceride and HDL. Three aspects are reviewed. 1) Clinical implications of human LPL gene variations: common mutations and their effects on plasma lipids and coronary heart disease are discussed. 2) LPL actions in the nervous system, liver, and heart: the discussion focuses on LPL and tissue lipid uptake. 3) LPL gene regulation: the LPL promoter and its regulatory elements are described.

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  13. What Are High Blood Cholesterol and Triglycerides?

    Science.gov (United States)

    ... Reduction Cholesterol What Are High Blood Cholesterol and Triglycerides? Cholesterol travels to the body’s cells through the ... doctor about medicines that can help. What are triglycerides? Triglycerides are the most common type of fat ...

  14. Obstructive Sleep Apnea and Non-alcoholic Fatty Liver Disease: Is the Liver Another Target?

    Directory of Open Access Journals (Sweden)

    Aibek eMirrakhimov

    2012-10-01

    Full Text Available Obstructive sleep apnea (OSA is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH. OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD. NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH, liver fibrosis and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure (CPAP treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1 IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA flux into the liver; (2 IH up-regulates lipid biosynthetic pathways in the liver; (3 IH induces oxidative stress in the liver; (4 IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

  15. Farnesoid X receptor up-regulates expression of Lipid transfer inhibitor protein in liver cells and mice

    Energy Technology Data Exchange (ETDEWEB)

    Li, Liangpeng [Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038 (China); Liu, Hong [Department of Hematology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037 (China); Peng, Jiahe; Wang, Yongchao; Zhang, Yan; Dong, Jinyu; Liu, Xiaohua; Guo, Dongmei [Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038 (China); Jiang, Yu, E-mail: yujiang61@gmail.com [Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Third Military Medical University, Chongqing 400038 (China)

    2013-11-29

    Highlights: •FXR up-regulates apoF. •It binds to ER1 element. •It activates apoF gene promoter. -- Abstract: Apolipoprotein F is a component protein mainly secreted by liver and resides on several lipoprotein classes. It can inhibit lipids transfer between different lipoproteins. FXR is a member of the nuclear receptor superfamily which is also highly expressed in the liver. It modulates bile acids synthesis and lipids metabolism by transcriptional regulation. We aimed to determine whether apoF can be regulated by FXR. The FXR agonist Chenodeoxycholic acid (CDCA) and GW4064 both can activate the expression of apoF in liver cell lines and in C57/BL6 mouse liver. This is dependent on the binding of FXR to the FXR element ER1 (−2904 to −2892 bp) in the apoF gene promoter. Taken together, we have identified apoF as likely another target gene of FXR.

  16. Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

    Energy Technology Data Exchange (ETDEWEB)

    Last, Jerold A [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Gohil, Kishorchandra [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Mathrani, Vivek C [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States); Kenyon, Nicholas J [Pulmonary and Critical Care Medicine, School of Medicine, Toxic Substances Program, 1131 Surge I, University of California, Davis, CA 95616-8723 (United States)

    2005-10-15

    Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-{kappa}B in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone.

  17. Systemic responses to inhaled ozone in mice: cachexia and down-regulation of liver xenobiotic metabolizing genes

    International Nuclear Information System (INIS)

    Last, Jerold A.; Gohil, Kishorchandra; Mathrani, Vivek C.; Kenyon, Nicholas J.

    2005-01-01

    Rats or mice acutely exposed to high concentrations of ozone show an immediate and significant weight loss, even when allowed free access to food and water. The mechanisms underlying this systemic response to ozone have not been previously elucidated. We have applied the technique of global gene expression analysis to the livers of C57BL mice acutely exposed to ozone. Mice lost up to 14% of their original body weight, with a 42% decrease in total food consumption. We previously had found significant up-regulation of genes encoding proliferative enzymes, proteins related to acute phase reactions and cytoskeletal functions, and other biomarkers of a cachexia-like inflammatory state in lungs of mice exposed to ozone. These results are consistent with a general up-regulation of different gene families responsive to NF-κB in the lungs of the exposed mice. In the present study, we observed significant down-regulation of different families of mRNAs in the livers of the exposed mice, including genes related to lipid and fatty acid metabolism, and to carbohydrate metabolism in this tissue, consistent with a systemic cachexic response. Several interferon-dependent genes were down-regulated in the liver, suggesting a possible role for interferon as a signaling molecule between lung and liver. In addition, transcription of several mRNAs encoding enzymes of xenobiotic metabolism in the livers of mice exposed to ozone was decreased, suggesting cytokine-mediated suppression of cytochrome P450 expression. This finding may explain a previously controversial report from other investigators more than 20 years ago of prolongation of pentobarbital sleeping time in mice exposed to ozone

  18. Zhx2 and Zbtb20: Novel regulators of postnatal alpha-fetoprotein repression and their potential role in gene reactivation during liver cancer

    Science.gov (United States)

    Peterson, Martha L.; Ma, Chunhong; Spear, Brett T.

    2012-01-01

    The mouse alpha-fetoprotein (AFP) gene is abundantly expressed in the fetal liver, normally silent in the adult liver but is frequently reactivated in hepatocellular carcinoma. The basis for AFP expression in the fetal liver has been studied extensively. However, the basis for AFP reactivation during hepatocarcinogenesis is not well understood. Two novel factors that control postnatal AFP repression, Zhx2 and Zbtb20, were recently identified. Here, we review the transcription factors that regulate AFP in the fetal liver, as well as Zhx2 and Zbtb20, and raise the possibility that the loss of these postnatal repressors may be involved in AFP reactivation in liver cancer. PMID:21216289

  19. Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver

    Energy Technology Data Exchange (ETDEWEB)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Mostovich, Lyudmila A. [The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117 (Russian Federation); Pustylnyak, Yuliya A. [Novosibirsk State University, Pirogova str., 2, Novosibirsk 630090 (Russian Federation); Pustylnyak, Vladimir O., E-mail: pustylnyak@ngs.ru [The Institute of Molecular Biology and Biophysics, Timakova str., 2/12, Novosibirsk 630117 (Russian Federation); Novosibirsk State University, Pirogova str., 2, Novosibirsk 630090 (Russian Federation); The Institute International Tomography Center of the Russian Academy of Sciences, Institutskaya str. 3-A, Novosibirsk 630090 (Russian Federation)

    2015-10-01

    MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α–CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α–CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. - Highlights: • CAR activation decreased the level of miR-122 in mouse livers. • CAR decreases

  20. Xenosensor CAR mediates down-regulation of miR-122 and up-regulation of miR-122 targets in the liver

    International Nuclear Information System (INIS)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Mostovich, Lyudmila A.; Pustylnyak, Yuliya A.; Pustylnyak, Vladimir O.

    2015-01-01

    MiR-122 is a major hepatic microRNA, accounting for more than 70% of the total liver miRNA population. It has been shown that miR-122 is associated with liver diseases, including hepatocellular carcinoma. Mir-122 is an intergenic miRNA with its own promoter. Pri-miR-122 expression is regulated by liver-enriched transcription factors, mainly by HNF4α, which mediates the expression via the interaction with a specific DR1 site. It has been shown that phenobarbital-mediated activation of constitutive androstane receptor (CAR), xenobiotic nuclear receptor, is associated with a decrease in miR-122 in the liver. In the present study, we investigated HNF4α–CAR cross-talk in the regulation of miR-122 levels and promitogenic signalling in mouse livers. The level of miR-122 was significantly repressed by treatment with 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP), which is an agonist of mouse CAR. ChIP assays demonstrated that TCPOBOP-activated CAR inhibited HNF4α transactivation by competing with HNF4α for binding to the DR1 site in the pri-miR-122 promoter. Such transcription factor replacement was strongly correlated with miR-122 down-regulation. Additionally, the decrease in miR-122 levels produced by CAR activation is accompanied by an increase in mRNA and cellular protein levels of E2f1 and its accumulation on the target cMyc gene promoter. The increase in accumulation of E2f1 on the target cMyc gene promoter is accompanied by an increase in cMyc levels and transcriptional activity. Thus, our results provide evidence to support the conclusion that CAR activation decreases miR-122 levels through suppression of HNF4α transcriptional activity and indirectly regulates the promitogenic protein cMyc. HNF4α–CAR cross-talk may provide new opportunities for understanding liver diseases and developing more effective therapeutic approaches to better drug treatments. - Highlights: • CAR activation decreased the level of miR-122 in mouse livers. • CAR decreases

  1. UPF2 is a critical regulator of liver development, function and regeneration

    DEFF Research Database (Denmark)

    Thoren, Lina A; Nørgaard, Gitte A; Weischenfeldt, Joachim

    2010-01-01

    regulatory potential of the NMD pathway in mammals will require the functional assessment of NMD in different tissues. METHODOLOGY/PRINCIPAL FINDINGS: Here we use mouse genetics to address the role of UPF2, a core NMD component, in the development, function and regeneration of the liver. We find that loss....... CONCLUSION/SIGNIFICANCE: Collectively, our data demonstrate the critical role of the NMD pathway in liver development, function and regeneration and highlights the importance of NMD for mammalian biology....... of NMD during fetal liver development is incompatible with postnatal life due to failure of terminal differentiation. Moreover, deletion of Upf2 in the adult liver results in hepatosteatosis and disruption of liver homeostasis. Finally, NMD was found to be absolutely required for liver regeneration...

  2. Regulation of fatty acid composition and lipid storage by thyroid hormone in mouse liver

    OpenAIRE

    Yao, Xuan; Hou, Sarina; Zhang, Duo; Xia, Hongfeng; Wang, Yu-Cheng; Jiang, Jingjing; Yin, Huiyong; Ying, Hao

    2014-01-01

    Background Thyroid hormones (THs) are potent hormones modulating liver lipid homeostasis. The perturbation of lipid homeostasis is a hallmark of non-alcoholic fatty liver disease (NAFLD), a very common liver disorder. It was reported that NAFLD patients were associated with higher incidence of hypothyroidism. However, whether abnormal thyroid function contributes to the pathogenesis of NAFLD remains unclear. Results We used in vivo models to investigate the influence of hypothyroidism and TH ...

  3. TMG-123, a novel glucokinase activator, exerts durable effects on hyperglycemia without increasing triglyceride in diabetic animal models.

    Science.gov (United States)

    Tsumura, Yoshinori; Tsushima, Yu; Tamura, Azusa; Hasebe, Makiko; Kanou, Masanobu; Kato, Hirotsugu; Kobayashi, Tsunefumi

    2017-01-01

    Glucokinase (GK) plays a critical role for maintaining glucose homeostasis with regulating glucose uptake in liver and insulin secretion in pancreas. GK activators have been reported to decrease blood glucose levels in patients with type 2 diabetes mellitus. However, clinical development of GK activators has failed due to the loss of glucose-lowering effects and increased plasma triglyceride levels after chronic treatment. Here, we generated a novel GK activator, TMG-123, examined its in vitro and in vivo pharmacological characteristics, and evaluated its risks of aforementioned clinical issues. TMG-123 selectively activated GK enzyme activity without increasing Vmax. TMG-123 improved glucose tolerance without increasing plasma insulin levels in both insulin-deficient (Goto-Kakizaki rats) and insulin-resistant (db/db mice) models. The beneficial effect on glucose tolerance was greater than results observed with clinically available antidiabetic drugs such as metformin and glibenclamide in Zucker Diabetic Fatty rats. TMG-123 also improved glucose tolerance in combination with metformin. After 4 weeks of administration, TMG-123 reduced the Hemoglobin A1c levels without affecting liver and plasma triglyceride levels in Goto-Kakizaki rats and Diet-Induced Obesity mice. Moreover, TMG-123 sustained its effect on Hemoglobin A1c levels even after 24 weeks of administration without affecting triglycerides. Taken together, these data indicate that TMG-123 exerts glucose-lowering effects in both insulin-deficient and -resistant diabetes, and sustains reduced Hemoglobin A1c levels without affecting hepatic and plasma triglycerides even after chronic treatment. Therefore, TMG-123 is expected to be an antidiabetic drug that overcomes the concerns previously reported with other GK activators.

  4. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Q. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China); Wang, L.X. [Department of Pharmacology, School of Medicine, Shandong University, Jinan (China); Zeng, J.P. [Department of Biochemistry, School of Medicine, Shandong University, Jinan (China); Liu, X.J.; Liang, X.M.; Zhou, Y.B. [Department of Microbiology, Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, School of Medicine, Shandong University, Jinan (China)

    2013-09-06

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis.

  5. Histone demethylase retinoblastoma binding protein 2 regulates the expression of α-smooth muscle actin and vimentin in cirrhotic livers

    International Nuclear Information System (INIS)

    Wang, Q.; Wang, L.X.; Zeng, J.P.; Liu, X.J.; Liang, X.M.; Zhou, Y.B.

    2013-01-01

    Liver cirrhosis is one of the most common diseases of Chinese patients. Herein, we report the high expression of a newly identified histone 3 lysine 4 demethylase, retinoblastoma binding protein 2 (RBP2), and its role in liver cirrhosis in humans. The siRNA knockdown of RBP2 expression in hepatic stellate cells (HSCs) reduced levels of α-smooth muscle actin (α-SMA) and vimentin and decreased the proliferation of HSCs; and overexpression of RBP2 increased α-SMA and vimentin levels. Treatment with transforming growth factor β (TGF-β) upregulated the expression of RBP2, α-SMA, and vimentin, and the siRNA knockdown of RBP2 expression attenuated TGF-β-mediated upregulation of α-SMA and vimentin expression and HSC proliferation. Furthermore, RBP2 was highly expressed in cirrhotic rat livers. Therefore, RBP2 may participate in the pathogenesis of liver cirrhosis by regulating the expression of α-SMA and vimentin. RBP2 may be a useful marker for the diagnosis and treatment of liver cirrhosis

  6. Kinetic and Related Determinants of Plasma Triglyceride Concentration in Abdominal Obesity: Multicenter Tracer Kinetic Study.

    Science.gov (United States)

    Borén, Jan; Watts, Gerald F; Adiels, Martin; Söderlund, Sanni; Chan, Dick C; Hakkarainen, Antti; Lundbom, Nina; Matikainen, Niina; Kahri, Juhani; Vergès, Bruno; Barrett, P Hugh R; Taskinen, Marja-Riitta

    2015-10-01

    Patients with obesity and diabetes mellitus have increased risk of cardiovascular disease. A major cause is an atherogenic dyslipidemia related primarily to elevated plasma concentrations of triglyceride-rich lipoproteins. The aim of this study was to clarify determinants of plasma triglyceride concentration. We focused on factors that predict the kinetics of very-low density lipoprotein 1 (VLDL1) triglycerides. A multicenter study using dual stable isotopes (deuterated leucine and glycerol) and multicompartmental modeling was performed to elucidate the kinetics of triglycerides and apoB in VLDL1 in 46 subjects with abdominal obesity and additional cardiometabolic risk factors. Results showed that plasma triglyceride concentrations were dependent on both the secretion rate (r=0.44, Ptriglycerides and VLDL1-apoB. Liver fat mass was independently and directly associated with secretion rates of VLDL1-triglycerides (r=0.56, Ptriglycerides (r=0.48, Ptriglyceride concentrations in abdominal obesity are determined by the kinetics of VLDL1 subspecies, catabolism being mainly dependent on apoC-III concentration and secretion on liver fat content. Reduction in liver fat and targeting apoC-III may be an effective approach for correcting triglyceride metabolism atherogenic dyslipidemia in obesity. © 2015 American Heart Association, Inc.

  7. Zonation of heme synthesis enzymes in mouse liver and their regulation by β-catenin and Ha-ras.

    Science.gov (United States)

    Braeuning, Albert; Schwarz, Michael

    2010-11-01

    Cytochrome P450 (CYP) hemoproteins play an important role in hepatic biotransformation. Recently, β-catenin and Ha-ras signaling have been identified as players controlling transcription of various CYP genes in mouse liver. The aim of the present study was to analyze the role of β-catenin and Ha-ras in the regulation of heme synthesis. Heme synthesis-related gene expression was analyzed in normal liver, in transgenic mice expressing activated β-catenin or Ha-ras, and in hepatomas. Regulation of the aminolevulinate dehydratase promoter was studied in vitro. Elevated expression of mRNAs and proteins involved in heme biosynthesis was linked to β-catenin activation in perivenous hepatocytes, in transgenic hepatocytes, and in hepatocellular tumors. Stimulation of the aminolevulinate dehydratase promoter by β-catenin was independent of the β-catenin/T-cell-specific transcription factor dimer. By contrast, activation of Ha-ras repressed heme synthesis-related gene expression. The present data suggest that β-catenin enhances the expression of both CYPs and heme synthesis-related genes, thus coordinating the availability of CYP apoprotein and its prosthetic group heme. The reciprocal regulation of heme synthesis by β-catenin and Ha-ras-dependent signaling supports our previous hypothesis that antagonistic action of these pathways plays a major role in the control of zonal gene expression in healthy mouse liver and aberrant expression patterns in hepatocellular tumors.

  8. Recent Progress on Liver Kinase B1 (LKB1: Expression, Regulation, Downstream Signaling and Cancer Suppressive Function

    Directory of Open Access Journals (Sweden)

    Ren-You Gan

    2014-09-01

    Full Text Available Liver kinase B1 (LKB1, known as a serine/threonine kinase, has been identified as a critical cancer suppressor in many cancer cells. It is a master upstream kinase of 13 AMP-activated protein kinase (AMPK-related protein kinases, and possesses versatile biological functions. LKB1 gene is mutated in many cancers, and its protein can form different protein complexes with different cellular localizations in various cell types. The expression of LKB1 can be regulated through epigenetic modification, transcriptional regulation and post-translational modification. LKB1 dowcnstream pathways mainly include AMPK, microtubule affinity regulating kinase (MARK, salt-inducible kinase (SIK, sucrose non-fermenting protein-related kinase (SNRK and brain selective kinase (BRSK signalings, etc. This review, therefore, mainly discusses recent studies about the expression, regulation, downstream signaling and cancer suppressive function of LKB1, which can be helpful for better understanding of this molecular and its significance in cancers.

  9. The effect of increasing levels of fish oil-containing structured triglycerides on protein metabolism in parenterally fed rats stressed by burn plus endotoxin.

    Science.gov (United States)

    Gollaher, C J; Fechner, K; Karlstad, M; Babayan, V K; Bistrian, B R

    1993-01-01

    This report investigates the effect of various levels of medium-chain/fish oil structured triglycerides on protein and energy metabolism in hypermetabolic rats. Male Sprague-Dawley rats (192 to 226 g) were continuously infused with isovolemic diets that provided 200 kcal/kg per day and 2 g of amino acid nitrogen per kilogram per day. The percentage of nonnitrogen calories as structured triglyceride was varied: no fat, 5%, 15%, or 30%. A 30% long-chain triglyceride diet was also provided as a control to compare the protein-sparing abilities of these two types of fat. Nitrogen excretion, plasma albumin, plasma triglycerides, and whole-body and liver and muscle protein kinetics were determined after 3 days of feeding. Whole-body protein breakdown, flux, and oxidation were similar in all groups. The 15% structured triglyceride diet maximized whole-body protein synthesis (p structured triglyceride (p triglycerides were markedly elevated in the 30% structured triglyceride-fed rats. The 30% structured triglyceride diet maintained plasma albumin levels better than those diets containing no fat, 5% medium-chain triglyceride/fish oil structured triglyceride, or 30% long-chain triglycerides. Nitrogen excretion was lower in animals receiving 30% of nonnitrogen calories as a structured triglyceride than in those receiving 30% as long-chain triglycerides, but this difference did not reach statistical significance (p = .1). These data suggest that protein metabolism is optimized when structured triglyceride is provided at relatively low dietary fat intakes.

  10. Novel polymeric materials from triglycerides

    Science.gov (United States)

    Triglycerides are good platforms for new polymeric products that can substitute for petroleum-based materials. As part of our research emphasis in sustainability and green polymer chemistry, we have explored a number of reactions in efforts to produce a wide range of value-added products. In this ...

  11. Liver X receptor α and farnesoid X receptor are major transcriptional regulators of OATP1B1.

    Science.gov (United States)

    Meyer Zu Schwabedissen, Henriette E; Böttcher, Kerstin; Chaudhry, Amarjit; Kroemer, Heyo K; Schuetz, Erin G; Kim, Richard B

    2010-11-01

    Organic anion transporting polypeptide 1B1 (OATP1B1) is a liver-enriched transporter involved in the hepatocellular uptake of many endogenous molecules and several structurally divergent drugs in clinical use. Although OATP1B1 coding region polymorphisms are known to make an impact on substrate drug disposition in humans, little is known regarding the mechanisms underlying the transcriptional regulation of this transporter. In this study, we note that messenger RNA (mRNA) expression of OATP1B1 in a large human liver bank exhibited marked interindividual variability that was not associated with coding region polymorphisms. Accordingly, we hypothesized that such variability in expression is reflective of nuclear receptor-mediated transcriptional regulation of this transporter. We tested prototypical ligands for the nuclear receptors pregnane X receptor (PXR), constitutive androstane receptor (CAR), liver X receptor (LXR) α, and farnesoid X receptor (FXR) in a human hepatoma-derived cell line and noted induction of OATP1B1 mRNA when the cells were treated with LXRα or FXR ligands. To confirm a direct role for LXRα and FXR to OATP1B1 expression, we performed detailed promoter analysis and cell-based reporter gene assays resulting in the identification of two functional FXR response elements and one LXRα response element. The direct interaction between nuclear receptors with the identified response elements was assessed using chromatin immunoprecipitation assays. Using isolated primary human hepatocytes, we show that LXRα or FXR agonists, but not PXR or CAR agonists, are capable of OATP1B1 induction. We note that OATP1B1 transcriptional regulation is under dual nuclear receptor control through the oxysterol sensing LXRα and the bile acid sensor FXR. Accordingly, the interplay between OATP1B1 and nuclear receptors may play an important and heretofore unrecognized role during cholestasis, drug-induced liver injury, and OATP1B1 induction-related drug interactions.

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

    Science.gov (United States)

    Kim, Kang Ho; Moore, David D

    2017-01-01

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

  13. Skeletal Muscle and Liver Lipidomics and the Regulation of FAT/CD36

    DEFF Research Database (Denmark)

    Jordy, Andreas Børsting

    induced obesity in mice, we observed an increased muscle and liver lipid content, analyzed by mass spectrometry, concomitant with decreased glucose tolerance. We observed that treadmill exercise-training in high-fat fed mice resulted in a reduction in the lipid content in the liver, but not in muscle...... that the current worldwide obesity epidemic has resulted in the increased prevalence of “metabolic disease clusters”, including type 2 diabetes, fatty liver disease and dyslipidemia. Excessive plasma lipids can result in the accumulation of lipid metabolites at ectopic sites including skeletal muscle and liver...... during isolated muscle contractions. On the contrary, previous observations suggest that a permanent relocation of FAT/CD36 protein to the sarcolemma induces intracellular lipid accumulation, resulting in insulin resistance. Therefore, FAT/CD36 has been linked to insulin resistance. Whether increased FAT...

  14. Interplay between FGF21 and insulin action in the liver regulates metabolism

    DEFF Research Database (Denmark)

    Emanuelli, Brice; Vienberg, Sara G; Smyth, Graham

    2014-01-01

    gluconeogenesis in these animals. Improvements in blood sugar were due in part to increased glucose uptake in brown fat, browning of white fat, and overall increased energy expenditure. These effects were preserved even after removal of the main interscapular brown fat pad. In contrast to its retained effects...... of insulin action in the liver by increasing energy metabolism via activation of brown fat and browning of white fat, but intact liver insulin action is required for FGF21 to control hepatic lipid metabolism....

  15. Cell volume regulation in the perfused liver of a freshwater air ...

    Indian Academy of Sciences (India)

    Madhu

    that hypo- and hyper-osmolarity caused transient efflux (5.68 ± 0.38 µmol/g liver) and uptake (6.38 ± 0.45 µmol/g liver) of taurine ... flowing, stagnant and polluted water bodies of ponds, lakes ... dehydration arising out of such extreme environmental situations. Thus ... of 28 ± 2ºC in plastic aquaria with 12 h:12 h light and.

  16. Regulation of low-density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase expression by Zingiber officinale in the liver of high-fat diet-fed rats.

    Science.gov (United States)

    Nammi, Srinivas; Kim, Moon S; Gavande, Navnath S; Li, George Q; Roufogalis, Basil D

    2010-05-01

    Zingiber officinale has been used to control lipid disorders and reported to possess remarkable cholesterol-lowering activity in experimental hyperlipidaemia. In the present study, the effect of a characterized and standardized extract of Zingiber officinale on the hepatic lipid levels as well as on the hepatic mRNA and protein expression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase was investigated in a high-fat diet-fed rat model. Rats were treated with an ethanol extract of Zingiber officinale (400 mg/kg) extract along with a high-fat diet for 6 weeks. The extract of Zingiber officinale significantly decreased hepatic triglyceride and tended to decrease hepatic cholesterol levels when administered over 6 weeks to the rats fed a high-fat diet. We found that in parallel, the extract up-regulated both LDL receptor mRNA and protein level and down-regulated HMG-CoA reductase protein expression in the liver of these rats. The metabolic control of body lipid homeostasis is in part due to enhanced cholesterol biosynthesis and reduced expression of LDL receptor sites following long-term consumption of high-fat diets. The present results show restoration of transcriptional and post-transcriptional changes in low-density lipoprotein and HMG CoA reductase by Zingiber officinale administration with a high-fat diet and provide a rational explanation for the effect of ginger in the treatment of hyperlipidaemia.

  17. Transition of Plasmodium sporozoites into liver stage-like forms is regulated by the RNA binding protein Pumilio

    KAUST Repository

    Gomes-Santos, Carina S. S.

    2011-05-19

    Many eukaryotic developmental and cell fate decisions that are effected post-transcriptionally involve RNA binding proteins as regulators of translation of key mRNAs. In malaria parasites (Plasmodium spp.), the development of round, non-motile and replicating exo-erythrocytic liver stage forms from slender, motile and cell-cycle arrested sporozoites is believed to depend on environmental changes experienced during the transmission of the parasite from the mosquito vector to the vertebrate host. Here we identify a Plasmodium member of the RNA binding protein family PUF as a key regulator of this transformation. In the absence of Pumilio-2 (Puf2) sporozoites initiate EEF development inside mosquito salivary glands independently of the normal transmission-associated environmental cues. Puf2- sporozoites exhibit genome-wide transcriptional changes that result in loss of gliding motility, cell traversal ability and reduction in infectivity, and, moreover, trigger metamorphosis typical of early Plasmodium intra-hepatic development. These data demonstrate that Puf2 is a key player in regulating sporozoite developmental control, and imply that transformation of salivary gland-resident sporozoites into liver stage-like parasites is regulated by a post-transcriptional mechanism. 2011 Gomes-Santos et al.

  18. PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Pei-Jie; Cai, Shuang-Peng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun, E-mail: lj@ahmu.edu.cn

    2016-02-01

    Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

  19. PTP1B confers liver fibrosis by regulating the activation of hepatic stellate cells

    International Nuclear Information System (INIS)

    Chen, Pei-Jie; Cai, Shuang-Peng; Yang, Yang; Li, Wan-Xia; Huang, Cheng; Meng, Xiao-Ming; Li, Jun

    2016-01-01

    Liver fibrosis is a reversible wound-healing response to chronic hepatic injuries. Activation of hepatic stellate cells (HSCs) plays a pivotal role in the development of hepatic fibrosis. The currently accepted mechanism for the resolution of liver fibrosis is the apoptosis and inactivation of activated HSCs. Protein tyrosine phosphatase 1B (PTP1B), a prototype of non-receptor protein tyrosine phosphatase, is proved to be a vital modulator in cardiac fibrogenesis. However, the precise role of PTP1B on liver fibrosis and HSC activation is still unclear. Our study showed that the expression of PTP1B was elevated in fibrotic liver but reduced after spontaneous recovery. Moreover, stimulation of HSC-T6 cells with transforming growth factor-β1 (TGF-β1) resulted in a dose/time-dependent increase of PTP1B mRNA and protein. Co-incubation of HSC-T6 cells with PTP1B-siRNA inhibited the cell proliferation and activation induced by TGF-β1. Additionally, both mRNA and protein of PTP1B were dramatically decreased in inactivated HSCs after treated with adipogenic differentiation mixture (MDI). Over-expression of PTP1B hindered the inactivation of HSC-T6 cells induced by MDI. These observations revealed a regulatory role of PTP1B in liver fibrosis and implied PTP1B as a potential therapeutic target. - Highlights: • The expression of PTP1B in the fibrotic livers and recovery livers • The expression of PTP1B in activated and inactivated HSCs • Blockade of PTP1B inhibited the TGF-β1-induced proliferation and activation of HSCs. • Over-expression of PTP1B abolished the inactivation of HSCs induced by MDI.

  20. The role of PTEN in regulation of hepatic macrophages activation and function in progression and reversal of liver fibrosis

    Energy Technology Data Exchange (ETDEWEB)

    Cheng, Yahui; Tian, Yuanyao; Xia, Jialu; Wu, Xiaoqin; Yang, Yang; Li, Xiaofeng; Huang, Cheng; Meng, Xiaoming; Ma, Taotao; Li, Jun, E-mail: lj@ahmu.edu.cn

    2017-02-15

    Activation of Kupffer cells (KCs) plays a pivotal role in the pathogenesis of liver fibrosis. The progression and reversal of CCl{sub 4}-induced mouse liver fibrosis showed a mixed induction of hepatic classical (M1) and alternative (M2) macrophage markers. Although the role of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) in modulating myeloid cell activation has recently been identified, its function in macrophage activation during hepatic fibrosis remains to be fully appreciated. In our study, PTEN expression of KCs was remarkably decreased in CCl{sub 4}-induced mice but increased to a near-normal level in reversed mice. Moreover, PTEN was significantly decreased in IL4-induced RAW 264.7 cells in vitro and lower expression of PTEN was observed in M2 macrophages in vivo. In addition, loss- and gain-of-function studies suggested that PTEN regulates M2 macrophages polarization via activation of PI3K/Akt/STAT6 signaling, but had a limited effect on M1 macrophages polarization in vitro. Additionally, Ly294002, a chemical inhibitor of PI3K/Akt, could dramatically down-regulate the hallmarks of M2 macrophages. In conclusion, PTEN mediates macrophages activation by PI3K/Akt/STAT6 signaling pathway, which provides novel compelling evidences on the potential of PTEN in liver injury and opens new cellular target for the pharmacological therapy of liver fibrosis. - Highlights: • CCl{sub 4} treatment triggered a mixed M1/M2 macrophage phenotype in fibrosis. • Lower expression of PTEN in murine M2 macrophages in vivo and vitro. • PTEN modulates M2 macrophages activation via PI3K/Akt/STAT6 signaling. • Provide a new cellular target modulate macrophage mediated hepatic fibrosis.

  1. Fimasartan Ameliorates Nonalcoholic Fatty Liver Disease through PPARδ Regulation in Hyperlipidemic and Hypertensive Conditions

    Directory of Open Access Journals (Sweden)

    Yong-Jik Lee

    2017-01-01

    Full Text Available To investigate the effects of fimasartan on nonalcoholic fatty liver disease in hyperlipidemic and hypertensive conditions, the levels of biomarkers related to fatty acid metabolism were determined in HepG2 and differentiated 3T3-L1 cells treated by high fatty acid and liver and visceral fat tissue samples of spontaneously hypertensive rats (SHRs given high-fat diet. In HepG2 cells and liver tissues, fimasartan was shown to increase the protein levels of peroxisome proliferator-activated receptor delta (PPARδ, phosphorylated 5′ adenosine monophosphate-activated protein kinase (p-AMPK, phosphorylated acetyl-CoA carboxylase (p-ACC, malonyl-CoA decarboxylase (MCD, medium chain acyl-CoA dehydrogenase (MCAD, and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α, and it led to a decrease in the protein levels of 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSDH1, fatty acid synthase (FAS, and tumor necrosis factor-alpha (TNF-α. Fimasartan decreased lipid contents in HepG2 and differentiated 3T3-L1 cells and liver tissues. In addition, fimasartan increased the adiponectin level in visceral fat tissues. The antiadipogenic effects of fimasartan were offset by PPARδ antagonist (GSK0660. Consequently, fimasartan ameliorates nonalcoholic fatty liver disease mainly through the activation of oxidative metabolism represented by PPARδ-AMPK-PGC-1α pathway.

  2. PPARα agonists up-regulate organic cation transporters in rat liver cells

    International Nuclear Information System (INIS)

    Luci, Sebastian; Geissler, Stefanie; Koenig, Bettina; Koch, Alexander; Stangl, Gabriele I.; Hirche, Frank; Eder, Klaus

    2006-01-01

    It has been shown that clofibrate treatment increases the carnitine concentration in the liver of rats. However, the molecular mechanism is still unknown. In this study, we observed for the first time that treatment of rats with the peroxisome proliferator activated receptor (PPAR)-α agonist clofibrate increases hepatic mRNA concentrations of organic cation transporters (OCTNs)-1 and -2 which act as transporters of carnitine into the cell. In rat hepatoma (Fao) cells, treatment with WY-14,643 also increased the mRNA concentration of OCTN-2. mRNA concentrations of enzymes involved in carnitine biosynthesis were not altered by treatment with the PPARα agonists in livers of rats and in Fao cells. We conclude that PPARα agonists increase carnitine concentrations in livers of rats and cells by an increased uptake of carnitine into the cell but not by an increased carnitine biosynthesis

  3. Triglyceride metabolism in exercising muscle.

    Science.gov (United States)

    Watt, Matthew J; Cheng, Yunsheng

    2017-10-01

    Triglycerides are stored within lipid droplets in skeletal muscle and can be hydrolyzed to produce fatty acids for energy production through β-oxidation and oxidative phosphorylation. While there was some controversy regarding the quantitative importance of intramyocellular triglyceride (IMTG) as a metabolic substrate, recent advances in proton magnetic resonance spectroscopy and confocal microscopy support earlier tracer and biopsy studies demonstrating a substantial contribution of IMTG to energy production, particularly during moderate-intensity endurance exercise. This review provides an update on the understanding of IMTG utilization during exercise, with a focus on describing the key regulatory proteins that control IMTG breakdown and how these proteins respond to acute exercise and in the adaptation to exercise training. This article is part of a Special Issue entitled: Recent Advances in Lipid Droplet Biology edited by Rosalind Coleman and Matthijs Hesselink. Copyright © 2017 Elsevier B.V. All rights reserved.

  4. Triglycerides in the Human Kidney Cortex: Relationship with Body Size

    Science.gov (United States)

    Bobulescu, Ion Alexandru; Lotan, Yair; Zhang, Jianning; Rosenthal, Tara R.; Rogers, John T.; Adams-Huet, Beverley; Sakhaee, Khashayar; Moe, Orson W.

    2014-01-01

    Obesity is associated with increased risk for kidney disease and uric acid nephrolithiasis, but the pathophysiological mechanisms underpinning these associations are incompletely understood. Animal experiments have suggested that renal lipid accumulation and lipotoxicity may play a role, but whether lipid accumulation occurs in humans with increasing body mass index (BMI) is unknown. The association between obesity and abnormal triglyceride accumulation in non-adipose tissues (steatosis) has been described in the liver, heart, skeletal muscle and pancreas, but not in the human kidney. We used a quantitative biochemical assay to quantify triglyceride in normal kidney cortex samples from 54 patients undergoing nephrectomy for localized renal cell carcinoma. In subsets of the study population we evaluated the localization of lipid droplets by Oil Red O staining and measured 16 common ceramide species by mass spectrometry. There was a positive correlation between kidney cortex trigyceride content and BMI (Spearman R = 0.27, P = 0.04). Lipid droplets detectable by optical microscopy had a sporadic distribution but were generally more prevalent in individuals with higher BMI, with predominant localization in proximal tubule cells and to a lesser extent in glomeruli. Total ceramide content was inversely correlated with triglycerides. We postulate that obesity is associated with abnormal triglyceride accumulation (steatosis) in the human kidney. In turn, steatosis and lipotoxicity may contribute to the pathogenesis of obesity-associated kidney disease and nephrolithiasis. PMID:25170827

  5. Hydrotreating of triglyceride containing gasoils

    Energy Technology Data Exchange (ETDEWEB)

    Krar, M.; Kasza, T.; Toth, C.; Baladincz, P.; Hancsok, J. (Univ. of Pannonia, Veszprem (Hungary)), Email: krarm@almos.uni-pannon.hu

    2009-07-01

    Because of the disadvantages of biodiesel, it is necessary to develop transformation methods, where excellent quality gas oil blending components are produced from triglycerides. An especially favourable opportunity could be the combination of the conversion of the triglycerides with a simultaneous upgrading of the gas oil stream. The main goal of our experiments was to investigate the feasibility of these two processes simultaneously in one catalytic system. In our experiments, sunflower oil (max. 25 %) gas oil blends were converted into products with gas oil boiling range. On the investigated catalyst under optimal process parameter combinations, product mixtures in the gas oil boiling point range with yield and excellent quality was produced successfully. The cetane number of the product mixtures were increased by 4-16 units, the CFPP values were increased by 5-7 deg C, when feedstock with 25 % sunflower oil content was used instead of feedstocks containing no sunflower oil. The reason is that the triglycerides were converted into normal paraffins, which are having high cetane number and poor cold-flow properties. It was concluded, that the blending of the sunflower oil into the gas oil did not reduce the HDS and HDA activity of the catalyst, however, its HDN activity significantly decreased. (orig.)

  6. Bone morphogenetic protein-2 is a negative regulator of hepatocyte proliferation downregulated in the regenerating liver

    NARCIS (Netherlands)

    Xu, Cui-Ping; Ji, Wen-Min; van den Brink, Gijs R.; Peppelenbosch, Maikel P.

    2006-01-01

    To characterize the expression and dynamic changes of bone morphogenetic protein (BMP)-2 in hepatocytes in the regenerating liver in rats after partial hepatectomy (PH), and examine the effects of BMP-2 on proliferation of human Huh7 hepatoma cells. Fifty-four adult male Wistar rats were randomly

  7. Bone morphogenetic protein-2 is a negative regulator of hepatocyte proliferation downregulated in the regenerating liver

    NARCIS (Netherlands)

    Xu, Cui-Ping; Ji, Wen-Min; van den Brink, Gijs R.; Peppelenbosch, Maikel P.

    2006-01-01

    AIM: To characterize the expression and dynamic changes of bone morphogenetic protein (BMP)-2 in hepatocytes in the regenerating liver in rats after partial hepatectomy (PH), and examine the effects of BMP-2 on proliferation of human Huh7 hepatoma cells. METHODS: Fifty-four adult male Wistar rats

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

    NARCIS (Netherlands)

    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

  9. p53-Dependent Nestin Regulation Links Tumor Suppression to Cellular Plasticity in Liver Cancer

    DEFF Research Database (Denmark)

    Tschaharganeh, Darjus F; Xue, Wen; Calvisi, Diego F

    2014-01-01

    The p53 tumor suppressor coordinates a series of antiproliferative responses that restrict the expansion of malignant cells, and as a consequence, p53 is lost or mutated in the majority of human cancers. Here, we show that p53 restricts expression of the stem and progenitor-cell-associated protei...... by p53 restricts cellular plasticity and tumorigenesis in liver cancer....

  10. Peroxisome proliferator activated receptor alpha regulates a male-specific cytochrome P450 in mouse liver.

    Science.gov (United States)

    Jeffery, Brett; Choudhury, Agharul I; Horley, Neill; Bruce, Mary; Tomlinson, Simon R; Roberts, Ruth A; Gray, Tim J B; Barrett, David A; Shaw, P Nicholas; Kendall, David; Bell, David R

    2004-09-15

    We set out to find if the strain-specific, male-specific hepatic expression of Cyp4a protein in mouse was due to expression of Cyp4a12 and to understand the genetic basis for reported differences in expression. 12-Lauric acid hydroxylase (LAH) activity was found to show higher levels in male ddY, but not C57Bl/6, mouse liver microsomes. The expression of Cyp4a12 mRNA was studied using RNAase protection assays in male and female liver and kidney of nine mouse strains. Cyp4a12 was found to be highly expressed in male liver and kidney, but at much lower levels in female liver and kidney, in all strains studied. Western blotting with an antibody specific for Cyp4a12 confirmed that Cyp4a12 was expressed in a male specific fashion in C57Bl/6 mouse liver. RNAase protection analysis for Cyp4a10 and 14 in ddY mice revealed that neither of these genes showed male-specific expression. To further investigate genetic factors that control male-specific Cyp4a12 expression, PPARalpha+/+ and -/- mice were studied, showing that total P450 and 12-LAH activity was male-specific in +/+, but not -/- mice. RNAase protection assays were used to confirm that Cyp4a12 was lower in -/- mice. However, the male-specific Slp and MUP-1 genes retained hepatic male-specific levels of expression in +/+ and -/- mice, showing that the decrease in Cyp4a12 was not a general effect on male-specific expression. Thus, PPARalpha has a specific effect on constitutive expression of Cyp4a12.

  11. The Effect of Alcohol on Postprandial and Fasting Triglycerides

    Directory of Open Access Journals (Sweden)

    Albert Van de Wiel

    2012-01-01

    Full Text Available Alcohol has a significant additive effect on the postprandial triglyceride peak when it accompanies a meal containing fat, especially saturated fat. This results from a decrease in the breakdown of chylomicrons and VLDL remnants due to an acute inhibitory effect of alcohol on lipoprotein lipase activity. Furthermore, alcohol increases the synthesis of large VLDL particles in the liver, which is the main source of triglycerides in the hypertriglyceridemia associated with chronic excessive alcohol intake. In case of chronic consumption, lipoprotein lipase activity seems to adapt itself. The effect of alcohol on adipose tissues is less clear. Sometimes, a severe hypertriglyceridemia induced by alcohol (SHIBA can be observed, especially in patients with type 2 diabetes mellitus and/or obesity increasing the risk of pancreatitis.

  12. Regulation of palmitoyl-CoA chain elongation by clofibric acid in the liver of Zucker fa/fa rats.

    Science.gov (United States)

    Toyama, Tomoaki; Kudo, Naomi; Mitsumoto, Atsushi; Kawashima, Yoichi

    2005-05-01

    The regulation of palmitoyl-CoA chain elongation (PCE) by clofibric acid [2-(4-chlorophenoxy)-2-methylpropionic acid] was investigated in comparison with stearoyl-CoA desaturase (SCD) in the liver of obese Zucker fa/fa rats. The proportion of oleic acid in the hepatic lipids of Zucker obese rats is 2.7 times higher than that of lean littermates. The activities of PCE and SCD in the liver of Zucker obese rats were markedly higher than in lean rats, and the hepatic uptake of 2-deoxyglucose (2-DG) was also higher in Zucker obese rats compared with lean rats. The increased activities of SCD and PCE in Zucker obese rats were due to the enhanced expression of mRNA of both SCD1 and rat FA elongase 2 (rELO2), but not SCD2 or rELO1. The proportion of oleic acid in the liver was significantly increased by the administration of clofibric acid to Zucker obese rats, and the hepatic PCE activity and rELO2 mRNA expression, but not the SCD activity or SCD1 mRNA expression, were increased in response to clofibric acid treatment. By contrast, the activities of both PCE and SCD and the mRNA expression of SCD1 and rELO2 in the liver were increased by the treatment of Zucker lean rats with clofibric acid. Multiple regression analysis, which was performed to determine the relationships involving PCE activity, SCD activity, and the proportion of oleic acid, revealed that the three parameters were significantly correlated and that the standardized partial regression coefficient of PCE was higher than that of SCD. These results indicate that oleic acid is synthesized by the concerted action of PCE and SCD and that PCE plays a crucial role in the formation of oleic acid when Zucker fa/fa rats are given clofibric acid.

  13. Vitamin K2-enhanced liver regeneration is associated with oval cell expansion and up-regulation of matrilin-2 expression in 2-AAF/PH rat model.

    Science.gov (United States)

    Lin, M; Sun, P; Zhang, G; Xu, X; Liu, G; Miao, H; Yang, Y; Xu, H; Zhang, L; Wu, P; Li, M

    2014-03-01

    Normal liver has a great potential of regenerative capacity after partial hepatectomy. In clinic, however, most patients receiving partial hepatectomy are usually suffering from chronic liver diseases with severely damaged hepatocyte population. Under these conditions, activation of hepatic progenitor cell (oval cell in rodents) population might be considered as an alternative mean to enhance liver functional recovery. Vitamin K2 has been shown to promote liver functional recovery in patients with liver cirrhosis. In this study, we explored the possibility of vitamin K2 treatment in activating hepatic oval cell for liver regeneration with the classic 2-acetamido-fluorene/partial hepatectomy (2-AAF/PH) model in Sprague-Dawley rats. In 2-AAF/PH animals, vitamin K2 treatment induced a dose-dependent increase of liver regeneration as assessed by the weight ratio of remnant liver versus whole body and by measuring serum albumin level. In parallel, a drastic expansion of oval cell population as assessed by anti-OV6 and anti-CK19 immunostaining was noticed in the periportal zone of the remnant liver. Since matrilin-2 was linked to oval cell proliferation and liver regeneration after partial hepatectomy, we assessed its expression at both the mRNA and protein levels. The results revealed a significant increase after vitamin K2 treatment in parallel with the expansion of oval cell population. Consistently, knocking down matrilin-2 expression in vivo largely reduced vitamin K2-induced liver regeneration and oval cell proliferation in 2-AAF/PH animals. In conclusion, these data suggest that vitamin K2 treatment enhances liver regeneration after partial hepatectomy, which is associated with oval cell expansion and matrilin-2 up-regulation.

  14. Ghrelin Attenuates Liver Fibrosis through Regulation of TGF-β1 Expression and Autophagy

    Directory of Open Access Journals (Sweden)

    Yuqing Mao

    2015-09-01

    Full Text Available Ghrelin is a stomach-derived growth hormone secretagogue that promotes various physiological effects, including energy metabolism and amelioration of inflammation. The purpose of this study was to investigate the protective mechanism of ghrelin against liver fibrosis. Liver fibrosis was induced in C57BL/6 mice by intraperitoneal injection of CCl4 (2.0 mL/kg of 10% CCl4 v/v solution in peanut oil two times per week for eight weeks. Ghrelin (10 μg/kg was intraperitoneally injected two times per week for eight weeks. A second murine liver fibrosis model was induced by bile duct ligation (BDL and concurrent ghrelin administration for four weeks. Hematoxylin eosin (H&E, and Masson’s trichrome were used to detect pathological changes to liver tissue. Western blotting was used to detect protein levels of transforming growth factor (TGF-β1, phosphorylated Smad3 (p-Smad3, I-collage, α-smooth muscle actin (α-SMA, matrix metalloproteinases (MMPs 2, tissue inhibitor of matrix metalloproteinases (TIMPs 1, phosphorylated NF-κB (p-NF-κB, and microtubule-associated protein light chain 3 (LC3. In addition, qRT-PCR was used to detect mRNA levels of TGF-β1, I-collage, α-SMA, MMP2, TIMP1 and LC3, while levels of TGF-β1, p-Smad3, I-collage, α-SMA, and LC3 were detected immunohistochemically. Levels of aspartate aminotransferase and alanine aminotransferase were significantly decreased by ghrelin treatment. Ghrelin administration also significantly reduced the extent of pathological changes in both murine liver fibrosis models. Expression levels of I-collage and α-SMA in both models were clearly reduced by ghrelin administration. Furthermore, ghrelin treatment decreased protein expression of TGF-β1 and p-Smad3. The protein levels of NF-κB and LC3 were increased in the CCl4- and BDL-treatment groups but were significantly reduced following ghrelin treatment. In addition, ghrelin inhibited extracellular matrix formation by decreasing NF-κB expression

  15. Distinct Molecular Signature of Murine Fetal Liver and Adult Hematopoietic Stem Cells Identify Novel Regulators of Hematopoietic Stem Cell Function.

    Science.gov (United States)

    Manesia, Javed K; Franch, Monica; Tabas-Madrid, Daniel; Nogales-Cadenas, Ruben; Vanwelden, Thomas; Van Den Bosch, Elisa; Xu, Zhuofei; Pascual-Montano, Alberto; Khurana, Satish; Verfaillie, Catherine M

    2017-04-15

    During ontogeny, fetal liver (FL) acts as a major site for hematopoietic stem cell (HSC) maturation and expansion, whereas HSCs in the adult bone marrow (ABM) are largely quiescent. HSCs in the FL possess faster repopulation capacity as compared with ABM HSCs. However, the molecular mechanism regulating the greater self-renewal potential of FL HSCs has not yet extensively been assessed. Recently, we published RNA sequencing-based gene expression analysis on FL HSCs from 14.5-day mouse embryo (E14.5) in comparison to the ABM HSCs. We reanalyzed these data to identify key transcriptional regulators that play important roles in the expansion of HSCs during development. The comparison of FL E14.5 with ABM HSCs identified more than 1,400 differentially expressed genes. More than 200 genes were shortlisted based on the gene ontology (GO) annotation term "transcription." By morpholino-based knockdown studies in zebrafish, we assessed the function of 18 of these regulators, previously not associated with HSC proliferation. Our studies identified a previously unknown role for tdg, uhrf1, uchl5, and ncoa1 in the emergence of definitive hematopoiesis in zebrafish. In conclusion, we demonstrate that identification of genes involved in transcriptional regulation differentially expressed between expanding FL HSCs and quiescent ABM HSCs, uncovers novel regulators of HSC function.

  16. The Dual Role of Nrf2 in Nonalcoholic Fatty Liver Disease: Regulation of Antioxidant Defenses and Hepatic Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Sílvia S. Chambel

    2015-01-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a progressive liver disease with ever-growing incidence in the industrialized world. It starts with the simple accumulation of lipids in the hepatocyte and can progress to the more severe nonalcoholic steatohepatitis (NASH, which is associated with inflammation, fibrosis, and cirrhosis. There is increasing awareness that reactive oxygen species and electrophiles are implicated in the pathogenesis of NASH. Transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2 is a positive regulator of the expression of a battery of genes involved in the protection against oxidative/electrophilic stress. In rodents, Nrf2 is also known to participate in hepatic fatty acid metabolism, as a negative regulator of genes that promote hepatosteatosis. We review relevant evidence in the literature that these two mechanisms may contribute to the protective role of Nrf2 in the development of hepatic steatosis and in the progression to steatohepatitis, particularly in young animals. We propose that age may be a key to explain contradictory findings in the literature. In summary, Nrf2 mediates the crosstalk between lipid metabolism and antioxidant defense mechanisms in experimental models of NAFLD, and the nutritional or pharmacological induction of Nrf2 represents a promising potential new strategy for its prevention and treatment.

  17. Liver protective effect of ursodeoxycholic acid includes regulation of ADAM17 activity

    Czech Academy of Sciences Publication Activity Database

    Buryová, Halka; Chalupský, Karel; Žbodáková, Olga; Kanchev, Ivan; Jiroušková, Markéta; Gregor, Martin; Sedláček, Radislav

    2013-01-01

    Roč. 13, 30.10.2013 (2013), s. 155-155 ISSN 1471-230X R&D Projects: GA ČR GAP305/10/2143; GA ČR GAP303/10/2044; GA AV ČR IAA500520812; GA MŠk ED1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : ursodeoxycholic acid * ADAM17 * shedding * cholestasis * liver Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.113, year: 2013

  18. Triglyceride-rich lipoprotein metabolism in women: roles of apoC-II and apoC-III.

    Science.gov (United States)

    Ooi, Esther M; Chan, Dick C; Hodson, Leanne; Adiels, Martin; Boren, Jan; Karpe, Fredrik; Fielding, Barbara A; Watts, Gerald F; Barrett, P Hugh R

    2016-08-01

    Experimental data suggest that apolipoprotein (apo) C-II and C-III regulate triglyceride-rich lipoprotein (TRL) metabolism, but there are limited studies in humans. We investigated the metabolic associations of TRLs with apoC-II and apoC-III concentrations and kinetics in women. The kinetics of plasma apoC-II, apoC-III and very low-density lipoprotein (VLDL) apoB-100 and triglycerides were measured in the postabsorptive state using stable isotopic techniques and compartmental modelling in 60 women with wide-ranging body mass index (19·5-32·9 kg/m(2) ). Plasma apoC-II and apoC-III concentrations were positively associated with the concentrations of plasma triglycerides, VLDL1 - and VLDL2 -apoB-100 and triglyceride (all P triglyceride concentration and VLDL1 triglyceride PR, while apoC-II fractional catabolic rate (FCR) was positively associated with VLDL1 triglyceride FCR (all P triglyceride kinetics. ApoC-III PR, but not FCR, was positively associated with VLDL1 triglyceride, and VLDL2 -apoB-100 and triglyceride concentrations (all P triglyceride kinetics. In multivariable analysis, including homoeostasis model assessment score, menopausal status and obesity, apoC-II concentration was significantly associated with plasma triglyceride, VLDL1 -apoB-100 and VLDL1 triglyceride concentrations and PR. Using the same multivariable analysis, apoC-III was significantly associated with plasma triglyceride and VLDL1 - and VLDL2 -apoB-100 and triglyceride concentrations and FCR. In women, plasma apoC-II and apoC-III concentrations are regulated by their respective PR and are significant, independent determinants of the kinetics and plasma concentrations of TRLs. © 2016 Stichting European Society for Clinical Investigation Journal Foundation.

  19. Dual-specificity tyrosine-regulated kinase 2 is a suppressor and potential prognostic marker for liver metastasis of colorectal cancer.

    Science.gov (United States)

    Ito, Daisuke; Yogosawa, Satomi; Mimoto, Rei; Hirooka, Shinichi; Horiuchi, Takashi; Eto, Ken; Yanaga, Katsuhiko; Yoshida, Kiyotsugu

    2017-08-01

    Colorectal cancer is a common cancer and a leading cause of cancer-related death worldwide. The liver is a dominant metastatic site for patients with colorectal cancer. Molecular mechanisms that allow colorectal cancer cells to form liver metastases are largely unknown. Activation of epithelial-mesenchymal transition is the key step for metastasis of cancer cells. We recently reported that dual-specificity tyrosine-regulated kinase 2 (DYRK2) controls epithelial-mesenchymal transition in breast cancer and ovarian serous adenocarcinoma. The aim of this study is to clarify whether DYRK2 regulates liver metastases of colorectal cancer. We show that the ability of cell invasion and migration was abrogated in DYRK2-overexpressing cells. In an in vivo xenograft model, liver metastatic lesions were markedly diminished by ectopic expression of DYRK2. Furthermore, we found that patients whose liver metastases expressed low DYRK2 levels had significantly worse overall and disease-free survival. Given the findings that DYRK2 regulates cancer cell metastasis, we concluded that the expression status of DYRK2 could be a predictive marker for liver metastases of colorectal cancer. © 2017 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

  20. The effects of space flight on some rat liver enzymes regulating carbohydrate and lipid metabolism

    Science.gov (United States)

    Abraham, S.; Lin, C. Y.; Klein, H. P.; Volkmann, C.

    We have examined, in the livers of rats carried aboard the Cosmos 936 biosatellite, the activities of about 30 enzymes concerned with carbohydrate and lipid metabolism. In addition to the enzyme studies, the levels of glycogen and of the individual fatty acids in hepatic lipids were determined. Livers from flight and ground control rats at recovery (R0) and 25 days after recovery (R25) were used for these analyses. For all parameters measured, the most meaningful comparisons are those made between flight stationary (FS) and flight centrifuged (FC) animals at R0. When these two groups of flight rats were compared at R0, statistically significant decreases in the activity levels of glycogen phosphorylase, α-glycerol phosphate acyl transferase, diglyceride acyl transferase, aconitase and 6-phosphogluconate dehydrogenase and an increase in the palmitoyl CoA desaturase were noted in the weightless group (FS). The significance of these findings was strengthened by the fact that all enzyme activities showing alterations at R0 returned to normal 25 days postflight. When liver glycogen and total fatty acids of the two sets of flight animals were determined, significant differences that could be attributed to reduced gravity were observed. The weightless group (FS) at R0 contained, on the average, more than twice the amount of glycogen than did the centrifuged controls (FC) and a remarkable shift in the ratio of palmitate to palmitoleate was noted. These metabolic alterations, both in enzyme levels and in hepatic constituents, appear to be characteristic of the weightless condition. Our data seem to justify the conclusion that centrifugation during flight is equivalent to terrestrial gravity.

  1. Homozygous carriers of the TCF7L2 rs7903146 T-allele show altered postprandial response in triglycerides and triglyceride-rich lipoproteins

    DEFF Research Database (Denmark)

    Engelbrechtsen, L; Hansen, T H; Mahendran, Y

    2017-01-01

    to CC carriers. Additionally, TT carriers had lower postprandial levels of total triglycerides (TG) (q = 0.03), VLDL-TG (q = 0.05, including medium, small and extra small, q = 0.048, q = 0.0009, q = 0.04, respectively), HDL-TG (triglycerides in high density lipoproteins q = 0.037) and S-HDL-TG (q = 0.......00003). In conclusion, TT carriers show altered postprandial triglyceride response, mainly influencing VLDL and HDL subclasses suggesting a genotype-mediated effect on hepatic lipid regulation....

  2. A disintegrin and metalloprotease 10 (ADAM10) is a central regulator of murine liver tissue homeostasis

    Czech Academy of Sciences Publication Activity Database

    Muller, M.; Wetzel, S.; Koehn-Gaone, J.; Chalupský, Karel; Luellmann-Rauch, R.; Barikbin, R.; Bergmann, J.; Woehner, B.; Žbodáková, Olga; Leuschner, I.; Gregor, Martin; Tiegs, G.; Rose-John, S.; Sedláček, Radislav; Tirnitz-Parker, J.E.E.; Saftig, P.; Schmidt-Arras, D.

    2016-01-01

    Roč. 7, č. 14 (2016), s. 17431-17441 ISSN 1949-2553 R&D Projects: GA ČR GAP302/11/2048; GA ČR GAP303/10/2044; GA ČR GA13-01710S; GA ČR GA15-23858S; GA MŠk(CZ) ED1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : ADAM10 * liver progenitor cell * c-Met * Notch * hepatocyte differentiation * Pathology Section Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.168, year: 2016

  3. Liver PPARα and UCP2 are involved in the regulation of obesity and lipid metabolism by swim training in genetically obese db/db mice

    International Nuclear Information System (INIS)

    Oh, Ki Sook; Kim, Mina; Lee, Jinmi; Kim, Min Jeong; Nam, Youn Shin; Ham, Jung Eun; Shin, Soon Shik; Lee, Chung Moo; Yoon, Michung

    2006-01-01

    Swim training for 6 weeks significantly decreased body weight gain, adipose tissue mass, and adipocyte size in both sexes of genetically obese db/db mice compared with their respective sedentary controls. Swim training also caused significant decreases in serum levels of free fatty acids, triglycerides, and total cholesterol in both sexes of obese mice. Concomitantly, hepatic mRNA levels of peroxisome proliferator-activated receptor α (PPARα) target enzymes responsible for mitochondrial and peroxisomal fatty acid β-oxidation were significantly increased by swim training. Moreover, mRNA levels of uncoupling protein 2 (UCP2) in liver were also markedly increased by swim training. In conclusion, these results suggest that swim training-induced transcriptional activation of hepatic PPARα target enzymes and UCP2 may effectively prevent body weight gain, adiposity, and lipid disorders caused by leptin receptor deficiency in both sexes of mice

  4. Regulation of memory - from the adrenal medulla to liver to astrocytes to neurons.

    Science.gov (United States)

    Gold, Paul E

    2014-06-01

    Epinephrine, released into blood from the adrenal medulla in response to arousing experiences, is a potent enhancer of learning and memory processing. This review examines mechanisms by which epinephrine exerts its effects on these cognitive functions. Because epinephrine is largely blocked from moving from blood to brain, it is likely that the hormone's effects on memory are mediated by peripheral actions. A classic effect of epinephrine is to act at the liver to break down glycogen stores, resulting in increased blood glucose levels. The increase in blood glucose provides additional energy substrates to the brain to buttress the processes needed for an experience to be learned and remembered. In part, it appears that the increased glucose may act in the brain in a manner akin to that evident in the liver, engaging glycogenolysis in astrocytes to provide an energy substrate, in this case lactate, to augment neuronal functions. Together, the findings reveal a mechanism underlying modulation of memory that integrates the physiological functions of multiple organ systems to support brain processes. This article is part of a Special Issue entitled 'Memory enhancement'. Copyright © 2014 Elsevier Inc. All rights reserved.

  5. REGULATION OF MEMORY – FROM THE ADRENAL MEDULLA TO LIVER TO ASTROCYTES TO NEURONS1

    Science.gov (United States)

    Gold, Paul E.

    2014-01-01

    Epinephrine, released into blood from the adrenal medulla in response to arousing experiences, is a potent enhancer of learning and memory processing. This review examines mechanisms by which epinephrine exerts its effects on these cognitive functions. Because epinephrine is largely blocked from moving from blood to brain, it is likely that the hormone's effects on memory are mediated by peripheral actions. A classic effect of epinephrine is to act at the liver to break down glycogen stores, resulting in increased blood glucose levels. The increase in blood glucose provides additional energy substrates to the brain to buttress the processes needed for an experience to be learned and remembered. In part, it appears that the increased glucose may act in the brain in a manner akin to that evident in the liver, engaging glycogenolysis in astrocytes to provide an energy substrate, in this case lactate, to augment neuronal functions. Together, the findings reveal a mechanism underlying modulation of memory that integrates the physiological functions of multiple organ systems to support brain processes. PMID:24406469

  6. Regulation of ODC activity in the thymus and liver of rats by adrenal hormones.

    Science.gov (United States)

    Zahner, S L; Prahlad, K V; Mitchell, J L

    1986-01-01

    The activity of L-ornithine decarboxylase (EC 4.1.1.17, ODC) has become a useful indicator of hormone responsiveness. Various regimens of dexamethasone, aldosterone and epinephrine, alone or in combination, were administered to adrenalectomized rats either in acute or chronic doses. In addition, adrenalectomized rats, which were chronically treated with aldosterone and epinephrine, were given a single injection of 50 micrograms dexamethasone and sacrificed at various time intervals after hormone treatment. Hepatic and thymic ODC activity was measured. The expected dexamethasone effect, an increase in hepatic and a decrease in thymic ODC, was observed. This study also revealed that aldosterone induced similar responses in these tissues. Epinephrine had the opposite effect since chronic administration of dexamethasone or aldosterone with epinephrine resulted in control levels of ODC. Furthermore, when aldosterone and epinephrine were chronically administered to adrenalectomized rats, to study the acute effects of dexamethasone on rat thymus and liver, the time course of the response in each tissue was found to be distinct. The influence of the adrenal gland on rat thymus and liver is not restricted only to glucocorticoids, but may also involve other hormones which it secretes.

  7. The liver plays an important role in the regulation of somatostatin-14 in the rat

    International Nuclear Information System (INIS)

    Raper, S.E.; Kothary, P.C.; Kokudo, N.; DelValle, J.; Eckhauser, F.E.

    1991-01-01

    Since little is known about the in vivo disposition of circulating somatostatin-14 (SRIF-14), we examined hepatic processing of SRIF-14 in the rat. Three minutes after the intraportal injection of iodine 125 ( 125 I)-labeled SRIF-14, 16.0 +/- 2.0% of the injected dose is localized to the liver. In the presence of unlabeled SRIF-14, hepatic uptake can be decreased by 68%. Five minutes after the intraportal injection of 125 I-SRIF-14, 9.5 +/- 1.4% of the tracer is localized to the liver, more than any other organ tested. Serial collections of bile reveal peak radioactivity at between 10 and 20 minutes. Simultaneous administration of unlabeled SRIF-14 decreases biliary radioactivity by 40%. HPLC analysis of radioactive bile reveals a chromatographic profile similar to that of intact SRIF and is 73% immunoprecipitable by an anti-SRIF antibody. Pretreatment with chloroquine, a lysosomal enzyme inhibitor, does not significantly decrease biliary radioactivity. We conclude that the data are consistent with saturable hepatic uptake and predominantly nonlysosomal transcellular transport

  8. Modulation of liver mitochondrial NOS is implicated in thyroid-dependent regulation of O(2) uptake.

    Science.gov (United States)

    Carreras, M C; Peralta, J G; Converso, D P; Finocchietto, P V; Rebagliati, I; Zaninovich, A A; Poderoso, J J

    2001-12-01

    Changes in O(2) uptake at different thyroid status have been explained on the basis of the modulation of mitochondrial enzymes and membrane biophysical properties. Regarding the nitric oxide (NO) effects, we tested whether liver mitochondrial nitric oxide synthase (mtNOS) participates in the modulation of O(2) uptake in thyroid disorders. Wistar rats were inoculated with 400 microCi (131)I (hypothyroid group), 20 microg thyroxine (T(4))/100 g body wt administered daily for 2 wk (hyperthyroid group) or vehicle (control). Basal metabolic rate, mitochondrial function, and mtNOS activity were analyzed. Systemic and liver mitochondrial O(2) uptake and cytochrome oxidase activity were lower in hypothyroid rats with respect to controls; mitochondrial parameters were further decreased by L-arginine (-42 and -34%, P activity (260%) were selectively increased in hypothyroidism and reverted by hormone replacement without changes in other nitric oxide isoforms. Moreover, mtNOS activity correlated with serum 3,5,3'-triiodothyronine (T(3)) and O(2) uptake. Increased mtNOS activity was also observed in skeletal muscle mitochondria from hypothyroid rats. Therefore, we suggest that modulation of mtNOS is a substantial part of thyroid effects on mitochondrial O(2) uptake.

  9. Nitro-Oleic Acid Reduces J774A.1 Macrophage Oxidative Status and Triglyceride Mass: Involvement of Paraoxonase2 and Triglyceride Metabolizing Enzymes.

    Science.gov (United States)

    Rosenblat, Mira; Rom, Oren; Volkova, Nina; Aviram, Michael

    2016-08-01

    Nitro-fatty acids possess anti-atherogenic properties, but their effects on macrophage oxidative status and lipid metabolism that play important roles in atherosclerosis development are unclear. This study compared the effects of nitro-oleic acid (OLA-NO2) with those of native oleic acid (OLA) on intracellular reactive oxygen species (ROS) generation, anti-oxidants and metabolism of triglycerides and cholesterol in J774A.1 macrophages. Upon incubating the cells with physiological concentrations of OLA-NO2 (0-1 µM) or with equivalent levels of OLA, ROS levels measured by 2, 7-dichlorofluorescein diacetate, decreased dose-dependently, but the anti-oxidative effects of OLA-NO2 were significantly augmented. Copper ion addition increased ROS generation in OLA treated macrophages without affecting OLA-NO2 treated cells. These effects could be attributed to elevated glutathione levels and to increased activity and expression of paraoxonase2 that were observed in OLA-NO2 vs OLA treated cells. Beneficial effects on triglyceride metabolism were noted in OLA-NO2 vs OLA treated macrophages in which cellular triglycerides were reduced due to attenuated biosynthesis and accelerated hydrolysis of triglycerides. Accordingly, OLA-NO2 treated cells demonstrated down-regulation of diacylglycerol acyltransferase1, the key enzyme in triglyceride biosynthesis, and increased expression of hormone-sensitive lipase and adipose triglyceride lipase that regulate triglyceride hydrolysis. Finally, OLA-NO2 vs OLA treatment resulted in modest but significant beneficial effects on macrophage cholesterol metabolism, reducing cholesterol biosynthesis rate and low density lipoprotein influx into the cells, while increasing high density lipoprotein-mediated cholesterol efflux from the macrophages. Collectively, compared with OLA, OLA-NO2 modestly but significantly reduces macrophage oxidative status and cellular triglyceride content via modulation of cellular anti-oxidants and triglyceride

  10. Regulation by carbohydrate and clofibric acid of palmitoyl-CoA chain elongation in the liver of rats.

    Science.gov (United States)

    Kudo, Naomi; Toyama, Tomoaki; Mitsumoto, Atsushi; Kawashima, Yoichi

    2003-05-01

    Regulation of palmitoyl-CoA chain elongation (PCE) and its contribution to oleic acid formation were investigated in rat liver in comparison with stearoyl-CoA desaturase (SCD). Hepatic PCE activity was induced by the administration of 20% wt/vol glucose or fructose in the drinking water of normal rats. In streptozotocin-induced diabetic rats, the activities of both PCE and SCD were suppressed, and fructose, but not glucose, feeding caused an increase in the activities of both enzymes. Treatment of normal rats with clofibric acid in combination with carbohydrate further increased PCE, but not SCD, activity. FA analysis of hepatic lipids revealed that the proportion of oleic acid (18:1 n-9) increased upon administration of carbohydrate or clofibric acid. The treatment of rats with clofibric acid in combination with carbohydrate greatly increased the proportion of 18:1 n-9. A significant correlation was observed between PCE activity and the hepatic proportion of 18:1 n-9 (r2 = 0.874, P 0.05). Taken together, these results suggest that carbohydrate induces PCE as well as SCD activity to increase the hepatic 18:1 content in rat liver, and the increased PCE activity seems to be responsible for the further increase in 18:1 n-9 when carbohydrate is administered in combination with clofibric acid.

  11. p73 regulates basal and starvation-induced liver metabolism in vivo

    OpenAIRE

    He, Zhaoyue; Agostini, Massimiliano; Liu, He; Melino, Gerry; Simon, Hans-Uwe

    2015-01-01

    As a member of the p53 gene family, p73 regulates cell cycle arrest, apoptosis, neurogenesis, immunity and inflammation. Recently, p73 has been shown to transcriptionally regulate selective metabolic enzymes, such as cytochrome c oxidase subunit IV isoform 1, glucose 6-phosphate dehydrogenase and glutaminase-2, resulting in significant effects on metabolism, including hepatocellular lipid metabolism, glutathione homeostasis and the pentose phosphate pathway. In order to further investigate th...

  12. Postprandial triglycerides and blood coagulation.

    Science.gov (United States)

    Silveira, A

    2001-01-01

    Most of our lifetime we spend in the postprandial state. Postprandial triglyceridemia may represent a procoagulant state involving disturbances of both blood coagulation and fibrinolysis, in particular due to elevation of the plasma levels of activated factor VII (VIIa) and plasminogen activator inhibitor (PAI-1). Therefore, disturbances of the hemostatic system might, at least partly, account for by the link between hypertriglyceridemia and coronary heart disease (CHD). Factor VIIa is the first enzyme of the blood coagulation system and serves a priming function for triggering of the clotting cascade. The coagulant activity of factor VII (VIIc, total activity of factor VII in plasma) was identified as an independent predictor of myocardial infarction in initially healthy middle-aged men, and particularly of fatal coronary events, and both serum cholesterol and triglyceride concentrations correlated positively with the VIIc level. Addition of fat to diet has been consistently shown to cause a rapid conversion of the factor VII zymogen into its active form (VIIa) whereas the concentration of total protein is unaffected. Postprandial activation of factor VII is dependent on lipolytic activity and it is mainly supported by large triglyceride-rich lipoprotein of the VLDL class. Studies in vivo with specific coagulation factor-deficient patients indicate that factor IX is essential for the postprandial activation of factor VII. The basal generation of thrombin seems to be unaffected by increased plasma levels of VIIa. However, since VIIa-tissue factor complex is responsible for the initiation of the coagulation cascade, increased generation of VIIa in the postprandial state would increase the potential for thrombin production in the event of plaque rupture. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of the plasminogen activators in the circulation and thereby the principal inhibitor of the fibrinolytic system. Postprandial

  13. DNMT1 is a Required Genomic Regulator for Murine Liver Histogenesis and Regeneration

    DEFF Research Database (Denmark)

    Kaji, Kosuke; Factor, Valentina M; Andersen, Jesper B

    2016-01-01

    as transcriptome and methylation profiling. Regenerative growth was induced by partial hepatectomy and exposure to CCl4 . The impact of Dnmt1 knockdown was also analyzed in hepatic progenitor cell (HPC) lines; proliferation, apoptosis, DNA damage and sphere formation were assessed. Dnmt1 loss in postnatal...... hepatocytes caused global hypomethylation, enhanced DNA damage response and initiated a senescence state causing a progressive inability to maintain tissue homeostasis and proliferate in response to injury. The liver regenerated via activation and repopulation from progenitors due to lineage......-dependent differences in Alb-Cre expression, providing a basis for selection of less mature and therefore less damaged HPC progeny. Consistently, an efficient knockdown of Dnmt1 in cultured HPCs caused severe DNA damage, cell cycle arrest, senescence and cell death. Mx1-Cre-driven deletion of Dnmt1 in adult quiescent...

  14. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis

    Directory of Open Access Journals (Sweden)

    Diane DeZwaan-McCabe

    2017-05-01

    Full Text Available The unfolded protein response (UPR, induced by endoplasmic reticulum (ER stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress.

  15. GCKR variants increase triglycerides while protecting from insulin resistance in Chinese children.

    Science.gov (United States)

    Shen, Yue; Wu, Lijun; Xi, Bo; Liu, Xin; Zhao, Xiaoyuan; Cheng, Hong; Hou, Dongqing; Wang, Xingyu; Mi, Jie

    2013-01-01

    Variants in gene encoding glucokinase regulator protein (GCKR) were found to have converse effects on triglycerides and glucose metabolic traits. We aimed to investigate the influence of GCKR variants for triglycerides and glucose metabolic traits in Chinese children and adults. We genotyped two GCKR variants rs1260326 and rs1260333 in children and adults, and analyzed the association between two variants and triglycerides, glucose, insulin and HOMA-IR using linear regression model, and estimated the effect on insulin resistance using logistic regression model. Rs1260326 and rs1260333 associated with increased triglycerides in children and adults (ptriglycerides in Chinese children and adults. Triglycerides-increasing alleles of GCKR variants reduce insulin and HOMA-IR index, and protect from insulin resistance in children. Our results suggested GCKR has an effect on development of insulin resistance in Chinese children.

  16. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea

    Science.gov (United States)

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-01-01

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment. PMID:27570415

  17. Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

    Science.gov (United States)

    Sagar, Nidhi Midhu; McFarlane, Michael; Nwokolo, Chuka; Bardhan, Karna Dev; Arasaradnam, Ramesh Pulendran

    2016-08-14

    Bile acids (BAs) are essential for the absorption of lipids. BA synthesis is inhibited through intestinal farnesoid X receptor (FXR) activity. BA sequestration is known to influence BA metabolism and control serum lipid concentrations. Animal data has demonstrated a regulatory role for the FXR in triglyceride metabolism. FXR inhibits hepatic lipogenesis by inhibiting the expression of sterol regulatory element binding protein 1c via small heterodimer primer activity. Conversely, FXR promotes free fatty acids oxidation by inducing the expression of peroxisome proliferator-activated receptor α. FXR can reduce the expression of microsomal triglyceride transfer protein, which regulates the assembly of very low-density lipoproteins (VLDL). FXR activation in turn promotes the clearance of circulating triglycerides by inducing apolipoprotein C-II, very low-density lipoproteins receptor (VLDL-R) and the expression of Syndecan-1 together with the repression of apolipoprotein C-III, which increases lipoprotein lipase activity. There is currently minimal clinical data on triglyceride metabolism in patients with bile acid diarrhoea (BAD). Emerging data suggests that a third of patients with BAD have hypertriglyceridemia. Further research is required to establish the risk of hypertriglyceridaemia in patients with BAD and elicit the mechanisms behind this, allowing for targeted treatment.

  18. Regulation of alternative macrophage activation in the liver following acetaminophen intoxication by stem cell-derived tyrosine kinase

    Energy Technology Data Exchange (ETDEWEB)

    Gardner, Carol R., E-mail: cgardner@pharmacy.rutgers.edu [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Hankey, Pamela [Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802 (United States); Mishin, Vladimir; Francis, Mary [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States); Yu, Shan [Department of Veterinary and Biomedical Science, Pennsylvania State University, University Park, PA 16802 (United States); Laskin, Jeffrey D. [Department of Environmental and Occupational Medicine, UMDNJ-Robert Wood Johnson Medical School, Piscataway, NJ 08854 (United States); Laskin, Debra L. [Department of Pharmacology and Toxicology, Rutgers University, Ernest Mario School of Pharmacy, Piscataway, NJ 08854 (United States)

    2012-07-15

    treated with acetaminophen. These data demonstrate that STK plays a role in regulating macrophage recruitment and activation in the liver following acetaminophen administration, and in hepatotoxicity. -- Highlights: ► STK regulates alternative macrophage activation after acetaminophen intoxication. ► Loss of STK results in increased sensitivity to acetaminophen. ► Increased toxicity involves oxidative stress and decreases in repair macrophages.

  19. Liver transplant

    Science.gov (United States)

    Hepatic transplant; Transplant - liver; Orthotopic liver transplant; Liver failure - liver transplant; Cirrhosis - liver transplant ... The donated liver may be from: A donor who has recently died and has not had liver injury. This type of ...

  20. Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase

    International Nuclear Information System (INIS)

    Ma, Noelle; Nicholson, Catherine J.; Wong, Michael; Holloway, Alison C.; Hardy, Daniel B.

    2014-01-01

    While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1 mg/kg/day) for two weeks prior to mating until weaning. At postnatal day 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway. - Highlights: • Our data reveals the links nicotine exposure in utero and long-term hypertriglyceridemia. • It is due to nicotine-induced augmented expression of hepatic FAS and LXRα activity. • Moreover, this involves nicotine-induced enhanced

  1. Fetal and neonatal exposure to nicotine leads to augmented hepatic and circulating triglycerides in adult male offspring due to increased expression of fatty acid synthase

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Noelle [Department of Physiology and Pharmacology, The University of Western Ontario (Canada); Department of Obstetrics and Gynecology, The University of Western Ontario (Canada); The Lawson Health Research Institute, The University of Western Ontario (Canada); Nicholson, Catherine J. [Department of Obstetrics and Gynecology, McMaster University (Canada); Wong, Michael [Department of Physiology and Pharmacology, The University of Western Ontario (Canada); Department of Obstetrics and Gynecology, The University of Western Ontario (Canada); The Lawson Health Research Institute, The University of Western Ontario (Canada); Holloway, Alison C. [Department of Obstetrics and Gynecology, McMaster University (Canada); Hardy, Daniel B., E-mail: Daniel.Hardy@schulich.uwo.ca [Department of Physiology and Pharmacology, The University of Western Ontario (Canada); Department of Obstetrics and Gynecology, The University of Western Ontario (Canada); The Children' s Health Research Institute, The University of Western Ontario (Canada); The Lawson Health Research Institute, The University of Western Ontario (Canada)

    2014-02-15

    While nicotine replacement therapy is assumed to be a safer alternative to smoking during pregnancy, the long-term consequences for the offspring remain elusive. Animal studies now suggest that maternal nicotine exposure during perinatal life leads to a wide range of adverse outcomes for the offspring including increased adiposity. The focus of this study was to investigate if nicotine exposure during pregnancy and lactation leads to alterations in hepatic triglyceride synthesis. Female Wistar rats were randomly assigned to receive daily subcutaneous injections of saline (vehicle) or nicotine bitartrate (1 mg/kg/day) for two weeks prior to mating until weaning. At postnatal day 180 (PND 180), nicotine exposed offspring exhibited significantly elevated levels of circulating and hepatic triglycerides in the male offspring. This was concomitant with increased expression of fatty acid synthase (FAS), the critical hepatic enzyme in de novo triglyceride synthesis. Given that FAS is regulated by the nuclear receptor Liver X receptor (LXRα), we measured LXRα expression in both control and nicotine-exposed offspring. Nicotine exposure during pregnancy and lactation led to an increase in hepatic LXRα protein expression and enriched binding to the putative LXRE element on the FAS promoter in PND 180 male offspring. This was also associated with significantly enhanced acetylation of histone H3 [K9,14] surrounding the FAS promoter, a hallmark of chromatin activation. Collectively, these findings suggest that nicotine exposure during pregnancy and lactation leads to an increase in circulating and hepatic triglycerides long-term via changes in the transcriptional and epigenetic regulation of the hepatic lipogenic pathway. - Highlights: • Our data reveals the links nicotine exposure in utero and long-term hypertriglyceridemia. • It is due to nicotine-induced augmented expression of hepatic FAS and LXRα activity. • Moreover, this involves nicotine-induced enhanced

  2. Aspects of plasma triglyceride metabolism in children

    NARCIS (Netherlands)

    P.P. Forget

    1975-01-01

    textabstractThis thesis aimed at investigating some aspects of plasma triglyceride metabolism in children. In the introduction general aspects of plasma triglyceride metabolism are presented. Chapter 1 reviews recent litterature data on the intravenous fat tolerance test and on plasma postheparin

  3. Crosstalk between thyroid hormone receptor and liver X receptor in the regulation of selective Alzheimer's disease indicator-1 gene expression.

    Directory of Open Access Journals (Sweden)

    Emi Ishida

    Full Text Available Selective Alzheimer's disease (AD indicator 1 (Seladin-1 has been identified as a gene down-regulated in the degenerated lesions of AD brain. Up-regulation of Seladin-1 reduces the accumulation of β-amyloid and neuronal death. Thyroid hormone (TH exerts an important effect on the development and maintenance of central nervous systems. In the current study, we demonstrated that Seladin-1 gene and protein expression in the forebrain was increased in thyrotoxic mice compared with that of euthyroid mice. However, unexpectedly, no significant decrease in the gene and protein expression was observed in hypothyroid mice. Interestingly, an agonist of liver X receptor (LXR, TO901317 (TO administration in vivo increased Seladin-1 gene and protein expression in the mouse forebrain only in a hypothyroid state and in the presence of mutant TR-β, suggesting that LXR-α would compensate for TR-β function to maintain Seladin-1 gene expression in hypothyroidism and resistance to TH. TH activated the mouse Seladin-1 gene promoter (-1936/+21 bp and site 2 including canonical TH response element (TRE half-site in the region between -159 and -154 bp is responsible for the positive regulation. RXR-α/TR-β heterodimerization was identified on site 2 by gel-shift assay, and chromatin immunoprecipitation assay revealed the recruitment of TR-β to site 2 and the recruitment was increased upon TH administration. On the other hand, LXR-α utilizes a distinct region from site 2 (-120 to -102 bp to activate the mouse Seladin-1 gene promoter. Taking these findings together, we concluded that TH up-regulates Seladin-1 gene expression at the transcriptional level and LXR-α maintains the gene expression.

  4. Regulation of rat liver cytochrome P450j, a high affinity N-nitrosodimethylamine demethylase (NDMAD)

    International Nuclear Information System (INIS)

    Thomas, P.E.; Bandiera, S.; Maines, S.L.; Ryan, D.E.; Levin, W.

    1987-01-01

    Purified IgG from sera of rabbits immunized with homogeneous P450j was absorbed to produce monospecific anti-P450j. Results using anti-P450j in ELISA show that rat liver microsomal P450j content decreases between 3 and 6 wks of age in both sexes. Several xenobiotics (Aroclor 1254, mirex and 3-methylcholanthrene) repressed P450j levels when administered to male rats. In contrast, hepatic levels of P450j were induced by isoniazid, dimethylsulfoxide, pyrazole, 4-methylpyrazole, ethanol and chemically-induced diabetes. P450j levels were measurable in kidney, whereas this isozyme was barely detectable in lung, ovaries and testes; however, extra-hepatic P450j was inducible by isoniazid. Between 80-90% of microsomal NDMAD was inhibited by anti-P450j whether the microsomes were isolated from untreated rats or animals administered inducers or repressors of P450j. Results obtained with the reconstituted system suggest that the remaining microsomal NDMAD resistant to antibody inhibition is the result of the inaccessibility of a certain proportion of P450j due to interference by NADPH-P450 reductase. P450j content and NDMAD activity correlated well in microsomes from rats of all treatment groups. The evidence indicates that P450j is the primary, and possibly only, microsomal catalyst of NDMAD at substrate concentrations relevant to hepatocarcinogenesis induced by NDMA

  5. Regulator of G-protein signaling-5 is a marker of hepatic stellate cells and expression mediates response to liver injury.

    Directory of Open Access Journals (Sweden)

    Arya J Bahrami

    Full Text Available Liver fibrosis is mediated by hepatic stellate cells (HSCs, which respond to a variety of cytokine and growth factors to moderate the response to injury and create extracellular matrix at the site of injury. G-protein coupled receptor (GPCR-mediated signaling, via endothelin-1 (ET-1 and angiotensin II (AngII, increases HSC contraction, migration and fibrogenesis. Regulator of G-protein signaling-5 (RGS5, an inhibitor of vasoactive GPCR agonists, functions to control GPCR-mediated contraction and hypertrophy in pericytes and smooth muscle cells (SMCs. Therefore we hypothesized that RGS5 controls GPCR signaling in activated HSCs in the context of liver injury. In this study, we localize RGS5 to the HSCs and demonstrate that Rgs5 expression is regulated during carbon tetrachloride (CCl4-induced acute and chronic liver injury in Rgs5LacZ/LacZ reporter mice. Furthermore, CCl4 treated RGS5-null mice develop increased hepatocyte damage and fibrosis in response to CCl4 and have increased expression of markers of HSC activation. Knockdown of Rgs5 enhances ET-1-mediated signaling in HSCs in vitro. Taken together, we demonstrate that RGS5 is a critical regulator of GPCR signaling in HSCs and regulates HSC activation and fibrogenesis in liver injury.

  6. [Inhibition of glycogen synthase kinase 3b activity regulates Toll-like receptor 4-mediated liver inflammation].

    Science.gov (United States)

    Ren, Feng; Zhang, Hai-yan; Piao, Zheng-fu; Zheng, Su-jun; Chen, Yu; Chen, De-xi; Duan, Zhong-ping

    2012-09-01

    -inflammatory cytokines IL-12 (control: 0.11 ± 0.05, inflammation: 0.85 ± 0.11, intervention: 0.43 ± 0.10; F = 2.67, P = 0.038), TNF-a, (control: 0.052 ± 0.012, inflammation: 8.11 ± 0.98, intervention: 3.9 ± 0.82; F = 4.13, P = 0.016), IL-6 (control: 0.22 ± 0.08, inflammation: 6.37 ± 0.81, intervention: 2.11 ± 0.63; F = 3.21, P = 0.024), and IL-1b (control: 0.12 ± 0.07, inflammation: 2.51 ± 0.62, and intervention: 1.28 ± 0.33; F = 2.22, P = 0.030). Inhibition of GSK3b selectively regulates the expression of anti-inflammatory and pro-inflammatory cytokines in liver Kupffer cells (liver macrophages). This process may be one of the mechanisms underlying the ability of GSK3b to ameliorate hepatic ischemia-reperfusion injury, possibly because inhibition of pro-inflammatory cytokines may indirectly mediate liver cell apoptosis.

  7. Physiological covalent regulation of rat liver branched-chain alpha-ketoacid dehydrogenase

    International Nuclear Information System (INIS)

    Harris, R.A.; Powell, S.M.; Paxton, R.; Gillim, S.E.; Nagae, H.

    1985-01-01

    A radiochemical assay was developed for measuring branched-chain alpha-ketoacid dehydrogenase activity of Triton X-100 extracts of freeze-clamped rat liver. The proportion of active (dephosphorylated) enzyme was determined by measuring enzyme activities before and after activation of the complex with a broad-specificity phosphoprotein phosphatase. Hepatic branched-chain alpha-ketoacid dehydrogenase activity in normal male Wistar rats was 97% active but decreased to 33% active after 2 days on low-protein (8%) diet and to 13% active after 4 days on the same diet. Restricting protein intake of lean and obese female Zucker rats also caused inactivation of hepatic branched-chain alpha-ketoacid dehydrogenase complex. Essentially all of the enzyme was in the active state in rats maintained for 14 days on either 30 or 50% protein diets. This was also the case for rats maintained on a commercial chow diet (minimum 23% protein). However, maintaining rats on 20, 8, and 0% protein diets decreased the percentage of the active form of the enzyme to 58, 10, and 7% of the total, respectively. Fasting of chow-fed rats for 48 h had no effect on the activity state of hepatic branched-chain alpha-ketoacid dehydrogenase, i.e., 93% of the enzyme remained in the active state compared to 97% for chow-fed rats. However, hepatic enzyme of rats maintained on 8% protein diet was 10% active before starvation and 83% active after 2 days of starvation. Thus, dietary protein deficiency results in inactivation of hepatic branched-chain alpha-ketoacid dehydrogenase complex, presumably as a consequence of low hepatic levels of branched-chain alpha-ketoacids

  8. Pancreatic Transdifferentiation and Glucose-Regulated Production of Human Insulin in the H4IIE Rat Liver Cell Line

    Directory of Open Access Journals (Sweden)

    Binhai Ren

    2016-04-01

    Full Text Available Due to the limitations of current treatment regimes, gene therapy is a promising strategy being explored to correct blood glucose concentrations in diabetic patients. In the current study, we used a retroviral vector to deliver either the human insulin gene alone, the rat NeuroD1 gene alone, or the human insulin gene and rat NeuroD1 genes together, to the rat liver cell line, H4IIE, to determine if storage of insulin and pancreatic transdifferentiation occurred. Stable clones were selected and expanded into cell lines: H4IIEins (insulin gene alone, H4IIE/ND (NeuroD1 gene alone, and H4IIEins/ND (insulin and NeuroD1 genes. The H4IIEins cells did not store insulin; however, H4IIE/ND and H4IIEins/ND cells stored 65.5 ± 5.6 and 1475.4 ± 171.8 pmol/insulin/5 × 106 cells, respectively. Additionally, several β cell transcription factors and pancreatic hormones were expressed in both H4IIE/ND and H4IIEins/ND cells. Electron microscopy revealed insulin storage vesicles in the H4IIE/ND and H4IIEins/ND cell lines. Regulated secretion of insulin to glucose (0–20 mmol/L was seen in the H4IIEins/ND cell line. The H4IIEins/ND cells were transplanted into diabetic immunoincompetent mice, resulting in normalization of blood glucose. This data shows that the expression of NeuroD1 and insulin in liver cells may be a useful strategy for inducing islet neogenesis and reversing diabetes.

  9. Peroxisome Proliferator-Activated Receptor Gamma Negatively Regulates the Differentiation of Bone Marrow-Derived Mesenchymal Stem Cells Toward Myofibroblasts in Liver Fibrogenesis

    Directory of Open Access Journals (Sweden)

    Shuangshuang Jia

    2015-11-01

    Full Text Available Background/Aims: Bone marrow-derived mesenchymal stem cells (BMSCs have been confirmed to have capacity to differentiate toward hepatic myofibroblasts, which contribute to fibrogenesis in chronic liver diseases. Peroxisome proliferator-activated receptor gamma (PPARγ, a ligand-activated transcription factor, has gained a great deal of recent attention as it is involved in fibrosis and cell differentiation. However, whether it regulates the differentiation of BMSCs toward myofibroblasts remains to be defined. Methods: Carbon tetrachloride or bile duct ligation was used to induce mouse liver fibrosis. Expressions of PPARγ, α-smooth muscle actin, collagen α1 (I and collagen α1 (III were detected by real-time RT-PCR and Western blot or immunofluorescence assay. Results: PPARγ expression was decreased in mouse fibrotic liver. In addition, PPARγ was declined during the differentiation of BMSCs toward myofibroblasts induced by transforming growth factor β1. Activation of PPARγ stimulated by natural or synthetic ligands suppressed the differentiation of BMSCs. Additionally, knock down of PPARγ by siRNA contributed to BMSC differentiation toward myofibroblasts. Furthermore, PPARγ activation by natural ligand significantly inhibited the differentiation of BMSCs toward myofibroblasts in liver fibrogenesis and alleviated liver fibrosis. Conclusions: PPARγ negatively regulates the differentiation of BMSCs toward myofibroblasts, which highlights a further mechanism implicated in the BMSC differentiation.

  10. Omega-3 fatty acid deficiency selectively up-regulates delta6-desaturase expression and activity indices in rat liver: prevention by normalization of omega-3 fatty acid status.

    Science.gov (United States)

    Hofacer, Rylon; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Magrisso, I Jack; Benoit, Stephen C; McNamara, Robert K

    2011-09-01

    This study investigated the effects of perinatal dietary omega-3 (n-3) fatty acid depletion and subsequent repletion on the expression of genes that regulate long-chain (LC) polyunsaturated fatty acid biosynthesis in rat liver and brain. It was hypothesized that chronic n-3 fatty acid deficiency would increase liver Fads1 and Fads2 messenger RNA (mRNA) expression/activity and that n-3 fatty acid repletion would normalize this response. Adult rats fed the n-3-free diet during perinatal development exhibited significantly lower erythrocyte, liver, and frontal cortex LCn-3 fatty acid composition and reciprocal elevations in LC omega-6 (n-6) fatty acid composition compared with controls (CONs) and repleted rats. Liver Fads2, but not Fads1, Elovl2, or Elovl5, mRNA expression was significantly greater in n-3-deficient (DEF) rats compared with CONs and was partially normalized in repleted rats. The liver 18:3n-6/18:2n-6 ratio, an index of delta6-desturase activity, was significantly greater in DEF rats compared with CON and repleted rats and was positively correlated with Fads2 mRNA expression among all rats. The liver 18:3n-6/18:2n-6 ratio, but not Fads2 mRNA expression, was also positively correlated with erythrocyte and frontal cortex LCn-6 fatty acid compositions. Neither Fads1 or Fads2 mRNA expression was altered in brain cortex of DEF rats. These results confirm previous findings that liver, but not brain, delta6-desaturase expression and activity indices are negatively regulated by dietary n-3 fatty acids. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Molecular Pathogenesis of Liver Steatosis Induced by Hepatitis C Virus

    Directory of Open Access Journals (Sweden)

    Cheng Jun

    2012-09-01

    Full Text Available Liver steatosis is a pathological hallmark in patients with chronic hepatitis C (CHC. Increased lipid uptake, decreased lipid secretion, increased lipid synthesis and decreased lipid degradation are all involved in pathogenesis of steatosis induced by hepatitic C virus (HCV infection. Level of low density lipoprotein receptor (LDL-R and activity of peroxisome proliferator-activated receptor (PPAR α is related to liver uptake of lipid from circulation, and affected by HCV. Secretion via microsomal triglyceride transfer protein (MTTP, and formation of very low density lipoprotein (VLDL have been hampered by HCV infection. Up-regulation of lipid synthesis related genes, such as sterol regulatory element-binding protein (SREBP-1, SREBP-2, SREBP-1c, fatty acid synthase (FASN, HMG CoA reductase (HMGCR, liver X receptor (LXR, acetyl-CoA carboxylase 1 (ACC1, hepatic CB (1 receptors, retinoid X receptor (RXR α, were the main stay of liver steatosis pathogenesis. Degradation of lipid in liver is decreased in patients with CHC. There is strong evidence that heterogeneity of HCV core genes of different genotypes affect their effects of liver steatosis induction. A mechanism in which steatosis is involved in HCV life cycle is emerging.

  12. Thrombospondin-1 is a novel negative regulator of liver regeneration after partial hepatectomy through transforming growth factor-beta1 activation in mice.

    Science.gov (United States)

    Hayashi, Hiromitsu; Sakai, Keiko; Baba, Hideo; Sakai, Takao

    2012-05-01

    The matricellular protein, thrombospondin-1 (TSP-1), is prominently expressed during tissue repair. TSP-1 binds to matrix components, proteases, cytokines, and growth factors and activates intracellular signals through its multiple domains. TSP-1 converts latent transforming growth factor-beta1 (TGF-β1) complexes into their biologically active form. TGF-β plays significant roles in cell-cycle regulation, modulation of differentiation, and induction of apoptosis. Although TGF-β1 is a major inhibitor of proliferation in cultured hepatocytes, the functional requirement of TGF-β1 during liver regeneration remains to be defined in vivo. We generated a TSP-1-deficient mouse model of a partial hepatectomy (PH) and explored TSP-1 induction, progression of liver regeneration, and TGF-β-mediated signaling during the repair process after hepatectomy. We show here that TSP-1-mediated TGF-β1 activation plays an important role in suppressing hepatocyte proliferation. TSP-1 expression was induced in endothelial cells (ECs) as an immediate early gene in response to PH. TSP-1 deficiency resulted in significantly reduced TGF-β/Smad signaling and accelerated hepatocyte proliferation through down-regulation of p21 protein expression. TSP-1 induced in ECs by reactive oxygen species (ROS) modulated TGF-β/Smad signaling and proliferation in hepatocytes in vitro, suggesting that the immediately and transiently produced ROS in the regenerating liver were the responsible factor for TSP-1 induction. We have identified TSP-1 as an inhibitory element in regulating liver regeneration by TGF-β1 activation. Our work defines TSP-1 as a novel immediate early gene that could be a potential therapeutic target to accelerate liver regeneration. Copyright © 2011 American Association for the Study of Liver Diseases.

  13. Transcriptional regulation of the human Liver X Receptor α gene by Hepatocyte Nuclear Factor 4α

    Energy Technology Data Exchange (ETDEWEB)

    Theofilatos, Dimitris; Anestis, Aristomenis [University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, 71003, Crete (Greece); Hashimoto, Koshi [Department of Preemptive Medicine and Metabolism, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-city, Tokyo, 113-8510 (Japan); Kardassis, Dimitris, E-mail: kardasis@imbb.forth.gr [University of Crete Medical School and Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology of Hellas, Heraklion, 71003, Crete (Greece)

    2016-01-15

    Liver X Receptors (LXRs) are sterol-activated transcription factors that play major roles in cellular cholesterol homeostasis, HDL biogenesis and reverse cholesterol transport. The aim of the present study was to investigate the mechanisms that control the expression of the human LXRα gene in hepatic cells. A series of reporter plasmids containing consecutive 5′ deletions of the hLXRα promoter upstream of the luciferase gene were constructed and the activity of each construct was measured in HepG2 cells. This analysis showed that the activity of the human LXRα promoter was significantly reduced by deleting the −111 to −42 region suggesting the presence of positive regulatory elements in this short proximal fragment. Bioinformatics data including motif search and ChIP-Seq revealed the presence of a potential binding motif for Hepatocyte Nuclear Factor 4 α (HNF-4α) in this area. Overexpression of HNF-4α in HEK 293T cells increased the expression of all LXRα promoter constructs except −42/+384. In line, silencing the expression of endogenous HNF-4α in HepG2 cells was associated with reduced LXRα protein levels and reduced activity of the −111/+384 LXRα promoter but not of the −42/+384 promoter. Using ChiP assays in HepG2 cells combined with DNAP assays we mapped the novel HNF-4α specific binding motif (H4-SBM) in the −50 to −40 region of the human LXRα promoter. A triple mutation in this H4-SBM abolished HNF-4α binding and reduced the activity of the promoter to 65% relative to the wild type. Furthermore, the mutant promoter could not be transactivated by HNF-4α. In conclusion, our data indicate that HNF-4α may have a wider role in cell and plasma cholesterol homeostasis by controlling the expression of LXRα in hepatic cells. - Highlights: • The human LXRα promoter contains a HNF-4α specific binding motif in the proximal −50/−40 region. • Mutations in this motif abolished HNF4α binding and transactivation of the h

  14. Transcriptional regulation of the human Liver X Receptor α gene by Hepatocyte Nuclear Factor 4α

    International Nuclear Information System (INIS)

    Theofilatos, Dimitris; Anestis, Aristomenis; Hashimoto, Koshi; Kardassis, Dimitris

    2016-01-01

    Liver X Receptors (LXRs) are sterol-activated transcription factors that play major roles in cellular cholesterol homeostasis, HDL biogenesis and reverse cholesterol transport. The aim of the present study was to investigate the mechanisms that control the expression of the human LXRα gene in hepatic cells. A series of reporter plasmids containing consecutive 5′ deletions of the hLXRα promoter upstream of the luciferase gene were constructed and the activity of each construct was measured in HepG2 cells. This analysis showed that the activity of the human LXRα promoter was significantly reduced by deleting the −111 to −42 region suggesting the presence of positive regulatory elements in this short proximal fragment. Bioinformatics data including motif search and ChIP-Seq revealed the presence of a potential binding motif for Hepatocyte Nuclear Factor 4 α (HNF-4α) in this area. Overexpression of HNF-4α in HEK 293T cells increased the expression of all LXRα promoter constructs except −42/+384. In line, silencing the expression of endogenous HNF-4α in HepG2 cells was associated with reduced LXRα protein levels and reduced activity of the −111/+384 LXRα promoter but not of the −42/+384 promoter. Using ChiP assays in HepG2 cells combined with DNAP assays we mapped the novel HNF-4α specific binding motif (H4-SBM) in the −50 to −40 region of the human LXRα promoter. A triple mutation in this H4-SBM abolished HNF-4α binding and reduced the activity of the promoter to 65% relative to the wild type. Furthermore, the mutant promoter could not be transactivated by HNF-4α. In conclusion, our data indicate that HNF-4α may have a wider role in cell and plasma cholesterol homeostasis by controlling the expression of LXRα in hepatic cells. - Highlights: • The human LXRα promoter contains a HNF-4α specific binding motif in the proximal −50/−40 region. • Mutations in this motif abolished HNF4α binding and transactivation of the h

  15. Chlorpromazine-induced perturbations of bile acids and free fatty acids in cholestatic liver injury prevented by the Chinese herbal compound Yin-Chen-Hao-Tang.

    Science.gov (United States)

    Yang, Qiaoling; Yang, Fan; Tang, Xiaowen; Ding, Lili; Xu, Ying; Xiong, Yinhua; Wang, Zhengtao; Yang, Li

    2015-04-16

    Yin-Chen-Hao-Tang (YCHT), a commonly used as a traditional chinese medicine for liver disease. Several studies indicated that YCHT may improving hepatic triglyceride metabolism and anti-apoptotic response as well as decreasing oxidative stress .However, little is known about the role of YCHT in chlorpromazine (CPZ) -induced chlolestatic liver injury. Therefore, we aimed to facilitate the understanding of the pathogenesis of cholestatic liver injury and evaluate the effect of Yin-Chen-Hao-Tang (YCHT) on chlorpromazine (CPZ)-induced cholestatic liver injury in rats based on the change of bile acids (BAs) and free fatty acids (FFAs) alone with the biochemical indicators and histological examination. We conducted an experiment on CPZ-induced cholestatic liver injury in Wistar rats with and without YCHT for nine consecutive days. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB), total bilirubin (TBIL), total cholesterol (TC), triglycerides (TG), low density lipoprotein-cholesterol (LDL-C) were measured to evaluate the protective effect of YCHT against chlorpromazine (CPZ)-induced cholestatic liver injury. Histopathology of the liver tissue showed that pathological injuries were relieved after YCHT pretreatment. In addition, ultra-performance lipid chromatography coupled with quadrupole mass spectrometry (UPLC-MS) and gas chromatography coupled with mass spectrometry (GC-MS) was applied to determine the content of bile acids, free fatty acids, respectively. Obtained data showed that YCHT attenuated the effect of CPZ-induced cholestatic liver injury, which was manifested by the serum biochemical parameters and histopathology of the liver tissue. YCHT regulated the lipid levels as indicated by the reversed serum levels of TC, TG, and LDL-C. YCHT also regulated the disorder of BA and FFA metabolism by CPZ induction. Results indicated that YCHT exerted a protective effect on CPZ-induced cholestasis liver injury. The variance of

  16. Blood Pressure Medications: Can They Raise My Triglycerides?

    Science.gov (United States)

    ... medications: Can they raise my triglycerides? Can some blood pressure medications cause an increase in triglycerides? Answers from Sheldon G. Sheps, M.D. Yes, some blood pressure medications can affect triglyceride and cholesterol levels. Hydrochlorothiazide ...

  17. PROPERTY ANALYSIS OF TRIGLYCERIDE-BASED THERMOSETS. (R829576)

    Science.gov (United States)

    Triglycerides with acrylate functionality were prepared from various oils andmodel triglycerides. The triglyceride-acrylates were homopolymerized and copolymerizedwith styrene. The cross-link densities of the resulting polymer networks werepredicted utilizing the F...

  18. Fructose, high fructose corn syrup, sucrose, and non-alcoholic liver disease

    Science.gov (United States)

    Nonalcoholic fatty liver disease (NAFLD), formerly called nonalcoholic steatohepatitis, is characterized by hepatic steatosis and abnormal triglyceride accumulation in liver cells. Its etiology, pathophysiology, and pathogenesis are still poorly understood. Some have suggested that the increased in...

  19. Carvedilol Improves Inflammatory Response, Oxidative Stress and Fibrosis in the Alcohol-Induced Liver Injury in Rats by Regulating Kuppfer Cells and Hepatic Stellate Cells.

    Directory of Open Access Journals (Sweden)

    Raimundo Fernandes de Araújo Júnior

    Full Text Available To evaluate the anti-inflammatory, anti-oxidant and antifibrotic effects of carvedilol (CARV in rats with ethanol-induced liver injury.Liver injury was induced by gavage administration of alcohol (7 g/kg for 28 consecutive days. Eighty Wistar rats were pretreated with oral CARV at 1, 3, or 5 mg/kg or with saline 1 h before exposure to alcohol. Liver homogenates were assayed for interleukin (IL-1β, IL-10, and tumor necrosis factor (TNF-α level as well as for myeloperoxidase (MPO activity and malonyldialdehyde (MDA and glutathione (GSH levels. Serum aspartate aminotransferase (AST activity and liver triglyceride (TG levels were also assayed. Immunohistochemical analyses of cyclooxygenase 2 (COX-2, receptor activator of nuclear factor kappa-B/ligand (RANK/RANKL, suppressor of cytokine signalling (SOCS1, the Kupffer cell marker IBA-1 (ionized calcium-binding adaptor molecule 1, intercellular adhesion molecule 1 (ICAM-1, superoxide dismutase (SOD-1, and glutathione peroxidase (GPx-1 expression were performed. Confocal microscopy analysis of IL-1β and NF-κB expression and real-time quantitative PCR analysis for TNFα, PCI, PCIII, and NF-κB were performed.CARV treatment (5 mg/kg during the alcohol exposure protocol was associated with reduced steatosis, hepatic cord degeneration, fibrosis and necrosis, as well as reduced levels of AST (p < 0.01, ALT (p < 0.01, TG (p < 0.001, MPO (p < 0.001, MDA (p < 0.05, and proinflammatory cytokines (IL-1β and TNF-α, both p < 0.05, and increased levels of the anti-inflammatory cytokine IL-10 (p < 0.001 and GSH (p < 0.05, compared to the alcohol-only group. Treatment with CARV 5 mg/kg also reduced expression levels of COX-2, RANK, RANKL, IBA-1, and ICAM-1 (all p < 0.05, while increasing expression of SOCS1, SOD-1, and GPx-1 (all p < 0.05 and decreasing expression of IL-1β and NF-κB (both, p < 0.05. Real-time quantitative PCR analysis showed that mRNA production of TNF-α, procollagen type I (PCI, procollagen

  20. Thyroid Hormone Receptor β (TRβ) and Liver X Receptor (LXR) Regulate Carbohydrate-response Element-binding Protein (ChREBP) Expression in a Tissue-selective Manner*

    Science.gov (United States)

    Gauthier, Karine; Billon, Cyrielle; Bissler, Marie; Beylot, Michel; Lobaccaro, Jean-Marc; Vanacker, Jean-Marc; Samarut, Jacques

    2010-01-01

    Thyroid hormone (TR) and liver X (LXR) receptors are transcription factors involved in lipogenesis. Both receptors recognize the same consensus DNA-response element in vitro. It was previously shown that their signaling pathways interact in the control of cholesterol elimination in the liver. In the present study, carbohydrate-response element-binding protein (ChREBP), a major transcription factor controlling the activation of glucose-induced lipogenesis in liver, is characterized as a direct target of thyroid hormones (TH) in liver and white adipose tissue (WAT), the two main lipogenic tissues in mice. Using genetic and molecular approaches, ChREBP is shown to be specifically regulated by TRβ but not by TRα in vivo, even in WAT where both TR isoforms are expressed. However, this isotype specificity is not found in vitro. This TRβ specific regulation correlates with the loss of TH-induced lipogenesis in TRβ−/− mice. Fasting/refeeding experiments show that TRβ is not required for the activation of ChREBP expression particularly marked in WAT following refeeding. However, TH can stimulate ChREBP expression in WAT even under fasting conditions, suggesting completely independent pathways. Because ChREBP has been described as an LXR target, the interaction of LXR and TRβ in ChREBP regulation was assayed both in vitro and in vivo. Each receptor recognizes a different response element on the ChREBP promoter, located only 8 bp apart. There is a cross-talk between LXR and TRβ signaling on the ChREBP promoter in liver but not in WAT where LXR does not regulate ChREBP expression. The molecular basis for this cross-talk has been determined in in vitro systems. PMID:20615868

  1. PHP14 regulates hepatic stellate cells migration in liver fibrosis via mediating TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway.

    Science.gov (United States)

    Xu, Anjian; Li, Yanmeng; Zhao, Wenshan; Hou, Fei; Li, Xiaojin; Sun, Lan; Chen, Wei; Yang, Aiting; Wu, Shanna; Zhang, Bei; Yao, Jingyi; Wang, Huan; Huang, Jian

    2018-02-01

    Hepatic fibrosis is characterized by the activation of hepatic stellate cells (HSCs). Migration of the activated HSCs to the site of injury is one of the key characteristics during the wound healing process. We have previously demonstrated that 14 kDa phosphohistidine phosphatase (PHP14) is involved in migration and lamellipodia formation of HSCs. However, the role of PHP14 in liver fibrosis remains unknown. In this study, we first assessed PHP14 expression and distribution in liver fibrotic tissues using western blot, immunohistochemistry, and double immunofluorescence staining. Next, we investigated the role of PHP14 in liver fibrosis and, more specifically, the migration of HSCs by Transwell assay and 3D collagen matrices assay. Finally, we explored the possible molecular mechanisms of the effects of PHP14 on these processes. Our results show that the PHP14 expression is up-regulated in fibrotic liver and mainly in HSCs. Importantly, TGF-β1 can induce PHP14 expression in HSCs accompanied with the activation of HSCs. Consistent with the previous study, PHP14 promotes HSCs migration, especially, promotes 3D floating collagen matrices contraction but inhibits stressed-released matrices contraction. Mechanistically, the PI3Kγ/AKT/Rac1 pathway is involved in migration regulated by PHP14. Moreover, PHP14 specifically mediates the TGF-β1 signaling to PI3Kγ/AKT pathway and regulates HSC migration, and thus participates in liver fibrosis. Our study identified the role of PHP14 in liver fibrosis, particularly HSC migration, and suggested a novel mediator of transducting TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway. PHP14 is up-regulated in fibrotic liver and activated hepatic stellate cells. The expression of PHP14 is induced by TGF-β1. The migration of hepatic stellate cells is regulated by PHP14. PHP14 is a mediator of TGF-β1 signaling to PI3Kγ/AKT/Rac1 pathway in hepatic stellate cells.

  2. Feedback regulation of bile acid synthesis in human liver: Importance of HNF-4α for regulation of CYP7A1

    International Nuclear Information System (INIS)

    Abrahamsson, Anna; Gustafsson, Ulf; Ellis, Ewa; Nilsson, Lisa-Mari; Sahlin, Staffan; Bjoerkhem, Ingemar; Einarsson, Curt

    2005-01-01

    A great number of nuclear factors are involved in the negative feedback mechanism regulating bile acid synthesis. There are two major ways for the negative feedback to effect the synthesis; the SHP-dependent, involving FXR, and the SHP-independent way, affecting HNF-4α. We studied 23 patients with gallstone disease. Eight patients were treated with chenodeoxycholic acid, 7 with cholestyramine prior to operation, and 8 served as controls. Liver biopsies were analyzed with Real-time-PCR. In the cholestyramine-treated group mRNA levels of CYP7A1 were increased about 10-fold. Treatment with CDCA decreased the mRNA levels of CYP7A1 by about 70%. The mRNA levels of CYP8B1, CYP27A1, and CYP7B1 were not significantly altered in the treated groups. The analysis of mRNA levels for HNF-4α showed 64% higher levels in the cholestyramine-treated group compared to the controls. These levels showed positive and highly significant correlation to the levels of mRNA of CYP7A1 when studied in all three groups together. FXR, SHP, and LRH-1/FTF were not significantly affected by the different treatments. Our results indicate that when bile acid synthesis is upregulated by cholestyramine treatment the SHP-independent pathway for controlling CYP7A1 transcription dominates over the SHP-dependent pathway

  3. Peroxisomal β-oxidation regulates whole body metabolism, inflammatory vigor, and pathogenesis of nonalcoholic fatty liver disease

    Science.gov (United States)

    Moreno-Fernandez, Maria E.; Giles, Daniel A.; Stankiewicz, Traci E.; Sheridan, Rachel; Karns, Rebekah; Cappelletti, Monica; Lampe, Kristin; Mukherjee, Rajib; Sina, Christian; Sallese, Anthony; Bridges, James P.; Hogan, Simon P.; Aronow, Bruce J.; Hoebe, Kasper

    2018-01-01

    Nonalcoholic fatty liver disease (NAFLD), a metabolic predisposition for development of hepatocellular carcinoma (HCC), represents a disease spectrum ranging from steatosis to steatohepatitis to cirrhosis. Acox1, a rate-limiting enzyme in peroxisomal fatty acid β-oxidation, regulates metabolism, spontaneous hepatic steatosis, and hepatocellular damage over time. However, it is unknown whether Acox1 modulates inflammation relevant to NAFLD pathogenesis or if Acox1-associated metabolic and inflammatory derangements uncover and accelerate potential for NAFLD progression. Here, we show that mice with a point mutation in Acox1 (Acox1Lampe1) exhibited altered cellular metabolism, modified T cell polarization, and exacerbated immune cell inflammatory potential. Further, in context of a brief obesogenic diet stress, NAFLD progression associated with Acox1 mutation resulted in significantly accelerated and exacerbated hepatocellular damage via induction of profound histological changes in hepatocytes, hepatic inflammation, and robust upregulation of gene expression associated with HCC development. Collectively, these data demonstrate that β-oxidation links metabolism and immune responsiveness and that a better understanding of peroxisomal β-oxidation may allow for discovery of mechanisms central for NAFLD progression. PMID:29563328

  4. Humanizing π-class glutathione S-transferase regulation in a mouse model alters liver toxicity in response to acetaminophen overdose.

    Directory of Open Access Journals (Sweden)

    Matthew P Vaughn

    Full Text Available Glutathione S-transferases (GSTs metabolize drugs and xenobiotics. Yet despite high protein sequence homology, expression of π-class GSTs, the most abundant of the enzymes, varies significantly between species. In mouse liver, hepatocytes exhibit high mGstp expression, while in human liver, hepatocytes contain little or no hGSTP1 mRNA or hGSTP1 protein. π-class GSTs are known to be critical determinants of liver responses to drugs and toxins: when treated with high doses of acetaminophen, mGstp1/2+/+ mice suffer marked liver damage, while mGstp1/2-/- mice escape liver injury.To more faithfully model the contribution of π-class GSTs to human liver toxicology, we introduced hGSTP1, with its exons, introns, and flanking sequences, into the germline of mice carrying disrupted mGstp genes. In the resultant hGSTP1+mGstp1/2-/- strain, π-class GSTs were regulated differently than in wild-type mice. In the liver, enzyme expression was restricted to bile duct cells, Kupffer cells, macrophages, and endothelial cells, reminiscent of human liver, while in the prostate, enzyme production was limited to basal epithelial cells, reminiscent of human prostate. The human patterns of hGSTP1 transgene regulation were accompanied by human patterns of DNA methylation, with bisulfite genomic sequencing revealing establishment of an unmethylated CpG island sequence encompassing the gene promoter. Unlike wild-type or mGstp1/2-/- mice, when hGSTP1+mGstp1/2-/- mice were overdosed with acetaminophen, liver tissues showed limited centrilobular necrosis, suggesting that π-class GSTs may be critical determinants of toxin-induced hepatocyte injury even when not expressed by hepatocytes.By recapitulating human π-class GST expression, hGSTP1+mGstp1/2-/- mice may better model human drug and xenobiotic toxicology.

  5. Shifts in dietary carbohydrate-lipid exposure regulate expression of the non-alcoholic fatty liver disease-associated gene PNPLA3/adiponutrin in mouse liver and HepG2 human liver cells.

    Science.gov (United States)

    Hao, Lei; Ito, Kyoko; Huang, Kuan-Hsun; Sae-tan, Sudathip; Lambert, Joshua D; Ross, A Catharine

    2014-10-01

    Patatin-like phospholipase domain containing 3 (PNPLA3, adiponutrin) has been identified as a modifier of lipid metabolism. To better understand the physiological role of PNPLA3/adiponutrin, we have investigated its regulation in intact mice and human hepatocytes under various nutritional/metabolic conditions. PNPLA3 gene expression was determined by real-time PCR in liver of C57BL/6 mice after dietary treatments and in HepG2 cells exposed to various nutritional/metabolic stimuli. Intracellular lipid content was determined in HepG2 cells after siRNA-mediated knockdown of PNPLA3. In vivo, mice fed a high-carbohydrate (HC) liquid diet had elevated hepatic lipid content, and PNPLA3 mRNA and protein expression, compared to chow-fed mice. Elevated expression was completely abrogated by addition of unsaturated lipid emulsion to the HC diet. By contrast, in mice with high-fat diet-induced steatosis, Pnpla3 expression did not differ compared to low-fat fed mice. In HepG2 cells, Pnpla3 expression was reversibly suppressed by glucose depletion and increased by glucose refeeding, but unchanged by addition of insulin and glucagon. Several unsaturated fatty acids each significantly decreased Pnpla3 mRNA, similar to lipid emulsion in vivo. However, Pnpla3 knockdown in HepG2 cells did not alter total lipid content in high glucose- or oleic acid-treated cells. Our results provide evidence that PNPLA3 expression is an early signal/signature of carbohydrate-induced lipogenesis, but its expression is not associated with steatosis per se. Under lipogenic conditions due to high-carbohydrate feeding, certain unsaturated fatty acids can effectively suppress both lipogenesis and PNPLA3 expression, both in vivo and in a hepatocyte cell line. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Elevated triglycerides may affect cystatin C recovery.

    Science.gov (United States)

    Witzel, Samantha H; Butts, Katherine; Filler, Guido

    2014-05-01

    The purpose of this study was to investigate the effect of triglyceride concentration on cystatin C (CysC) measurements. Serum samples collected from 10 nephrology patients, 43 to 78years of age, were air centrifuged to separate aqueous and lipid layers. The lipid layer from each patient was pooled together to create a mixture with a high triglyceride concentration. This pooled lipid layer was mixed with each of the ten patient aqueous layers in six different ratios. Single factor ANOVA was used to assess whether CysC recovery was affected by triglyceride levels. Regression analysis was used to develop a formula to correct for the effect of triglycerides on CysC measurement, based on samples from 6 randomly chosen patients from our study population. The formula was validated with the 4 remaining samples. The analysis revealed a significant reduction in measured CysC with increasing concentrations of triglycerides (Pearson r=-0.56, ptriglycerides: Subsequent Bland-Altman plots revealed a bias (mean±1 standard deviation [SD]) of -3.7±15.6% for the data used to generate the correction formula and a bias of 3.52±9.38% for the validation set. Our results suggest that triglyceride concentrations significantly impact cystatin C measurements and that this effect may be corrected in samples that cannot be sufficiently clarified by air centrifugation using the equation that we developed. Copyright © 2014 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  7. Association of serum retinoic acid with hepatic steatosis and liver injury in nonalcoholic fatty liver disease.

    Science.gov (United States)

    Liu, Yan; Chen, Hongen; Wang, Jingjing; Zhou, Wenjing; Sun, Ruifang; Xia, Min

    2015-07-01

    Retinoic acid (RA), an active metabolite of vitamin A (retinol), has been implicated in the regulation of lipid metabolism and hepatic steatosis in animal models. However, the relation between RA and liver histology in patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) is unknown. This study aimed at examining the association of RA with NAFLD and NASH in Chinese subjects. Serum RA concentration was determined by ELISA in 41 control subjects, 45 patients with NAFLD, and 38 patients with NASH. The associations of RA with adiposity, serum glucose, lipid profiles, and markers of liver damage were studied. Moreover, both mRNA and protein levels of retinoic X receptor α (RXRα) in the liver were analyzed in subjects with different degrees of hepatic steatosis. Serum RA concentrations in patients with NAFLD (1.42 ± 0.47 ng/mL) and NASH (1.14 ± 0.26 ng/mL) were significantly lower than those in control subjects (2.70 ± 0.52 ng/mL) (P hepatic steatosis. Both serum RA concentrations and RXRα mRNA levels were inversely correlated with intrahepatic triglyceride content (r = -0.700, P hepatic lipid metabolism and insulin resistance. This trial was registered at clinicaltrials.gov as NCT01940263. © 2015 American Society for Nutrition.

  8. Ginkgo biloba extract mitigates liver fibrosis and apoptosis by regulating p38 MAPK, NF-κB/IκBα, and Bcl-2/Bax signaling

    Directory of Open Access Journals (Sweden)

    Wang YY

    2015-12-01

    Full Text Available Yuanyuan Wang, Rong Wang, Yujie Wang, Ruqin Peng, Yan Wu, Yongfang Yuan Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China Background: Liver fibrosis is the consequence of diverse liver injuries and can eventually develop into liver cirrhosis. Ginkgo biloba extract (GBE is an extract from dried ginkgo leaves that has many pharmacological effects because of its various ingredients and has been shown to be hepatoprotective. Purpose and methods: Aimed to investigate the underlying protective mechanisms of GBE on carbon tetrachloride (CCl4-induced liver fibrosis in rats. Male Sprague Dawley rats were randomly divided into four groups: control group (C, model group (M, low-dose group (L, and high-dose group (H. Liver fibrosis was induced by CCl4 groups M, L, and H: group C was administered saline. In addition, GBE at different doses was used to treat groups L and H. Results: The results of hematoxylin and eosin staining, Masson’s trichrome staining, a liver function index, and a liver fibrosis index showed that GBE application noticeably mitigated fibrosis and improved the function of the liver. The western blotting and immunohistochemistry analyses indicated that GBE reduced liver fibrosis not only by inhibiting p38 MAPK and NF-κBp65 via inhibition of IκBα degradation but also by inhibiting hepatocyte apoptosis via downregulation of Bax, upregulation of Bcl-2, and subsequent inhibition of caspase-3 activation. Inflammation-associated factors and hepatic stellate cell (HSC-activation markers further demonstrated that GBE could effectively inhibit HSC activation and inflammation as a result of its regulation of p38 MAPK and nuclear factor-kappa B/IκBα signaling. Conclusion: Our findings indicated a novel role for GBE in the treatment of liver fibrosis. The potential mechanisms may be associated with the following signaling pathways: 1 the p38 MAPK

  9. Low-ω3 Fatty Acid and Soy Protein Attenuate Alcohol-Induced Fatty Liver and Injury by Regulating the Opposing Lipid Oxidation and Lipogenic Signaling Pathways

    Directory of Open Access Journals (Sweden)

    Karina Reyes-Gordillo

    2016-01-01

    Full Text Available Chronic ethanol-induced downregulation of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α and upregulation of peroxisome proliferator-activated receptor gamma coactivator 1-beta (PGC1β affect hepatic lipid oxidation and lipogenesis, respectively, leading to fatty liver injury. Low-ω3 fatty acid (Low-ω3FA that primarily regulates PGC1α and soy protein (SP that seems to have its major regulatory effect on PGC1β were evaluated for their protective effects against ethanol-induced hepatosteatosis in rats fed with Lieber-deCarli control or ethanol liquid diets with high or low ω3FA fish oil and soy protein. Low-ω3FA and SP opposed the actions of chronic ethanol by reducing serum and liver lipids with concomitant decreased fatty liver. They also prevented the downregulation of hepatic Sirtuin 1 (SIRT1 and PGC1α and their target fatty acid oxidation pathway genes and attenuated the upregulation of hepatic PGC1β and sterol regulatory element-binding protein 1c (SREBP1c and their target lipogenic pathway genes via the phosphorylation of 5′ adenosine monophosphate-activated protein kinase (AMPK. Thus, these two novel modulators attenuate ethanol-induced hepatosteatosis and consequent liver injury potentially by regulating the two opposing lipid oxidation and lipogenic pathways.

  10. Antioxidant, antiapoptotic and amino acid balance regulating activities of 1,7-dihydroxy-3,4,8-trimethoxyxanthone against dimethylnitrosamine-induced liver fibrosis.

    Directory of Open Access Journals (Sweden)

    Xi-Yuan Zheng

    Full Text Available Liver fibrosis represents the consequences of a sustained wound healing response to chronic liver injury which could be caused by viral, autoimmune, drugs, and so on. Unfortunately, there was no effective therapy available for liver fibrosis in clinic. In this study, we identified the anti-fibrotic effects of 1,7-dihydroxy-3,4,8-trimethoxyxanthone (ZYC-1 on the dimethylnitrosamine (DMN-induced rat model. ZYC-1 was isolated from Swertia punicea Hemsl and was administrated to DMN-induced rat model. ZYC decreased the hyaluronic acid (HA, type IV collagen (CIV and hydroxyproline (Hyp levels and inhibited the expression of α smooth muscle actin (α-SMA and transforming growth factor beta 1 (TGF-1β. The anti-fibrotic effect of ZYC-1 was also confirmed by Sirius Red staining. Finally, we identified 42 differentially expressed proteins by using proteomics analysis after ZYC-1 treatment, of which 17 were up-regulated and 25 were down-regulated. These Most of the 42 proteins are involved in the oxidative stress pathway, the mitochondrial-mediated apoptotic pathway and the amino acid metabolism pathway. Our study presented the first elucidated mechanisms of xanthone on liver fibrosis in vivo. This study pointed out that ZYC-1 may be used as a lead compound for hepatofibrosis treatment.

  11. PCSK9 and triglyceride-rich lipoprotein metabolism.

    Science.gov (United States)

    Druce, I; Abujrad, H; Ooi, T C

    2015-07-20

    Pro-protein convertase subtilisin-kexin 9 (PCSK9) is known to affect low-density lipoprotein (LDL) metabolism, but there are indications from several lines of research that it may also influence the metabolism of other lipoproteins, especially triglyceride-rich lipoproteins (TRL). This review summarizes the current data on this possible role of PCSK9. A link between PCSK9 and TRL has been suggested through the demonstration of (1) a correlation between plasma PCSK9 and triglyceride (TG) levels in health and disease, (2) a correlation between plasma PCSK9 and markers of carbohydrate metabolism, which is closely related to TG metabolism, (3) an effect of TG-lowering fibrate therapy on plasma PCSK9 levels, (4) an effect of PCSK9 on postprandial lipemia, (5) an effect of PCSK9 on adipose tissue biology, (6) an effect of PCSK9 on apolipoprotein B production from the liver and intestines, (7) an effect of PCSK9 on receptors other than low density lipoprotein receptor (LDLR) that are involved in TRL metabolism, and (8) an effect of anti-PCSK9 therapy on serum TG levels. The underlying mechanisms are unclear but starting to emerge. © 2015 the Journal of Biomedical Research. All rights reserved.

  12. On the mechanism of regulation of the catalase synthesis rate in the rat liver in the course of acute radiation disease

    International Nuclear Information System (INIS)

    Komov, V.P.; Rakhmanina, T.F.

    1976-01-01

    A method has been proposed to determine the activity of factors that regulate the rate of catalase synthesis in the rat liver at the stage of translation. The analysis of certain normal and pathologic parameters of these factors suggests a possibility of interpreting more definitely the effect of radiation on the catalase synthesis. Marked changes have been found both in the structure and the activity of the given factors in the course of the development of radiation damage

  13. Hepatitis C virus core protein induces dysfunction of liver sinusoidal endothelial cell by down-regulation of silent information regulator 1.

    Science.gov (United States)

    Sun, Li-Jie; Yu, Jian-Wu; Shi, Yu-Guang; Zhang, Xiao-Yu; Shu, Meng-Ni; Chen, Mo-Yang

    2018-05-01

    Hepatic fibrosis is a frequent feature of chronic hepatitis C virus (HCV) infection. Some evidence has suggested the potential role of silent information regulator 1 (SIRT1) in organ fibrosis. The aim of this study was to investigate the effect of HCV core protein on expression of SIRT1 of liver sinusoidal endothelial cell (LSEC) and function of LSEC. LSECs were co-cultured with HepG2 cells or HepG2 cells expressing HCV core protein and LSECs cultured alone were used as controls. After co-culture, the activity and expression levels of mRNA and protein of SIRT1 in LSEC were detected by a SIRT1 fluorometric assay kit, real time-PCR (RT-PCR), Western blot, respectively. The levels of adiponectin receptor 2 (AdipoR2), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were measured by Western blot. Cluster of differentiation 31 (CD31), CD14, and von Willebrand factor (vWf) of LSECs was performed by flow cytometry. The level of reactive oxygen species (ROS) was assayed. Malondialdehyde (MDA), superoxide dismutase (SOD), adiponectin, nitric oxide (NO), and endothelin-1 (ET-1) levels in the co-culture supernatant were measured. The co-culture supernatant was then used to cultivate LX-2 cells. The levels of α-smooth muscle actin (ASMA) and transforming growth factor-β1 (TGF-β1) protein in LX-2 cells were measured by Western blot. Compared with LSEC co-cultured with HepG2 cells group, in LSEC co-cultured with HepG2-core cells group, the activity and expression level of mRNA and protein of SIRT1 reduced; the level of adiponectin reduced and the expression level of AdipoR2 protein decreased; ROS levels increased; the expression level of eNOS, VEGF protein decreased; and the expression level of CD14 decreased; the expression level of vWf and CD31 increased; NO and SOD levels decreased; whereas ET-1 and MDA levels increased; the levels of ASMA and TGF-β1 protein in LX-2 cells increased. SIRT1 activator improved the above-mentioned changes

  14. Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase.

    Science.gov (United States)

    Lee, Ju-Hee; Baek, Su Youn; Jang, Eun Jeong; Ku, Sae Kwang; Kim, Kyu Min; Ki, Sung Hwan; Kim, Chang-Eop; Park, Kwang Il; Kim, Sang Chan; Kim, Young Woo

    2018-06-01

    Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor α (LXRα)-mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRα agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid β-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver. Copyright © 2018. Published by Elsevier B.V.

  15. Regulation of p53 by reversible post-transcriptional and post-translational mechanisms in liver and skeletal muscle of an anoxia tolerant turtle, Trachemys scripta elegans.

    Science.gov (United States)

    Zhang, Jing; Biggar, Kyle K; Storey, Kenneth B

    2013-01-15

    The red-eared slider turtle (Trachemys scripta elegans) exhibits well-developed natural anoxia tolerance that depends on multiple biochemical adaptations, including anoxia-induced hypometabolism. We hypothesized that signaling by the p53 protein could aid in establishing the hypometabolic state by arresting the cell cycle, protecting against DNA damage as well as altering pathways of energy metabolism. Immunoblotting was used to evaluate the regulation and post-transcriptional modifications of p53 in liver and skeletal muscle of red-eared slider turtles subjected to 5h or 20h of anoxic submergence. Tissue specific regulation of p53 was observed with the liver showing a more rapid activation of p53 in response to anoxia as well as differential expression of seven serine phosphorylation and two lysine acetylation sites when compared with skeletal muscle. Protein expression of MDM2, a major p53 inhibitor, was also examined but did not change during anoxia. Reverse-transcriptase PCR was used to assess transcript levels of selected p53 target genes (14-3-3σ, Gadd45α and Pgm) and one microRNA (miR-34a); results showed down-regulation of Pgm and up-regulation of the other three. These findings show an activation of p53 in response to anoxia exposure and suggest an important role for the p53 stress response pathway in regulating natural anoxia tolerance and hypometabolism in a vertebrate facultative anaerobe. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Liver Transplant

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  17. Hepatocyte Hypoxia Inducible Factor-1 Mediates the Development of Liver Fibrosis in a Mouse Model of Nonalcoholic Fatty Liver Disease.

    Directory of Open Access Journals (Sweden)

    Omar A Mesarwi

    Full Text Available Obstructive sleep apnea (OSA is associated with the progression of non-alcoholic fatty liver disease (NAFLD to steatohepatitis and fibrosis. This progression correlates with the severity of OSA-associated hypoxia. In mice with diet induced obesity, hepatic steatosis leads to liver tissue hypoxia, which worsens with exposure to intermittent hypoxia. Emerging data has implicated hepatocyte cell signaling as an important factor in hepatic fibrogenesis. We hypothesized that hepatocyte specific knockout of the oxygen sensing α subunit of hypoxia inducible factor-1 (HIF-1, a master regulator of the global response to hypoxia, may be protective against the development of liver fibrosis.Wild-type mice and mice with hepatocyte-specific HIF-1α knockout (Hif1a-/-hep were fed a high trans-fat diet for six months, as a model of NAFLD. Hepatic fibrosis was evaluated by Sirius red stain and hydroxyproline assay. Liver enzymes, fasting insulin, and hepatic triglyceride content were also assessed. Hepatocytes were isolated from Hif1a-/-hep mice and wild-type controls and were exposed to sustained hypoxia (1% O2 or normoxia (16% O2 for 24 hours. The culture media was used to reconstitute type I collagen and the resulting matrices were examined for collagen cross-linking.Wild-type mice on a high trans-fat diet had 80% more hepatic collagen than Hif1a-/-hep mice (2.21 μg collagen/mg liver tissue, versus 1.23 μg collagen/mg liver tissue, p = 0.03, which was confirmed by Sirius red staining. Body weight, liver weight, mean hepatic triglyceride content, and fasting insulin were similar between groups. Culture media from wild-type mouse hepatocytes exposed to hypoxia allowed for avid collagen cross-linking, but very little cross-linking was seen when hepatocytes were exposed to normoxia, or when hepatocytes from Hif1a-/-hep mice were used in hypoxia or normoxia.Hepatocyte HIF-1 mediates an increase in liver fibrosis in a mouse model of NAFLD, perhaps due to liver

  18. Ikkefastende triglycerider og risiko for iskamisk apopleksi--sekundaerpublikation

    DEFF Research Database (Denmark)

    Freiberg, Jacob J; Tybjaerg-Hansen, Anne; Jensen, Jan Skov

    2009-01-01

    The role of triglycerides in the risk of ischemic stroke remains controversial. We tested the hypothesis that increased levels of nonfasting triglycerides are associated with ischemic stroke in the general population. Men with a nonfasting triglyceride level 5 mmol/l had a multivariable, adjusted...... hazard ratio for ischemic stroke of 2.5 (95% confidence interval: 1.3-4.8) compared with men with a nonfasting triglyceride level triglycerides is associated with risk of ischemic stroke...

  19. [Nonfasting triglycerides and risk of ischemic stroke--secondary publication

    DEFF Research Database (Denmark)

    Freiberg, J.J.; Tybjaerg-Hansen, A.; Jensen, J.S.

    2009-01-01

    The role of triglycerides in the risk of ischemic stroke remains controversial. We tested the hypothesis that increased levels of nonfasting triglycerides are associated with ischemic stroke in the general population. Men with a nonfasting triglyceride level 5 mmol/l had a multivariable, adjusted...... hazard ratio for ischemic stroke of 2.5 (95% confidence interval: 1.3-4.8) compared with men with a nonfasting triglyceride level triglycerides is associated with risk of ischemic stroke Udgivelsesdato...

  20. Comparison of the effects of enteral feeding with continuous and intermittent parenteral nutrition on hepatic triglyceride secretion in human beings

    International Nuclear Information System (INIS)

    Isabel-Martinez, L.; Skinner, C.; Parkin, A.; Hall, R.I.

    1989-01-01

    Plasma triglyceride turnover was measured during steady-state conditions in 22 postoperative patients. Nine had received nutritional support with an enteral regimen, seven had received an equivalent regimen as continuous parenteral nutrition, and six received the same parenteral regimen as a cyclical infusion. After 5 days of nutritional support, each patient received an intravenous bolus of tritiated glycerol. Plasma radiolabeled triglyceride content was measured during the subsequent 24 hours. The data were analyzed by means of a simple deterministic model of plasma triglyceride kinetics and compared with the results obtained by stochastic analysis. The rates of hepatic triglyceride secretion obtained by deterministic analysis were higher than those obtained by the stochastic approach. However, the mode of delivery of the nutritional regimen did not affect the rate of hepatic triglyceride secretion regardless of the method of analysis. The results suggest that neither complete nutritional bypass of the gastrointestinal tract nor interruption of parenteral nutrition in an attempt to mimic normal eating has any effect on hepatic triglyceride secretion. Any beneficial effect that enteral feeding or cyclical parenteral nutrition may have on liver dysfunction associated with standard parenteral nutrition appears to be unrelated to changes in hepatic triglyceride secretion

  1. Fasting-induced G0/G1 switch gene 2 and FGF21 expression in the liver are under regulation of adipose tissue derived fatty acids

    Science.gov (United States)

    Jaeger, Doris; Schoiswohl, Gabriele; Hofer, Peter; Schreiber, Renate; Schweiger, Martina; Eichmann, Thomas O.; Pollak, Nina M.; Poecher, Nadja; Grabner, Gernot F.; Zierler, Kathrin A.; Eder, Sandra; Kolb, Dagmar; Radner, Franz P.W.; Preiss-Landl, Karina; Lass, Achim; Zechner, Rudolf; Kershaw, Erin E.; Haemmerle, Guenter

    2015-01-01

    Background & Aims Adipose tissue (AT)-derived fatty acids (FAs) are utilized for hepatic triacylglycerol (TG) generation upon fasting. However, their potential impact as signaling molecules is not established. Herein we examined the role of exogenous AT-derived FAs in the regulation of hepatic gene expression by investigating mice with a defect in AT-derived FA supply to the liver. Methods Plasma FA levels, tissue TG hydrolytic activities and lipid content were determined in mice lacking the lipase co-activator comparative gene identification-58 (CGI-58) selectively in AT (CGI-58-ATko) applying standard protocols. Hepatic expression of lipases, FA oxidative genes, transcription factors, ER stress markers, hormones and cytokines were determined by qRT-PCR, Western blotting and ELISA. Results Impaired AT-derived FA supply upon fasting of CGI-58-ATko mice causes a marked defect in liver PPARα-signaling and nuclear CREBH translocation. This severely reduced the expression of respective target genes such as the ATGL inhibitor G0/G1 switch gene-2 (G0S2) and the endocrine metabolic regulator FGF21. These changes could be reversed by lipid administration and raising plasma FA levels. Impaired AT-lipolysis failed to induce hepatic G0S2 expression in fasted CGI-58-ATko mice leading to enhanced ATGL-mediated TG-breakdown strongly reducing hepatic TG deposition. On high fat diet, impaired AT-lipolysis counteracts hepatic TG accumulation and liver stress linked to improved systemic insulin sensitivity. Conclusions AT-derived FAs are a critical regulator of hepatic fasting gene expression required for the induction of G0S2-expression in the liver to control hepatic TG-breakdown. Interfering with AT-lipolysis or hepatic G0S2 expression represents an effective strategy for the treatment of hepatic steatosis. PMID:25733154

  2. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

    Science.gov (United States)

    Peng, Hao; Gu, Wei; Li, Min; Chen, Zhe

    2018-01-01

    Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane) on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. PMID:29343942

  3. High fat diet-induced non alcoholic fatty liver disease in rats is associated with hyperhomocysteinemia caused by down regulation of the transsulphuration pathway

    Directory of Open Access Journals (Sweden)

    Napolitano Mariarosaria

    2011-04-01

    Full Text Available Abstract Background Hyperhomocysteinemia (HHcy causes increased oxidative stress and is an independent risk factor for cardiovascular disease. Oxidative stress is now believed to be a major contributory factor in the development of non alcoholic fatty liver disease, the most common liver disorder worldwide. In this study, the changes which occur in homocysteine (Hcy metabolism in high fat-diet induced non alcoholic fatty liver disease (NAFLD in rats were investigated. Methods and results After feeding rats a standard low fat diet (control or a high fat diet (57% metabolisable energy as fat for 18 weeks, the concentration of homocysteine in the plasma was significantly raised while that of cysteine was lowered in the high fat as compared to the control diet fed animals. The hepatic activities of cystathionine β-synthase (CBS and cystathionine γ-lyase (CGS, the enzymes responsible for the breakdown of homocysteine to cysteine via the transsulphuration pathway in the liver, were also significantly reduced in the high fat-fed group. Conclusions These results indicate that high fat diet-induced NAFLD in rats is associated with increased plasma Hcy levels caused by down-regulation of hepatic CBS and CGL activity. Thus, HHcy occurs at an early stage in high fat diet-induced NAFLD and is likely to contribute to the increased risk of cardiovascular disease associated with the condition.

  4. Long-term effect of medium-chain triglyceride on hepatic enzymes catalyzing lipogenesis and cholesterogenesis in rats

    International Nuclear Information System (INIS)

    Takase, Sachiko; Morimoto, Ayami; Nakanishi, Mayumi; Muto, Yasutoshi.

    1977-01-01

    This study was conducted to investigate the long-term effect of dietary medium-chain triglyceride (MCT) as compared with that of corn oil feeding on lipid metabolism in rats. Both serum cholesterol and triglyceride levels in MCT-fed rats showed significant decrease during the experimental period of eight weeks, although liver cholesterol and triglyceride contents were not distinguishable between the two groups. Significant elevation of the activity of lipogenic enzymes, such as fatty acid synthetase (FAS) and malic enzyme (ME) of the liver, was observed in MCT-fed rats without any fat accumulation of the liver (fatty liver). The increase of lipogenic enzyme activity was accompanied by a significant reduction of essential fatty acids (EFA) such as 18:2 (ωsigma) and 20:4 (ωsigma) in total liver lipid. In contrast, hepatic β-hydroxy-β-methylglutaryl CoA(HMG-CoA) reductase activity was significantly decreased in MCT-fed rats, that would play an important role in achieving hypocholesterolemia. From these results obtained in a long-term experiment, it is concluded that exogenous MCT depresses the key enzyme catalyzing cholesterol synthesis with a concomitant elevation of lipogenic enzyme activity in the rat liver. (auth.)

  5. Role of liver progenitors in liver regeneration.

    Science.gov (United States)

    Best, Jan; Manka, Paul; Syn, Wing-Kin; Dollé, Laurent; van Grunsven, Leo A; Canbay, Ali

    2015-02-01

    During massive liver injury and hepatocyte loss, the intrinsic regenerative capacity of the liver by replication of resident hepatocytes is overwhelmed. Treatment of this condition depends on the cause of liver injury, though in many cases liver transplantation (LT) remains the only curative option. LT for end stage chronic and acute liver diseases is hampered by shortage of donor organs and requires immunosuppression. Hepatocyte transplantation is limited by yet unresolved technical difficulties. Since currently no treatment is available to facilitate liver regeneration directly, therapies involving the use of resident liver stem or progenitor cells (LPCs) or non-liver stem cells are coming to fore. LPCs are quiescent in the healthy liver, but may be activated under conditions where the regenerative capacity of mature hepatocytes is severely impaired. Non-liver stem cells include embryonic stem cells (ES cells) and mesenchymal stem cells (MSCs). In the first section, we aim to provide an overview of the role of putative cytokines, growth factors, mitogens and hormones in regulating LPC response and briefly discuss the prognostic value of the LPC response in clinical practice. In the latter section, we will highlight the role of other (non-liver) stem cells in transplantation and discuss advantages and disadvantages of ES cells, induced pluripotent stem cells (iPS), as well as MSCs.

  6. Short-term weight loss and hepatic triglyceride reduction: evidence of a metabolic advantage with dietary carbohydrate restriction123

    OpenAIRE

    Browning, Jeffrey D; Baker, Jonathan A; Rogers, Thomas; Davis, Jeannie; Satapati, Santhosh; Burgess, Shawn C

    2011-01-01

    Background: Individuals with nonalcoholic fatty liver disease (NAFLD) have excess intrahepatic triglycerides. This is due, in part, to increased hepatic synthesis of fat from carbohydrates via lipogenesis. Although weight loss is currently recommended to treat NAFLD, little attention has been given to dietary carbohydrate restriction.

  7. 1200 nt rat liver mRNA identified by differential hybridization exhibits coordinate regulation with 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase

    International Nuclear Information System (INIS)

    Tanaka, R.D.; Clarke, C.F.; Fogelman, A.M.; Edwards, P.A.

    1986-01-01

    Differential hybridization has been used to identify genes in rat liver that encode transcripts which are increased by the drugs cholestyramine and mevinolin and are decreased by dietary cholesterol. This approach should prove useful in isolating and identifying coordinately regulated genes involved in the isoprene biosynthetic pathway. Rat liver poly (A) + RNA was isolated from animals fed diets supplemented with either cholestyramine and mevinolin or with cholesterol. Radiolabeled cDNAs generated from these two RNA preparations were used to screen a rat cDNAs library. A preliminary screen of 10,000 recombinants has led to the identification of a clone with an insert of 1200 bp that hybridizes to a mRNA species of about 1200 nt. The level of this RNA species in rat liver is elevated by the drugs cholestyramine and mevinolin and is decreased by cholesterol feeding. This RNA species is also decreased by mevalonate administration to rats. The regulation of this 1200 nt mRNA species mirrors that of HMG CoA reductase and HMG CoA synthase. It seems very likely that this 1200 nt mRNA encodes a polypeptide which is involved in the isoprene biosynthetic pathway

  8. The Flavonoid Quercetin Ameliorates Liver Inflammation and Fibrosis by Regulating Hepatic Macrophages Activation and Polarization in Mice

    Directory of Open Access Journals (Sweden)

    Xi Li

    2018-02-01

    Full Text Available At present, there are no effective antifibrotic drugs for patients with chronic liver disease; hence, the development of antifibrotic therapies is urgently needed. Here, we performed an experimental and translational study to investigate the potential and underlying mechanism of quercetin treatment in liver fibrosis, mainly focusing on the impact of quercetin on macrophages activation and polarization. BALB/c mice were induced liver fibrosis by carbon tetrachloride (CCl4 for 8 weeks and concomitantly treated with quercetin (50 mg/kg or vehicle by daily gavage. Liver inflammation, fibrosis, and hepatic stellate cells (HSCs activation were examined. Moreover, massive macrophages accumulation, M1 macrophages and their related markers, such as tumor necrosis factor (TNF-α, interleukin (IL-1β, IL-6, and monocyte chemotactic protein-1 (MCP-1 in livers were analyzed. In vitro, we used Raw 264.7 cells to examine the effect of quercetin on M1-polarized macrophages activation. Our results showed that quercetin dramatically ameliorated liver inflammation, fibrosis, and inhibited HSCs activation. These results were attributed to the reductive recruitment of macrophages (F4/80+ and CD68+ into the liver in quercetin-treated fibrotic mice confirmed by immunostaining and expression levels of marker molecules. Importantly, quercetin strongly inhibited M1 polarization and M1-related inflammatory cytokines in fibrotic livers when compared with vehicle-treated mice. In vitro, studies further revealed that quercetin efficiently inhibited macrophages activation and M1 polarization, as well as decreased the mRNA expression of M1 macrophage markers such as TNF-α, IL-1β, IL-6, and nitric oxide synthase 2. Mechanistically, the inhibition of M1 macrophages by quercetin was associated with the decreased levels of Notch1 expression on macrophages both in vivo and in vitro. Taken together, our data indicated that quercetin attenuated CCl4-induced liver inflammation and

  9. lowered serum triglyceride levels among chronic hepatitis b-infected

    African Journals Online (AJOL)

    User

    about the effect of the two pathological stages of chronic hepatitis B (CHB) infection – chronic- symptomatic and ... 2 hepatitis B disease and plasma metabolite dys- regulation has become the subject of interest by most biomedical researchers over the past dec- ade. The liver as a ..... leukin – 1, and interferon – α stimulate.

  10. Polymerization of epoxidized triglycerides with fluorosulfonic acid

    Science.gov (United States)

    The use of triglycerides as agri-based renewable raw materials for the development of new products is highly desirable in view of uncertain future petroleum prices. A new method of polymerizing epoxidized soybean oil has been devised with the use of fluorosulfonic acid. Depending on the reaction con...

  11. GPIHBP1 and Plasma Triglyceride Metabolism

    DEFF Research Database (Denmark)

    Fong, Loren G; Young, Stephen G; Beigneux, Anne P

    2016-01-01

    GPIHBP1, a GPI-anchored protein in capillary endothelial cells, is crucial for the lipolytic processing of triglyceride-rich lipoproteins (TRLs). GPIHBP1 shuttles lipoprotein lipase (LPL) to its site of action in the capillary lumen and is essential for the margination of TRLs along capillaries -...

  12. Abetalipoproteinemia: A novel mutation of microsomal triglyceride ...

    African Journals Online (AJOL)

    Hager Barakizou

    2016-01-25

    Jan 25, 2016 ... Abetalipoproteinemia: A novel mutation of microsomal triglyceride transfer protein (MTP) gene in a young Tunisian patient. Hager Barakizou a,. *, Souha Gannouni a. , Khalil Messaoui a. , Mathilde Difilippo b. ,. Agne`s Sassolas b. , Fethi Bayoudh a a Department of Pediatrics, Military Hospital of Tunis, ...

  13. Towards microalgal triglycerides in the commodity markets

    NARCIS (Netherlands)

    Benvenuti, Giulia; Ruiz, Jesús; Lamers, Packo P.; Bosma, Rouke; Wijffels, René H.; Barbosa, Maria J.

    2017-01-01

    Background: Microalgal triglycerides (TAGs) hold great promise as sustainable feedstock for commodity industries. However, to determine research priorities and support business decisions, solid techno-economic studies are essential. Here, we present a techno-economic analysis of two-step TAG

  14. estimations of cholesterol, triglycerides and fractionation

    African Journals Online (AJOL)

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    *Corresponding author. E-mail: eiadeyeye@yahoo.com. ESTIMATIONS OF CHOLESTEROL, TRIGLYCERIDES AND FRACTIONATION OF. LIPOPROTEINS IN SERUM SAMPLES OF SOME NIGERIAN FEMALE SUBJECTS. E.I. Adeyeye1* and I. Oluwadare2. 1Department of Chemistry, University of Ado Ekiti, P.M.B. 5363, ...

  15. Glucose and triglyceride lowering activity of Pterocarpus ...

    African Journals Online (AJOL)

    The leaf extracts of P. santalinoides possess triglyceride and glucose lowering properties in dexamethasone induced hyperlipidemia and insulin resistance and could be of therapeutic value in the management of metabolic syndrome. Key words: Pterocarpus santalinoides, leaf extracts, glucose tolerance, hyperlipidemia, ...

  16. Tanshinol ameliorates CCl4-induced liver fibrosis in rats through the regulation of Nrf2/HO-1 and NF-κB/IκBα signaling pathway

    Directory of Open Access Journals (Sweden)

    Wang R

    2018-05-01

    Full Text Available Rong Wang,* Jing Wang,* Fuxing Song, Shengnan Li, Yongfang Yuan Department of Pharmacy, Shanghai 9th People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China *These authors contributed equally to this work Abstract: Tanshinol, a water-soluble component isolated from Salvia miltiorrhiza Bunge, has a variety of biological activities involving anti-fibrotic effect. However, the exact role and the underlying mechanisms remain largely unclear. This study mainly focused on the anti-hepatic fibrotic activities and mechanisms of tanshinol on carbon tetrachloride (CCl4-induced liver fibrosis in rats via anti-oxidative and anti-inflammation pathways. The rats were divided into 4 groups as follows: control, model, tanshinol 20 mg/kg, and tanshinol 40 mg/kg. Except for the control group, CCl4 was used to induce liver fibrosis processing for 8 weeks, meanwhile rats in tanshinol groups were intraperitoneally injected with additional tanshinol. Control group simultaneously received the same volumes of olive oil and saline. The potentially protective effect and mechanisms of tanshinol on liver fibrosis in rats were evaluated. The serum levels of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were obviously lower in the tanshinol treatment groups related to model group. Compared with the model group, the levels of hyaluronic acid, type IV collagen, Laminin (LN, and procollagen III peptide (PIIIP in serum were significantly decreased after tanshinol treatment. Furthermore, tanshinol could regulate Nrf2/HO-1 signaling pathway and increase the level of superoxide dismutase (SOD and glutathione peroxidase (GSH-Px, and also decrease the level of malondialdehyde (MDA to against damage induced by oxidative stress. Simultaneously tanshinol could regulate nuclear factor kappa B signaling pathway to inhibit expression of inflammation factors, including transforming growth factor-β, tumor necrosis factor-α, Cox-2

  17. Metabolism of triglyceride-rich nascent rat hepatic high density lipoproteins

    International Nuclear Information System (INIS)

    Winkler, K.E.; Marsh, J.B.

    1989-01-01

    Nascent high density lipoprotein (HDL) and nascent very low density lipoprotein (VLDL) were isolated from rat livers that had been perfused with [3H]glycerol to label the triglyceride. When injected into intact rats, the labeled HDL-triglyceride disappeared as rapidly as the VLDL-triglyceride, with only 10% of the injected label remaining in the plasma after 30 min. The protein moiety of nascent HDL was labeled with [35S]methionine in a similar fashion and the labeled nascent HDL was separated into nonretained (NR) and retained (R) fractions by heparin-Sepharose affinity chromatography. When injected into rats, 55% of the injected label in nascent fraction NR and 72% of that in nascent fraction R was recovered from plasma at 30 min, compared to only 10% of the triglyceride label from unfractionated nascent HDL, indicating dissociation of triglyceride and apolipoprotein clearance. The plasma decay curves for both triglyceride and protein were biexponential. By 5 min, 15% of the 35S label remaining in plasma represented apoE and apoC that had been transferred from nascent HDL fractions NR and R to the d less than 1.063 g/ml fraction of plasma. Plasma HDL was labeled in vivo with [35S]methionine, separated into fractions NR and R, and the clearance of the two plasma HDL fractions was compared with that of the corresponding nascent HDL fractions. Except for a faster rate of removal of the nascent HDL fractions during the first 5 min, the serum decay curves were very similar

  18. Glucokinase links Kruppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease

    NARCIS (Netherlands)

    Bechmann, Lars P.; Gastaldelli, Amalia; Vetter, Diana; Patman, Gillian L.; Pascoe, Laura; Hannivoort, Rebekka A.; Lee, Ursula E.; Fiel, Isabel; Munoz, Ursula; Ciociaro, Demetrio; Lee, Young-Min; Buzzigoli, Emma; Miele, Luca; Hui, Kei Y.; Bugianesi, Elisabetta; Burt, Alastair D.; Day, Christopher P.; Mari, Andrea; Agius, Loranne; Walker, Mark; Friedman, Scott L.; Reeves, Helen L.

    The polymorphism, KLF6-IVS1-27A, in the Kruppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development

  19. Ananas comosus L. Leaf Phenols and p-Coumaric Acid Regulate Liver Fat Metabolism by Upregulating CPT-1 Expression

    Directory of Open Access Journals (Sweden)

    Weidong Xie

    2014-01-01

    Full Text Available In this study, we aimed to investigate the effect and action mechanisms of pineapple leaf phenols (PLPs on liver fat metabolism in high-fat diet-fed mice. Results show that PLP significantly reduced abdominal fat and liver lipid accumulation in high-fat diet-fed mice. The effects of PLP were comparable with those of FB. Furthermore, at the protein level, PLP upregulated the expression of carnitine palmitoyltransferase 1 (CPT-1, whereas FB had no effects on CPT-1 compared with the HFD controls. Regarding mRNA expression, PLP mainly promoted the expression of CPT-1, PGC1a, UCP-1, and AMPK in the mitochondria, whereas FB mostly enhanced the expression of Ech1, Acox1, Acaa1, and Ehhadh in peroxisomes. PLP seemed to enhance fat metabolism in the mitochondria, whereas FB mainly exerted the effect in peroxisomes. In addition, p-coumaric acid (CA, one of the main components from PLP, significantly inhibited fat accumulation in oleic acid-induced HepG2 cells. CA also significantly upregulated CPT-1 mRNA and protein expressions in HepG2 cells. We, firstly, found that PLP enhanced liver fat metabolism by upregulating CPT-1 expression in the mitochondria and might be promising in treatment of fatty liver diseases as alternative natural products. CA may be one of the active components of PLP.

  20. JTT-130, a microsomal triglyceride transfer protein (MTP inhibitor lowers plasma triglycerides and LDL cholesterol concentrations without increasing hepatic triglycerides in guinea pigs

    Directory of Open Access Journals (Sweden)

    Shrestha Sudeep

    2005-09-01

    Full Text Available Abstract Background Microsomal transfer protein inhibitors (MTPi have the potential to be used as a drug to lower plasma lipids, mainly plasma triglycerides (TG. However, studies with animal models have indicated that MTPi treatment results in the accumulation of hepatic TG. The purpose of this study was to evaluate whether JTT-130, a unique MTPi, targeted to the intestine, would effectively reduce plasma lipids without inducing a fatty liver. Methods Male guinea pigs (n = 10 per group were used for this experiment. Initially all guinea pigs were fed a hypercholesterolemic diet containing 0.08 g/100 g dietary cholesterol for 3 wk. After this period, animals were randomly assigned to diets containing 0 (control, 0.0005 or 0.0015 g/100 g of MTPi for 4 wk. A diet containing 0.05 g/100 g of atorvastatin, an HMG-CoA reductase inhibitor was used as the positive control. At the end of the 7th week, guinea pigs were sacrificed to assess drug effects on plasma and hepatic lipids, composition of LDL and VLDL, hepatic cholesterol and lipoprotein metabolism. Results Plasma LDL cholesterol and TG were 25 and 30% lower in guinea pigs treated with MTPi compared to controls (P Conclusion These results suggest that JTT-130 could have potential clinical applications due to its plasma lipid lowering effects with no alterations in hepatic lipid concentrations.

  1. Dichlorodiphenyltrichloroethane technical mixture regulates cell cycle and apoptosis genes through the activation of CAR and ERα in mouse livers

    Energy Technology Data Exchange (ETDEWEB)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A. [Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Timakova str., 2, 630117 (Russian Federation); Pustylnyak, Vladimir O., E-mail: pustylnyak@ngs.ru [Institute of Molecular Biology and Biophysics SB RAMS, Novosibirsk, Timakova str., 2, 630117 (Russian Federation); Novosibirsk State University, Novosibirsk, Pirogova str., 2, 630090 (Russian Federation)

    2013-09-01

    Dichlorodiphenyltrichloroethane (DDT) is a widely used organochlorine pesticide and a xenoestrogen that promotes rodent hepatomegaly and tumours. A recent study has shown significant correlation between DDT serum concentration and liver cancer incidence in humans, but the underlying mechanisms remain elusive. We hypothesised that a mixture of DDT isomers could exert effects on the liver through pathways instead of classical ERs. The acute effects of a DDT mixture containing the two major isomers p,p′-DDT (85%) and o,p′-DDT (15%) on CAR and ERα receptors and their cell cycle and apoptosis target genes were studied in mouse livers. ChIP results demonstrated increased CAR and ERα recruitment to their specific target gene binding sites in response to the DDT mixture. The results of real-time RT-PCR were consistent with the ChIP data and demonstrated that the DDT was able to activate both CAR and ERα in mouse livers, leading to target gene transcriptional increases including Cyp2b10, Gadd45β, cMyc, Mdm2, Ccnd1, cFos and E2f1. Western blot analysis demonstrated increases in cell cycle progression proteins cMyc, Cyclin D1, CDK4 and E2f1 and anti-apoptosis proteins Mdm2 and Gadd45β. In addition, DDT exposure led to Rb phosphorylation. Increases in cell cycle progression and anti-apoptosis proteins were accompanied by a decrease in p53 content and its transcriptional activity. However, the DDT was unable to stimulate the β-catenin signalling pathway, which can play an important role in hepatocyte proliferation. Thus, our results indicate that DDT treatment may result in cell cycle progression and apoptosis inhibition through CAR- and ERα-mediated gene activation in mouse livers. These findings suggest that the proliferative and anti-apoptotic conditions induced by CAR and ERα activation may be important contributors to the early stages of hepatocarcinogenesis as produced by DDT in rodent livers. - Highlights: • DDT activated both CAR and ERα and their cell

  2. Dichlorodiphenyltrichloroethane technical mixture regulates cell cycle and apoptosis genes through the activation of CAR and ERα in mouse livers

    International Nuclear Information System (INIS)

    Kazantseva, Yuliya A.; Yarushkin, Andrei A.; Pustylnyak, Vladimir O.

    2013-01-01

    Dichlorodiphenyltrichloroethane (DDT) is a widely used organochlorine pesticide and a xenoestrogen that promotes rodent hepatomegaly and tumours. A recent study has shown significant correlation between DDT serum concentration and liver cancer incidence in humans, but the underlying mechanisms remain elusive. We hypothesised that a mixture of DDT isomers could exert effects on the liver through pathways instead of classical ERs. The acute effects of a DDT mixture containing the two major isomers p,p′-DDT (85%) and o,p′-DDT (15%) on CAR and ERα receptors and their cell cycle and apoptosis target genes were studied in mouse livers. ChIP results demonstrated increased CAR and ERα recruitment to their specific target gene binding sites in response to the DDT mixture. The results of real-time RT-PCR were consistent with the ChIP data and demonstrated that the DDT was able to activate both CAR and ERα in mouse livers, leading to target gene transcriptional increases including Cyp2b10, Gadd45β, cMyc, Mdm2, Ccnd1, cFos and E2f1. Western blot analysis demonstrated increases in cell cycle progression proteins cMyc, Cyclin D1, CDK4 and E2f1 and anti-apoptosis proteins Mdm2 and Gadd45β. In addition, DDT exposure led to Rb phosphorylation. Increases in cell cycle progression and anti-apoptosis proteins were accompanied by a decrease in p53 content and its transcriptional activity. However, the DDT was unable to stimulate the β-catenin signalling pathway, which can play an important role in hepatocyte proliferation. Thus, our results indicate that DDT treatment may result in cell cycle progression and apoptosis inhibition through CAR- and ERα-mediated gene activation in mouse livers. These findings suggest that the proliferative and anti-apoptotic conditions induced by CAR and ERα activation may be important contributors to the early stages of hepatocarcinogenesis as produced by DDT in rodent livers. - Highlights: • DDT activated both CAR and ERα and their cell

  3. Atypical antipsychotic medications increase postprandial triglyceride and glucose levels in male rats: relationship with stearoyl-CoA desaturase activity.

    Science.gov (United States)

    McNamara, Robert K; Jandacek, Ronald; Rider, Therese; Tso, Patrick; Cole-Strauss, Allyson; Lipton, Jack W

    2011-06-01

    Recent preclinical and clinical evidence suggests that the stearoyl-CoA desaturase-1 (Scd1) enzyme plays a key role in the regulation of triglyceride (TG) biosynthesis and insulin sensitivity, and in vitro studies have found that antipsychotic medications up-regulate Scd1 mRNA expression. To investigate these effects in vivo, rats were treated with risperidone (1.5, 3, and 6mg/kg/d), paliperidone (1.5, 3, and 6mg/kg/d), olanzapine (2.5, 5, and 10mg/kg/d), quetiapine (5, 10, and 20mg/kg/d), haloperidol (1, and 3mg/kg/d) or vehicle through their drinking water for 40days. Effects on liver Scd1 mRNA expression and an index of Scd1 activity (the plasma 18:1/18:0 ratio, 'desaturation index') were determined, as were postprandial plasma triglyceride (TG), glucose, insulin, and polyunsaturated fatty acid (PUFA) levels. All atypical antipsychotics increased the plasma 18:1/18:0 ratio, but not liver Scd1 mRNA expression, at doses found to also increase plasma TG levels. Among all rats (n=122), the plasma 18:1/18:0 ratio accounted for 56% of the variance in TG concentrations. The plasma 18:1/18:0 ratio was also positively associated with erythrocyte and heart membrane phospholipid 18:1n-9 composition. All antipsychotics except risperidone increased glucose levels at specific doses, and none of the antipsychotics significantly altered insulin levels. The plasma 18:1/18:0 ratio accounted for 20% of the variance in glucose levels. Plasma omega-3 and omega-6 PUFA levels were inversely correlated with the plasma 18:1/18:0 ratio and TG and glucose levels. These in vivo data demonstrate that different atypical antipsychotic medications increase the plasma 18:1/18:0 ratio in association with elevations in postprandial TG and glucose levels, and that concomitant elevations in PUFA biosynthesis oppose these effects. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Up-regulation of calreticulin in mouse liver tissues after long-term irradiation with low-dose-rate gamma rays.

    Science.gov (United States)

    Yi, Lan; Hu, Nan; Yin, Jie; Sun, Jing; Mu, Hongxiang; Dai, Keren; Ding, Dexin

    2017-01-01

    The biological effects of low-dose or low-dose-rate ionizing radiation on normal tissues has attracted attention. Based on previous research, we observed the morphology of liver tissues of C57BL/6J mice that received irradiation dose rates increased. Additionally, differential protein expression in liver tissues was analyzed using a proteomics approach. Compared with the matched group in the 2D gel analysis of the irradiated groups, 69 proteins had ≥ 1.5-fold changes in expression. Twenty-three proteins were selected based on ≥2.5-fold change in expression, and 22 of them were meaningful for bioinformatics and protein fingerprinting analysis. These molecules were relevant to cytoskeleton processes, cell metabolism, biological defense, mitochondrial damage, detoxification and tumorigenesis. The results from real-time PCR and western blot (WB) analyses showed that calreticulin (CRT) was up-regulated in the irradiated groups, which indicates that CRT may be relevant to stress reactions when mouse livers are exposed to low-dose irradiation and that low-dose-rate ionizing radiation may pose a cancer risk. The CRT protein can be a potential candidate for low-dose or low-dose-rate ionizing radiation early-warning biomarkers. However, the underlying mechanism requires further investigation.

  5. Nonfasting triglycerides, cholesterol, and ischemic stroke in the general population

    DEFF Research Database (Denmark)

    Varbo, Anette; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne

    2011-01-01

    Current guidelines on stroke prevention have recommendations on desirable cholesterol levels, but not on nonfasting triglycerides. We compared stepwise increasing levels of nonfasting triglycerides and cholesterol for their association with risk of ischemic stroke in the general population....

  6. The common P446L polymorphism in GCKR inversely modulates fasting glucose and triglyceride levels and reduces type 2 diabetes risk in the DESIR prospective general French population.

    Science.gov (United States)

    Vaxillaire, Martine; Cavalcanti-Proença, Christine; Dechaume, Aurélie; Tichet, Jean; Marre, Michel; Balkau, Beverley; Froguel, Philippe

    2008-08-01

    Hepatic glucokinase (GCK) is a key regulator of glucose storage and disposal in the liver, where its activity is competitively modulated, with respect to glucose, by binding to glucokinase regulatory protein (GCKR) in the presence of fructose 6-phosphate. Genome-wide association studies for type 2 diabetes identified GCKR as a potential locus for modulating triglyceride levels. We evaluated, in a general French population, the contribution of the GCKR rs1260326-P446L polymorphism to quantitative metabolic parameters and to dyslipidemia and hyperglycemia risk. Genotype effects of rs1260326 were studied in 4,833 participants from the prospective DESIR (Data from an Epidemiological Study on the Insulin Resistance syndrome) cohort both at inclusion and using the measurements at follow-up. The minor T-allele of rs1260326 was strongly associated with lower fasting glucose (-1.43% per T-allele; P = 8 x 10(-13)) and fasting insulin levels (-4.23%; P = 3 x 10(-7)), lower homeostasis model assessment of insulin resistance index (-5.69%; P = 1 x 10(-8)), and, conversely, higher triglyceride levels (3.41%; P = 1 x 10(-4)) during the 9-year study. These effects relate to a lower risk of hyperglycemia (odds ratio [OR] 0.79 [95% CI 0.70-0.88]; P = 4 x 10(-5)) and of incident cases during the study (hazard ratio [HR] 0.83 [0.74-0.95]; P = 0.005). Moreover, an additive effect of GCKR rs1260326(T) and GCK (-30G) alleles conferred lower fasting glycemia (P = 1 x 10(-13)), insulinemia (P = 5 x 10(-6)), and hyperglycemia risk (P = 1 x 10(-6)). GCKR-L446 carriers are protected against type 2 diabetes despite higher triglyceride levels and risk of dyslipidemia, which suggests a potential molecular mechanism by which these two components of the metabolic syndrome can be dissociated.

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

    Science.gov (United States)

    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.

  8. GPIHBP1 and Plasma Triglyceride Metabolism.

    Science.gov (United States)

    Fong, Loren G; Young, Stephen G; Beigneux, Anne P; Bensadoun, André; Oberer, Monika; Jiang, Haibo; Ploug, Michael

    2016-07-01

    GPIHBP1, a GPI-anchored protein in capillary endothelial cells, is crucial for the lipolytic processing of triglyceride-rich lipoproteins (TRLs). GPIHBP1 shuttles lipoprotein lipase (LPL) to its site of action in the capillary lumen and is essential for the margination of TRLs along capillaries - such that lipolytic processing can proceed. GPIHBP1 also reduces the unfolding of the LPL catalytic domain, thereby stabilizing LPL catalytic activity. Many different GPIHBP1 mutations have been identified in patients with severe hypertriglyceridemia (chylomicronemia), the majority of which interfere with folding of the protein and abolish its capacity to bind and transport LPL. The discovery of GPIHBP1 has substantially revised our understanding of intravascular triglyceride metabolism but has also raised many new questions for future research. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. Up-regulation of hepatic Acyl CoA: Diacylglycerol acyltransferase-1 (DGAT-1) expression in nephrotic syndrome.

    Science.gov (United States)

    Vaziri, Nosratola D; Kim, Choong H; Phan, Dennis; Kim, Sara; Liang, Kaihui

    2004-07-01

    Nephrotic syndrome is associated with hypercholesterolemia, hypertriglyceridemia, and marked elevations of plasma low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL). Hypertriglyceridemia in nephrotic syndrome is accompanied by increased hepatic fatty acid synthesis, elevated triglyceride secretion, as well as lipoprotein lipase, VLDL-receptor, and hepatic triglyceride lipase deficiencies, which lead to impaired clearance of triglyceride-rich lipoproteins. Acyl CoA: diacylglycerol acyltransferase (DGAT) is a microsomal enzyme that joins acyl CoA to 1, 2-diacylglycerol to form triglyceride. Two distinct DGATs (DGAT-1 and DGAT2) have recently been identified in the liver and other tissues. The present study tested the hypothesis that the reported increase in hepatic triglyceride secretion in nephrotic syndrome may be caused by up-regulation of DGAT. Male Sprague-Dawley rats were rendered nephrotic by two sequential injections of puromycin aminonucleoside (130 mg/kg on day 1 and 60 mg/kg on day 14) and studied on day 30. Placebo-treated rats served as controls. Hepatic DGAT-1 and DGAT-2 mRNA abundance and enzymatic activity were measured. The nephrotic group exhibited heavy proteinuria, hypoalbuminemia, hypercholesterolemia, hypertriglyceridemia, and marked elevation of VLDL concentration. Hepatic DGAT-1 mRNA, DGAT-1, and total DGAT activity were significantly increased, whereas DGAT-2 mRNA abundance and activity were unchanged in the nephrotic rats compared to the control animals. The functional significance of elevation of DGAT activity was illustrated by the reduction in microsomal free fatty acid concentration in the liver of nephrotic animals. Nephrotic syndrome results in up-regulation of hepatic DGAT-1 expression and activity, which can potentially contribute to the associated hypertriglyceridemia by enhancing triglyceride synthesis. Thus, it appears that both depressed catabolism and increased synthetic capacity contribute to

  10. Sexually dimorphic effects of maternal nutrient reduction on expression of genes regulating cortisol metabolism in fetal baboon adipose and liver tissues.

    Science.gov (United States)

    Guo, Chunming; Li, Cun; Myatt, Leslie; Nathanielsz, Peter W; Sun, Kang

    2013-04-01

    Maternal nutrient reduction (MNR) during fetal development may predispose offspring to chronic disease later in life. Increased regeneration of active glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) in metabolic tissues is fundamental to the developmental programming of metabolic syndrome, but underlying mechanisms are unknown. Hexose-6-phosphate dehydrogenase (H6PD) generates NADPH, the cofactor for 11β-HSD1 reductase activity. CCAAT/enhancer binding proteins (C/EBPs) and the glucocorticoid receptor (GR) regulate 11β-HSD1 expression. We hypothesize that MNR increases expression of fetal C/EBPs, GR, and H6PD, thereby increasing expression of 11β-HSD1 and reductase activity in fetal liver and adipose tissues. Pregnant MNR baboons ate 70% of what controls ate from 0.16 to 0.9 gestation (term, 184 days). Cortisol levels in maternal and fetal circulations increased in MNR pregnancies at 0.9 gestation. MNR increased expression of 11β-HSD1; H6PD; C/EBPα, -β, -γ; and GR in female but not male perirenal adipose tissue and in male but not female liver at 0.9 gestation. Local cortisol level and its targets PEPCK1 and PPARγ increased correspondingly in adipose and liver tissues. C/EBPα and GR were found to be bound to the 11β-HSD1 promoter. In conclusion, sex- and tissue-specific increases of 11β-HSD1, H6PD, GR, and C/EBPs may contribute to sexual dimorphism in the programming of exaggerated cortisol regeneration in liver and adipose tissues and offsprings' susceptibility to metabolic syndrome.

  11. Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease.

    Science.gov (United States)

    Ter Horst, Kasper W; Serlie, Mireille J

    2017-09-06

    Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be used for gluconeogenesis and de novo lipogenesis (DNL). Fructose-derived precursors also act as nutritional regulators of the transcription factors, including ChREBP and SREBP1c, that regulate the expression of hepatic gluconeogenesis and DNL genes. In support of these mechanisms, fructose intake increases hepatic gluconeogenesis and DNL and raises plasma glucose and triglyceride levels in humans. However, epidemiological and fructose-intervention studies have had inconclusive results with respect to liver fat, and there is currently no good human evidence that fructose, when consumed in isocaloric amounts, causes more liver fat accumulation than other energy-dense nutrients. In this review, we aim to provide an overview of the seemingly contradicting literature on fructose and NAFLD. We outline fructose physiology, the mechanisms that link fructose to NAFLD, and the available evidence from human studies. From this framework, we conclude that the cellular mechanisms underlying hepatic fructose metabolism will likely reveal novel targets for the treatment of NAFLD, dyslipidemia, and hepatic insulin resistance. Finally, fructose-containing sugars are a major source of excess calories, suggesting that a reduction of their intake has potential for the prevention of NAFLD and other obesity-related diseases.

  12. Triglycerides as an early pathophysiological marker of endothelial dysfunction in nondiabetic women with a previous history of gestational diabetes.

    Science.gov (United States)

    Sokup, Alina; Góralczyk, Barbara; Góralczyk, Krzysztof; Rość, Danuta

    2012-02-01

    To investigate whether baseline triglyceride levels are associated with early glucose dysregulation and/or cardiovascular risk in women with a previous history of gestational diabetes. Prospective postpregnancy cohort study. Polish university hospitals. Participants included 125 women with previous gestational diabetes and 40 women with normal glucose regulation during pregnancy. All women were studied 2-24 months (mean 12 ± 10 months) after the index pregnancy. Women with previous gestational diabetes were divided into tertiles in accordance with baseline triglyceride levels. We assessed glucose regulation (oral glucose tolerance test), insulin resistance (homeostasis model assessment), markers of endothelial dysfunction (soluble: intercellular adhesion molecule-1, vascular cell adhesion molecule-1, E-selectin, tissue plasminogen activator antigen, von Willebrand factor antigen), fibrinolysis (plasminogen activator inhibitor antigen), inflammation (high-sensitivity C-reactive protein) and lipid levels. Women with previous gestational diabetes (78% normal glucose regulation, 22% impaired glucose tolerance) had a high cardiometabolic risk profile compared with control women (100% normal glucose regulation). Baseline triglycerides >0.83 mmol/l were associated with a higher prevalence of impaired glucose tolerance, higher high-sensitivity C-reactive protein and triglyceride/high-density lipoprotein-cholesterol ratio. Triglycerides >1.22 mmol/l were associated with higher body fat indexes, higher insulin resistance, higher levels of endothelial dysfunction biomarkers, higher plasminogen activator inhibitor antigen and dyslipidemia. Only E-selectin was independently associated with triglyceride levels. Baseline triglyceride levels are a cardiovascular risk marker as well as a pathophysiological parameter independently associated with endothelial dysfunction in nondiabetic women with previous gestational diabetes at 2-24 months after an index pregnancy. Normalization of

  13. Aqueous extract of Tribulus terrestris Linn induces cell growth arrest and apoptosis by down-regulating NF-κB signaling in liver cancer cells.

    Science.gov (United States)

    Kim, Hye Jin; Kim, Jin Chul; Min, Jung Sun; Kim, Mi-Jee; Kim, Ji Ae; Kor, Myung Ho; Yoo, Hwa Seung; Ahn, Jeong Keun

    2011-06-14

    A medicinal herb Tribulus terrestris Linn has been used to treat various diseases including hepatocellular carcinoma. The aim of the present study was to investigate the anticancer activity of Tribulus terrestris Linn (TT) in liver cancer cells. The antitumor activity of aqueous TT extract was analyzed by testing the cytotoxicity and the effect on clonogenecity in HepG2 cells. Apoptosis and cell cycle arrest induced by TT were dissected by flow cytometry and its inhibitory effect on NF-κB activity was determined by analyzing the expression levels of NF-κB/IκB subunit proteins. The suppression of NF-κB-regulated gene expression by TT was assessed by RT-PCR. TT extract repressed clonogenecity and proliferation, induced apoptosis, and enhanced accumulation in the G0/G1 phase of liver cancer cells. It also turned out that TT extract inhibited NF-κB-dependent reporter gene expression and NF-κB subunit p50 expression, while it enhanced the cellular level of IκBα by inhibiting the phosphorylation and degradation of IκBα. In addition, IKK activity was inhibited in a dose-dependent manner. Furthermore, TT extract suppressed the transcription of genes associated with cell cycle regulation, anti-apoptosis, and invasion. These data showed that TT extract blocks proliferation and induces apoptosis in human liver cancer cells through the inhibition of NF-κB signaling. Aqueous TT extract can be used as an anticancer drug for hepatocellular carcinoma patients. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  14. Alcohol extract of North American ginseng (Panax quinquefolius) reduces fatty liver, dyslipidemia, and other complications of metabolic syndrome in a mouse model.

    Science.gov (United States)

    Singh, Ratnesh K; Lui, Edmund; Wright, David; Taylor, Adrian; Bakovic, Marica

    2017-09-01

    We investigated whether North American ginseng (Panax quinquefolius) could reduce development of the metabolic syndrome phenotype in a mouse model (ETKO) of the disease. Young ETKO mice have no disease but similar to humans start to develop the fatty liver, hypertriglyceridemia, obesity, and insulin resistance at 25-30 weeks of age, and the disease continues to progress with ageing. ETKO mice were orally given an ethanol extract of ginseng roots at 4 and 32 weeks of age. Treatments with ginseng eliminated the ETKO fatty liver, reduced hepatic and intestinal lipoprotein secretion, and reduced the level of circulating lipids. Improvements by ginseng treatments were manifested as a reduction in the expression of genes involved in the regulation of fatty acid and triglyceride (fat) synthesis and secretion by the lipoproteins on one hand, and the stimulation of fatty acid oxidation and triglyceride degradation by lipolysis on the other hand. These processes altogether improved glucose, fatty acid, and triglyceride metabolism, reduced liver fat load, and reversed the progression of metabolic syndrome. These data confirm that treatments with North American ginseng could alleviate metabolic syndrome through the maintenance of a better balance between glucose and fatty acid metabolism, lipoprotein secretion, and energy homeostasis in disease-prone states.

  15. [Effects of Chinese herbal medicines for regulating liver qi on expression of 5-hydroxytryptamine 3B receptor in hypothalamic tissues of rats with anger emotion].

    Science.gov (United States)

    Ge, Qing-fang; Zhang, Hui-yun

    2011-08-01

    To explore the central mechanisms of anger emotion and the effects of Chinese herbal medicines for regulating liver qi on the anger emotion and the expression level of 5-hydroxytryptamine 3B receptor (5-HT3BR) in rat hypothalamus. Rat models of anger-in or anger-out emotions were prepared by the methods of resident intruder paradigm. There were five groups in this study: control, anger-in model, Jingqianshu Granule-treated anger-in, anger-out model and Jingqianping Granule-treated anger-out groups. The treatment groups were orally given Jingqianshu granules and Jingqianping granules respectively, and the model groups and the normal control group were given sterile water. Open-field test and sucrose preference test were used to evaluate behavioristics of the rats. Semi-quantitative reverse transcription-polymerase chain reaction and Western blot methods were used to detect the expression levels of 5-HT3BR mRNA and protein in the rat hypothalamus. The expression of 5-HT3BR in hypothalamus of anger-in model rats increased obviously (Pexpressions of 5-HT3BR in the treatment groups were significantly improved (Pexpression and the anger-out emotion can obviously reduce its expression. Chinese herbal medicines for regulating liver qi may treat anger emotion in rats by improving the hypothalamic 5-HT3BR protein and gene expression levels.

  16. Eicosapentaenoic Acid-Enriched Phosphatidylcholine Attenuated Hepatic Steatosis Through Regulation of Cholesterol Metabolism in Rats with Nonalcoholic Fatty Liver Disease.

    Science.gov (United States)

    Liu, Yanjun; Shi, Di; Tian, Yingying; Liu, Yuntao; Zhan, Qiping; Xu, Jie; Wang, Jingfeng; Xue, Changhu

    2017-02-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Disturbed cholesterol metabolism plays a crucial role in the development of NAFLD. The present study was conducted to evaluate the effects of EPA-PC extracted from sea cucumber on liver steatosis and cholesterol metabolism in NAFLD. Male Wistar rats were randomly divided into seven groups (normal control group, model group, lovastatin group, low- and high-dose EPA groups, and low- and high-dose EPA-PC groups). Model rats were established by administering a diet containing 1% orotic acid. To determine the possible cholesterol metabolism promoting mechanism of EPA-PC, we analyzed the transcription of key genes and transcriptional factors involved in hepatic cholesterol metabolism. EPA-PC dramatically alleviated hepatic lipid accumulation, reduced the serum TC concentration, and elevated HDLC levels in NAFLD rats. Fecal neutral cholesterol excretion was also promoted by EPA-PC administration. Additionally, EPA-PC decreased the mRNA expression of hydroxymethyl glutaric acid acyl (HMGR) and cholesterol 7α-hydroxylase (CYP7A), and increased the transcription of sterol carrying protein 2 (SCP2). Moreover, EPA-PC stimulated the transcription of peroxisome proliferators-activated receptor α (PPARα) and adenosine monophosphate activated protein kinase (AMPK) as well as its modulators, liver kinase B1 (LKB1) and Ca 2+ /calmodulin-dependent kinase kinase (CAMKK). Based on the results, the promoting effects of EPA-PC on NAFLD may be partly associated with the suppression of cholesterol synthesis via HMGR inhibition and the enhancement of fecal cholesterol excretion through increased SCP2 transcription. The underlying mechanism may involve stimulation of PPARα and AMPK.

  17. Regulation of collagen production in freshly isolated cell populations from normal and cirrhotic rat liver: Effect of lactate

    International Nuclear Information System (INIS)

    Cerbon-Ambriz, J.; Cerbon-Solorzano, J.; Rojkind, M.

    1991-01-01

    Previous work has shown that lactic acid, and to a lesser extent pyruvic acid, is able to increase collagen synthesis significantly in liver slices of CCl4-treated rats but not normal rats. The purpose of this report is to document which cells in the cirrhotic liver are responsible for the lactate-stimulated increase in collagen synthesis. It was found that (a) incorporation of 3H-proline into protein-bound 3H-hydroxyproline is increased threefold to fourfold in hepatocytes from CCl4-treated rats as compared with normal rat hepatocytes; (b) neither the hepatocytes from normal nor those from CCl4-treated rats modify their collagen synthesizing capacity when 30 mmol/L lactic acid was added to the incubation medium; (c) nonparenchymal cells obtained from livers of CCl4-treated rats synthesize much less collagen than hepatocytes, but their synthesis is stimulated twofold by lactic acid; (d) from the different nonparenchymal cells, only fat-storing (Ito) cells increase collagen synthesis when lactic acid is present in the incubation medium. These results suggest that the increased lactic acid levels observed in patients with alcoholic hepatic cirrhosis may play an important role in the development of fibrosis by stimulating collagen production by fat-storing (Ito) cells

  18. Hepatoprotective effect of kaempferol against alcoholic liver injury in mice.

    Science.gov (United States)

    Wang, Meng; Sun, Jianguo; Jiang, Zhihui; Xie, Wenyan; Zhang, Xiaoying

    2015-01-01

    Kaempferol is a biologically active component present in various plants. The hepatoprotective effect of kaempferol in drug-induced liver injury has been proven, while its effect against alcoholic liver injury (ALI) remains unclear. Hence, the present study aimed to evaluate the effect of kaempferol against ALI in mice. The experimental ALI mice model was developed and the mice were treated with different doses of kaempferol for 4 weeks. The liver functions were observed by monitoring the following parameters: Aspartate aminotransferase (AST/GOT) and alanine aminotransferase (ALT/GPT) levels in serum; histopathological studies of liver tissue; oxidative stress by hydrogen peroxide (H2O2), superoxide dismutase (SOD) and glutathione (GSH); the lipid peroxidation status by malondialdehyde (MDA) and lipid accumulation by triglyceride (TG) level in serum; and the expression levels and activities of a key microsomal enzyme cytochrome 2E1 (CYP2E1), by both in vitro and in vivo methods. The ALI mice (untreated) showed clear symptoms of liver injury, such as significantly increased levels of oxidative stress, lipid peroxidation and excessive CYP2E1 expression and activity. The mice treated with different kaempferol dosages exhibited a significant decrease in the oxidative stress as well as lipid peroxidation, and increased anti-oxidative defense activity. The kaempferol treatment has significantly reduced the expression level and activity of hepatic CYP2E1, thus indicating that kaempferol could down regulate CYP2E1. These findings show the hepatoprotective properties of kaempferol against alcohol-induced liver injury by attenuating the activity and expression of CYP2E1 and by enhancing the protective role of anti-oxidative defense system.

  19. CREBH Regulates Systemic Glucose and Lipid Metabolism

    Directory of Open Access Journals (Sweden)

    Yoshimi Nakagawa

    2018-05-01

    Full Text Available The cyclic adenosine monophosphate (cAMP-responsive element-binding protein H (CREBH, encoded by CREB3L3 is a membrane-bound transcriptional factor that primarily localizes in the liver and small intestine. CREBH governs triglyceride metabolism in the liver, which mediates the changes in gene expression governing fatty acid oxidation, ketogenesis, and apolipoproteins related to lipoprotein lipase (LPL activation. CREBH in the small intestine reduces cholesterol transporter gene Npc1l1 and suppresses cholesterol absorption from diet. A deficiency of CREBH in mice leads to severe hypertriglyceridemia, fatty liver, and atherosclerosis. CREBH, in synergy with peroxisome proliferator-activated receptor α (PPARα, has a crucial role in upregulating Fgf21 expression, which is implicated in metabolic homeostasis including glucose and lipid metabolism. CREBH binds to and functions as a co-activator for both PPARα and liver X receptor alpha (LXRα in regulating gene expression of lipid metabolism. Therefore, CREBH has a crucial role in glucose and lipid metabolism in the liver and small intestine.

  20. From whole body to cellular models of hepatic triglyceride metabolism: man has got to know his limitations.

    Science.gov (United States)

    Green, Charlotte J; Pramfalk, Camilla; Morten, Karl J; Hodson, Leanne

    2015-01-01

    The liver is a main metabolic organ in the human body and carries out a vital role in lipid metabolism. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, encompassing a spectrum of conditions from simple fatty liver (hepatic steatosis) through to cirrhosis. Although obesity is a known risk factor for hepatic steatosis, it remains unclear what factor(s) is/are responsible for the primary event leading to retention of intrahepatocellular fat. Studying hepatic processes and the etiology and progression of disease in vivo in humans is challenging, not least as NAFLD may take years to develop. We present here a review of experimental models and approaches that have been used to assess liver triglyceride metabolism and discuss their usefulness in helping to understand the aetiology and development of NAFLD. Copyright © 2015 the American Physiological Society.

  1. Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics.

    Science.gov (United States)

    Bauer, Robert C; Khetarpal, Sumeet A; Hand, Nicholas J; Rader, Daniel J

    2016-04-01

    Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. Copyright © 2016. Published by Elsevier Ltd.

  2. Determining triglyceride reductions needed for clinical impact in severe hypertriglyceridemia.

    Science.gov (United States)

    Christian, Jennifer B; Arondekar, Bhakti; Buysman, Erin K; Jacobson, Terry A; Snipes, Rose G; Horwitz, Ralph I

    2014-01-01

    Patients with severe hypertriglyceridemia have an increased risk of cardiovascular disease and pancreatitis. Target triglyceride levels associated with clinical benefit for patients with severe hypertriglyceridemia are not currently known. This study evaluates the association between lower follow-up triglyceride levels and incidence of clinical events for patients with severe hypertriglyceridemia. By using claims data from 2 large US healthcare databases, we conducted a retrospective cohort study and identified 41,210 adults with severe hypertriglyceridemia (triglycerides ≥ 500 mg/dL) between June 2001 and September 2010. The date of the first severe hypertriglyceridemia laboratory result was the index date. Patients were categorized into 1 of 5 triglyceride ranges (severe hypertriglyceridemia with follow-up triglyceride levels severe hypertriglyceridemia with follow-up triglyceride levels 200 to 299 mg/dL and 300 to 399 mg/dL (P severe hypertriglyceridemia with the lowest follow-up triglyceride levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  3. Pretreatment of liver grafts in vivo by γ-aminobutyric acid receptor regulation reduces cold ischemia/warm reperfusion injury in rat

    Science.gov (United States)

    Hori, Tomohide; Gardner, Lindsay B.; Hata, Toshiyuki; Chen, Feng; Baine, Ann-Marie T.; Uemoto, Shinji; Nguyen, Justin H.

    2014-01-01

    Summary Background: Gamma-aminobutyric acid (GABA) is found throughout the body. The regulation of GABA receptor (GABAR) reduces oxidative stress (OS). Ischemia/reperfusion injury after orthotopic liver transplantation (OLT) causes OS-induced graft damage. The effects of GABAR regulation in donors in vivo were investigated. Material/Methods: Donor rats received saline, a GABAR agonist or GABAR antagonist 4 h before surgery. Recipient rats were divided into four groups according to the donor treatments: laparotomy, OLT with saline, OLT with GABAR agonist and OLT with GABAR antagonist. Histopathological, biochemical and immunohistological examinations were performed at 6, 12 and 24 h after OLT. Protein assays were performed at 6 h after OLT. The 4-hydroxynonenal (4-HNE), ataxia-telangiectasia mutated kinase (ATM), phosphorylated histone H2AX (γH2AX), phosphatidylinositol-3 kinase (PI3K), Akt and superoxide dismutase (SOD) were assessed by western blot analysis. Results: In the univariate analysis, histopathological and biochemical profiles verified that the GABAR agonist reduced graft damage. Immunohistology revealed that the GABAR agonist prevented the induction of apoptosis. Measurement of 4-4-HNE levels confirmed OS-induced damage after OLT, and the GABAR agonist improved this damage. In the γH2AX, PI3K, Akt and antioxidant enzymes (SODs), ATM and H2AX were greatly increased after OLT, and were reduced by the GABAR agonist. In the multivariate analyses between multiple groups, histopathological assessment, aspartate aminotransferase level, immunohistological examinations for apoptotic induction and γH2AX showed statistical differences. Conclusions: A specific agonist demonstrated regulation of GABAR in vivo in the liver. This activation in vivo reduced OS after OLT via the ATM/H2AX pathway. PMID:23792534

  4. New therapeutic strategies for canine liver disease; Growth factors and liver progenitor cells

    NARCIS (Netherlands)

    Arends, B.

    2008-01-01

    The liver has the unique capacity to regulate its mass after loss of functional liver cells due to liver disease, injury, and/or toxicity. Unfortunately, in the course of chronic liver disease this meticulously regulated regeneration process is imbalanced resulting in a decreased regenerative

  5. Liver Hemangioma

    Science.gov (United States)

    Liver hemangioma Overview A liver hemangioma (he-man-jee-O-muh) is a noncancerous (benign) mass in the liver. A liver hemangioma is made up of a tangle of blood vessels. Other terms for a liver hemangioma are hepatic hemangioma and cavernous hemangioma. Most ...

  6. Free methionine supplementation limits alcohol-induced liver damage in rats

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Bode, C.; Bode, J.C.

    1998-01-01

    Alcohol feeding to rats that were submitted to a jejunoileal bypass operation has been shown to result in liver damage being comparable with alcohol-induced liver disease in man. In the present study, a striking effect of free methionine consumption on histological liver injury, triglyceride accu...

  7. Glycogen storage disease type Ia: linkage of glucose, glycogen, lactic acid, triglyceride, and uric acid metabolism.

    Science.gov (United States)

    Sever, Sakine; Weinstein, David A; Wolfsdorf, Joseph I; Gedik, Reyhan; Schaefer, Ernst J

    2012-01-01

    A female presented in infancy with hypotonia, undetectable serum glucose, lactic acidosis, and triglycerides >5000 mg/dL. The diagnosis of type 1A glycogen storage disease was made via the result of a liver biopsy, which showed increased glycogen and absent glucose-6-phosphatase enzyme activity. The patient was treated with dextrose administered orally, which was replaced by frequent feedings of cornstarch, which resulted in an improvement of her metabolic parameters. At age 18 years of age, she had marked hypertriglyceridemia (3860 mg/dL) and eruptive xanthomas and was treated with fenofibrate, atorvastatin, and fish oil. At age 29 years she was noted to have multiple liver adenomas, severe anemia, and hyperuricemia. Aggressive cornstarch therapy was commenced with a goal of maintaining her blood glucose levels >75 mg/dL and lactate levels triglycerides 179, high-density lipoprotein cholesterol 32, and calculated low-density lipoprotein cholesterol 154. Her weight was stable with a body mass index of 24.8 kg/m(2). Her liver adenomas had decreased in size, and her anemia and hyperuricemia had improved. She was homozygous for the R83C missense mutation in G6PC. Our data indicate that optimized metabolic control to maintain blood glucose levels >75 mg/dL is critical in the management of this disease. Copyright © 2012. Published by Elsevier Inc.

  8. Plasma lipids, lipoproteins, and triglyceride turnover in eu- and hypo-thyroid rats and rats on a hypocaloric diet.

    Science.gov (United States)

    Dory, L; Krause, B R; Roheim, P S

    1981-08-01

    Lipid and lipoprotein concentration, and triglyceride turnover were studied in control, thyroidectomized, and pair-fed control rats (pair-fed to match the food intake of the thyroidectomized rats). Thyroidectomy induced a significant increase in plasma cholesterol (and low density lipoprotein) concentrations and a decrease in plasma triglyceride (and very low density lipoprotein) concentrations. Changes in similar direction but of smaller magnitude were observed in the plasma of the pair-fed control rats. To further investigate triglyceride metabolism in these three groups of animals, triglyceride turnover was studied in fasted, unrestrained, and unanesthetized rats, following injection of [2-3H]glycerol. Peak incorporation of [2-3H]glycerol into plasma triglyceride occurred in all three groups of animals at 25 min after precursor administration, although the maximal incorporation was substantially lower in the thyroidectomized group than in either of the control groups. Thereafter, plasma triglyceride radioactivity decayed monoexponentially with a half-life of 24 +/- 1 min for both normal and pair-fed control rats, compared with the half-life of 41 +/- 3 min observed in the thyroidectomized rats. The calculated apparent fractional catabolic rates were thus 0.029 min-1 for both control groups and only 0.017 min-1 for the thyroidectomized animals. The apparent total catabolic rates of plasma triglyceride were 299 +/- 11, 138 +/- 11, and 48 +/- 4 micrograms triglyceride . min-1 for the normal controls, pair-fed controls, and thyroidectomized rats, respectively. These data further emphasize the importance of thyroid hormones in regulating plasma lipid and lipoprotein metabolism and, specifically, indicate that hypothyroidism results in a reduction of triglyceride secretion into, and the removal from, circulation. Furthermore, evidence was presented that the decreased caloric intake of the hypothyroid animals cannot, in itself, account for this observation.

  9. Liver biopsy

    Science.gov (United States)

    Biopsy - liver; Percutaneous biopsy ... the biopsy needle to be inserted into the liver. This is often done by using ultrasound. The ... the chance of damage to the lung or liver. The needle is removed quickly. Pressure will be ...

  10. Hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia in sucrose-fed obese rats via two pathways.

    Science.gov (United States)

    Uebanso, Takashi; Taketani, Yutaka; Fukaya, Makiko; Sato, Kazusa; Takei, Yuichiro; Sato, Tadatoshi; Sawada, Naoki; Amo, Kikuko; Harada, Nagakatsu; Arai, Hidekazu; Yamamoto, Hironori; Takeda, Eiji

    2009-07-01

    The mechanism by which replacement of some dietary carbohydrates with protein during weight loss favors lipid metabolism remains obscure. In this study, we investigated the effect of an energy-restricted, high-protein/low-carbohydrate diet on lipid metabolism in obese rats. High-sucrose-induced obese rats were assigned randomly to one of two energy-restricted dietary interventions: a carbohydrate-based control diet (CD) or a high-protein diet (HPD). Lean rats of the same age were assigned as normal control. There was significantly greater improvement in fatty liver and hypertriglyceridemia with the HPD diet relative to the CD diet. Expression of genes regulated by fibroblast growth factor-21 (FGF21) and involved in liver lipolysis and lipid utilitization, such as lipase and acyl-CoA oxidase, increased in obese rats fed the HPD. Furthermore, there was an inverse correlation between levels of FGF21 gene expression (regulated by glucagon/insulin balance) and increased triglyceride concentrations in liver from obese rats. Expression of hepatic stearoyl-CoA desaturase-1 (SCD1), regulated primarily by the dietary carbohydrate, was also markedly reduced in the HPD group (similar to plasma triglyceride levels in fasting animals) relative to the CD group. In conclusion, a hypocaloric high-protein diet improves fatty liver and hypertriglyceridemia effectively relative to a carbohydrate diet. The two cellular pathways at work behind these benefits include stimulation of hepatic lipolysis and lipid utilization mediated by FGF21 and reduction of hepatic VLDL-TG production by SCD1 regulation.

  11. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis

    International Nuclear Information System (INIS)

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao; Cao, Di; Yu, Weibang; Zhao, Zhongxiang; Huang, Min; Jin, Jing

    2017-01-01

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. - Highlights: • VPA induced hepatic steatosis and modulated genes associated with lipid metabolism. • CD36-mediated fatty acid uptake contributed to VPA-induced lipid accumulation. • PA increased the hepatic

  12. Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis

    Energy Technology Data Exchange (ETDEWEB)

    Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China); Cao, Di [School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou (China); Yu, Weibang [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China); Zhao, Zhongxiang [School of Chinese Materia Medica, Guangzhou University of Chinese Medicine, Guangzhou (China); Huang, Min [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China); Jin, Jing, E-mail: jinjing@mail.sysu.edu.cn [School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou (China)

    2017-06-01

    Steatosis is the characteristic type of VPA-induced hepatotoxicity and may result in life-threatening hepatic lesion. Approximately 61% of patients treated with VPA have been diagnosed with hepatic steatosis through ultrasound examination. However, the mechanisms underlying VPA-induced intracellular fat accumulation are not yet fully understood. Here we demonstrated the involvement of fatty acid uptake and lipogenesis in VPA-induced hepatic steatosis in vitro and in vivo by using quantitative real-time PCR (qRT-PCR) analysis, western blotting analysis, fatty acid uptake assays, Nile Red staining assays, and Oil Red O staining assays. Specifically, we found that the expression of cluster of differentiation 36 (CD36), an important fatty acid transport, and diacylglycerol acyltransferase 2 (DGAT2) were significantly up-regulated in HepG2 cells and livers of C57B/6J mice after treatment with VPA. Furthermore, VPA treatment remarkably enhanced the efficiency of fatty acid uptake mediated by CD36, while this effect was abolished by the interference with CD36-specific siRNA. Also, VPA treatment significantly increased DGAT2 expression as a result of the inhibition of mitogen-activated protein kinase kinase (MEK) – extracellular regulated kinase (ERK) pathway; however, DGAT2 knockdown significantly alleviated VPA-induced intracellular lipid accumulation. Additionally, we also found that sterol regulatory element binding protein-1c (SREBP-1c)-mediated fatty acid synthesis may be not involved in VPA-induced hepatic steatosis. Overall, VPA-triggered over-regulation of CD36 and DGAT2 could be helpful for a better understanding of the mechanisms underlying VPA-induced hepatic steatosis and may offer novel therapeutic strategies to combat VPA-induced hepatotoxicity. - Highlights: • VPA induced hepatic steatosis and modulated genes associated with lipid metabolism. • CD36-mediated fatty acid uptake contributed to VPA-induced lipid accumulation. • PA increased the hepatic

  13. Portulaca oleracea L. alleviates liver injury in streptozotocin-induced diabetic mice

    Directory of Open Access Journals (Sweden)

    Zheng G

    2017-12-01

    Full Text Available Guoyin Zheng,1,* Fengfeng Mo,2,* Chen Ling,3,* Hao Peng,1 Wei Gu,1 Min Li,2 Zhe Chen1 1Department of Traditional Chinese Medicine, Changhai Hospital, 2Department of Military Hygiene, Second Military Medical University, 3Department of Biology, School of Life Science, Fudan University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: Purslane is a widespread succulent herb that exhibits various pharmacological effects. The purpose of this study was to evaluate the protective effect of Portulaca oleracea L. (purslane on streptozotocin-induced diabetes in mice. Oral glucose-tolerance tests were carried out to assess blood glucose levels and body weight and food intake were recorded. The biochemical parameters anti-aspartate aminotransferase, alanine aminotransferase, insulin, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα were also measured. The pathological condition of liver tissues were examined by hematoxylin–eosin staining. Rho, ROCK1, ROCK2, NFκBp65, p-NFκBp65, IκBα, and p-IκBα expression in liver tissue were analyzed by Western blot. Purslane increased body weight and decreased food intake. Purslane also significantly reduced concentrations of glucose, anti-aspartate aminotransferase, alanine ­aminotransferase, triglycerides, total cholesterol, IL-6, IL-1β, and TNFα in serum. Serum insulin was elevated with purslane treatment. In addition, pathologic liver changes in diabetic mice were also alleviated by purslane. Obtained data revealed that purslane restored the levels of Rho–NFκB signaling-related proteins in comparison with those of diabetic mice. Above all, it can be assumed that purslane might play a positive role in regulating streptozotocin-induced liver injury through suppressing the Rho–NFκB pathway. Keywords: Portulaca oleracea L., diabetes, liver injury, Rho–NFκB

  14. Exceptionally elevated triglyceride in severe lipemia retinalis

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    Yin HY

    2016-10-01

    Full Text Available Han Y Yin,1–3 Roberto Warman,2,4 Edward H Suh,2 Anny MS Cheng2,3 1Wayne State University, School of Medicine, Detroit, MI, 2Department of Ophthalmology, Florida International University, Herbert Wertheim College of Medicine, 3Ocular Surface Center, Miami, 4Division of Pediatric Ophthalmology, Nicklaus Children’s Hospital, Miami, FL, USA Purpose: To report a case of successful treatment for severe lipemia retinalis with extreme severe hypertriglyceridemia (sHTG.Design: Observational case report.Observations: A 6-week-old infant with severe lipemia retinalis manifested diffuse creamy retinal vessels complicated with vulvar xanthomas. Extreme sHTG with 185-folds of the normal level was reported. Chromosome microarray and lipid gene sequencing confirmed a homozygous lipoprotein lipase gene coding mutation.Results: Under strict adherence to a high medium-chain triglycerides formula and discontinuation of breast milk, the lipemia retinalis and vulval lesions resolved along with a stable plasma lipid level throughout the follow-up period of 6 months.Conclusion: Strict adherence to a low-fat diet without breast milk appears to be effective in treating infants with severe lipemia retinalis associated with exceptionally high triglycerides. Keywords: hypertriglyceride, infant, lipemia retinalis, lipoprotein lipase gene

  15. Integration of liver gene co-expression networks and eGWAs analyses highlighted candidate regulators implicated in lipid metabolism in pigs.

    Science.gov (United States)

    Ballester, Maria; Ramayo-Caldas, Yuliaxis; Revilla, Manuel; Corominas, Jordi; Castelló, Anna; Estellé, Jordi; Fernández, Ana I; Folch, Josep M

    2017-04-19

    In the present study, liver co-expression networks and expression Genome Wide Association Study (eGWAS) were performed to identify DNA variants and molecular pathways implicated in the functional regulatory mechanisms of meat quality traits in pigs. With this purpose, the liver mRNA expression of 44 candidates genes related with lipid metabolism was analysed in 111 Iberian x Landrace backcross animals. The eGWAS identified 92 eSNPs located in seven chromosomal regions and associated with eight genes: CROT, CYP2U1, DGAT1, EGF, FABP1, FABP5, PLA2G12A, and PPARA. Remarkably, cis-eSNPs associated with FABP1 gene expression which may be determining the C18:2(n-6)/C18:3(n-3) ratio in backfat through the multiple interaction of DNA variants and genes were identified. Furthermore, a hotspot on SSC8 associated with the gene expression of eight genes was identified and the TBCK gene was pointed out as candidate gene regulating it. Our results also suggested that the PI3K-Akt-mTOR pathway plays an important role in the control of the analysed genes highlighting nuclear receptors as the NR3C1 or PPARA. Finally, sex-dimorphism associated with hepatic lipid metabolism was identified with over-representation of female-biased genes. These results increase our knowledge of the genetic architecture underlying fat composition traits.

  16. Maternal resveratrol intake during lactation attenuates hepatic triglyceride and fatty acid synthesis in adult male rat offspring

    Directory of Open Access Journals (Sweden)

    Masato Tanaka

    2017-03-01

    regulates the lipogenic pathway by activating genes involved in triglyceride and fatty acid synthesis. The present study showed significant downregulation of hepatic fatty acid synthase (FAS and acetyl-CoA carboxylase (ACC levels in the CR group. These results indicated that maternal resveratrol intake during lactation suppressed SREBP-1c cleavage and nuclear translocation and repressed SREBP-1c target gene expression such as FAS and ACC in the livers of adult male offspring. These changes attenuate hepatic triacylglycerol and fatty acid synthesis in adult male offspring.

  17. Effect of CAR activation on selected metabolic pathways in normal and hyperlipidemic mouse livers.

    Science.gov (United States)

    Rezen, Tadeja; Tamasi, Viola; Lövgren-Sandblom, Anita; Björkhem, Ingemar; Meyer, Urs A; Rozman, Damjana

    2009-08-19

    Detoxification in the liver involves activation of nuclear receptors, such as the constitutive androstane receptor (CAR), which regulate downstream genes of xenobiotic metabolism. Frequently, the metabolism of endobiotics is also modulated, resulting in potentially harmful effects. We therefore used 1,4-Bis [2-(3,5-dichloropyridyloxy)] benzene (TCPOBOP) to study the effect of CAR activation on mouse hepatic transcriptome and lipid metabolome under conditions of diet-induced hyperlipidemia. Using gene expression profiling with a dedicated microarray, we show that xenobiotic metabolism, PPARalpha and adipocytokine signaling, and steroid synthesis are the pathways most affected by TCPOBOP in normal and hyperlipidemic mice. TCPOBOP-induced CAR activation prevented the increased hepatic and serum cholesterol caused by feeding mice a diet containing 1% cholesterol. We show that this is due to increased bile acid metabolism and up-regulated removal of LDL, even though TCPOBOP increased cholesterol synthesis under conditions of hyperlipidemia. Up-regulation of cholesterol synthesis was not accompanied by an increase in mature SREBP2 protein. As determined by studies in CAR -/- mice, up-regulation of cholesterol synthesis is however CAR-dependent; and no obvious CAR binding sites were detected in promoters of cholesterogenic genes. TCPOBOP also affected serum glucose and triglyceride levels and other metabolic processes in the liver, irrespective of the diet. Our data show that CAR activation modulates hepatic metabolism by lowering cholesterol and glucose levels, through effects on PPARalpha and adiponectin signaling pathways, and by compromising liver adaptations to hyperlipidemia.

  18. Bioinformatical Analysis of Organ-Related (Heart, Brain, Liver, and Kidney and Serum Proteomic Data to Identify Protein Regulation Patterns and Potential Sepsis Biomarkers

    Directory of Open Access Journals (Sweden)

    Andreas Hohn

    2018-01-01

    Full Text Available During the last years, proteomic studies have revealed several interesting findings in experimental sepsis models and septic patients. However, most studies investigated protein alterations only in single organs or in whole blood. To identify possible sepsis biomarkers and to evaluate the relationship between protein alteration in sepsis affected organs and blood, proteomics data from the heart, brain, liver, kidney, and serum were analysed. Using functional network analyses in combination with hierarchical cluster analysis, we found that protein regulation patterns in organ tissues as well as in serum are highly dynamic. In the tissue proteome, the main functions and pathways affected were the oxidoreductive activity, cell energy generation, or metabolism, whereas in the serum proteome, functions were associated with lipoproteins metabolism and, to a minor extent, with coagulation, inflammatory response, and organ regeneration. Proteins from network analyses of organ tissue did not correlate with statistically significantly regulated serum proteins or with predicted proteins of serum functions. In this study, the combination of proteomic network analyses with cluster analyses is introduced as an approach to deal with high-throughput proteomics data to evaluate the dynamics of protein regulation during sepsis.

  19. Differential regulation of PGC-1α expression in rat liver and skeletal muscle in response to voluntary running

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    Azhar Salman

    2010-04-01

    Full Text Available Abstract Background The beneficial actions of exercise training on lipid, glucose and energy metabolism and insulin sensitivity appear to be in part mediated by PGC-1α. Previous studies have shown that spontaneously exercised rats show at rest enhanced responsiveness to exogenous insulin, lower plasma insulin levels and increased skeletal muscle insulin sensitivity. This study was initiated to examine the functional interaction between exercise-induced modulation of skeletal muscle and liver PGC-1α protein expression, whole body insulin sensitivity, and circulating FFA levels as a measure of whole body fatty acid (lipid metabolism. Methods Two groups of male Wistar rats (2 Mo of age, 188.82 ± 2.77 g BW were used in this study. One group consisted of control rats placed in standard laboratory cages. Exercising rats were housed individually in cages equipped with running wheels and allowed to run at their own pace for 5 weeks. At the end of exercise training, insulin sensitivity was evaluated by comparing steady-state plasma glucose (SSPG concentrations at constant plasma insulin levels attained during the continuous infusion of glucose and insulin to each experimental group. Subsequently, soleus and plantaris muscle and liver samples were collected and quantified for PGC-1α protein expression by Western blotting. Collected blood samples were analyzed for glucose, insulin and FFA concentrations. Results Rats housed in the exercise wheel cages demonstrated almost linear increases in running activity with advancing time reaching to maximum value around 4 weeks. On an average, the rats ran a mean (Mean ± SE of 4.102 ± 0.747 km/day and consumed significantly more food as compared to sedentary controls (P P P P Conclusion These data suggest that PGC-1α most likely plays a restricted role in exercise-mediated improvements in insulin resistance (sensitivity and lowering of circulating FFA levels.

  20. Zingerone suppresses liver inflammation induced by antibiotic mediated endotoxemia through down regulating hepatic mRNA expression of inflammatory markers in Pseudomonas aeruginosa peritonitis mouse model.

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    Lokender Kumar

    Full Text Available Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP and inflammatory cytokines (MIP-2, IL-6 and TNF-α were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2 indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti

  1. Zingerone suppresses liver inflammation induced by antibiotic mediated endotoxemia through down regulating hepatic mRNA expression of inflammatory markers in Pseudomonas aeruginosa peritonitis mouse model.

    Science.gov (United States)

    Kumar, Lokender; Chhibber, Sanjay; Harjai, Kusum

    2014-01-01

    Antibiotic-induced endotoxin release is associated with high mortality rate even when appropriate antibiotics are used for the treatment of severe infections in intensive care units. Since liver is involved in systemic clearance and detoxification of endotoxin hence it becomes a primary target organ for endotoxin mediated inflammation. Currently available anti-inflammatory drugs give rise to serious side effects. Hence, there is an urgent need for safe and effective anti-inflammatory therapy. It is likely that anti-inflammatory phytochemicals and neutraceutical agents may have the potential to reduce the endotoxin mediated inflammation and complications associated with endotoxin release. Keeping this in mind, the present study was planned to evaluate the hepatoprotective potential of zingerone (active compound of zingiber officinale) against liver inflammation induced by antibiotic mediated endotoxemia. The selected antibiotics capable of releasing high content of endotoxin were employed for their in vivo efficacy in P.aeruginosa peritonitis model. Released endotoxin induced inflammation and zingerone as co-anti-inflammatory therapy significantly reduced inflammatory response. Improved liver histology and reduced inflammatory markers MDA, RNI, MPO, tissue damage markers (AST, ALT, ALP) and inflammatory cytokines (MIP-2, IL-6 and TNF-α) were indicative of therapeutic potential of zingerone. The mechanism of action of zingerone may be related to significant inhibition of the mRNA expression of inflammatory markers (TLR4, RelA, NF-kB2, TNF- α, iNOS, COX-2) indicating that zingerone interferes with cell signalling pathway and suppresses hyper expression of cell signaling molecules of inflammatory pathway. Zingerone therapy significantly protected liver from endotoxin induced inflammatory damage by down regulating biochemical as well as molecular markers of inflammation. In conclusion, this study provides evidence that zingerone is a potent anti

  2. 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

  3. Redox regulation of antioxidant enzymes: post-translational modulation of catalase and glutathione peroxidase activity by resveratrol in diabetic rat liver.

    Science.gov (United States)

    Sadi, Gökhan; Bozan, Davut; Yildiz, Huseyin Bekir

    2014-08-01

    Resveratrol is a strong antioxidant that exhibits blood glucose-lowering effects, which might contribute to its usefulness in preventing complications associated with diabetes. The present study aimed to investigate resveratrol effects on catalase (CAT) and glutathione peroxidase (GPx) gene and protein expression, their phosphorylation states and activities in rat liver of STZ-induced diabetes. Diabetes increased the levels of total protein phosphorylation and p-CAT, while mRNA expression, protein levels, and activity were reduced. Although diabetes induced transcriptional repression over GPx, it did not affect the protein levels and activity. When resveratrol was administered to diabetic rats, an increase in activity was associated with an increase in p-GPx levels. Decrease in Sirtuin1 (SIRT1) and nuclear factor erythroid 2-related factor (Nrf2) and increase in nuclear factor kappa B (NFκB) gene expression in diabetes were associated with a decrease in CAT and GPx mRNA expression. A possible compensatory mechanism for reduced gene expression of antioxidant enzymes is proved to be nuclear translocation of redox-sensitive Nrf2 and NFκB in diabetes which is confirmed by the increase in nuclear and decrease in cytoplasmic protein levels of Nrf2 and NFκB. Taken together, these findings revealed that an increase in the oxidized state in diabetes intricately modified the cellular phosphorylation status and regulation of antioxidant enzymes. Gene regulation of antioxidant enzymes was accompanied by nuclear translocation of Nrf2 and NFκB. Resveratrol administration also activated a coordinated cytoprotective response against diabetes-induced changes in liver tissues.

  4. Antisense oligonucleotide inhibition of apolipoprotein C-III reduces plasma triglycerides in rodents, nonhuman primates, and humans.

    Science.gov (United States)

    Graham, Mark J; Lee, Richard G; Bell, Thomas A; Fu, Wuxia; Mullick, Adam E; Alexander, Veronica J; Singleton, Walter; Viney, Nick; Geary, Richard; Su, John; Baker, Brenda F; Burkey, Jennifer; Crooke, Stanley T; Crooke, Rosanne M

    2013-05-24

    Elevated plasma triglyceride levels have been recognized as a risk factor for the development of coronary heart disease. Apolipoprotein C-III (apoC-III) represents both an independent risk factor and a key regulatory factor of plasma triglyceride concentrations. Furthermore, elevated apoC-III levels have been associated with metabolic syndrome and type 2 diabetes mellitus. To date, no selective apoC-III therapeutic agent has been evaluated in the clinic. To test the hypothesis that selective inhibition of apoC-III with antisense drugs in preclinical models and in healthy volunteers would reduce plasma apoC-III and triglyceride levels. Rodent- and human-specific second-generation antisense oligonucleotides were identified and evaluated in preclinical models, including rats, mice, human apoC-III transgenic mice, and nonhuman primates. We demonstrated the selective reduction of both apoC-III and triglyceride in all preclinical pharmacological evaluations. We also showed that inhibition of apoC-III was well tolerated and not associated with increased liver triglyceride deposition or hepatotoxicity. A double-blind, placebo-controlled, phase I clinical study was performed in healthy subjects. Administration of the human apoC-III antisense drug resulted in dose-dependent reductions in plasma apoC-III, concomitant lowering of triglyceride levels, and produced no clinically meaningful signals in the safety evaluations. Antisense inhibition of apoC-III in preclinical models and in a phase I clinical trial with healthy subjects produced potent, selective reductions in plasma apoC-III and triglyceride, 2 known risk factors for cardiovascular disease. This compelling pharmacological profile supports further clinical investigations in hypertriglyceridemic subjects.

  5. Polyploidization of liver cells.

    Science.gov (United States)

    Celton-Morizur, Séverine; Desdouets, Chantal

    2010-01-01

    Eukaryotic organisms usually contain a diploid complement of chromosomes. However, there are a number of exceptions. Organisms containing an increase in DNA content by whole number multiples of the entire set of chromosomes are defined as polyploid. Cells that contain more than two sets of chromosomes were first observed in plants about a century ago and it is now recognized that polyploidy cells form in many eukaryotes under a wide variety of circumstance. Although it is less common in mammals, some tissues, including the liver, show a high percentage of polyploid cells. Thus, during postnatal growth, the liver parenchyma undergoes dramatic changes characterized by gradual polyploidization during which hepatocytes of several ploidy classes emerge as a result of modified cell-division cycles. This process generates the successive appearance of tetraploid and octoploid cell classes with one or two nuclei (mononucleated or binucleated). Liver cells polyploidy is generally considered to indicate terminal differentiation and senescence and to lead both to the progressive loss of cell pluripotency and a markedly decreased replication capacity. In adults, liver polyploidization is differentially regulated upon loss of liver mass and liver damage. Interestingly, partial hepatectomy induces marked cell proliferation followed by an increase in liver ploidy. In contrast, during hepatocarcinoma (HCC), growth shifts to a nonpolyploidizing pattern and expansion of the diploid hepatocytes population is observed in neoplastic nodules. Here we review the current state of understanding about how polyploidization is regulated during normal and pathological liver growth and detail by which mechanisms hepatocytes become polyploid.

  6. Functional microRNA high throughput screening reveals miR-9 as a central regulator of liver oncogenesis by affecting the PPARA-CDH1 pathway

    International Nuclear Information System (INIS)

    Drakaki, Alexandra; Hatziapostolou, Maria; Polytarchou, Christos; Vorvis, Christina; Poultsides, George A.; Souglakos, John; Georgoulias, Vassilis; Iliopoulos, Dimitrios

    2015-01-01

    Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths, reflecting the aggressiveness of this type of cancer and the absence of effective therapeutic regimens. MicroRNAs have been involved in the pathogenesis of different types of cancers, including liver cancer. Our aim was to identify microRNAs that have both functional and clinical relevance in HCC and examine their downstream signaling effectors. MicroRNA and gene expression levels were measured by quantitative real-time PCR in HCC tumors and controls. A TargetScan algorithm was used to identify miR-9 downstream direct targets. A high-throughput screen of the human microRNAome revealed 28 microRNAs as regulators of liver cancer cell invasiveness. MiR-9, miR-21 and miR-224 were the top inducers of HCC invasiveness and also their expression was increased in HCC relative to control liver tissues. Integration of the microRNA screen and expression data revealed miR-9 as the top microRNA, having both functional and clinical significance. MiR-9 levels correlated with HCC tumor stage and miR-9 overexpression induced SNU-449 and HepG2 cell growth, invasiveness and their ability to form colonies in soft agar. Bioinformatics and 3′UTR luciferase analyses identified E-cadherin (CDH1) and peroxisome proliferator-activated receptor alpha (PPARA) as direct downstream effectors of miR-9 activity. Inhibition of PPARA suppressed CDH1 mRNA levels, suggesting that miR-9 regulates CDH1 expression directly through binding in its 3′UTR and indirectly through PPARA. On the other hand, miR-9 inhibition of overexpression suppressed HCC tumorigenicity and invasiveness. PPARA and CDH1 mRNA levels were decreased in HCC relative to controls and were inversely correlated with miR-9 levels. Taken together, this study revealed the involvement of the miR-9/PPARA/CDH1 signaling pathway in HCC oncogenesis. The online version of this article (doi:10.1186/s12885-015-1562-9) contains supplementary material, which is

  7. Role of PTP1B in POMC neurons during chronic high-fat diet: sex differences in regulation of liver lipids and glucose tolerance.

    Science.gov (United States)

    Aberdein, Nicola; Dambrino, Robert J; do Carmo, Jussara M; Wang, Zhen; Mitchell, Laura E; Drummond, Heather A; Hall, John E

    2018-03-01

    Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator of leptin receptor signaling and may contribute to leptin resistance in diet-induced obesity. Although PTP1B inhibition has been suggested as a potential weight loss therapy, the role of specific neuronal PTP1B signaling in cardiovascular and metabolic regulation and the importance of sex differences in this regulation are still unclear. In this study, we investigated the impact of proopiomelanocortin (POMC) neuronal PTP1B deficiency in cardiometabolic regulation in male and female mice fed a high-fat diet (HFD). When compared with control mice (PTP1B flox/flox ), male and female mice deficient in POMC neuronal PTP1B (PTP1B flox/flox /POMC-Cre) had attenuated body weight gain (males: -18%; females: -16%) and fat mass (males: -33%; female: -29%) in response to HFD. Glucose tolerance was improved by 40%, and liver lipid accumulation was reduced by 40% in PTP1B/POMC-Cre males but not in females. When compared with control mice, deficiency of POMC neuronal PTP1B did not alter mean arterial pressure (MAP) in male or female mice (males: 112 ± 1 vs. 112 ± 1 mmHg in controls; females: 106 ± 3 vs. 109 ± 3 mmHg in controls). Deficiency of POMC neuronal PTP1B also did not alter MAP response to acute stress in males or females compared with control mice (males: Δ32 ± 0 vs. Δ29 ± 4 mmHg; females: Δ22 ± 2 vs. Δ27 ± 4 mmHg). These data demonstrate that POMC-specific PTP1B deficiency improved glucose tolerance and attenuated diet-induced fatty liver only in male mice and attenuated weight gain in males and females but did not enhance the MAP and HR responses to a HFD or to acute stress.

  8. EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA); Scientific Opinion on the substantiation of health claims related to medium-chain triglycerides and reduction in body weight (ID 643, 677, 1614) pursuant to Article 13(1) of Regulation (EC) No 1924/2006

    DEFF Research Database (Denmark)

    Tetens, Inge

    claims in relation to medium-chain triglycerides and reduction in body weight. The scientific substantiation is based on the information provided by the Member States in the consolidated list of Article 13 health claims and references that EFSA has received from Member States or directly from...... stakeholders. The food constituent that is the subject of the health claims is medium-chain triglycerides. In the context of the references provided, the Panel assumes that the food constituent which is the subject of the health claims is medium-chain fatty acids, which should replace long-chain fatty acids...... in triglycerides in order to obtain the claimed effect. The Panel considers that the food constituent, medium-chain fatty acids, which is the subject of the health claims, is sufficiently characterised in relation to the claimed effect. The claimed effect is “weight management”. The target population is assumed...

  9. Quantitative evaluation of fatty liver by computed tomography in rabbits

    International Nuclear Information System (INIS)

    Kawata, R.; Sakata, K.; Kunieda, T.; Saji, S.; Doi, H.; Nozawa, Y.

    1984-01-01

    Biochemical, histologic, and computed tomographic (CT) examinations of the liver were performed in 32 rabbits in which fatty liver was induced by prolonged intravenous fat infusion. In two groups of rabbits, in which 2 and 4 g/kg/day of fat emulsion was administered, respectively, posttreatment reduction in CT value of mild degree was observed. In the group that received 8 g/kg/day of fat emulsion, posttreatment change in CT value was sufficient for a diagnosis of fatty liver of moderate degree. Reduction in CT value in fatty liver might be due largely to accumulation of triglyceride and cholesterol in the liver cells. Significant correlation was found between changes in CT value of the liver and degrees of histological fat accumulation in the liver cells. Consecutive measurement of CT values of the liver during prolonged intravenous hyperalimentation is a nonagressive method of diagnosing fatty liver

  10. DGAT and triglyceride synthesis: a new target for obesity treatment?

    Science.gov (United States)

    Chen, H C; Farese, R V

    2000-07-01

    Because triglycerides are considered essential for survival and their synthesis has been thought to occur through a single mechanism, inhibiting triglyceride synthesis has been largely unexplored as a possible target for obesity treatment. However, recent studies indicate that mice lacking acyl CoA:diacylglycerol acyltransferase (DGAT), a key enzyme in triglyceride synthesis, are viable and resistant to diet-induced obesity. Unexpectedly, this resistance is caused by a mechanism involving increased energy expenditure. These findings suggest that inhibiting specific components of triglyceride synthesis, such as DGAT, is feasible and may represent a novel approach to treating obesity.

  11. Adipocyte triglyceride turnover and lipolysis in lean and overweight subjects.

    Science.gov (United States)

    Rydén, Mikael; Andersson, Daniel P; Bernard, Samuel; Spalding, Kirsty; Arner, Peter

    2013-10-01

    Human obesity is associated with decreased triglyceride turnover and impaired lipolysis in adipocytes. We determined whether such defects also occur in subjects with only moderate increase in fat mass. Human abdominal subcutaneous adipose tissue was investigated in healthy, nonobese subjects [body mass index (BMI) > 17 kg/m(2) and BMI lean subjects (P = 0.017) with triglyceride T1/2 of 14 and 9 months, respectively (P = 0.04). Triglyceride age correlated positively with BMI (P = 0.002) but not with adipocyte volume (P = 0.2). Noradrenaline-, isoprenaline- or dibutyryl cyclic AMP-induced lipolysis was inversely correlated with triglyceride age (P maintenance of excess body fat.

  12. Zonal down-regulation and redistribution of the multidrug resistance protein 2 during bile duct ligation in rat liver

    NARCIS (Netherlands)

    Paulusma, C. C.; Kothe, M. J.; Bakker, C. T.; Bosma, P. J.; van Bokhoven, I.; van Marle, J.; Bolder, U.; Tytgat, G. N.; Oude Elferink, R. P.

    2000-01-01

    We have studied regulation of the multidrug resistance protein 2 (mrp2) during bile duct ligation (BDL) in the rat. In hepatocytes isolated after 16, 48, and 72 hours of BDL, mrp2-mediated dinitrophenyl-glutathione (DNP-GS) transport was decreased to 65%, 33%, and 33% of control values,

  13. Mesenchymal stem cells improve mouse non-heart-beating liver graft survival by inhibiting Kupffer cell apoptosis via TLR4-ERK1/2-Fas/FasL-caspase3 pathway regulation

    Directory of Open Access Journals (Sweden)

    Yang Tian

    2016-10-01

    Full Text Available Abstract Background Liver transplantation is the optimal treatment option for end-stage liver disease, but organ shortages dramatically restrict its application. Donation after cardiac death (DCD is an alternative approach that may expand the donor pool, but it faces challenges such as graft dysfunction, early graft loss, and cholangiopathy. Moreover, DCD liver grafts are no longer eligible for transplantation after their warm ischaemic time exceeds 30 min. Mesenchymal stem cells (MSCs have been proposed as a promising therapy for treatment of certain liver diseases, but the role of MSCs in DCD liver graft function remains elusive. Methods In this study, we established an arterialized mouse non-heart-beating (NHB liver transplantation model, and compared survival rates, cytokine and chemokine expression, histology, and the results of in vitro co-culture experiments in animals with or without MSC infusion. Results MSCs markedly ameliorated NHB liver graft injury and improved survival post-transplantation. Additionally, MSCs suppressed Kupffer cell apoptosis, Th1/Th17 immune responses, chemokine expression, and inflammatory cell infiltration. In vitro, PGE2 secreted by MSCs inhibited Kupffer cell apoptosis via TLR4-ERK1/2-caspase3 pathway regulation. Conclusion Our study uncovers a protective role for MSCs and elucidates the underlying immunomodulatory mechanism in an NHB liver transplantation model. Our results suggest that MSCs are uniquely positioned for use in future clinical studies owing to their ability to protect DCD liver grafts, particularly in patients for whom DCD organs are not an option according to current criteria.

  14. Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years

    DEFF Research Database (Denmark)

    Justesen, Johanne M; Andersson, Ehm Astrid; Allin, Kristine H

    2016-01-01

    Blood concentrations of triglycerides are influenced by genetic factors as well as a number of environmental factors, including adiposity and glucose homeostasis. The aim was to investigate the association between a serum triglyceride weighted genetic risk score (wGRS) and changes in fasting serum...... triglyceride level over 5 years and to test whether the effect of the wGRS was modified by 5 year changes of adiposity, insulin resistance, and lifestyle factors. A total of 3,474 nondiabetic individuals from the Danish Inter99 cohort participated in both the baseline and 5 year follow-up physical examinations...... and had information on the wGRS comprising 39 genetic variants. In a linear regression model adjusted for age, sex, and baseline serum triglyceride, the wGRS was associated with increased serum triglyceride levels over 5 years [per allele effect = 1.3% (1.0-1.6%); P = 1.0 × 10(-17)]. This triglyceride...

  15. Liver X receptor β regulates the development of the dentate gyrus and autistic-like behavior in the mouse.

    Science.gov (United States)

    Cai, Yulong; Tang, Xiaotong; Chen, Xi; Li, Xin; Wang, Ying; Bao, Xiaohang; Wang, Lian; Sun, Dayu; Zhao, Jinghui; Xing, Yan; Warner, Margaret; Xu, Haiwei; Gustafsson, Jan-Åke; Fan, Xiaotang

    2018-03-20

    The dentate gyrus (DG) of the hippocampus is a laminated brain region in which neurogenesis begins during early embryonic development and continues until adulthood. Recent studies have implicated that defects in the neurogenesis of the DG seem to be involved in the genesis of autism spectrum disorders (ASD)-like behaviors. Liver X receptor β (LXRβ) has recently emerged as an important transcription factor involved in the development of laminated CNS structures, but little is known about its role in the development of the DG. Here, we show that deletion of the LXRβ in mice causes hypoplasia in the DG, including abnormalities in the formation of progenitor cells and granule cell differentiation. We also found that expression of Notch1, a central mediator of progenitor cell self-renewal, is reduced in LXRβ-null mice. In addition, LXRβ deletion in mice results in autistic-like behaviors, including abnormal social interaction and repetitive behavior. These data reveal a central role for LXRβ in orchestrating the timely differentiation of neural progenitor cells within the DG, thereby providing a likely explanation for its association with the genesis of autism-related behaviors in LXRβ-deficient mice.

  16. Zearalenone (ZEN and Its Influence on Regulation of Gene Expression in Carp (Cyprinus carpio L. Liver Tissue

    Directory of Open Access Journals (Sweden)

    Constanze Pietsch

    2017-09-01

    Full Text Available Zearalenone (ZEN is a frequently-occurring mycotoxin in both animal and fish feeds. In order to characterize its effects on carp, three groups of fish were fed for 28 days with feeds contaminated with three different levels of ZEN (low: 332 µg kg−1, medium: 621 µg kg−1, and high: 797 µg kg−1 feed. The reversibility of the effects of ZEN was assessed by feeding all of the groups with uncontaminated feed for a further 14 days. Gene expression of immune genes in the liver tissue of the fish was analysed, revealing reduced expressions of immune, antioxidative, and estrogen-related genes after the fish had been exposed to ZEN. However, the expression of vacuole-type H+ ATPase increased substantially with ZEN exposure, thus supporting the previously-reported sensitivity of lysosomal functions to ZEN. Feeding the fish with a ZEN-free diet for a further two weeks changed the effects of ZEN on the expression of some genes, including the expressions of the cytokines IL-1β, IL-8, IL-10, and arginase 2, which were not influenced after four weeks of treatment, but showed lower values after the recovery phase in fish previously treated with ZEN compared with the control group. In summary, this study confirmed the broad effects of ZEN on different essential functions in carp and suggests that the current maximum allowable levels in compound feed are too high to prevent damage to fish.

  17. Zearalenone (ZEN) and Its Influence on Regulation of Gene Expression in Carp (Cyprinus carpio L.) Liver Tissue.

    Science.gov (United States)

    Pietsch, Constanze

    2017-09-15

    Zearalenone (ZEN) is a frequently-occurring mycotoxin in both animal and fish feeds. In order to characterize its effects on carp, three groups of fish were fed for 28 days with feeds contaminated with three different levels of ZEN (low: 332 µg kg -1 , medium: 621 µg kg -1 , and high: 797 µg kg -1 feed). The reversibility of the effects of ZEN was assessed by feeding all of the groups with uncontaminated feed for a further 14 days. Gene expression of immune genes in the liver tissue of the fish was analysed, revealing reduced expressions of immune, antioxidative, and estrogen-related genes after the fish had been exposed to ZEN. However, the expression of vacuole-type H⁺ ATPase increased substantially with ZEN exposure, thus supporting the previously-reported sensitivity of lysosomal functions to ZEN. Feeding the fish with a ZEN-free diet for a further two weeks changed the effects of ZEN on the expression of some genes, including the expressions of the cytokines IL-1β, IL-8, IL-10, and arginase 2, which were not influenced after four weeks of treatment, but showed lower values after the recovery phase in fish previously treated with ZEN compared with the control group. In summary, this study confirmed the broad effects of ZEN on different essential functions in carp and suggests that the current maximum allowable levels in compound feed are too high to prevent damage to fish.

  18. Epimorphin regulates bile duct formation via effects on mitosis orientation in rat liver epithelial stem-like cells.

    Directory of Open Access Journals (Sweden)

    Junnian Zhou

    Full Text Available Understanding how hepatic precursor cells can generate differentiated bile ducts is crucial for studies on epithelial morphogenesis and for development of cell therapies for hepatobiliary diseases. Epimorphin (EPM is a key morphogen for duct morphogenesis in various epithelial organs. The role of EPM in bile duct formation (DF from hepatic precursor cells, however, is not known. To address this issue, we used WB-F344 rat epithelial stem-like cells as model for bile duct formation. A micropattern and a uniaxial static stretch device was used to investigate the effects of EPM and stress fiber bundles on the mitosis orientation (MO of WB cells. Immunohistochemistry of liver tissue sections demonstrated high EPM expression around bile ducts in vivo. In vitro, recombinant EPM selectively induced DF through upregulation of CK19 expression and suppression of HNF3alpha and HNF6, with no effects on other hepatocytic genes investigated. Our data provide evidence that EPM guides MO of WB-F344 cells via effects on stress fiber bundles and focal adhesion assembly, as supported by blockade EPM, beta1 integrin, and F-actin assembly. These blockers can also inhibit EPM-induced DF. These results demonstrate a new biophysical action of EPM in bile duct formation, during which determination of MO plays a crucial role.

  19. Plasma glucose, cholesterol, triglyceride, and glycerol concentrations in the postmature rabbit.

    Science.gov (United States)

    Harlow, A C; Roux, J F; Shapiro, M I

    1980-02-15

    Plasma cholesterol, triglycerides, glycerol, and glucose concentrations were measured in term and postmature rabbits. The data show that the term and postmature mothers have significantly higher glycemia than their fetuses. However, triglyceride and cholesterol concentrations are lower in the postmature mother than in her fetus. Postmature fetuses are characterized by very high plasma triglyceride and cholesterol concentrations. The results demonstrate that postmaturity is accompanied by maternal and fetal lipid metabolic changes related to a decrease in the transfer of maternal fatty acids through the placenta and to a diminution in fetal liver glucose utilization. The postmature fetus is then in a relative state of fasting and must rely on its own supply of fuel (glycogen and lipids) to provide cells for growth and survival. The maternal metabolic changes can possibly be explained by a decreased utilization of maternal substrates by the fetus, the placenta becoming insufficient. The close interrelationship of fetal and maternal lipid metabolism with the activity of the placenta suggests that an accurate knowledge of the metabolic changes taking place in the fetus during alteration of the maternal environment is indispensable to the understanding of the short- and long-term effects of maternal disease on the fetus.

  20. Modulation by geraniol of gene expression involved in lipid metabolism leading to a reduction of serum-cholesterol and triglyceride levels.

    Science.gov (United States)

    Galle, Marianela; Kladniew, Boris Rodenak; Castro, María Agustina; Villegas, Sandra Montero; Lacunza, Ezequiel; Polo, Mónica; de Bravo, Margarita García; Crespo, Rosana

    2015-07-15

    Geraniol (G) is a natural isoprenoid present in the essential oils of several aromatic plants, with various biochemical and pharmacologic properties. Nevertheless, the mechanisms of action of G on cellular metabolism are largely unknown. We propose that G could be a potential agent for the treatment of hyperlipidemia that could contribute to the prevention of cardiovascular disease. The aim of the present study was to advance our understanding of its mechanism of action on cholesterol and TG metabolism. NIH mice received supplemented diets containing 25, 50, and 75 mmol G/kg chow. After a 3-week treatment, serum total-cholesterol and triglyceride levels were measured by commercial kits and lipid biosynthesis determined by the [(14)C] acetate incorporated into fatty acids plus nonsaponifiable and total hepatic lipids of the mice. The activity of the mRNA encoding HMGCR-the rate-limiting step in cholesterol biosynthesis-along with the enzyme levels and catalysis were assessed by real-time RT-PCR, Western blotting, and HMG-CoA-conversion assays, respectively. In-silico analysis of several genes involved in lipid metabolism and regulated by G in cultured cells was also performed. Finally, the mRNA levels encoded by the genes for the low-density-lipoprotein receptor (LDLR), the sterol-regulatory-element-binding transcription factor (SREBF2), the very-low-density-lipoprotein receptor (VLDLR), and the acetyl-CoA carboxylase (ACACA) were determined by real-time RT-PCR. Plasma total-cholesterol and triglyceride levels plus hepatic fatty-acid, total-lipid, and nonsaponifiable-lipid biosynthesis were significantly reduced by feeding with G. Even though an up-regulation of the mRNA encoding HMGCR occurred in the G treated mouse livers, the protein levels and specific activity of the enzyme were both inhibited. G also enhanced the mRNAs encoding the LDL and VLDL receptors and reduced ACACA mRNA, without altering the transcription of the mRNA encoding the SREBF2. The following

  1. Liver X receptor regulates hepatic nuclear O-GlcNAc signaling and carbohydrate responsive element-binding protein activity

    DEFF Research Database (Denmark)

    Bindesbøll, Christian; Fan, Qiong; Nørgaard, Rikke C

    2015-01-01

    in response to feeding, which is believed to be mediated by insulin. We have previously shown that LXRs are targets for glucose-hexosamine-derived O-linked β-N-acetylglucosamine (O-GlcNAc) modification enhancing their ability to regulate SREBP-1c promoter activity in vitro. To elucidate insulin...... of glycolytic and lipogenic enzymes, including glucokinase (GK), SREBP-1c, ChREBPα, and the newly identified shorter isoform ChREBPβ. Furthermore, glucose-dependent increases in LXR/retinoid X receptor-regulated luciferase activity driven by the ChREBPα promoter was mediated, at least in part, by O-GlcNAc...... transferase (OGT) signaling in Huh7 cells. Moreover, we show that LXR and OGT interact and colocalize in the nucleus and that loss of LXRs profoundly reduced nuclear O-GlcNAc signaling and ChREBPα promoter binding activity in vivo. In summary, our study provides evidence that LXRs act as nutrient and glucose...

  2. The ANGPTL3-4-8 model, a molecular mechanism for triglyceride trafficking

    OpenAIRE

    Zhang, Ren

    2016-01-01

    Lipoprotein lipase (LPL) is a rate-limiting enzyme for hydrolysing circulating triglycerides (TG) into free fatty acids that are taken up by peripheral tissues. Postprandial LPL activity rises in white adipose tissue (WAT), but declines in the heart and skeletal muscle, thereby directing circulating TG to WAT for storage; the reverse is true during fasting. However, the mechanism for the tissue-specific regulation of LPL activity during the fed?fast cycle has been elusive. Recent identificati...

  3. Triglyceride kinetics in fasted and fed E.coli septic rats

    International Nuclear Information System (INIS)

    Lanza-Jacoby, S.; Tabares, A.

    1990-01-01

    The mechanism for the development of hypertriglyceridemia during gram-negative sepsis was studies by examining the liver production and clearance of very-low-density lipoprotein (VLDL) triglyceride (TG). To assess the liver output and peripheral clearance the kinetics of VLDL-TG were determined by a constant intravenous infusion of [2- 3 H] glycerol-labeled VLDL in fasted control, fasted E. coli-treated, fed control, and fed E.coli-treated rats. Lewis inbred rats, 275-300 g, were made septic with 8 x 10 7 live E.coli colonies per 100 g body weight. Twenty-four hours following E.coli injection serum TG of fasted E.coli-treated rats was elevated by 170% which was attributed to a 67% decrease in the clearance rate of VLDL-TG in fasted E.coli-treated rats compared with their fasted controls. The secretion of VLDL-TG declined by 31% in the livers of the fasted E.coli-treated rats which was accompanied by a 2-fold increase in the composition of liver TG. In a second series of experiments control and E.coli-treated rats were fed intragastrically (IG) a balanced solution containing glucose plus fat as the sources of nonprotein calories. Serum TG were 26% lower in the fed E.coli-treated rats because the clearance rate increased by 86%. The secretion of TG in the fed septic rats increased by 40% but this difference was not significant. In the septic rat the ability to clear triglycerides from the plasma depends upon the nutritional state

  4. Calorie Restricted High Protein Diets Downregulate Lipogenesis and Lower Intrahepatic Triglyceride Concentrations in Male Rats

    Directory of Open Access Journals (Sweden)

    Lee M. Margolis

    2016-09-01

    Full Text Available The purpose of this investigation was to assess the influence of calorie restriction (CR alone, higher-protein/lower-carbohydrate intake alone, and combined CR higher-protein/lower-carbohydrate intake on glucose homeostasis, hepatic de novo lipogenesis (DNL, and intrahepatic triglycerides. Twelve-week old male Sprague Dawley rats consumed ad libitum (AL or CR (40% restriction, adequate (10%, or high (32% protein (PRO milk-based diets for 16 weeks. Metabolic profiles were assessed in serum, and intrahepatic triglyceride concentrations and molecular markers of de novo lipogenesis were determined in liver. Independent of calorie intake, 32% PRO tended to result in lower homeostatic model assessment of insulin resistance (HOMA-IR values compared to 10% PRO, while insulin and homeostatic model assessment of β-cell function (HOMA-β values were lower in CR than AL, regardless of protein intake. Intrahepatic triglyceride concentrations were 27.4 ± 4.5 and 11.7 ± 4.5 µmol·g−1 lower (p < 0.05 in CR and 32% PRO compared to AL and 10% PRO, respectively. Gene expression of fatty acid synthase (FASN, stearoyl-CoA destaurase-1 (SCD1 and pyruvate dehydrogenase kinase, isozyme 4 (PDK4 were 45% ± 1%, 23% ± 1%, and 57% ± 1% lower (p < 0.05, respectively, in CR than AL, regardless of protein intake. Total protein of FASN and SCD were 50% ± 1% and 26% ± 1% lower (p < 0.05 in 32% PRO compared to 10% PRO, independent of calorie intake. Results from this investigation provide evidence that the metabolic health benefits associated with CR—specifically reduction in intrahepatic triglyceride content—may be enhanced by consuming a higher-protein/lower-carbohydrate diet.

  5. The effect of bacterial sepsis severity on triglyceride value

    Science.gov (United States)

    Fahila, R.; Kembaren, T.; Rahimi, A.

    2018-03-01

    Sepsis can increase the amount of triglyceride as well as change the functional and structural components of lipoproteins. The triglyceride level is directly proportional to the severity of sepsis and associated with a systemic inflammatory response. The study aims to determine the correlation between the severity of bacterial sepsis with triglyceride value. An observational study with case control design from January2017 to March 2017 in 30 sepsis and 30 non-sepsis patients at H. Adam Malik General Hospital Medan. We examined Procalcitonin (PCT) and triglyceride level on the 1st, 3rd and 5th day and then analyzed using MannWhitney to assess their correlation.The triglyceride value in the sepsis group was 120 ± 5.1 mg/dl on day 1, non-sepsis 117.53 ± 36.37mg/dl. However, on the fifth day, the sepsis group of triglyceride values was 124.2±50.29mg/dl and the non-sepsis group triglyceride values 134.03±68.12mg/dl. There was no specific connection between the severity of sepsis and triglyceride value in a patient with sepsis.

  6. Alternative Production of Fatty Acid Methyl Esters from Triglycerides ...

    African Journals Online (AJOL)

    The catalysts activity was tested in thermocatalytic cracking of triglyceride; a direct conversion process for fatty acid methyl esters (biodiesel). The SZ1 not only exhibited higher conversion of triglycerides but higher fatty acid methyl esters (FAMEs) yields of approximately 59% after 3h as compared to SZ2 (32%). In addition ...

  7. Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

    NARCIS (Netherlands)

    Dallinga-Thie, G. M.; van Tol, A.; Hattori, H.; van Vark-van der Zee, L. C.; Jansen, H.; Sijbrands, E. J. G.

    2006-01-01

    Variation in the human apolipoprotein (APO) A5 gene (APOA5) is associated with elevated plasma triglycerides. However, data on the exact role of plasma concentrations of APOA5 in human triglyceride homeostasis are lacking. In the present study, we estimated plasma APOA5 levels in patients with type

  8. Plasma apolipoprotein A5 and triglycerides in type 2 diabetes

    NARCIS (Netherlands)

    Dallinga-Thie, GM; Van Tol, A; Hattori, H; van Vark-van de Zee, LC; Jansen, H; Sijbrands, EJG

    Aims/hypothesis: Variation in the human apolipoprotein (APO) A5 gene (APOA5) is associated with elevated plasma triglycerides. However, data on the exact role of plasma concentrations of APOA5 in human triglyceride homeostasis are lacking. In the present study, we estimated plasma APOA5 levels in

  9. Heterozygous deficiency of endoglin decreases insulin and hepatic triglyceride levels during high fat diet.

    Directory of Open Access Journals (Sweden)

    Daniel Beiroa

    Full Text Available Endoglin is a transmembrane auxiliary receptor for transforming growth factor-beta (TGF-beta that is predominantly expressed on proliferating endothelial cells. It plays a wide range of physiological roles but its importance on energy balance or insulin sensitivity has been unexplored. Endoglin deficient mice die during midgestation due to cardiovascular defects. Here we report for first time that heterozygous endoglin deficiency in mice decreases high fat diet-induced hepatic triglyceride content and insulin levels. Importantly, these effects are independent of changes in body weight or adiposity. At molecular level, we failed to detect relevant changes in the insulin signalling pathway at basal levels in liver, muscle or adipose tissues that could explain the insulin-dependent effect. However, we found decreased triglyceride content in the liver of endoglin heterozygous mice fed a high fat diet in comparison to their wild type littermates. Overall, our findings indicate that endoglin is a potentially important physiological mediator of insulin levels and hepatic lipid metabolism.

  10. Different exercise protocols improve metabolic syndrome markers, tissue triglycerides content and antioxidant status in rats

    Directory of Open Access Journals (Sweden)

    Botezelli José D

    2011-12-01

    Full Text Available Abstract Background An increase in the prevalence of obesity entails great expenditure for governments. Physical exercise is a powerful tool in the combat against obesity and obesity-associated diseases. This study sought to determine the effect of three different exercise protocols on metabolic syndrome and lipid peroxidation markers and the activity of antioxidant enzymes in adult Wistar rats (120 days old. Methods Animals were randomly divided into four groups: the control (C group was kept sedentary throughout the study; the aerobic group (A swam1 h per day, 5 days per week, at 80% lactate threshold intensity; the strength group (S performed strength training with four series of 10 jumps, 5 days per week; and the Concurrent group (AS was trained using the aerobic protocol three days per week and the strength protocol two days per week. Results Groups A and S exhibited a reduction in body weight compared to group C. All exercised animals showed a reduction in triglyceride concentrations in fatty tissues and the liver. Exercised animals also exhibited a reduction in lipid peroxidation markers (TBARS and an increase in serum superoxide dismutase activity. Animals in group A had increased levels of liver catalase and superoxide dismutase activities. Conclusions We concluded that all physical activity protocols improved the antioxidant systems of the animals and decreased the storage of triglycerides in the investigated tissues.

  11. Low Nonfasting Triglycerides and Reduced All-Cause Mortality

    DEFF Research Database (Denmark)

    Thomsen, Mette; Varbo, Anette; Tybjærg-Hansen, Anne

    2014-01-01

    BACKGROUND: Increased nonfasting plasma triglycerides marking increased amounts of cholesterol in remnant lipoproteins are important risk factors for cardiovascular disease, but whether lifelong reduced concentrations of triglycerides on a genetic basis ultimately lead to reduced all......-cause mortality is unknown. We tested this hypothesis. METHODS: Using individuals from the Copenhagen City Heart Study in a mendelian randomization design, we first tested whether low concentrations of nonfasting triglycerides were associated with reduced all-cause mortality in observational analyses (n = 13 957......); second, whether genetic variants in the triglyceride-degrading enzyme lipoprotein lipase, resulting in reduced nonfasting triglycerides and remnant cholesterol, were associated with reduced all-cause mortality (n = 10 208). RESULTS: During a median 24 and 17 years of 100% complete follow-up, 9991...

  12. ER Stress Inhibits Liver Fatty Acid Oxidation while Unmitigated Stress Leads to Anorexia-Induced Lipolysis and Both Liver and Kidney Steatosis.

    Science.gov (United States)

    DeZwaan-McCabe, Diane; Sheldon, Ryan D; Gorecki, Michelle C; Guo, Deng-Fu; Gansemer, Erica R; Kaufman, Randal J; Rahmouni, Kamal; Gillum, Matthew P; Taylor, Eric B; Teesch, Lynn M; Rutkowski, D Thomas

    2017-05-30

    The unfolded protein response (UPR), induced by endoplasmic reticulum (ER) stress, regulates the expression of factors that restore protein folding homeostasis. However, in the liver and kidney, ER stress also leads to lipid accumulation, accompanied at least in the liver by transcriptional suppression of metabolic genes. The mechanisms of this accumulation, including which pathways contribute to the phenotype in each organ, are unclear. We combined gene expression profiling, biochemical assays, and untargeted lipidomics to understand the basis of stress-dependent lipid accumulation, taking advantage of enhanced hepatic and renal steatosis in mice lacking the ER stress sensor ATF6α. We found that impaired fatty acid oxidation contributed to the early development of steatosis in the liver but not the kidney, while anorexia-induced lipolysis promoted late triglyceride and free fatty acid accumulation in both organs. These findings provide evidence for both direct and indirect regulation of peripheral metabolism by ER stress. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  13. Betatrophin: A liver-derived hormone for the pancreatic β-cell proliferation.

    Science.gov (United States)

    Raghow, Rajendra

    2013-12-15

    The pancreatic β-cell failure which invariably accompanies insulin resistance in the liver and skeletal muscle is a hallmark of type-2 diabetes mellitus (T2DM). The persistent hyperglycemia of T2DM is often treated with anti-diabetic drugs with or without subcutaneous insulin injections, neither of which mimic the physiological glycemic control seen in individuals with fully functional pancreas. A sought after goal for the treatment of T2DM has been to harness the regenerative potential of pancreatic β-cells that might obviate a need for exogenous insulin injections. A new study towards attaining this aim was reported by Yi et al, who have characterized a liver-derived protein, named betatrophin, capable of inducing pancreatic β-cell proliferation in mice. Using a variety of in vitro and in vivo methods, Yi et al, have shown that betatrophin was expressed mainly in the liver and adipose tissue of mice. Exogenous expression of betatrophin in the liver led to dramatic increase in the pancreatic β-cell mass and higher output of insulin in mice that also concomitantly elicited improved glucose tolerance. The authors discovered that betatrophin was also present in the human plasma. Surprisingly, betatrophin has been previously described by three other names, i.e., re-feeding-induced fat and liver protein, lipasin and atypical angiopoeitin-like 8, by three independent laboratories, as nutritionally regulated liver-enriched factors that control serum triglyceride levels and lipid metabolism. Yi et al demonstration of betatrophin, as a circulating hormone that regulates β-cell proliferation, if successfully translated in the clinic, holds the potential to change the course of current therapies for diabetes.

  14. Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan.

    Science.gov (United States)

    Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

    2017-06-01

    Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females.

  15. Clinical characteristics of patients with diabetes mellitus and fatty liver diagnosed by liver/spleen Hounsfield units on CT scan

    Science.gov (United States)

    Sakitani, Kosuke; Enooku, Kenichiro; Kubo, Hirokazu; Tanaka, Akifumi; Arai, Hisakatsu; Kawazu, Shoji; Koike, Kazuhiko

    2017-01-01

    Objective The leading cause of liver injuries in diabetes mellitus may be associated with fatty liver. We aimed to elucidate the relationship between fatty liver and diabetes characteristics. Methods Retrospectively, 970 patients with diabetes were analysed. Fatty liver was diagnosed when the liver/spleen Hounsfield unit ratio by computed tomography was below 0.9. Clinical diabetes characteristics were compared between patients with and without fatty liver. Results Of 970 patients (717 male and 253 female; mean age 64.4 years), 175 males (24.4%) and 60 females (23.7%) had fatty liver. None of the 28 patients with type 1 diabetes had fatty liver. In male patients with type 2 diabetes, age, visceral adipose tissue (VAT), albumin, alanine amino-transferase (ALT), and triglycerides were independently associated with fatty liver. In females, age and bilirubin were associated with fatty liver. Conclusions Fatty liver is associated with type 2 diabetes characteristics, including younger age and elevated VAT, albumin, ALT, and triglycerides in males and younger age and elevated bilirubin levels in females. PMID:28553763

  16. Interleukin-1β regulates fat-liver crosstalk in obesity by auto-paracrine modulation of adipose tissue inflammation and expandability.

    Directory of Open Access Journals (Sweden)

    Ori Nov

    Full Text Available The inflammasome has been recently implicated in obesity-associated dys-metabolism. However, of its products, the specific role of IL-1β was clinically demonstrated to mediate only the pancreatic beta-cell demise, and in mice mainly the intra-hepatic manifestations of obesity. Yet, it remains largely unknown if IL-1β, a cytokine believed to mainly function locally, could regulate dysfunctional inter-organ crosstalk in obesity. Here we show that High-fat-fed (HFF mice exhibited a preferential increase of IL-1β in portal compared to systemic blood. Moreover, portally-drained mesenteric fat transplantation from IL-1βKO donors resulted in lower pyruvate-glucose flux compared to mice receiving wild-type (WT transplant. These results raised a putative endocrine function for visceral fat-derived IL-1β in regulating hepatic gluconeogenic flux. IL-1βKO mice on HFF exhibited only a minor or no increase in adipose expression of pro-inflammatory genes (including macrophage M1 markers, Mac2-positive crown-like structures and CD11b-F4/80-double-positive macrophages, all of which were markedly increased in WT-HFF mice. Further consistent with autocrine/paracrine functions of IL-1β within adipose tissue, adipose tissue macrophage lipid content was increased in WT-HFF mice, but significantly less in IL-1βKO mice. Ex-vivo, adipose explants co-cultured with primary hepatocytes from WT or IL-1-receptor (IL-1RI-KO mice suggested only a minor direct effect of adipose-derived IL-1β on hepatocyte insulin resistance. Importantly, although IL-1βKOs gained weight similarly to WT-HFF, they had larger fat depots with similar degree of adipocyte hypertrophy. Furthermore, adipogenesis genes and markers (pparg, cepba, fabp4, glut4 that were decreased by HFF in WT, were paradoxically elevated in IL-1βKO-HFF mice. These local alterations in adipose tissue inflammation and expansion correlated with a lower liver size, less hepatic steatosis, and preserved insulin

  17. The effect of a short-term hypocaloric diet on liver gene expression and metabolic risk factors in obese women.

    Science.gov (United States)

    Hietaniemi, M; Jokela, M; Rantala, M; Ukkola, O; Vuoristo, J T; Ilves, M; Rysä, J; Kesäniemi, Y

    2009-03-01

    Most gene expression studies examining the effect of obesity and weight loss have been performed using adipose tissue. However, the liver also plays a central role in maintaining energy balance. We wanted to study the effects of a hypocaloric diet on overall hepatic gene expression and metabolic risk factors. The study subjects were middle-aged, obese women. The diet intervention subjects (n=12) were on a hypocaloric, low-fat diet for 8 weeks with a daily energy intake of 5.0 MJ (1200 kcal), while the control subjects (n=19) maintained their weight. Liver biopsies were taken at the end of the diet period during a gallbladder operation. Hepatic gene expression was analyzed using microarrays by comparing the gene expression profiles from four subjects per group. A global decrease in gene expression was observed with 142 down-regulated genes and only one up-regulated gene in the diet intervention group. The diet resulted in a mean weight loss of 5% of body weight. Triglyceride and fasting insulin concentrations decreased significantly after the diet. The global decrease in hepatic gene expression was unexpected but the results are interesting, since they included several genes not previously linked to weight reduction. However, since the comparison was made only after the weight reduction, other factors in addition to weight loss may also have been involved in the differences in gene expression between the groups. The decrease in triglyceride and fasting plasma insulin concentrations is in accordance with results from previous weight-loss studies.

  18. Coronary triglyceride deposition in contemporary advanced diabetics.

    Science.gov (United States)

    Ikeda, Yoshihiko; Zaima, Nobuhiro; Hirano, Ken-ichi; Mano, Masayuki; Kobayashi, Kunihisa; Yamada, Sohsuke; Yamaguchi, Satoshi; Suzuki, Akira; Kanzaki, Hideaki; Hamasaki, Toshimitsu; Kotani, Jun-ichi; Kato, Seiya; Nagasaka, Hironori; Setou, Mitsutoshi; Ishibashi-Ueda, Hatsue

    2014-07-01

    It is of importance to clarify pathophysiology of diabetic heart diseases such as heart failure and coronary artery disease. We reported a novel clinical phenotype called triglyceride deposit cardiomyovasculopathy (TGCV), showing aberrant TG accumulation in both coronary arteries and myocardium, in a cardiac transplant recipient. Here, we examined autopsied diabetics for TG deposition in cardiovasculature. Consecutive series of hearts from advanced diabetes mellitus (DM) subjects (DM group: DMG, n = 20) and those from age- and sex-matched non-diabetic controls (non DM group: NDMG, n = 20) were examined. The diagnostic criteria of 'advanced DM' was made based on 2014 Clinical Practice Recommendations proposed by the American Diabetes Association. The mean duration of DM was 15.8 years. All DMG suffered from heart diseases including coronary artery diseases and 14 subjects had multi-vessel disease. Tissue TG contents were measured biochemically. Coronary arterial TG contents was significantly higher in DMG compared with NDMG. Spatial distribution of TG in transverse sections of coronary arteries showed TG deposition mainly in smooth muscle cells by Imaging Mass Spectrometry. Abundant TG deposition in coronary artery might be associated with advanced DM. © 2014 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.

  19. Liver Immunology

    Science.gov (United States)

    Bogdanos, Dimitrios P.; Gao, Bin; Gershwin, M. Eric

    2014-01-01

    The liver is the largest organ in the body and is generally regarded by non-immunologists as not having lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates a tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and is also instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena which if are not controlled by regulatory lymphoid populations may lead to the induction of autoimmune liver diseases. Liver-related lymphoid subpopulations also act as critical antigen-presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events which lead to immune-mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discus select, but not all, immune mediated liver disease and attempt to place these data in the context of human autoimmunity. PMID:23720323

  20. Metabolism of defined structured triglyceride particles compared to mixtures of medium and long chain triglycerides intravenously infused in dogs.

    Science.gov (United States)

    Simoens, Ch; Deckelbaum, R J; Carpentier, Y A

    2004-08-01

    The present study aimed to determine whether including medium-chain fatty acids (MCFA) in specifically designed structured triglycerides (STG) with a MCFA in sn-1 and sn-3 positions and a long-chain (LC) FA in sn-2 position (MLM) would lead to different effects on plasma lipids and FA distribution into plasma and tissue lipids by comparison to a mixture of separate MCT and LCT molecules (MMM/LLL). The fatty acid (FA) composition was comparable in both lipid emulsions. Lipids were infused over 9h daily, in 2 groups of dogs (n = 6 each), for 28 days as a major component (55% of the non-protein energy intake) of total parenteral nutrition (TPN). Blood samples were obtained on specific days, before starting and just before stopping TPN. The concentration of plasma lipids was measured before starting and before stopping TPN on days 1, 2, 3, 4, 5, 8, 10, 12, 16 and 28. Biopsies were obtained from liver, muscle and adipose tissue 15 days before starting, and again on the day following cessation of TPN. In addition, the spleen was removed after the TPN period. FA composition in plasma and tissue lipids was analysed by gas liquid chromatography in different lipid components of plasma and tissues. No differences in either safety or tolerance parameters were detected between both lipid preparations. A lower rise of plasma TG (P < 0.05) was observed during MLM infusion, indicating a faster elimination rate of MLM vs MMM/LLL emulsion. In spite of the differences of TG molecules which would be assumed to affect the site of FA delivery and metabolic fate, FA distribution in phospholipids (PL) of hepatic and extrahepatic tissues did not substantially differ between both emulsions. Copyright 2003 Elsevier Ltd.

  1. in Human Liver Diseases

    Directory of Open Access Journals (Sweden)

    Minoru Fujimoto

    2010-01-01

    Full Text Available Toll-like receptor (TLR signaling pathways are strictly coordinated by several mechanisms to regulate adequate innate immune responses. Recent lines of evidence indicate that the suppressor of cytokine signaling (SOCS family proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses. SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation. Thus, SOCS1 is an important regulator for both cytokine and TLR-induced responses. As an immune organ, the liver contains various types of immune cells such as T cells, NK cells, NKT cells, and Kupffer cells and is continuously challenged with gut-derived bacterial and dietary antigens. SOCS1 may be implicated in pathophysiology of the liver. The studies using SOCS1-deficient mice revealed that endogenous SOCS1 is critical for the prevention of liver diseases such as hepatitis, cirrhosis, and cancers. Recent studies on humans suggest that SOCS1 is involved in the development of various liver disorders in humans. Thus, SOCS1 and other SOCS proteins are potential targets for the therapy of human liver diseases.

  2. Liver spots

    Science.gov (United States)

    ... skin changes - liver spots; Senile or solar lentigines; Skin spots - aging; Age spots ... Liver spots are changes in skin color that occur in older skin. The coloring may be due to aging, exposure to the sun ...

  3. Liver Diseases

    Science.gov (United States)

    Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases: Diseases caused by viruses, such as hepatitis ...

  4. Liver disease

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the ...

  5. Cardiac expression of microsomal triglyceride transfer protein is increased in obesity and serves to attenuate cardiac triglyceride accumulation.

    Directory of Open Access Journals (Sweden)

    Emil D Bartels

    Full Text Available Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP; the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease.

  6. MiR-150 deficiency ameliorated hepatosteatosis and insulin resistance in nonalcoholic fatty liver disease via targeting CASP8 and FADD-like apoptosis regulator.

    Science.gov (United States)

    Zhuge, Baozhong; Li, Guohong

    2017-12-16

    The prevalence of Non-alcoholic fatty liver diseases (NAFLD) increased rapidly in the world. However, the pathogenesis of is still unclear. Hepatic steatosis and insulin resistance are considered to be central to the pathophysiology of NAFLD. MicroRNAs are short non-coding RNAs and has been reported to be involved in pathogenesis of NAFLD and related metabolic diseases. Here, we investigated the mechanisms by which miR-150 regulate hepatic steatosis and insulin resistance in high fat diet (HFD) induced NAFLD model. The expression of miR-150 was up-regulated dramatically in both human NAFLD patients and HFD mice model, as well as in hepatocytes treated with oleic acid. miR-150 deficiency ameliorated the hepatic steatosis and insulin resistance significantly in NAFLD mice. miR-150 deficiency decreased the expression of genes related to fatty acid uptake, synthesis and gluconeogenesis, while increased the expression of genes related to fatty acid β-oxidation. Further, we identified that CFLAR is a direct downstream target of miR-150. Overexpression of miR-150 reduced both the mRNA and protein levels of CFLAR in vitro. And overexpression of miR-150 significantly inhibited the luciferase activity of CFLAR 3'-UTR, while the effect of miR-150 was blocked when the binding site of miR-150 within the CFLAR 3'-UTR was mutated. We also found that miR-150 deficiency decreased the expression of p-Jnk1 and p-Ask1, while the effect of miR-150 on steatosis and insulin signaling was blocked by CFLAR overexpression. In conclusion, our data indicated that miR-150 potentially contributes to the hepatic steatosis and insulin resistance in NAFLD. miR-150/CFLAR pathway may be a new therapeutic strategy against NAFLD. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. The independent relationship between triglycerides and coronary heart disease

    Science.gov (United States)

    Morrison, Alan; Hokanson, John E

    2009-01-01

    Aims: The aim was to review epidemiologic studies to reassess whether serum levels of triglycerides should be considered independently of high-density lipoprotein-cholesterol (HDL-C) as a predictor of coronary heart disease (CHD). Methods and results: We systematically reviewed population-based cohort studies in which baseline serum levels of triglycerides and HDL-C were included as explanatory variables in multivariate analyses with the development of CHD (coronary events or coronary death) as dependent variable. A total of 32 unique reports describing 38 cohorts were included. The independent association between elevated triglycerides and risk of CHD was statistically significant in 16 of 30 populations without pre-existing CHD. Among populations with diabetes mellitus or pre-existing CHD, or the elderly, triglycerides were not significantly independently associated with CHD in any of 8 cohorts. Triglycerides and HDL-C were mutually exclusive predictors of coronary events in 12 of 20 analyses of patients without pre-existing CHD. Conclusions: Epidemiologic studies provide evidence of an association between triglycerides and the development of primary CHD independently of HDL-C. Evidence of an inverse relationship between triglycerides and HDL-C suggests that both should be considered in CHD risk estimation and as targets for intervention. PMID:19436658

  8. The independent relationship between triglycerides and coronary heart disease.

    Science.gov (United States)

    Morrison, Alan; Hokanson, John E

    2009-01-01

    The aim was to review epidemiologic studies to reassess whether serum levels of triglycerides should be considered independently of high-density lipoprotein-cholesterol (HDL-C) as a predictor of coronary heart disease (CHD). We systematically reviewed population-based cohort studies in which baseline serum levels of triglycerides and HDL-C were included as explanatory variables in multivariate analyses with the development of CHD (coronary events or coronary death) as dependent variable. A total of 32 unique reports describing 38 cohorts were included. The independent association between elevated triglycerides and risk of CHD was statistically significant in 16 of 30 populations without pre-existing CHD. Among populations with diabetes mellitus or pre-existing CHD, or the elderly, triglycerides were not significantly independently associated with CHD in any of 8 cohorts. Triglycerides and HDL-C were mutually exclusive predictors of coronary events in 12 of 20 analyses of patients without pre-existing CHD. Epidemiologic studies provide evidence of an association between triglycerides and the development of primary CHD independently of HDL-C. Evidence of an inverse relationship between triglycerides and HDL-C suggests that both should be considered in CHD risk estimation and as targets for intervention.

  9. Genetics of Triglycerides and the Risk of Atherosclerosis.

    Science.gov (United States)

    Dron, Jacqueline S; Hegele, Robert A

    2017-07-01

    Plasma triglycerides are routinely measured with a lipid profile, and elevated plasma triglycerides are commonly encountered in the clinic. The confounded nature of this trait, which is correlated with numerous other metabolic perturbations, including depressed high-density lipoprotein cholesterol (HDL-C), has thwarted efforts to directly implicate triglycerides as causal in atherogenesis. Human genetic approaches involving large-scale populations and high-throughput genomic assessment under a Mendelian randomization framework have undertaken to sort out questions of causality. We review recent large-scale meta-analyses of cohorts and population-based sequencing studies designed to address whether common and rare variants in genes whose products are determinants of plasma triglycerides are also associated with clinical cardiovascular endpoints. The studied loci include genes encoding lipoprotein lipase and proteins that interact with it, such as apolipoprotein (apo) A-V, apo C-III and angiopoietin-like proteins 3 and 4, and common polymorphisms identified in genome-wide association studies. Triglyceride-raising variant alleles of these genes showed generally strong associations with clinical cardiovascular endpoints. However, in most cases, a second lipid disturbance-usually depressed HDL-C-was concurrently associated. While the findings collectively shift our understanding towards a potential causal role for triglycerides, we still cannot rule out the possibilities that triglycerides are a component of a joint phenotype with low HDL-C or that they are but markers of deeper causal metabolic disturbances that are not routinely measured in epidemiological-scale genetic studies.

  10. O-linked N-acetylglucosamine transferase enhances secretory clusterin expression via liver X receptors and sterol response element binding protein regulation in cervical cancer.

    Science.gov (United States)

    Kim, Min Jun; Choi, Mee Young; Lee, Dong Hoon; Roh, Gu Seob; Kim, Hyun Joon; Kang, Sang Soo; Cho, Gyeong Jae; Kim, Yoon Sook; Choi, Wan Sung

    2018-01-12

    O-linked N-acetylglucosamine transferase (OGT) expression is increased in various cancer types, indicating the potential importance of O-GlcNAcylation in tumorigenesis. Secretory clusterin (sCLU) is involved in cancer cell proliferation and drug resistance, and recently, liver X receptors (LXRs) and sterol response element binding protein-1 (SREBP-1) were reported to regulate sCLU transcription. Here, we found that sCLU is significantly increased in cervical cancer cell lines, which have higher expression levels of O-GlcNAc and OGT than keratinocytes. OGT knockdown decreased expression of LXRs, SREBP-1 and sCLU through hypo-O-GlcNAcylation of LXRs. Additionally, treatment with Thiamet G, O-GlcNAcase OGA inhibitor, increased expression of O-GlcNAcylation and sCLU, and high glucose increased levels of LXRs, SREBP-1 and sCLU in HeLa cells. Moreover, OGT knockdown induced G 0 /G 1 phase cell cycle arrest and late apoptosis in cisplatin-treated HeLa cells, and decreased viability compared to OGT intact HeLa cells. Taken together, these findings suggest that OGT, O-GlcNAcylated LXRs, and SREBP-1 increase sCLU expression in cervical cancer cells, which contributes to drug resistance.

  11. [Effects of three Wenyang Jianpi Tang on cell proliferation and apoptosis of nonalcoholic fatty liver cells].

    Science.gov (United States)

    Yang, Jia-Yao; Tao, Dong-Qing; Liu, Song; Zhang, Shu; Ma, Wei; Shi, Zhao-Hong

    2017-04-01

    To investigate the effects of Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang on the cell proliferation and apoptosis of nonalcoholic fatty liver cells through the nonalcoholic fatty liver cell model established by inducing L02 cells with oleic acid. Different concentrations of oleic acid were added into L02 cells to induce the nonalcoholic fatty liver cell model. Oil red O staining was used to observe fatty droplets of fatty liver cells. Automatic biochemical analyzer was used to detect the levels of aspartic transaminase(AST), alanine aminotransferase(ALT), total cholesterol(TC), and triglyceride(TG) in the cell supernatants. There were five groups, namely normal group, model group, model and Sijunzi Tang group, model and Lizhong Tang group, and model and Fuzi Lizhong Tang group. The cell proliferation and apoptosis of the five groups were detected by MTT colorimetry test and flow cytometer. The expressions of PCNA, cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, Bax and Bcl-2 proteins of the five groups were detected by Western blot. The oil red O staining results showed that the optimum concentration of oleic acid that was used to induce nonalcoholic fatty liver cell models was 80 mg•L-1. The levels of AST, ALT, TC and TG in the nonalcoholic fatty liver cell supernatants were higher than that in normal liver cell supernatants(PTang, Lizhong Tang and Fuzi Lizhong Tang could effectively promote the cell proliferation, and inhibit the cellular apoptosis of nonalcoholic fatty liver cells(PTang showed the best effect. Western blot results showed that Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang could down-regulate the expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9 and Bax proteins, and up-regulate the expressions of PCNA and Bcl-2 proteins of nonalcoholic fatty liver cells. And Fuzi Lizhong Tang showed the best effect. In conclusion, all of Sijunzi Tang, Lizhong Tang and Fuzi Lizhong Tang could effectively promote the cell

  12. Towards microalgal triglycerides in the commodity markets.

    Science.gov (United States)

    Benvenuti, Giulia; Ruiz, Jesús; Lamers, Packo P; Bosma, Rouke; Wijffels, René H; Barbosa, Maria J

    2017-01-01

    Microalgal triglycerides (TAGs) hold great promise as sustainable feedstock for commodity industries. However, to determine research priorities and support business decisions, solid techno-economic studies are essential. Here, we present a techno-economic analysis of two-step TAG production (growth reactors are operated in continuous mode such that multiple batch-operated stress reactors are inoculated and harvested sequentially) for a 100-ha plant in southern Spain using vertically stacked tubular photobioreactors. The base case is established with outdoor pilot-scale data and based on current process technology. For the base case, production costs of 6.7 € per kg of biomass containing 24% TAG (w/w) were found. Several scenarios with reduced production costs were then presented based on the latest biological and technological advances. For instance, much effort should focus on increasing the photosynthetic efficiency during the stress and growth phases, as this is the most influential parameter on production costs (30 and 14% cost reduction from base case). Next, biological and technological solutions should be implemented for a reduction in cooling requirements (10 and 4.5% cost reduction from base case when active cooling is avoided and cooling setpoint is increased, respectively). When implementing all the suggested improvements, production costs can be decreased to 3.3 € per kg of biomass containing 60% TAG (w/w) within the next 8 years. With our techno-economic analysis, we indicated a roadmap for a substantial cost reduction. However, microalgal TAGs are not yet cost efficient when compared to their present market value. Cost-competiveness strictly relies on the valorization of the whole biomass components and on cheaper PBR designs (e.g. plastic film flat panels). In particular, further research should focus on the development and commercialization of PBRs where active cooling is avoided and stable operating temperatures are maintained by the water

  13. Quantitative proteomics analysis reveals perturbation of lipid metabolic pathways in the liver of Atlantic cod (Gadus morhua) treated with PCB 153.

    Science.gov (United States)

    Yadetie, Fekadu; Oveland, Eystein; Døskeland, Anne; Berven, Frode; Goksøyr, Anders; Karlsen, Odd André

    2017-04-01

    PCB 153 is one of the most abundant PCB congeners detected in biological samples. It is a persistent compound that is still present in the environment despite the ban on production and use of PCBs in the late 1970s. It has strong tendencies to bioaccumulate and biomagnify in biota, and studies have suggested that it is an endocrine and metabolic disruptor. In order to study mechanisms of toxicity, we exposed Atlantic cod (Gadus morhua) to various doses of PCB 153 (0, 0.5, 2 and 8mg/kg body weight) for two weeks and examined the effects on expression of liver proteins using label-free quantitative proteomics. Label-free liquid chromatography-mass spectrometry analysis of the liver proteome resulted in the quantification of 1272 proteins, of which 78 proteins were differentially regulated in the PCB 153-treated dose groups compared to the control group. Functional enrichment analysis showed that pathways significantly affected are related to lipid metabolism, cytoskeletal remodeling, cell cycle and cell adhesion. Importantly, the main effects appear to be on lipid metabolism, with up-regulation of enzymes in the de novo fatty acid synthesis pathway, consistent with previous transcriptomics results. Increased plasma triglyceride levels were also observed in the PCB 153 treated fish, in agreement with the induction of the lipogenic genes and proteins. The results suggest that PCB 153 perturbs lipid metabolism in the Atlantic cod liver. Elevated levels of lipogenic enzymes and plasma triglycerides further suggest increased synthesis of fatty acids and triglycerides. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. The occurrence of triglycerides in Namibian Shelf diatomaceous ooze

    Science.gov (United States)

    Boon, Jaap J.; Irene, W.; Rijpstra, C.; de Leeuw, J. W.; Burlingame, A. L.

    1980-01-01

    The triglyceride fraction, isolated from extractable lipids of a diatomaceous ooze off shore Walvis Bay (S.W. Africa) by TLC methods, was analyzed by direct probe low and high resolution mass spectrometry. The mass spectral data reveal the fatty acid moieties and their relative distribution in the triglycerides identified. The C 12, C 14, C 15 and C 16 are the major composing fatty acid moieties. The triglycerides are thought to be present in protective structures such as diatom spores, which were found to be present by scanning electron microscopy.

  15. UV irradiation promotes the accumulation of triglyceride in Lipomyces lipofer

    International Nuclear Information System (INIS)

    Konno, A.; Suzuki, Y.; Ogawa, T.; Taniuchi, T.

    2009-01-01

    Yeasts of the genus Lipomyces are known as fat yeasts, and they store large amounts of lipids. Because the major lipid produced by Lipomyces is triglyceride, which can be used as a food and energy resource, the control of lipid production by Lipomyces sp. is an important issue. Here we report the effects of UV irradiation on lipid production in Lipomyces lipofer cells. UV irradiation (315-400 nm) led to a 4-fold increase in the amount of triglyceride per cell. We discovered a novel phenomenon, that UV irradiation promotes triglyceride accumulation in L. lipofer. (author)

  16. Atorvastatin reduces lipid accumulation in the liver by activating protein kinase A-mediated phosphorylation of perilipin 5.

    Science.gov (United States)

    Gao, Xing; Nan, Yang; Zhao, Yuanlin; Yuan, Yuan; Ren, Bincheng; Sun, Chao; Cao, Kaiyu; Yu, Ming; Feng, Xuyang; Ye, Jing

    2017-12-01

    Statins have been proven to be effective in treating non-alcoholic fatty liver disease (NAFLD). Recently, it was reported that statins decreased the hepatic expression of perilipin 5 (Plin5), a lipid droplet (LD)-associated protein, which plays critical roles in regulating lipid accumulation and lipolysis in liver. However, the function and regulation mechanism of Plin5 have not yet been well-established in NAFLD treatment with statins. In this study, we observed that atorvastatin moderately reduced the expression of Plin5 in livers without changing the protein level of Plin5 in the hepatic LD fraction of mice fed with high-fat diet (HFD). Intriguingly, atorvastatin stimulated the PKA-mediated phosphorylation of Plin5 and reduced the triglyceride (TG) accumulation in hepatocytes with overexpression of wide type (Plin5-WT) compared to serine-155 mutant Plin5 (Plin5-S155A). Moreover, PKA-stimulated FA release of purified LDs carrying Plin5-WT but not Plin5-S155A. Glucagon, a PKA activator, stimulated the phosphorylation of Plin5-WT and inhibited its interaction with CGI-58. The results indicated that atorvastatin promoted lipolysis and reduced TG accumulation in the liver by increasing PKA-mediated phosphorylation of Plin5. This new mechanism of lipid-lowering effects of atorvastatin might provide a new strategy for NAFLD treatment. Copyright © 2017. Published by Elsevier B.V.

  17. Common variants associated with plasma triglycerides and risk for coronary artery disease

    DEFF Research Database (Denmark)

    Do, R.; Willer, C. J.; Schmidt, E. M.

    2013-01-01

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common...

  18. Common variants associated with plasma triglycerides and risk for coronary artery disease

    NARCIS (Netherlands)

    Do, Ron; Willer, Cristen J.; Schmidt, Ellen M.; Sengupta, Sebanti; Gao, Chi; Peloso, Gina M.; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L.; Mora, Samia; Beckmann, Jacques S.; Bragg-Gresham, Jennifer L.; Chang, Hsing-Yi; Demirkan, Ayşe; den Hertog, Heleen M.; Donnelly, Louise A.; Ehret, Georg B.; Esko, Tõnu; Feitosa, Mary F.; Ferreira, Teresa; Fischer, Krista; Fontanillas, Pierre; Fraser, Ross M.; Freitag, Daniel F.; Gurdasani, Deepti; Heikkilä, Kauko; Hyppönen, Elina; Isaacs, Aaron; Jackson, Anne U.; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kettunen, Johannes; Kleber, Marcus E.; Li, Xiaohui; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Magnusson, Patrik K. E.; Mangino, Massimo; Mihailov, Evelin; Montasser, May E.; Müller-Nurasyid, Martina; Nolte, Ilja M.; O'Connell, Jeffrey R.; Palmer, Cameron D.; Perola, Markus; Petersen, Ann-Kristin; Sanna, Serena; Saxena, Richa; Service, Susan K.; Shah, Sonia; Shungin, Dmitry; Sidore, Carlo; Song, Ci; Strawbridge, Rona J.; Surakka, Ida; Tanaka, Toshiko; Teslovich, Tanya M.; Thorleifsson, Gudmar; van den Herik, Evita G.; Voight, Benjamin F.; Volcik, Kelly A.; Waite, Lindsay L.; Wong, Andrew; Wu, Ying; Zhang, Weihua; Absher, Devin; Asiki, Gershim; Barroso, Inês; Been, Latonya F.; Bolton, Jennifer L.; Bonnycastle, Lori L.; Brambilla, Paolo; Burnett, Mary S.; Cesana, Giancarlo; Dimitriou, Maria; Doney, Alex S. F.; Döring, Angela; Elliott, Paul; Epstein, Stephen E.; Eyjolfsson, Gudmundur Ingi; Gigante, Bruna; Goodarzi, Mark O.; Grallert, Harald; Gravito, Martha L.; Groves, Christopher J.; Hallmans, Göran; Hartikainen, Anna-Liisa; Hayward, Caroline; Hernandez, Dena; Hicks, Andrew A.; Holm, Hilma; Hung, Yi-Jen; Illig, Thomas; Jones, Michelle R.; Kaleebu, Pontiano; Kastelein, John J. P.; Khaw, Kay-Tee; Kim, Eric; Klopp, Norman; Komulainen, Pirjo; Kumari, Meena; Langenberg, Claudia; Lehtimäki, Terho; Lin, Shih-Yi; Lindström, Jaana; Loos, Ruth J. F.; Mach, François; McArdle, Wendy L.; Meisinger, Christa; Mitchell, Braxton D.; Müller, Gabrielle; Nagaraja, Ramaiah; Narisu, Narisu; Nieminen, Tuomo V. M.; Nsubuga, Rebecca N.; Olafsson, Isleifur; Ong, Ken K.; Palotie, Aarno; Papamarkou, Theodore; Pomilla, Cristina; Pouta, Anneli; Rader, Daniel J.; Reilly, Muredach P.; Ridker, Paul M.; Rivadeneira, Fernando; Rudan, Igor; Ruokonen, Aimo; Samani, Nilesh; Scharnagl, Hubert; Seeley, Janet; Silander, Kaisa; Stančáková, Alena; Stirrups, Kathleen; Swift, Amy J.; Tiret, Laurence; Uitterlinden, Andre G.; van Pelt, L. Joost; Vedantam, Sailaja; Wainwright, Nicholas; Wijmenga, Cisca; Wild, Sarah H.; Willemsen, Gonneke; Wilsgaard, Tom; Wilson, James F.; Young, Elizabeth H.; Zhao, Jing Hua; Adair, Linda S.; Arveiler, Dominique; Assimes, Themistocles L.; Bandinelli, Stefania; Bennett, Franklyn; Bochud, Murielle; Boehm, Bernhard O.; Boomsma, Dorret I.; Borecki, Ingrid B.; Bornstein, Stefan R.; Bovet, Pascal; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C.; Chen, Yii-Der Ida; Collins, Francis S.; Cooper, Richard S.; Danesh, John; Dedoussis, George; de Faire, Ulf; Feranil, Alan B.; Ferrières, Jean; Ferrucci, Luigi; Freimer, Nelson B.; Gieger, Christian; Groop, Leif C.; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hingorani, Aroon; Hirschhorn, Joel N.; Hofman, Albert; Hovingh, G. Kees; Hsiung, Chao Agnes; Humphries, Steve E.; Hunt, Steven C.; Hveem, Kristian; Iribarren, Carlos; Järvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kaprio, Jaakko; Kesäniemi, Antero; Kivimaki, Mika; Kooner, Jaspal S.; Koudstaal, Peter J.; Krauss, Ronald M.; Kuh, Diana; Kuusisto, Johanna; Kyvik, Kirsten O.; Laakso, Markku; Lakka, Timo A.; Lind, Lars; Lindgren, Cecilia M.; Martin, Nicholas G.; März, Winfried; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Metspalu, Andres; Moilanen, Leena; Morris, Andrew D.; Munroe, Patricia B.; Njølstad, Inger; Pedersen, Nancy L.; Power, Chris; Pramstaller, Peter P.; Price, Jackie F.; Psaty, Bruce M.; Quertermous, Thomas; Rauramaa, Rainer; Saleheen, Danish; Salomaa, Veikko; Sanghera, Dharambir K.; Saramies, Jouko; Schwarz, Peter E. H.; Sheu, Wayne H.-H.; Shuldiner, Alan R.; Siegbahn, Agneta; Spector, Tim D.; Stefansson, Kari; Strachan, David P.; Tayo, Bamidele O.; Tremoli, Elena; Tuomilehto, Jaakko; Uusitupa, Matti; van Duijn, Cornelia M.; Vollenweider, Peter; Wallentin, Lars; Wareham, Nicholas J.; Whitfield, John B.; Wolffenbuttel, Bruce H. R.; Altshuler, David; Ordovas, Jose M.; Boerwinkle, Eric; Palmer, Colin N. A.; Thorsteinsdottir, Unnur; Chasman, Daniel I.; Rotter, Jerome I.; Franks, Paul W.; Ripatti, Samuli; Cupples, L. Adrienne; Sandhu, Manjinder S.; Rich, Stephen S.; Boehnke, Michael; Deloukas, Panos; Mohlke, Karen L.; Ingelsson, Erik; Abecasis, Goncalo R.; Daly, Mark J.; Neale, Benjamin M.; Kathiresan, Sekar

    2013-01-01

    Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common

  19. Loss of FTO in adipose tissue decreases Angptl4 translation and alters triglyceride metabolism.

    Science.gov (United States)

    Wang, Chao-Yung; Shie, Shian-Sen; Wen, Ming-Shien; Hung, Kuo-Chun; Hsieh, I-Chang; Yeh, Ta-Sen; Wu, Delon

    2015-12-15

    A common variant of the FTO (fat mass- and obesity-associated) gene is a risk factor for obesity. We found that mice with an adipocyte-specific deletion of FTO gained more weight than control mice on a high-fat diet. Analysis of mice lacking FTO in adipocytes fed a normal diet or adipocytes from these mice revealed alterations in triglyceride metabolism that would be expected to favor increased fatty acid storage by adipose tissue. Mice lacking FTO in adipocytes showed increased serum triglyceride breakdown and clearance, which was associated with lower serum triglyceride concentrations. In addition, lipolysis in response to β-adrenergic stimulation was decreased in adipocytes and ex vivo adipose explants from the mutant mice. FTO is a nucleic acid demethylase that removes N(6)-methyladenosine (m(6)A) from mRNAs. We found that FTO bound to Angptl4, which encodes an adipokine that stimulates intracellular lipolysis in adipocytes. Unexpectedly, the adipose tissue of fasted or fed mice lacking FTO in adipocytes had greater Angptl4 mRNA abundance. However, after high-fat feeding, the mutant mice had less Angptl4 protein and more m(6)A-modified Angptl4 than control mice, suggesting that lack of FTO prevented the translation of Angptl4. Injection of Angptl4-encoding adenovirus into mice lacking FTO in adipocytes restored serum triglyceride concentrations and lipolysis to values similar to those in control mice and abolished excessive weight gain from a high-fat diet. These results reveal that FTO regulates fatty acid mobilization in adipocytes and thus body weight in part through posttranscriptional regulation of Angptl4. Copyright © 2015, American Association for the Advancement of Science.

  20. Correlation of hepatic {sup 18}F-fluorodeoxyglucose uptake with fatty liver

    Energy Technology Data Exchange (ETDEWEB)

    An, Young Sil; Yoon, Joon Kee; Hong, Seon Pyo; Joh, Chul Woo; Yoon, Seok Nam [Ajou University School of Medicine, Suwon (Korea, Republic of)

    2006-10-15

    Liver demonstrates heterogeneous FDG uptake and sometimes it shows abnormally increased uptake even though there is no malignant tissue. However, there was no previous study to correlate these various pattern of hepatic FDG uptake with benign liver disease. Therefore, we evaluated the significance of hepatic FDG uptake associated with various clinical factors including fatty liver, liver function tests and lipid profiles. We reviewed a total of 188 patients (male/female: 120/68, mean age: 50 {+-} 9) who underwent PET/CT for screening of malignancy. Patients with DM, impaired glucose tolerance, previous severe hepatic disease or long-term medication history were excluded. The FDG uptake in liver was analyzed semi-quantitatively using ROI on transaxial images (segment 8) and we compared mean standardized uptake value (SUV) between fatty liver and non-fatty liver group. We also evaluated the correlation between hepatic FDG uptake and various clinical factors including serum liver function test (ALT, AST), {gamma} -GT, total cholesterol and triglyceride concentration. The effect of alcoholic history and body mass index on hepatic FDG uptake was analyzed within the fatty liver patients. The hepatic FDG uptake of fatty liver group was significantly higher than that of non-fatty liver group. Serum total cholesterol and triglyceride concentration showed significant correlation with hepatic FDG uptake. However, there was no significant correlation between other factors (ALT, AST, and {gamma} -GT) and FDG uptake. Also there was no difference of mean SUV between normal and abnormal groups on the basis of alcoholic history and body mass index within fatty liver patients. Fatty liver and high serum triglyceride concentration were the independent factors affecting hepatic FDG uptake according to multivariate analysis. In conclusion, hepatic FDG uptake was strongly correlated with fatty liver and serum triglyceride concentration.

  1. Correlation of hepatic 18F-fluorodeoxyglucose uptake with fatty liver

    International Nuclear Information System (INIS)

    An, Young Sil; Yoon, Joon Kee; Hong, Seon Pyo; Joh, Chul Woo; Yoon, Seok Nam

    2006-01-01

    Liver demonstrates heterogeneous FDG uptake and sometimes it shows abnormally increased uptake even though there is no malignant tissue. However, there was no previous study to correlate these various pattern of hepatic FDG uptake with benign liver disease. Therefore, we evaluated the significance of hepatic FDG uptake associated with various clinical factors including fatty liver, liver function tests and lipid profiles. We reviewed a total of 188 patients (male/female: 120/68, mean age: 50 ± 9) who underwent PET/CT for screening of malignancy. Patients with DM, impaired glucose tolerance, previous severe hepatic disease or long-term medication history were excluded. The FDG uptake in liver was analyzed semi-quantitatively using ROI on transaxial images (segment 8) and we compared mean standardized uptake value (SUV) between fatty liver and non-fatty liver group. We also evaluated the correlation between hepatic FDG uptake and various clinical factors including serum liver function test (ALT, AST), γ -GT, total cholesterol and triglyceride concentration. The effect of alcoholic history and body mass index on hepatic FDG uptake was analyzed within the fatty liver patients. The hepatic FDG uptake of fatty liver group was significantly higher than that of non-fatty liver group. Serum total cholesterol and triglyceride concentration showed significant correlation with hepatic FDG uptake. However, there was no significant correlation between other factors (ALT, AST, and γ -GT) and FDG uptake. Also there was no difference of mean SUV between normal and abnormal groups on the basis of alcoholic history and body mass index within fatty liver patients. Fatty liver and high serum triglyceride concentration were the independent factors affecting hepatic FDG uptake according to multivariate analysis. In conclusion, hepatic FDG uptake was strongly correlated with fatty liver and serum triglyceride concentration

  2. Schisandra sphenanthera extract (Wuzhi Tablet protects against chronic-binge and acute alcohol-induced liver injury by regulating the NRF2-ARE pathway in mice

    Directory of Open Access Journals (Sweden)

    Xuezhen Zeng

    2017-09-01

    Full Text Available Alcohol abuse leads to alcoholic liver disease and no effective therapy is currently available. Wuzhi Tablet (WZ, a preparation of extract from Schisandra sphenanthera that is a traditional hepato-protective herb, exerted a significant protective effect against acetaminophen-induced liver injury in our recent studies, but whether WZ can alleviate alcohol-induced toxicity remains unclear. This study aimed to investigate the contribution of WZ to alcohol-induced liver injury by using chronic-binge and acute models of alcohol feeding. The activities of ALT and AST in serum were assessed as well as the level of GSH and the activity of SOD in the liver. The expression of CYP2E1 and proteins in the NRF2-ARE signaling pathway including NRF2, GCLC, GCLM, HO-1 were measured, and the effect of WZ on NRF2 transcriptional activity was determined. We found that both models resulted in liver steatosis accompanied by increased transaminase activities, but that liver injury was significantly attenuated by WZ. WZ administration also inhibited CYP2E1 expression induced by alcohol, and elevated the level of GSH and the activity of SOD in the liver. Moreover, the NRF2-ARE signaling pathway was activated by WZ and the target genes were all upregulated. Furthermore, WZ significantly activated NRF2 transcriptional activity. Collectively, our study demonstrates that WZ protected against alcohol-induced liver injury by reducing oxidative stress and improving antioxidant defense, possibly by activating the NRF2-ARE pathway.

  3. Nonfasting triglycerides and risk of myocardial infarction, ischemic heart disease, and death in men and women

    DEFF Research Database (Denmark)

    Nordestgaard, Børge G; Benn, Marianne; Schnohr, Peter

    2007-01-01

    Elevated nonfasting triglycerides indicate the presence of remnant lipoproteins, which may promote atherosclerosis.......Elevated nonfasting triglycerides indicate the presence of remnant lipoproteins, which may promote atherosclerosis....

  4. Elevated triglycerides: A matter of the heart and pancreas

    African Journals Online (AJOL)

    Remnant cholesterol = total cholesterol − high-density lipoprotein. (HDL) cholesterol − low-density lipoprotein (LDL) cholesterol[4]. The relative risk of CVD ... hyperlipidaemia with a total cholesterol to triglyceride ratio of 2:1. Environmental ...

  5. Plasma Triglyceride and Cholesterol Levels in Normotensive and ...

    African Journals Online (AJOL)

    Plasma Triglyceride and Cholesterol Levels in Normotensive and Hypertensive Pregnant and Parturient Nigerian Women. Kashope D. Thomas, Oyebola G. Adeosun, Norah O. Akinola, Uche Onwudiegwu, Alexander T. Owolabi ...

  6. CT evaluation of the bile ducts in patients with fatty liver

    International Nuclear Information System (INIS)

    Quint, L.E.; Glazer, G.M.

    1984-01-01

    Computed tomographic (CT) evaluation of the bile ducts in the fatty liver can be difficult, since hepatic attenuation decreases with increased triglyceride content, and liver parenchyma may become isodense with bile. Forty-seven patients with fatty infiltration of the liver were retrospectively identified. In 7 of these patients, attenuation of liver and bile differed by less than 10 HU. In 2 patients, dilated intrahepatic ducts were invisible using CT, because bile was isodense with fatty liver parenchyma. Thus, the fatty liver presents a potential pitfall in CT evaluation of the bile ducts. For maximal accuracy scans should be obtained both before and after administration of intravenous urographic contrast material

  7. Entwicklung eines kontinuierlichen Verfahrens zur enzymkatalysierten Synthese eines strukturierten Triglycerides

    OpenAIRE

    Stadler, Hans-Gerhard

    2005-01-01

    Ausgangspunkt für die in der vorliegenden Arbeit durchgeführten Entwicklung eines kontinuierlichen Verfahrens zur Synthese des strukturierten Triglycerides 1,3-Oleyl-2-palmitoylglycerin war die von Schmid [Schmid 1999] entwickelte lipase-katalysierte Zwei-Schritt-Synthese für strukturierte Triglyceride vom Typ ABA [European Patent Application; EP 0 882 797 A2]. In der ersten Reaktionsstufe dieser zweistufigen Umesterung wird in einer Folgereaktion das Substrat Tripalmitin mit Hilfe ein...

  8. Cholesterol, Triglycerides, and the Five-Factor Model of Personality

    OpenAIRE

    Sutin, Angelina R.; Terracciano, Antonio; Deiana, Barbara; Uda, Manuela; Schlessinger, David; Lakatta, Edward G.; Costa, Paul T.

    2010-01-01

    Unhealthy lipid levels are among the leading controllable risk factors for coronary heart disease. To identify the psychological factors associated with dyslipidemia, this study investigates the personality correlates of cholesterol (total, LDL, and HDL) and triglycerides. A community-based sample (N=5,532) from Sardinia, Italy, had their cholesterol and triglyceride levels assessed and completed a comprehensive personality questionnaire, the NEO-PI-R. All analyses controlled for age, sex, BM...

  9. Elastin in the Liver

    Directory of Open Access Journals (Sweden)

    Jiri Kanta

    2016-10-01

    Full Text Available A characteristic feature of liver cirrhosis is the accumulation of large amounts of connective tissue with the prevailing content of type I collagen. Elastin is a minor connective tissue component in normal liver but it is actively synthesized by hepatic stellate cells and portal fibroblasts in diseased liver. The accumulation of elastic fibers in later stages of liver fibrosis may contribute to the decreasing reversibility of the disease with advancing time. Elastin is formed by polymerization of tropoelastin monomers. It is an amorphous protein highly resistant to the action of proteases that forms the core of elastic fibers. Microfibrils surrounding the core are composed of fibrillins that bind a number of proteins involved in fiber formation. They include microfibril-associated glycoproteins (MAGPs, microfibrillar-associated proteins (MFAPs and fibulins. Lysyl oxidase (LOX and lysyl oxidase-like proteins (LOXLs are responsible for tropoelastin cross-linking and polymerization. TGF-β complexes attached to microfibrils release this cytokine and influence the behavior of the cells in the neighborhood. The role of TGF-β as the main profibrotic cytokine in the liver is well-known and the release of the cytokines of TGF-β superfamily from their storage in elastic fibers may affect the course of fibrosis. Elastic fibres are often studied in the tissues where they provide elasticity and resilience but their role is no longer viewed as purely mechanical. Tropoelastin, elastin polymer and elastin peptides resulting from partial elastin degradation influence fibroblastic and inflammatory cells as well as angiogenesis. A similar role may be performed by elastin in the liver. This article reviews the results of the research of liver elastic fibers on the backgound of the present knowledge of elastin biochemistry and physiology. The regulation of liver elastin synthesis and degradation may be important for the outcome of liver fibrosis.

  10. Fatty Liver

    International Nuclear Information System (INIS)

    Filippone, A.; Digiovandomenico, V.; Digiovandomenico, E.; Genovesi, N.; Bonomo, L.

    1991-01-01

    The authors report their experience with the combined use of US and CT in the study of diffuse and subtotal fatty infiltration of the liver. An apparent disagreement was initially found between the two examinations in the study of fatty infiltration. Fifty-five patients were studied with US and CT of the upper abdomen, as suggested by clinics. US showed normal liver echogenicity in 30 patients and diffuse increased echogenicity (bright liver) in 25 cases. In 5 patients with bright liver, US demonstrated a solitary hypoechoic area, appearing as a 'skip area', in the quadrate lobe. In 2 patients with bright liver, the hypoechoic area was seen in the right lobe and exhibited no typical US features of 'Skip area'. Bright liver was quantified by measuring CT density of both liver and spleen. The relative attenuation values of spleen and liver were compared on plain and enhanced CT scans. In 5 cases with a hypoechoic area in the right lobe, CT findings were suggestive of hemangioma. A good correlation was found between broght liver and CT attenuation values, which decrease with increasing fat content of the liver. Moreover, CT attenuation values confirmed US findings in the study of typical 'skip area', by demonstrating normal density - which suggests that CT can characterize normal tissue in atypical 'skip area'

  11. Lack of liver glycogen causes hepatic insulin resistance and steatosis in mice.

    Science.gov (United States)

    Irimia, Jose M; Meyer, Catalina M; Segvich, Dyann M; Surendran, Sneha; DePaoli-Roach, Anna A; Morral, Nuria; Roach, Peter J

    2017-06-23

    Disruption of the Gys2 gene encoding the liver isoform of glycogen synthase generates a mouse strain (LGSKO) that almost completely lacks hepatic glycogen, has impaired glucose disposal, and is pre-disposed to entering the fasted state. This study investigated how the lack of liver glycogen increases fat accumulation and the development of liver insulin resistance. Insulin signaling in LGSKO mice was reduced in liver, but not muscle, suggesting an organ-specific defect. Phosphorylation of components of the hepatic insulin-signaling pathway, namely IRS1, Akt, and GSK3, was decreased in LGSKO mice. Moreover, insulin stimulation of their phosphorylation was significantly suppressed, both temporally and in an insulin dose response. Phosphorylation of the insulin-regulated transcription factor FoxO1 was somewhat reduced and insulin treatment did not elicit normal translocation of FoxO1 out of the nucleus. Fat overaccumulated in LGSKO livers, showing an aberrant distribution in the acinus, an increase not explained by a reduction in hepatic triglyceride export. Rather, when administered orally to fasted mice, glucose was directed toward hepatic lipogenesis as judged by the activity, protein levels, and expression of several fatty acid synthesis genes, namely, acetyl-CoA carboxylase, fatty acid synthase, SREBP1c, chREBP, glucokinase, and pyruvate kinase. Furthermore, using cultured primary hepatocytes, we found that lipogenesis was increased by 40% in LGSKO cells compared with controls. Of note, the hepatic insulin resistance was not associated with increased levels of pro-inflammatory markers. Our results suggest that loss of liver glycogen synthesis diverts glucose toward fat synthesis, correlating with impaired hepatic insulin signaling and glucose disposal. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  12. Cardiac expression of microsomal triglyceride transfer protein is increased in obesity and serves to attenuate cardiac triglyceride accumulation

    DEFF Research Database (Denmark)

    Bartels, Emil D; Nielsen, Jan M; Hellgren, Lars I

    2009-01-01

    Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via...... secretion of apolipoproteinB-containing (apoB) lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP); the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism...... remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression...

  13. Structural Insights into Triglyceride Storage Mediated by Fat Storage-Inducing Transmembrane (FIT) Protein 2

    Science.gov (United States)

    Gross, David A.; Snapp, Erik L.; Silver, David L.

    2010-01-01

    Fat storage-Inducing Transmembrane proteins 1 & 2 (FIT1/FITM1 and FIT2/FITM2) belong to a unique family of evolutionarily conserved proteins localized to the endoplasmic reticulum that are involved in triglyceride lipid droplet formation. FIT proteins have been shown to mediate the partitioning of cellular triglyceride into lipid droplets, but not triglyceride biosynthesis. FIT proteins do not share primary sequence homology with known proteins and no structural information is available to inform on the mechanism by which FIT proteins function. Here, we present the experimentally-solved topological models for FIT1 and FIT2 using N-glycosylation site mapping and indirect immunofluorescence techniques. These methods indicate that both proteins have six-transmembrane-domains with both N- and C-termini localized to the cytosol. Utilizing this model for structure-function analysis, we identified and characterized a gain-of-function mutant of FIT2 (FLL(157-9)AAA) in transmembrane domain 4 that markedly augmented the total number and mean size of lipid droplets. Using limited-trypsin proteolysis we determined that the FLL(157-9)AAA mutant has enhanced trypsin cleavage at K86 relative to wild-type FIT2, indicating a conformational change. Taken together, these studies indicate that FIT2 is a 6 transmembrane domain-containing protein whose conformation likely regulates its activity in mediating lipid droplet formation. PMID:20520733

  14. Structural insights into triglyceride storage mediated by fat storage-inducing transmembrane (FIT protein 2.

    Directory of Open Access Journals (Sweden)

    David A Gross

    2010-05-01

    Full Text Available Fat storage-Inducing Transmembrane proteins 1 & 2 (FIT1/FITM1 and FIT2/FITM2 belong to a unique family of evolutionarily conserved proteins localized to the endoplasmic reticulum that are involved in triglyceride lipid droplet formation. FIT proteins have been shown to mediate the partitioning of cellular triglyceride into lipid droplets, but not triglyceride biosynthesis. FIT proteins do not share primary sequence homology with known proteins and no structural information is available to inform on the mechanism by which FIT proteins function. Here, we present the experimentally-solved topological models for FIT1 and FIT2 using N-glycosylation site mapping and indirect immunofluorescence techniques. These methods indicate that both proteins have six-transmembrane-domains with both N- and C-termini localized to the cytosol. Utilizing this model for structure-function analysis, we identified and characterized a gain-of-function mutant of FIT2 (FLL(157-9AAA in transmembrane domain 4 that markedly augmented the total number and mean size of lipid droplets. Using limited-trypsin proteolysis we determined that the FLL(157-9AAA mutant has enhanced trypsin cleavage at K86 relative to wild-type FIT2, indicating a conformational change. Taken together, these studies indicate that FIT2 is a 6 transmembrane domain-containing protein whose conformation likely regulates its activity in mediating lipid droplet formation.

  15. Diet and liver apoptosis in rats: a particular metabolic pathway.

    Science.gov (United States)

    Monteiro, Maria Emilia Lopes; Xavier, Analucia Rampazzo; Azeredo, Vilma Blondet

    2017-03-30

    Various studies have indicated an association between modifi cation in dietary macronutrient composition and liver apoptosis. To explain how changes in metabolic pathways associated with a high-protein, high-fat, and low-carbohydrate diet causes liver apoptosis. Two groups of rats were compared. An experimental diet group (n = 8) using a high-protein (59.46%), high-fat (31.77%), and low-carbohydrate (8.77%) diet versus a control one (n = 9) with American Institute of Nutrition (AIN)-93-M diet. Animals were sacrificed after eight weeks, the adipose tissue weighed, the liver removed for flow cytometry analysis, and blood collected to measure glucose, insulin, glucagon, IL-6, TNF, triglycerides, malondialdehyde, and β-hydroxybutyrate. Statistical analysis was carried out using the unpaired and parametric Student's t-test and Pearson's correlation coeffi ents. Significance was set at p triglycerides lower levels compared with the control group. The results show a positive and significant correlation between the percentage of nonviable hepatocytes and malondialdehyde levels (p = 0.0217) and a statistically significant negative correlation with triglycerides levels (p = 0.006). Results suggest that plasmatic malondialdehyde and triglyceride levels are probably good predictors of liver damage associated with an experimental low-carbohydrate diet in rats.

  16. Pharmacoeconomics of parenteral nutrition in surgical and critically ill patients receiving structured triglycerides in China.

    Science.gov (United States)

    Wu, Guo Hao; Ehm, Alexandra; Bellone, Marco; Pradelli, Lorenzo

    2017-01-01

    A prior meta-analysis showed favorable metabolic effects of structured triglyceride (STG) lipid emulsions in surgical and critically ill patients compared with mixed medium-chain/long-chain triglycerides (MCT/LCT) emulsions. Limited data on clinical outcomes precluded pharmacoeconomic analysis. We performed an updated meta-analysis and developed a cost model to compare overall costs for STGs vs MCT/LCTs in Chinese hospitals. We searched Medline, Embase, Wanfang Data, the China Hospital Knowledge Database, and Google Scholar for clinical trials comparing STGs to mixed MCT/LCTs in surgical or critically ill adults published between October 10, 2013 and September 19, 2015. Newly identified studies were pooled with the prior studies and an updated meta-analysis was performed. A deterministic simulation model was used to compare the effects of STGs and mixed MCT/LCT's on Chinese hospital costs. The literature search identified six new trials, resulting in a total of 27 studies in the updated meta-analysis. Statistically significant differences favoring STGs were observed for cumulative nitrogen balance, pre- albumin and albumin concentrations, plasma triglycerides, and liver enzymes. STGs were also associated with a significant reduction in the length of hospital stay (mean difference, -1.45 days; 95% confidence interval, -2.48 to -0.43; p=0.005) versus mixed MCT/LCTs. Cost analysis demonstrated a net cost benefit of ¥675 compared with mixed MCT/LCTs. STGs are associated with improvements in metabolic function and reduced length of hospitalization in surgical and critically ill patients compared with mixed MCT/LCT emulsions. Cost analysis using data from Chinese hospitals showed a corresponding cost benefit.

  17. Measurement and correlation of solubility of carbon dioxide in triglycerides

    International Nuclear Information System (INIS)

    Howlader, Md Shamim; French, William Todd; Toghiani, Hossein; Hartenbower, Ben; Pearson, Larry; DuBien, Janice; Rai, Neeraj

    2017-01-01

    Graphical abstract: Comparison of experimental results with correlation for solubility of CO 2 in triglycerides as a function pressure at two different temperatures of 289.15 and 303.15 K, respectively. - Highlights: • New pressure drop gas apparatus was developed to determine the solubility of gases in liquids. • Solubility of CO 2 in triglycerides was measured at different temperatures and pressures. • Experimental solubility data were correlated using three thermodynamic models. • Enthalpy, entropy and Gibbs energy of dissolution for CO 2 -triglyceride were determined. - Abstract: A new pressure drop solubility gas apparatus was developed to determine the solubility of carbon dioxide in canola oil, a triglyceride consisting primarily of oleic, linoleic, and alpha linoleic acid radicals. Solubility of CO 2 in triglycerides was determined at different temperatures (283.2–303.2 K) and pressures (600–2450 kPa). It was found that the solubility of CO 2 in triglycerides is higher than that of pure water because triglycerides lack strong hydrogen bond networks that exist in liquid water at the ambient conditions. The experimental solubility was correlated using Krichevsky–Kasarnovsky (KK), Mather-Jou (MJ), and Carvalho-Coutinho (CC) correlations. We find that KK and MJ equations can predict the solubility with higher accuracy. The enthalpy and entropy of absorption of CO 2 were calculated using the van’t Hoff plot and were found to be −7.165 kJ.mol −1 , and −28.791 J.mol −1 .K −1 , respectively.

  18. Disruptive cell cycle regulation involving epigenetic downregulation of Cdkn2a (p16Ink4a) in early-stage liver tumor-promotion facilitating liver cell regeneration in rats

    International Nuclear Information System (INIS)

    Tsuchiya, Takuma; Wang, Liyun; Yafune, Atsunori; Kimura, Masayuki; Ohishi, Takumi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-01-01

    Cell cycle aberration was immunohistochemically examined in relation to preneoplastic liver cell foci expressing glutathione S-transferase placental form (GST-P) at early stages of tumor-promotion in rats with thioacetamide (TAA), a hepatocarcinogen facilitating liver cell regeneration. Immunoexpression of p16 Ink4a following exposure to other hepatocarcinogens/promoters and its DNA methylation status were also analyzed during early and late tumor-promotion stages. GST-P + liver cell foci increased cell proliferation and decreased apoptosis when compared with surrounding liver cells. In concordance with GST-P + foci, checkpoint proteins at G 1 /S (p21 Cip1 , p27 Kip1 and p16 Ink4a ) and G 2 /M (phospho-checkpoint kinase 1, Cdc25c and phospho-Wee1) were either up- or downregulated. Cellular distribution within GST-P + foci was either increased or decreased with proteins related to G 2 -M phase or DNA damage (topoisomerase IIα, phospho-histone H2AX, phospho-histone H3 and Cdc2). In particular, p16 Ink4a typically downregulated in GST-P + foci and regenerative nodules at early tumor-promotion stage with hepatocarcinogens facilitating liver cell regeneration and in neoplastic lesions at late tumor-promotion stage with hepatocarcinogens/promoters irrespective of regenerating potential. Hypermethylation at exon 2 of Cdkn2a was detected at both early- and late-stages. Thus, diverse disruptive expression of G 1 /S and G 2 /M proteins, which allows for clonal selection of GST-P + foci, results in the acquisition of multiple aberrant phenotypes to disrupt checkpoint function. Moreover, increased DNA-damage responses within GST-P + foci may be the signature of genetic alterations. Intraexonic hypermethylation may be responsible for p16 Ink4a -downregulation, which facilitates cell cycle progression in early preneoplastic lesions produced by repeated cell regeneration and late-stage neoplastic lesions irrespective of the carcinogenic mechanism.

  19. Effect of 6-Month Calorie Restriction and Exercise on Serum and Liver Lipids and Markers of Liver Function

    Science.gov (United States)

    Larson-Meyer, D. Enette; Newcomer, Bradley R.; Heilbronn, Leonie K.; Volaufova, Julia; Smith, Steven R.; Alfonso, Anthony J.; Lefevre, Michael; Rood, Jennifer C.; Williamson, Donald A.; Ravussin, Eric

    2009-01-01

    objective Nonalcoholic fatty liver disease (NAFLD) and its association with insulin resistance are increasingly recognized as major health burdens. The main objectives of this study were to assess the relation between liver lipid content and serum lipids, markers of liver function and inflammation in healthy overweight subjects, and to determine whether caloric restriction (CR) (which improves insulin resistance) reduces liver lipids in association with these same measures. Methods and Procedures Forty-six white and black overweight men and women (BMI = 24.7-31.3 kg/m2) were randomized to “control (CO)” = 100% energy requirements; “CR” = 25%; “caloric restriction and increased structured exercise (CR+EX)”= 12.5% CR + 12.5% increase in energy expenditure through exercise; or “low-calorie diet (LCD)” = 15% weight loss by liquid diet followed by weight-maintenance, for 6 months. Liver lipid content was assessed by magnetic resonance spectroscopy (MRS) and computed tomography (CT). Lipid concentrations, markers of liver function (alanine aminotransferase (ALT), alkaline phosphatase (ALK)), and whole-body inflammation (tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP)) were measured in fasting blood. Results At baseline, increased liver lipid content (by MRS) correlated (P triglyceride (r = 0.52), ALT (r = 0.42), and hsCRP (r = 0.33) concentrations after adjusting for sex, race, and alcohol consumption. With CR, liver lipid content was significantly lowered by CR, CR+EX, and LCD (detected by MRS only). The reduction in liver lipid content, however, was not significantly correlated with the reduction in triglycerides (r = 0.26; P = 0.11) or with the changes in ALT, high-density lipoprotein (HDL)-cholesterol, or markers of whole-body inflammation. Discussion CR may be beneficial for reducing liver lipid and lowering triglycerides in overweight subjects without known NAFLD. PMID:18421281

  20. Esculetin ameliorates hepatic fibrosis in high fat diet induced non-alcoholic fatty liver disease by regulation of FoxO1 mediated pathway.

    Science.gov (United States)

    Pandey, Anuradha; Raj, Priyank; Goru, Santosh Kumar; Kadakol, Almesh; Malek, Vajir; Sharma, Nisha; Gaikwad, Anil Bhanudas

    2017-08-01

    Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is associated with oxidative stress, inflammation and fibrotic cascades. In this study, we aimed to examine the effects of Esculetin, a well-known anti-oxidant on TGF-β1 mediated liver fibrosis and FoxO1 activity. A non-genetic murine model for NAFLD was developed by chronic high fat diet (HFD) (58% calories from fats) feeding in Wistar rats. The plasma biochemical parameters, liver function tests, oxidative stress, and histopathological alterations were assessed. The alterations in extracellular matrix (ECM) deposition and FoxO1 activity were assessed by immunohistochemistry. The aberrations in plasma parameters, liver functioning, morphometric and microscopic changes in liver structure of HFD fed rats were significantly improved by treatment with Esculetin. Liver fibrosis, identified in the form of collagen deposition and expression of fibrotic proteins like TGF-β1 and fibronectin was also markedly controlled by Esculetin. The expression of phospho-FoxO1 was found to be reduced in HFD fed rats' liver, showing an increase in activation of FoxO1 under insulin resistant and hyperglycemic states. Esculetin treatment could improve phospho-FoxO1 expression, thus showing its ability to act on Akt/PI3K/FoxO1 pathway. As per the previous studies, a potential therapy for NAFLD may be the one with multi-faceted actions on insulin resistance, oxidative stress, inflammation and fibrosis. This study demonstrates the efficiency of Esculetin in improving liver fibrosis in HFD induced NAFLD. Copyright © 2017 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

  1. CCAAT/Enhancer Binding Protein-β Is a Transcriptional Regulator of Peroxisome-Proliferator-Activated Receptor-γ Coactivator-1α in the Regenerating Liver

    OpenAIRE

    Wang, Haitao; Peiris, T. Harshani; Mowery, A.; Le Lay, John; Gao, Yan; Greenbaum, Linda E.

    2008-01-01

    The transcriptional coactivator peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) is induced in the liver in response to fasting and coordinates the activation of targets necessary for increasing energy production for gluconeogenesis and ketogenesis. After partial hepatectomy, the liver must restore its mass while maintaining metabolic homeostasis to ensure survival. Here we report that PGC-1α is rapidly and dramatically induced after hepatectomy, with an amplitude of induc...

  2. 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).

    Science.gov (United States)

    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.

  3. Liver Disease

    Science.gov (United States)

    ... and ridding your body of toxic substances. Liver disease can be inherited (genetic) or caused by a variety of factors that damage the ... that you can't stay still. Causes Liver disease has many ... or semen, contaminated food or water, or close contact with a person who is ...

  4. Liver scintigraphy

    International Nuclear Information System (INIS)

    Tateno, Yukio

    1996-01-01

    Liver scintigraphy can be classified into 3 major categories according to the properties of the radiopharmaceuticals used, i.e., methods using radiopharmaceuticals which are (1) incorporated by hepatocytes, (2) taken up by reticulo endothelial cells, and (3) distributed in the blood pool of the liver. Of these three categories, the liver scintigraphy of the present research falls into category 2. Radiopharmaceuticals which are taken up by endothelial cells include 198 Au colloids and 99m Tc-labelled colloids. Liver scintigraphy takes advantage of the property by which colloidal microparticles are phagocytosed by Kupffer cells, and reflect the distribution of endothelial cells and the intensity of their phagocytic capacity. This examination is indicated in the following situations: (i) when you suspect a localized intrahepatic lesion (tumour, abscess, cyst, etc.), (ii) when you want to follow the course of therapy of a localized lesion, (iii) when you suspect liver cirrhosis, (iv) when you want to know the severity of liver cirrhosis or hepatitis, (v) when there is hepatomegaly and you want to determine the morphology of the liver, (vi) differential diagnosis of upper abdominal masses, and (vii) when there are abnormalities of the right diaphragm and you want to know their relation to the liver

  5. Liver regeneration

    NARCIS (Netherlands)

    Chamuleau, R. A.; Bosman, D. K.

    1988-01-01

    Despite great advances in analysing hemodynamic, morphological and biochemical changes during the process of liver regeneration, the exact (patho)physiological mechanism is still unknown. A short survey of literature is given of the kinetics of liver regeneration and the significance of different

  6. Freshwater Clam Extract Ameliorates Triglyceride and Cholesterol Metabolism through the Expression of Genes Involved in Hepatic Lipogenesis and Cholesterol Degradation in Rats

    Directory of Open Access Journals (Sweden)

    Thomas Laurent

    2013-01-01

    Full Text Available The freshwater clam (Corbicula spp. is a popular edible bivalve and has been used as a folk remedy for liver disease in Asia. As a Chinese traditional medicine, it is said that freshwater clam ameliorates alcoholic intoxication and cholestasis. In this study, to estimate the practical benefit of freshwater clam extract (FCE, we compared the effects of FCE and soy protein isolate (SPI on triglyceride and cholesterol metabolism in rats. FCE and SPI lowered serum cholesterol, and FCE tended to reduce serum triglycerides. FCE enhanced fecal sterol excretion and hepatic mRNA levels of CYP7A1 and ABCG5 more substantially than SPI; however, both diets reduced hepatic cholesterol. Both of the diets similarly suppressed liver lipids improved Δ9-desaturated fatty acid profile, and FCE was associated with a reduction in FAS and SCD1 mRNA levels. Hepatic transcriptome analysis revealed that inhibition of lipogenesis-related gene expression may contribute to downregulation of hepatic triglycerides by FCE. FCE would have better potential benefits for preventing metabolic disorders, through greater improvement of metabolism of triglycerides and cholesterol, likely through a mechanism similar to SPI.

  7. [Residual risk: The roles of triglycerides and high density lipoproteins].

    Science.gov (United States)

    Grammer, Tanja; Kleber, Marcus; Silbernagel, Günther; Scharnagl, Hubert; März, Winfried

    2016-06-01

    In clinical trials, the reduction of LDL-cholesterol (LDL-C) with statins reduces the incidence rate of cardiovascular events by approximately one third. This means, that a sizeable "residual risk" remains. Besides high lipoprotein (a), disorders in the metabolism of triglyceride-rich lipoproteins and high density liproteins have been implicated as effectors of the residual risk. Both lipoprotein parameters correlate inversely with each other. Therefore, the etiological contributions of triglycerides and / or of HDL for developing cardiovascular disease can hardly be estimated from either observational studies or from intervention studies. The largely disappointing results of intervention studies with inhibitors of the cholesteryl ester transfer protein and in particular the available set of genetically-epidemiological studies suggest that in the last decade, the importance of HDL cholesterol has been overvalued, while the importance of triglycerides has been underestimated. High triglycerides not always atherogenic, but only if they are associated with the accumulation relatively cholesterol-enriched, incompletely catabolized remnants of chylomicrons and very low density lipoproteins (familial type III hyperlipidemia, metabolic syndrome, diabetes mellitus). The normalization of the concentration of triglycerides and remnants by inhibiting the expression of apolipoprotein C3 is hence a new, promising therapeutic target. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors.

    Science.gov (United States)

    Cheng, Jun; Song, Xuekun; Ao, Lu; Chen, Rou; Chi, Meirong; Guo, You; Zhang, Jiahui; Li, Hongdong; Zhao, Wenyuan; Guo, Zheng; Wang, Xianlong

    2018-01-01

    Background & Aims : Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma. Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified "liver-specific" genes whose expression levels ranked among the bottom 10% ("unexpressed") of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples. Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5 , were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment.

  9. Pemulihan Kadar Glikogen Serta Peningkatan Konsumsi Glukosa dan Trigliserida Saat Aktivitas Fisik Pascapemberian Ekstrak Kulit Buah Manggis (GLYCOGEN RECOVERY AND INCREASE CONSUMPTION OF GLUCOSE AND TRIGLYCERIDE DURING PHYSICAL ACTIVITIES AFTER ADMINISTRA

    OpenAIRE

    I Nyoman Arsana; Ni Ketut Ayu Juliasih

    2016-01-01

    This study was aimed to investigate the effect of mangosteen rind on the glycogen recovery of themuscle and the liver, and the glucose and the triglyceride consumption during physical activities. ARandomized Block Design was applied with four treatments: control (K), physical activity (KF), physicalactivity and extract (FE),extract (E). The extract dosage was 400 mg/kg bodyweight/day administered forfour weeks. The assessed variables were the muscle glycogen, the liver glycogen, the blood gly...

  10. Comparative analyses of DHA-Phosphatidylcholine and recombination of DHA-Triglyceride with Egg-Phosphatidylcholine or Glycerylphosphorylcholine on DHA repletion in n-3 deficient mice

    OpenAIRE

    Wu, Fang; Wang, Dan-dan; Wen, Min; Che, Hong-xia; Xue, Chang-hu; Yanagita, Teruyoshi; Zhang, Tian-tian; Wang, Yu-ming

    2017-01-01

    Background Docosahexaenoic acid (DHA) is important for optimal neurodevelopment and brain function during the childhood when the brain is still under development. Methods The effects of DHA-Phosphatidylcholine (DHA-PC) and the recombination of DHA-Triglyceride with egg PC (DHA-TG + PC) or α-Glycerylphosphorylcholine (DHA-TG + α-GPC) were comparatively analyzed on DHA recovery and the DHA accumulation kinetics in tissues including cerebral cortex, erythrocyte, liver, and testis were evaluated ...

  11. Skeletal muscle apolipoprotein B expression reduces muscular triglyceride accumulation

    DEFF Research Database (Denmark)

    Bartels, Emil D; Ploug, Thorkil; Størling, Joachim

    2014-01-01

    Abstract Background. Lipid accumulation in skeletal muscle is associated with impaired insulin sensitivity in type 2 diabetes. In cardiac myocytes, lipoprotein secretion controlled by apolipoproteinB (apoB) and microsomal triglyceride transfer protein (MTP) affects lipid homeostasis. Design. In t...... accumulation and attenuates peripheral insulin resistance in obese mice........ In this study, we investigated whether expression of a human apoB transgene affects triglyceride accumulation and insulin sensitivity in skeletal muscle in fat fed obese mice. Results. Expression of apoB and MTP mRNA and the human apoB transgene was seen in skeletal muscle of the transgene mice. Human apo......Abstract Background. Lipid accumulation in skeletal muscle is associated with impaired insulin sensitivity in type 2 diabetes. In cardiac myocytes, lipoprotein secretion controlled by apolipoproteinB (apoB) and microsomal triglyceride transfer protein (MTP) affects lipid homeostasis. Design...

  12. Protective effects of glycyrrhizic acid against non-alcoholic fatty liver disease in mice.

    Science.gov (United States)

    Sun, Xue; Duan, Xingping; Wang, Changyuan; Liu, Zhihao; Sun, Pengyuan; Huo, Xiaokui; Ma, Xiaodong; Sun, Huijun; Liu, Kexin; Meng, Qiang

    2017-07-05

    Non-alcoholic fatty liver disease (NAFLD) has become a predictive factor of death from many diseases. The purpose of the present study is to investigate the protective effect of glycyrrhizic acid (GA), a natural triterpene glycoside, on NAFLD induced by a high-fat diet (HFD) in mice, and further to elucidate the mechanisms underlying GA protection. GA treatment significantly reduced the relative liver weight, serum ALT, AST activities, levels of serum lipid, blood glucose and insulin. GA suppressed lipid accumulation in liver. Further mechanism investigation indicated that GA reduced hepatic lipogenesis via downregulating SREBP-1c, FAS and SCD1 expression, increased fatty acids β-oxidation via an increase in PPARα, CPT1α and ACADS, and promoted triglyceride metabolism through inducing LPL activity. Furthermore, GA reduced gluconeogenesis through repressing PEPCK and G6Pase, and increased glycogen synthesis through an induction in gene expression of PDase and GSK3β. In addition, GA increased insulin sensitivity through upregulating phosphorylation of IRS-1 and IRS-2. In conclusion, GA produces protective effect against NAFLD, due to regulation of genes involved in lipid, glucose homeostasis and insulin sensitivity. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Nanoparticles containing a liver X receptor agonist inhibit inflammation and atherosclerosis.

    Science.gov (United States)

    Zhang, Xue-Qing; Even-Or, Orli; Xu, Xiaoyang; van Rosmalen, Mariska; Lim, Lucas; Gadde, Suresh; Farokhzad, Omid C; Fisher, Edward A

    2015-01-28

    Liver X receptor (LXR) signaling pathways regulate lipid metabolism and inflammation, which has generated widespread interest in developing synthetic LXR agonists as potential therapeutics for the management of atherosclerosis. In this study, it is demonstrated that nanoparticles (NPs) containing the synthetic LXR agonist GW3965 (NP-LXR) exert anti-inflammatory effects and inhibit the development of atherosclerosis without causing hepatic steatosis. These NPs are engineered through self-assembly of a biodegradable diblock poly(lactide-co-glycolide)-b-poly(ethylene glycol) (PLGA-b-PEG) copolymer. NP-LXR is significantly more effective than free GW3965 at inducing LXR-target gene expression and suppressing inflammatory factors in macrophages in vitro and in vivo. Additionally, the NPs elicit negligible lipogenic gene stimulation in the liver. Using the Ldlr (-/-) mouse model of atherosclerosis, abundant colocalization of fluorescently labeled NPs within plaque macrophages following systemic administration is seen. Notably, six intravenous injections of NP-LXR over 2 weeks markedly reduce the CD68-positive cell (macrophage) content of plaques (by 50%) without increasing total cholesterol or triglycerides in the liver and plasma. Together, these findings identify GW3965-encapsulated PLGA-b-PEG NPs as a promising nanotherapeutic approach to combat atherosclerosis, providing the benefits of LXR agonists without their adverse effects on hepatic and plasma lipid metabolism. © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver

    Science.gov (United States)

    Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Cicerchi, Christina; Li, Nanxing; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Le, Myphuong; Garcia, Gabriela E.; Thomas, Jeffrey B.; Rivard, Christopher J.; Andres-Hernando, Ana; Hunter, Brandi; Schreiner, George; Rodriguez-Iturbe, Bernardo; Sautin, Yuri Y.; Johnson, Richard J.

    2012-01-01

    Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver. PMID:23112875

  15. Role of intestinal mucosal barrier in the development and progression of nonalcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    ZHANG Yuanyuan

    2016-12-01

    Full Text Available The incidence of non-alcoholic fatty liver disease (NAFLD has been increasing year by year in China. Intestinal mucosa is the largest organ for bacterial storage, and intestinal mucosal barrier includes biological barrier, mechanical barrier, immunological barrier, and chemical barrier. This article investigates the important role of intestinal mucosal barrier function in the pathogenesis of NAFLD. As for the intestinal biological barrier, abnormalities in gut microbiota occur earlier than obesity and other metabolic disorders; small intestinal bacterial overgrowth may affect energy metabolism, promote insulin resistance, and get involved in the pathogenesis of NAFLD; regulation of gut microbiota has a certain clinical effect in the treatment of NAFLD. Intestinal mechanical barrier impairment increases the mucosal permeability and is associated with intestinal dysbacteriosis. The changes in intestinal immunological barrier may be associated with obesity, metabolic disorders, and liver inflammation. The changes in intestinal chemical barrier can inhibit the synthesis and secretion of very low-density lipoprotein and low-density lipoprotein in hepatocytes and may result in triglyceride deposition in the liver. It is pointed out that the research on intestinal mucosal barrier function provides promising prospects for the prevention and treatment of NAFLD.

  16. [Liver transplantation].

    Science.gov (United States)

    Pompili, Maurizio; Mirante, Vincenzo Giorgio; Rapaccini, Gian Ludovico; Gasbarrini, Giovanni

    2004-01-01

    Liver transplantation represents the first choice treatment for patients with fulminant acute hepatitis and for patients with chronic liver disease and advanced functional failure. Patients in the waiting list for liver transplantation are classified according to the severity of their clinical conditions (evaluated using staging systems mostly based on hematochemical parameters related to liver function). This classification, together with the blood group and the body size compatibility, remains the main criterion for organ allocation. The main indications for liver transplantation are cirrhosis (mainly HCV-, HBV- and alcohol-related) and hepatocellular carcinoma emerging in cirrhosis in adult patients, biliary atresia and some inborn errors of metabolism in pediatric patients. In adults the overall 5-year survival ranges between 60 and 70%, in both American and European series. Even better results have been reported for pediatric patients: in fact, the 5-year survival rate for children ranges between 70 and 80% in the main published series. In this study we evaluated the main medical problems correlated with liver transplantation such as immunosuppressive treatment, acute and chronic rejection, infectious complications, the recurrence of the liver disease leading to transplantation, and cardiovascular and metabolic complications.

  17. Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice.

    Science.gov (United States)

    Geerling, Janine J; Boon, Mariëtte R; van der Zon, Gerard C; van den Berg, Sjoerd A A; van den Hoek, Anita M; Lombès, Marc; Princen, Hans M G; Havekes, Louis M; Rensen, Patrick C N; Guigas, Bruno

    2014-03-01

    Metformin is the first-line drug for the treatment of type 2 diabetes. Besides its well-characterized antihyperglycemic properties, metformin also lowers plasma VLDL triglyceride (TG). In this study, we investigated the underlying mechanisms in APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism. We found that metformin markedly lowered plasma total cholesterol and TG levels, an effect mostly due to a decrease in VLDL-TG, whereas HDL was slightly increased. Strikingly, metformin did not affect hepatic VLDL-TG production, VLDL particle composition, and hepatic lipid composition but selectively enhanced clearance of glycerol tri[(3)H]oleate-labeled VLDL-like emulsion particles into brown adipose tissue (BAT). BAT mass and lipid droplet content were reduced in metformin-treated mice, pointing to increased BAT activation. In addition, both AMP-activated protein kinase α1 (AMPKα1) expression and activity and HSL and mitochondrial content were increased in BAT. Furthermore, therapeutic concentrations of metformin increased AMPK and HSL activities and promoted lipolysis in T37i differentiated brown adipocytes. Collectively, our results identify BAT as an important player in the TG-lowering effect of metformin by enhancing VLDL-TG uptake, intracellular TG lipolysis, and subsequent mitochondrial fatty acid oxidation. Targeting BAT might therefore be considered as a future therapeutic strategy for the treatment of dyslipidemia.

  18. Inhibition of gastrin-stimulated gastric acid secretion by medium-chain triglycerides and long-chain triglycerides in healthy young men.

    NARCIS (Netherlands)

    Maas, M.I.M.; Hopman, W.P.M.; Katan, M.B.; Jansen, J.B.M.J.

    1996-01-01

    Long-chain triglycerides inhibit gastric acid secretion, but the effect of medium-chain triglycerides in humans is unknown. We compared the effects of intraduodenally perfused saline, medium-chain and long-chain triglycerides on gastrin-stimulated gastric acid secretion and cholecystokinin release.

  19. Emerging roles of Lipasin as a critical lipid regulator.

    Science.gov (United States)

    Zhang, Ren; Abou-Samra, Abdul B

    2013-03-15

    Patients with metabolic syndrome are at high risk for developing atherosclerotic cardiovascular diseases and diabetes. In addition to total cholesterol, LDL-C and HDL-C, elevated plasma triglycerides (TG) are increasingly recognized as an independent risk factor for cardiovascular diseases. Recently 3 groups independently reported the identification and characterization of a novel blood lipid regulator, Lipasin/RIFL/ANGPTL8, which here is referred to as Lipasin for its lipoprotein lipase inhibition effect and for being a circulating factor denoted by 'in'. Being highly enriched in the liver, Lipasin is a hepatocyte-derived circulating factor that regulates plasma TG levels. Lipasin is nutritionally regulated, as its mRNA levels in liver and fat as well as its protein level in serum are reduced by fasting. Mice deficient for Lipasin have lower serum TG levels; conversely, its adenovirus-mediated overexpression increases serum TG levels, in part, through promoting ANGPTL3 cleavage, releasing its N-terminal domain that inhibits lipoprotein lipase. Lipasin sequence variations are associated with LDL-C and HDL-C concentrations in humans. Being lipogenic, Lipasin is highly induced during adipogenesis. Levels of Lipasin and ANGPTL4 show opposite changes in response to fasting or cold environment. Lipasin, a novel but atypical ANGPTL family member, is emerging as a critical lipid regulator and a potential drug target. Copyright © 2013 Elsevier Inc. All rights reserved.

  20. Benign Liver Tumors

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  1. Liver Function Tests

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  2. Progression of Liver Disease

    Science.gov (United States)

    ... Liver Function Tests Clinical Trials Liver Transplant FAQs Medical Terminology Diseases of the Liver Alagille Syndrome Alcohol-Related ... the Liver The Progression of Liver Disease FAQs Medical Terminology HOW YOU CAN HELP Sponsorship Ways to Give ...

  3. Liver (Hepatocellular) Cancer Screening

    Science.gov (United States)

    ... Treatment Liver Cancer Prevention Liver Cancer Screening Research Liver (Hepatocellular) Cancer Screening (PDQ®)–Patient Version What is ... These are called diagnostic tests . General Information About Liver (Hepatocellular) Cancer Key Points Liver cancer is a ...

  4. Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation.

    Science.gov (United States)

    Kim, Chai-Wan; Addy, Carol; Kusunoki, Jun; Anderson, Norma N; Deja, Stanislaw; Fu, Xiaorong; Burgess, Shawn C; Li, Cai; Ruddy, Marcie; Chakravarthy, Manu; Previs, Steve; Milstein, Stuart; Fitzgerald, Kevin; Kelley, David E; Horton, Jay D

    2017-08-01

    Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1 month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Regulation

    International Nuclear Information System (INIS)

    Ballereau, P.

    1999-01-01

    The different regulations relative to nuclear energy since the first of January 1999 are given here. Two points deserve to be noticed: the decree of the third august 1999 authorizing the national Agency for the radioactive waste management to install and exploit on the commune of Bures (Meuse) an underground laboratory destined to study the deep geological formations where could be stored the radioactive waste. The second point is about the uranium residues and the waste notion. The judgment of the administrative tribunal of Limoges ( 9. july 1998) forbidding the exploitation of a storage installation of depleted uranium considered as final waste and qualifying it as an industrial waste storage facility has been annulled bu the Court of Appeal. It stipulated that, according to the law number 75663 of the 15. july 1965, no criteria below can be applied to depleted uranium: production residue (possibility of an ulterior enrichment), abandonment of a personal property or simple intention to do it ( future use aimed in the authorization request made in the Prefecture). This judgment has devoted the primacy of the waste notion on this one of final waste. (N.C.)

  6. A nuclear factor I-like activity and a liver-specific repressor govern estrogen-regulated in vitro transcription from the Xenopus laevis vitellogenin B1 promoter.

    Science.gov (United States)

    Corthésy, B; Cardinaux, J R; Claret, F X; Wahli, W

    1989-12-01

    A hormone-controlled in vitro transcription system derived from Xenopus liver nuclear extracts was exploited to identify novel cis-acting elements within the vitellogenin gene B1 promoter region. In addition to the already well-documented estrogen-responsive element (ERE), two elements were found within the 140 base pairs upstream of the transcription initiation site. One of them, a negative regulatory element, is responsible for the lack of promoter activity in the absence of the hormone and, as demonstrated by DNA-binding assays, interacts with a liver-specific transcription factor. The second is required in association with the estrogen-responsive element to mediate hormonal induction and is recognized by the Xenopus liver homolog of nuclear factor I.

  7. Protective effects of C-phycocyanin on alcohol-induced acute liver injury in mice

    Science.gov (United States)

    Xia, Dong; Liu, Bing; Luan, Xiying; Sun, Junyan; Liu, Nana; Qin, Song; Du, Zhenning

    2016-03-01

    Excessive alcohol consumption leads to liver disease. Extensive evidence suggests that C-phycocyanin (C-PC), a chromophore phycocyanobilin derived from Spirulina platensis, exerts protective effects against chemical-induced organ damage. In this study, we investigated whether C-PC could protect against ethanol-induced acute liver injury. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), triglyceride (TG), total cholesterol (CHOL), low-density lipoprotein (LDL), liver homogenate malondialdehyde (MDA), superoxide dismutase (SOD) content were measured, and pathological examination of liver sections were examined. C-PC showed obvious inhibitory effects on serum ALT, AST, TG, CHOL, LDL and MDA, and SOD content significantly increased in the liver. The structure of hepatic lobules was clear, liver sinus returned to normal, and liver cell cords were arranged in neat rows. Cloudiness, swelling, inflammatory cell infiltration and spotty necrosis of liver cells were significantly reduced. Therefore, C-PC can significantly protect against ethanol-induced acute liver injury.

  8. Enlarged Liver

    Science.gov (United States)

    ... of liver damage. Medicinal herbs. Certain herbs, including comfrey, ma huang and mistletoe, can increase your risk ... herbs to avoid include germander, chaparral, senna, mistletoe, comfrey, ma huang, valerian root, kava, celand