Heterozygous deficiency of endoglin decreases insulin and hepatic triglyceride levels during high fat diet.

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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.

Effect of aubergine (Solanum melongena on serum and hepatic cholesterol and triglycerides in rats

Directory of Open Access Journals (Sweden)

Marcelo E Silva

1999-01-01

Full Text Available The present work reports the effect of aubergine extract on serum and hepatic cholesterol and triglycerides levels in adult rats. Fisher rats were divided into three groups: the first one received a normolipidic diet and water , serving as a control; the other two received a hypercholesterolaemic diet with 30% vegetable oil and 1% cholesterol, one of these being given water while the other was given an aubergine extract. After 28 days the animals were sacrificed and serum and hepatic cholesterol and triglycerides levels were assessed. The obtained results indicated that under the experimental conditions employed, the aubergine extract increased serum and decreased hepatic cholesterol and had little or no effect on both serum and hepatic triglycerides.A beringela (Solanum melongena tem sido apontada como possuidora da capacidade de reduzir o colesterol sérico. O chá do vegetal vem sendo utilizado com este propósito, devido ao interesse na descoberta de formas alternativas para o controle da hipercolesterolemia. No presente trabalho testou-se o efeito do chá de beringela nos níveis séricos e hepáticos de colesterol e triglicerídeos em ratos adultos. Ratos Fisher foram divididos em três grupos: o primeiro recebeu dieta normolipídica ad libitum e água para beber, funcionando como controle; os outros dois receberam dieta hipercolesterolêmica com 30% de óleo vegetal e 1% de colesterol, sendo dada a um destes grupos água para beber, enquanto que o outro recebeu apenas chá de beringela. Após 28 dias os animais foram sacrificados e dosaram-se os níveis de colesterol e triglicerídeos séricos e hepáticos. Os resultados obtidos indicam que, nas condições experimentais utilizadas, o chá de beringela eleva o colesterol sérico, reduz o hepático e tem pouco ou nenhum efeito sobre os triglicerídeos, tanto séricos quanto hepáticos.

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

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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.

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

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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.

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

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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.

SULF2 strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus

NARCIS (Netherlands)

Hassing, H. Carlijne; Surendran, R. Preethi; Derudas, Bruno; Verrijken, An; Francque, Sven M.; Mooij, Hans L.; Bernelot Moens, Sophie J.; Hart, Leen M. 't; Nijpels, Giel; Dekker, Jacqueline M.; Williams, Kevin Jon; Stroes, Erik S. G.; van Gaal, Luc F.; Staels, Bart; Nieuwdorp, Max; Dallinga-Thie, Geesje M.

2014-01-01

Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene

SULF2 Strongly Prediposes to Fasting and Postprandial Triglycerides in Patients with Obesity and Type 2 Diabetes Mellitus

NARCIS (Netherlands)

Hassing, H.C.; Surendran, R.P.; Derudas, B.; Verrijken, A.; Francque, S.M.; Mooij, H.L.; Moens, S.J.B.; 't Hart, L.M.; Nijpels, G.; Dekker, J.M.; Williams, K.J.; Stroes, E.S.G.; van Gaal, L.F.; Staels, B.; Nieuwdorp, M.; Dallinga-Thie, G.M.

2014-01-01

Objective Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2

Okara, a By-Product of Tofu Manufacturing, Modifies Triglyceride Metabolism at the Intestinal and Hepatic Levels.

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Nagata, Yasuo; Yamasaki, Shiho; Torisu, Norihiro; Suzuki, Taishi; Shimamoto, Saya; Tamaru, Shizuka; Tanaka, Kazunari

2016-01-01

Irrespective of a well-known hypocholesterolemic action, a few studies have shown a hypotriglyceridemic potential of okara, a by-product of tofu manufacturing. Okara was fed to rats at the level of 2.5 and 5.0% as dietary protein for 4 wk, and serum and hepatic lipid levels were determined. In addition, soy flour, which has a well-known hypolipidemic action, was used to compare effects on lipid metabolism. Mechanisms of action were further evaluated by measuring hepatic enzyme activity, gene expression of lipid metabolism-related proteins and fecal excretion of lipids. Feeding the okara diets resulted in a significantly lower weight of the liver and adipose tissue in a dose-dependent manner. Serum triglyceride levels were more than 50% lower in rats fed the okara diets compared to those fed the control diet. Enzyme activities of fatty acid synthesis were significantly lowered by the okara diet. Fecal weight was significantly higher in the okara group than in the control group, and fecal excretion of steroids tended to be higher. Therefore, a relatively low amount of okara may exert hypotriglyceridemic action in rats in part through decreased hepatic triglyceride synthesis. The present study also suggests an involvement of intestinal events in altered lipid metabolism in rats fed the okara diets.

Mechanisms of intrahepatic triglyceride accumulation

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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

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.

Effects of short-term high-fat, high-energy diet on hepatic and myocardial triglyceride content in healthy men

NARCIS (Netherlands)

van der Meer, Rutger W.; Hammer, Sebastiaan; Lamb, Hildo J.; Frölich, Marijke; Diamant, Michaela; Rijzewijk, Luuk J.; de Roos, Albert; Romijn, Johannes A.; Smit, Johannes W. A.

2008-01-01

An association has been suggested between elevated plasma nonesterified fatty acid (NEFA) levels, myocardial triglyceride (TG) accumulation, and myocardial function. Our objective was to investigate the effects of an elevation of plasma NEFA by a high-fat, high-energy (HFHE) diet on hepatic and

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

level of DGAT2 through inhibiting MEK-ERK pathway and enhanced triglyceride synthesis. • SREBP-1c-mediated fatty acid synthesis was not involved in VPA-induced hepatic steatosis.

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

level of DGAT2 through inhibiting MEK-ERK pathway and enhanced triglyceride synthesis. • SREBP-1c-mediated fatty acid synthesis was not involved in VPA-induced hepatic steatosis.

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

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

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.

Domains of apolipoprotein E contributing to triglyceride and cholesterol homeostasis in vivo. Carboxyl-terminal region 203-299 promotes hepatic very low density lipoprotein-triglyceride secretion

NARCIS (Netherlands)

Kypreos, K.E.; Dijk, K.W. van; Zee, A. van der; Havekes, L.M.; Zannis, V.I.

2001-01-01

Apolipoprotein (apo) E has been implicated in cholesterol and triglyceride homeostasis in humans. At physiological concentration apoE promotes efficient clearance of apoE-containing lipoprotein remnants. However, high apoE plasma levels correlate with high plasma triglyceride levels. We have used

The odd-carbon medium-chain fatty triglyceride triheptanoin does not reduce hepatic steatosis.

Science.gov (United States)

Comhair, Tine M; Garcia Caraballo, Sonia C; Dejong, Cornelis H C; Lamers, Wouter H; Koehler, S Eleonore

2017-02-01

Non-alcoholic fatty-liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Previously, we showed that a high-protein diet minimized diet-induced development of fatty liver and even reversed pre-existing steatosis. A high-protein diet leads to amino-acid catabolism, which in turn causes anaplerosis of the tricarboxylic-acid (TCA) cycle. Therefore, we hypothesized that anaplerosis of the TCA cycle could be responsible for the high-protein diet-induced improvement of NAFLD by channeling amino acids into the TCA cycle. Next we considered that an efficient anaplerotic agent, the odd-carbon medium-chain triglyceride triheptanoin (TH), might have similar beneficial effects. C57BL/6J mice were fed low-fat (8en%) or high-fat (42en%) oleate-containing diets with or without 15en% TH for 3 weeks. TH treatment enhanced the hepatic capacity for fatty-acid oxidation by a selective increase in hepatic Ppara, Acox, and Cd36 expression, and a decline in plasma acetyl-carnitines. It also induced pyruvate cycling through an increased hepatic PCK1 protein concentration and it increased thermogenesis reflected by an increased Ucp2 mRNA content. TH, however, did not reduce hepatic lipid content. The comparison of the present effects of dietary triheptanoin with a previous study by our group on protein supplementation shows that the beneficial effects of the high-protein diet are not mimicked by TH. This argues against anaplerosis as the sole explanatory mechanism for the anti-steatotic effect of a high-protein diet. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

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Li Y

2017-09-01

Full Text Available Yanmei Li,1,2 Ruibing Su,3 Shuqin Xu,2 Qingjun Huang,1 Haiyun Xu1,2 1The Mental Health Center, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China; 2Department of Anatomy, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China; 3Department of Forensics and Pathology, Shantou University Medical College, Shantou, Guangdong Province, People’s Republic of China Abstract: Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects. Keywords: artesunate, clozapine, dyslipidemia, hepatic steatosis, schizophrenia 

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.)

Loss of triglycerides and carotenoids in human milk after processing.

Science.gov (United States)

Tacken, K J M; Vogelsang, A; van Lingen, R A; Slootstra, J; Dikkeschei, B D; van Zoeren-Grobben, D

2009-11-01

Human milk (HM) is considered to be the best nutrition for preterm infants. However, storage, heating or tube feeding can cause a decline in essential nutrients, which can lead to the loss of antioxidant vitamins, resulting in an increased risk for oxygen radical diseases. Recently we found that carotenoids, present in human milk, can play a role in the antioxidant protection of preterm infants. In this study we evaluated the effect of processing HM and infant formula on the triglycerides and carotenoid concentrations. The triglyceride, alpha- and beta-carotene, lutein and lycopene concentrations of 30 samples of mature HM of mothers who delivered a term infant and 10 samples of infant formula were measured after refrigeration, freezing, microwave heating and tube feeding with and without exposure to normal light and phototherapy, imitating the clinical feeding routine in the NICU. After tube feeding triglyceride, lutein and beta-carotene concentrations decreased with 33%, 35% and 26% respectively. The decrease in triglycerides in HM accounts for 16% of the total caloric intake of neonates. Triglyceride and carotenoid concentrations in HM remained stable after refrigeration, freezing or low temperature microwave heating, except for lutein which decreased after refrigeration and freezing. In infant formula no differences were found. Mature human milk can be stored safely in a freezer and heated in a microwave oven without loss of fat or carotenoids. The clinically important loss of fat during tube feeding is probably the most important contributing factor to the decrease in lutein and beta-carotene in tube feeding, with only a small role for peroxidation during light-exposure.

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

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.

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.

CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

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Cheng, Jie; Krausz, Kristopher W. [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States); Li, Feng; Ma, Xiaochao [Department of Pharmacology, Toxicology and Therapeutics, The University of Kansas Medical Center, 4089 KLSIC, MS 1018, 3901 Rainbow Boulevard, Kansas City, KS 66160 (United States); Gonzalez, Frank J., E-mail: fjgonz@helix.nih.gov [Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892 (United States)

2013-01-15

Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

CYP2E1-dependent elevation of serum cholesterol, triglycerides, and hepatic bile acids by isoniazid

International Nuclear Information System (INIS)

Cheng, Jie; Krausz, Kristopher W.; Li, Feng; Ma, Xiaochao; Gonzalez, Frank J.

2013-01-01

Isoniazid is the first-line medication in the prevention and treatment of tuberculosis. Isoniazid is known to have a biphasic effect on the inhibition–induction of CYP2E1 and is also considered to be involved in isoniazid-induced hepatotoxicity. However, the full extent and mechanism of involvement of CYP2E1 in isoniazid-induced hepatotoxicity remain to be thoroughly investigated. In the current study, isoniazid was administered to wild-type and Cyp2e1-null mice to investigate the potential toxicity of isoniazid in vivo. The results revealed that isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice, but produced elevated serum cholesterol and triglycerides, and hepatic bile acids in wild-type mice, as well as decreased abundance of free fatty acids in wild-type mice and not in Cyp2e1-null mice. Metabolomic analysis demonstrated that production of isoniazid metabolites was elevated in wild-type mice along with a higher abundance of bile acids, bile acid metabolites, carnitine and carnitine derivatives; these were not observed in Cyp2e1-null mice. In addition, the enzymes responsible for bile acid synthesis were decreased and proteins involved in bile acid transport were significantly increased in wild-type mice. Lastly, treatment of targeted isoniazid metabolites to wild-type mice led to similar changes in cholesterol, triglycerides and free fatty acids. These findings suggest that while CYP2E1 is not involved in isoniazid-induced hepatotoxicity, while an isoniazid metabolite might play a role in isoniazid-induced cholestasis through enhancement of bile acid accumulation and mitochondria β-oxidation. -- Highlights: ► Isoniazid metabolites were elevated only in wild-type mice. ► Isoniazid caused no hepatotoxicity in wild-type and Cyp2e1-null mice. ► Isoniazid elevated serum cholesterol and triglycerides, and hepatic bile acids. ► Bile acid transporters were significantly decreased in isoniazid-treated mice.

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

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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.

De novo synthesis of milk triglycerides in humans

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Mammary gland (MG) de novo lipogenesis contributes significantly to milk fat in animals but little is known in humans. Objective: To test the hypothesis that the incorporation of 13C carbons from [U-13C]glucose into fatty acids (FA) and glycerol in triglycerides (TG) will be greater: 1) in milk tha...

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....

FATTY-ACID COMPOSITION OF HUMAN-MILK TRIGLYCERIDE SPECIES - POSSIBLE CONSEQUENCES FOR OPTIMAL STRUCTURES OF INFANT FORMULA TRIGLYCERIDES

NARCIS (Netherlands)

WINTER, CH; HOVING, EB; MUSKIET, FAJ

1993-01-01

Human milk triglycerides (TGs) were separated into 14 fractions by silver ion high-performance liquid chromatography (HPLC) with light-scattering detection (LSD). Subsequent fractionation by reversed-phase HPLC-LSD resulted in 75 subfractions. The major 48 were analysed by gas chromatography for

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

Theories about evolutionary origins of human hepatitis B virus in primates and humans

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Breno Frederico de Carvalho Dominguez Souza

2014-09-01

Conclusion: Some hypotheses about the evolutionary origins of human hepatitis B virus have been debated since the ‘90s. One theory suggested a New World origin because of the phylogenetic co-segregation between some New World human hepatitis B virus genotypes F and H and woolly monkey human hepatitis B virus in basal sister-relationship to the Old World non-human primates and human hepatitis B virus variants. Another theory suggests an Old World origin of human hepatitis B virus, and that it would have been spread following prehistoric human migrations over 100,000 years ago. A third theory suggests a co-speciation of human hepatitis B virus in non-human primate hosts because of the proximity between the phylogeny of Old and New World non-human primate and their human hepatitis B virus variants. The importance of further research, related to the subject in South American wild fauna, is paramount and highly relevant for understanding the origin of human hepatitis B virus.

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.

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

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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

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

Lipid composition of hepatic and adipose tissues from normal cats and from cats with idiopathic hepatic lipidosis.

Science.gov (United States)

Hall, J A; Barstad, L A; Connor, W E

1997-01-01

The purpose of this study was to characterize the lipid classes in hepatic and adipose tissues from cats with idiopathic hepatic lipidosis (IHL). Concentrations of triglyceride, phospholipid phosphorus, and free and total cholesterol were determined in lipid extracts of liver homogenates from 5 cats with IHL and 5 healthy control cats. Total fatty acid composition of liver and adipose tissue was also compared. Triglyceride accounted for 34% of liver by weight in cats with IHL (338 +/- 38 mg/g wet liver) versus 1% in control cats (9.9 +/- 1.0 mg/g wet liver, P hepatic tissue in the 2 groups differed; palmitate was higher (19.5 +/- 1.1% of total fatty acids in cats with IHL versus 9.2 +/- 2.7% in controls, P hepatic triglyceride in cats with IHL is the mobilization of fatty acids from adipose tissue.

Jiao Tai Wan Attenuates Hepatic Lipid Accumulation in Type 2 Diabetes Mellitus

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Zhaoyi Huang

2013-01-01

Full Text Available Jiao Tai Wan (JTW, a Chinese herbal formula containing Rhizoma Coptidis and Cortex Cinnamomi, has been used for diabetic treatment for many years. The aim of this study was to determine the main components in JTW and to investigate the effects of JTW on hepatic lipid accumulation in diabetic rats and humans. JTW extract was prepared and the main components were assayed by HPLC. An animal model of diabetes mellitus was established and JTW was administered intragastrically. In the clinical study, diabetic patients with poor glycemic control were treated with JTW. Blood glucose and lipid parameters, liver histology, hepatic triglyceride content and lipogenic gene expression were examined. Our data demonstrated that JTW significantly improved hyperglycemia, hyperlipidemia and hepatic lipid accumulation in diabetic rats. This was accompanied by the down-regulation of acetyl coenzyme A carboxylase (ACC and fatty acid synthase (FAS protein expressions, and the up-regulation of AMP-activated protein kinase (AMPK and phosphorylated-ACC (pACC protein expressions in the liver tissues. Diabetic patients also exhibited decreases in their hepatic triglyceride content. The results suggest that JTW attenuates hepatic lipid accumulation in diabetic rats and humans. These beneficial effects are possibly associated with the inhibition of lipogenic gene expression in the liver.

Hepatic beta-oxidation and carnitine palmitoyltransferase I in neonatal pigs after dietary treatments of clofibric acid, isoproterenol, and medium-chain triglycerides.

Science.gov (United States)

Peffer, Pasha Lyvers; Lin, Xi; Odle, Jack

2005-06-01

A suckling piglet model was used to study nutritional and pharmacologic means of stimulating hepatic fatty acid beta-oxidation. Newborn pigs were fed milk diets containing either long- or medium-chain triglycerides (LCT or MCT). The long-chain control diet was supplemented further with clofibric acid (0.5%) or isoproterenol (40 ppm), and growth was monitored for 10-12 days. Clofibrate increased rates of hepatic peroxisomal and mitochondrial beta-oxidation of [1-(14)C]-palmitate by 60 and 186%, respectively. Furthermore, malonyl-CoA sensitive carnitine palmitoyltransferase (CPT I) activity increased 64% (P clofibrate. Increased CPT I activity was not congruent with changes in message, as elevated abundance of CPT I mRNA was not detected (P = 0.16) when assessed by qRT-PCR. Neither rates of beta-oxidation nor CPT activities were affected by dietary MCT or by isoproterenol treatment (P > 0.1). Collectively, these findings indicate that clofibrate effectively induced hepatic CPT activity concomitant with increased fatty acid beta-oxidation.

Influence of chronic stress on the compositions of hepatic cholesterol and triglyceride in male Wistar rats fed a high fat diet.

Science.gov (United States)

Gao, Siyuan; Han, Xue; Fu, Jihua; Yuan, Xiaoling; Sun, Xing; Li, Qiang

2012-07-01

  We determined the influence of chronic stress (CS) on the compositions of hepatic cholesterol and triglyceride (TG) in rats fed a high fat diet (HFD).   Male Wistar rats were fed either a standard diet or a HFD and half of the HFD fed rats were given CS (electric foot shock assisted with noise) for 8 weeks.   Compared with the control group, the levels of hepatic total cholesterol (TC) and TG were significantly elevated in the HFD and HFD with chronic stress (HFD+CS) groups, and the more severe elevations of them were found in the HFD group. Inversely, the more severe elevations of hepatic water-soluble parts of TC and TG were found in the HFD+CS group, as the elevations of low-density lipoprotein cholesterol, very low-density lipoprotein cholesterol in liver and serum, tumor necrosis factor-α, interleukin-1β and malondialdehyde in liver. Meanwhile, downregulated mRNA expressions of hepatic liver X receptor-α (LXR-α) and peroxisome proliferator-activated receptor-γ (PPAR-γ) were also more severe in the HFD+CS group.   CS can aggravate the high levels of water-soluble compositions of hepatic TC and TG induced by HFD as it aggravates hepatic inflammation and oxidative stress; in spite of that, however, it cannot further promote hepatic lipidosis. This is consistent with the downregulated mRNA expressions of LXR-α and PPAR-γ. © 2012 The Japan Society of Hepatology.

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.

Theories about evolutionary origins of human hepatitis B virus in primates and humans.

Science.gov (United States)

Souza, Breno Frederico de Carvalho Dominguez; Drexler, Jan Felix; Lima, Renato Santos de; Rosário, Mila de Oliveira Hughes Veiga do; Netto, Eduardo Martins

2014-01-01

The human hepatitis B virus causes acute and chronic hepatitis and is considered one of the most serious human health issues by the World Health Organization, causing thousands of deaths per year. There are similar viruses belonging to the Hepadnaviridae family that infect non-human primates and other mammals as well as some birds. The majority of non-human primate virus isolates were phylogenetically close to the human hepatitis B virus, but like the human genotypes, the origins of these viruses remain controversial. However, there is a possibility that human hepatitis B virus originated in primates. Knowing whether these viruses might be common to humans and primates is crucial in order to reduce the risk to humans. To review the existing knowledge about the evolutionary origins of viruses of the Hepadnaviridae family in primates. This review was done by reading several articles that provide information about the Hepadnaviridae virus family in non-human primates and humans and the possible origins and evolution of these viruses. The evolutionary origin of viruses of the Hepadnaviridae family in primates has been dated back to several thousand years; however, recent analyses of genomic fossils of avihepadnaviruses integrated into the genomes of several avian species have suggested a much older origin of this genus. Some hypotheses about the evolutionary origins of human hepatitis B virus have been debated since the '90s. One theory suggested a New World origin because of the phylogenetic co-segregation between some New World human hepatitis B virus genotypes F and H and woolly monkey human hepatitis B virus in basal sister-relationship to the Old World non-human primates and human hepatitis B virus variants. Another theory suggests an Old World origin of human hepatitis B virus, and that it would have been spread following prehistoric human migrations over 100,000 years ago. A third theory suggests a co-speciation of human hepatitis B virus in non-human primate

Hepatitis B Virus, Hepatitis C Virus and Human Immunodeficiency ...

African Journals Online (AJOL)

Background: The epidemiology of viral hepatitis and Human immunodeficiency virus (HIV) during pregnancy is of great importance for health planners and program managers. However, few published data on viral hepatitis and HIV are available in Sudan especially during pregnancy. Objectives: The current study was ...

The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis

Energy Technology Data Exchange (ETDEWEB)

Feingold, K.R.; Soued, M.; Serio, M.K.; Adi, S.; Moser, A.H.; Grunfeld, C. (Univ. of California, San Francisco (USA))

1990-06-01

In this study, we determined the effects of tumor necrosis factor (TNF) on serum lipid levels and hepatic lipid synthesis in animals whose diets and feeding conditions were varied to induce changes in baseline serum lipid levels and/or rates of hepatic lipid synthesis. In animals studied at both the nadir and peak of the diurnal cycle of hepatic lipid synthesis, TNF acutely increases serum triglyceride levels, stimulates hepatic fatty acid synthesis, and increases the quantity of newly synthesized fatty acids found in the serum. Similarly, in animals ingesting either high-sucrose or cholesterol-enriched diets, TNF induces the characteristic rapid increase in serum triglyceride levels, hepatic fatty acid synthesis, and quantity of labeled fatty acids in the serum. In animals fed a diet high in triglycerides, using either corn oil or lard, TNF stimulates hepatic fatty acid synthesis and increases the quantity of newly synthesized fatty acids in the serum, but serum triglyceride levels do not change. However, TNF inhibits gastric emptying, which results in a marked decrease in fat absorption in TNF-treated animals. It is likely that a decrease in the dietary contribution to serum triglyceride levels during high-triglyceride feeding counterbalances the increased hepatic contribution induced by TNF treatment. In animals fasted before TNF administration there was no acute change in either serum lipid levels, hepatic fatty acid synthesis, or the quantity of labeled fatty acids in the serum. Thus, TNF stimulates hepatic fatty acid synthesis and increases serum triglyceride levels under many diverse dietary conditions, suggesting that there is a strong linkage between the immune system and lipid metabolism that is independent of most dietary manipulations and may be of fundamental importance in the body's response to infection.

The effect of diet on tumor necrosis factor stimulation of hepatic lipogenesis

International Nuclear Information System (INIS)

Feingold, K.R.; Soued, M.; Serio, M.K.; Adi, S.; Moser, A.H.; Grunfeld, C.

1990-01-01

In this study, we determined the effects of tumor necrosis factor (TNF) on serum lipid levels and hepatic lipid synthesis in animals whose diets and feeding conditions were varied to induce changes in baseline serum lipid levels and/or rates of hepatic lipid synthesis. In animals studied at both the nadir and peak of the diurnal cycle of hepatic lipid synthesis, TNF acutely increases serum triglyceride levels, stimulates hepatic fatty acid synthesis, and increases the quantity of newly synthesized fatty acids found in the serum. Similarly, in animals ingesting either high-sucrose or cholesterol-enriched diets, TNF induces the characteristic rapid increase in serum triglyceride levels, hepatic fatty acid synthesis, and quantity of labeled fatty acids in the serum. In animals fed a diet high in triglycerides, using either corn oil or lard, TNF stimulates hepatic fatty acid synthesis and increases the quantity of newly synthesized fatty acids in the serum, but serum triglyceride levels do not change. However, TNF inhibits gastric emptying, which results in a marked decrease in fat absorption in TNF-treated animals. It is likely that a decrease in the dietary contribution to serum triglyceride levels during high-triglyceride feeding counterbalances the increased hepatic contribution induced by TNF treatment. In animals fasted before TNF administration there was no acute change in either serum lipid levels, hepatic fatty acid synthesis, or the quantity of labeled fatty acids in the serum. Thus, TNF stimulates hepatic fatty acid synthesis and increases serum triglyceride levels under many diverse dietary conditions, suggesting that there is a strong linkage between the immune system and lipid metabolism that is independent of most dietary manipulations and may be of fundamental importance in the body's response to infection

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.

Metabolic imaging of human kidney triglyceride content: reproducibility of proton magnetic resonance spectroscopy.

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Sebastiaan Hammer

Full Text Available OBJECTIVE: To assess the feasibility of renal proton magnetic resonance spectroscopy for quantification of triglyceride content and to compare spectral quality and reproducibility without and with respiratory motion compensation in vivo. MATERIALS AND METHODS: The Institutional Review Board of our institution approved the study protocol, and written informed consent was obtained. After technical optimization, a total of 20 healthy volunteers underwent renal proton magnetic resonance spectroscopy of the renal cortex both without and with respiratory motion compensation and volume tracking. After the first session the subjects were repositioned and the protocol was repeated to assess reproducibility. Spectral quality (linewidth of the water signal and triglyceride content were quantified. Bland-Altman analyses and a test by Pitman were performed. RESULTS: Linewidth changed from 11.5±0.4 Hz to 10.7±0.4 Hz (all data pooled, p<0.05, without and with respiratory motion compensation respectively. Mean % triglyceride content in the first and second session without respiratory motion compensation were respectively 0.58±0.12% and 0.51±0.14% (P = NS. Mean % triglyceride content in the first and second session with respiratory motion compensation were respectively 0.44±0.10% and 0.43±0.10% (P = NS between sessions and P = NS compared to measurements with respiratory motion compensation. Bland-Altman analyses showed narrower limits of agreement and a significant difference in the correlated variances (correlation of -0.59, P<0.05. CONCLUSION: Metabolic imaging of the human kidney using renal proton magnetic resonance spectroscopy is a feasible tool to assess cortical triglyceride content in humans in vivo and the use of respiratory motion compensation significantly improves spectral quality and reproducibility. Therefore, respiratory motion compensation seems a necessity for metabolic imaging of renal triglyceride content in vivo.

Prevalence of hepatitis B surface antigen, hepatitis C and Human ...

African Journals Online (AJOL)

Objective: Human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C viruses (HCV) are major causes of mortality and morbidity worldwide. They are also among the commonest transfusiontransmissible infectious agents. Students of higher institutions are often used as voluntary unpaid donors by many ...

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.

Mice lacking prostaglandin E receptor subtype 4 manifest disrupted lipid metabolism attributable to impaired triglyceride clearance.

Science.gov (United States)

Cai, Yin; Ying, Fan; Song, Erfei; Wang, Yu; Xu, Aimin; Vanhoutte, Paul M; Tang, Eva Hoi-Ching

2015-12-01

Upon high-fat feeding, prostaglandin E receptor subtype 4 (EP4)-knockout mice gain less body weight than their EP4(+/+) littermates. We investigated the cause of the lean phenotype. The mice showed a 68.8% reduction in weight gain with diminished fat mass that was not attributable to reduced food intake, fat malabsorption, or increased energy expenditure. Plasma triglycerides in the mice were elevated by 244.9%. The increase in plasma triglycerides was independent of changes in hepatic very low density lipoprotein (VLDL)-triglyceride production or intestinal chylomicron-triglyceride synthesis. However, VLDL-triglyceride clearance was drastically impaired in the EP4-knockout mice. The absence of EP4 in mice compromised the activation of lipoprotein lipase (LPL), the key enzyme responsible for trafficking of plasma triglycerides into peripheral tissues. Deficiency in EP4 reduced hepatic mRNA expression of the transcriptional factor cAMP response element binding protein H (by 36.8%) and LPL activators, including apolipoprotein (Apo)a5 (by 40.2%) and Apoc2 (by 61.3%). In summary, the lean phenotype of EP4-deficient mice resulted from reduction in adipose tissue and accretion of other peripheral organs caused by impaired triglyceride clearance. The findings identify a new metabolic dimension in the physiologic role played by endogenous EP4. © FASEB.

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.

Effect of cholesterol and triglycerides levels on the rheological behavior of human blood

Science.gov (United States)

Moreno, Leonardo; Calderas, Fausto; Sanchez-Olivares, Guadalupe; Medina-Torres, Luis; Sanchez-Solis, Antonio; Manero, Octavio

2015-02-01

Important public health problems worldwide such as obesity, diabetes, hyperlipidemia and coronary diseases are quite common. These problems arise from numerous factors, such as hyper-caloric diets, sedentary habits and other epigenetic factors. With respect to Mexico, the population reference values of total cholesterol in plasma are around 200 mg/dL. However, a large proportion has higher levels than this reference value. In this work, we analyze the rheological properties of human blood obtained from 20 donors, as a function of cholesterol and triglyceride levels, upon a protocol previously approved by the health authorities. Samples with high and low cholesterol and triglyceride levels were selected and analyzed by simple-continuous and linear-oscillatory shear flow. Rheometric properties were measured and related to the structure and composition of human blood. In addition, rheometric data were modeled by using several constitutive equations: Bautista-Manero-Puig (BMP) and the multimodal Maxwell equations to predict the flow behavior of human blood. Finally, a comparison was made among various models, namely, the BMP, Carreau and Quemada equations for simple shear rate flow. An important relationship was found between cholesterol, triglycerides and the structure of human blood. Results show that blood with high cholesterol levels (400 mg/dL) has flow properties fully different (higher viscosity and a more pseudo-plastic behavior) than blood with lower levels of cholesterol (tendency to Newtonian behavior or viscosity plateau at low shear rates).

Metformin lowers plasma triglycerides by promoting VLDL-triglyceride clearance by brown adipose tissue in mice.

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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.

Hepatitis C virus core protein induces hepatic steatosis via Sirt1-dependent pathway.

Science.gov (United States)

Zhang, Chuanhai; Wang, Jingjing; Zhang, Hanlin; Liu, Shunai; Lee, Hyuek Jong; Jin, Wanzhu; Cheng, Jun

2018-05-01

Hepatic steatosis is a common feature of patients with chronic hepatitis C. Previous reports have shown that the overexpression of hepatitis C virus core-encoding sequences (hepatitis C virus genotypes 3a and 1b) significantly induces intracellular triglyceride accumulation. However, the underlying mechanism has not yet been revealed. To investigate whether Sirt1 is involved in hepatitis C virus-mediated hepatic steatosis, the overexpression of hepatitis C virus core 1b protein and Sirt1 and the knockdown of Sirt1 in HepG2 cells were performed. To confirm the results of the cellular experiment liver-specific Sirt1 KO mice with lentivirus-mediated hepatitis C virus core 1b overexpression were studied. Our results show that hepatitis C virus core 1b protein overexpression led to the accumulation of triglycerides in HepG2 cells. Notably the expression of PPARγ2 was dramatically increased at both the mRNA and protein levels by hepatitis C virus core 1b overexpression. The protein expression of Sirt1 is an upstream regulator of PPARγ2 and was also significantly increased after core 1b overexpression. In addition, the overexpression or knockdown of Sirt1 expression alone was sufficient to modulate p300-mediated PPARγ2 deacetylation. In vivo studies showed that hepatitis C virus core protein 1b-induced hepatic steatosis was attenuated in liver-specific Sirt1 KO mice by downregulation of PPARγ2 expression. Sirt1 mediates hepatitis C virus core protein 1b-induced hepatic steatosis by regulation of PPARγ2 expression. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans

NARCIS (Netherlands)

ter Horst, Kasper W.; Gilijamse, Pim W.; Versteeg, Ruth I.; Ackermans, Mariette T.; Nederveen, Aart J.; la Fleur, Susanne E.; Romijn, Johannes A.; Nieuwdorp, Max; Zhang, Dongyan; Samuel, Varman T.; Vatner, Daniel F.; Petersen, Kitt F.; Shulman, Gerald I.; Serlie, Mireille J.

2017-01-01

Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in

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.

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

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

Directory of Open Access Journals (Sweden)

Fang Yan

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

Influences of apolipoprotein E on soluble and heparin-immobilized hepatic lipase

International Nuclear Information System (INIS)

Landis, B.A.; Rotolo, F.S.; Meyers, W.C.; Clark, A.B.; Quarfordt, S.H.

1987-01-01

The effect of human apolipoprotein E (apoE), either alone or in combination with apoC, on the lipolysis of a radiolabeled triglyceride emulsion was studied with hepatic lipase in solution and immobilized on heparin-Sepharose. The soluble hepatic lipase was inhibited, whereas the heparin-immobilized lipase was stimulated by apoE. This stimulation was attenuated by combining apoE with either apoC-II or C-III. The heparin-immobilized lipase demonstrated much less lipolysis of the zwitterionic phosphatidylcholine-stabilized triglyceride emulsion than did the soluble enzyme. This difference was less when the emulsion was stabilized by a nonionic detergent. apoE inhibited lipase activity when assayed under conditions (0.4 M NaCl) of bound enzyme and unbound substrate. Increasing the emulsion apoE content beyond optimum inhibited lipolysis by the immobilized enzyme. Kinetic analysis of phosphatidylcholine-stabilized triglyceride emulsions revealed a significant decrease in immobilized enzyme K/sub m/ and an increase in V/sub max/ when the emulsion was supplemented with apoE. Distributing the immobilized lipase in clustered aggregates produced more lipolysis than when the same enzyme content was uniformly bound

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.

Cocaine use may modify HIV/ART-associated myocardial steatosis and hepatic steatosis.

Science.gov (United States)

Lai, Shenghan; Gerstenblith, Gary; Moore, Richard D; Celentano, David D; Bluemke, David A; Treisman, Glenn; Liu, Chia-Ying; Li, Ji; Chen, Shaoguang; Kickler, Thomas; Lai, Hong

2017-08-01

It has been recognized that myocardial and hepatic steatosis may be more prevalent in HIV-infected individuals on antiretroviral therapy (ART); however, factors associated with these conditions have not been thoroughly investigated. The goals of this study were (1) to identify the risk factors for myocardial and hepatic steatosis in HIV-infected African Americans (AAs) and explore whether ART use is independently associated with myocardial and hepatic steatosis, and (2) to examine whether and how cocaine use influences any associations of ART use with myocardial and hepatic steatosis. Between June 2010 and December 2013, 220 HIV-infected AAs in Baltimore, Maryland, were enrolled in a study investigating HIV/ART-associated myocardial and hepatic damage. Proton magnetic resonance spectroscopy was performed to quantify myocardial and hepatic triglyceride contents. Sociodemographic, medical and laboratory data were also obtained. Robust regression model was employed to perform primary statistical analysis. Robust regression analyses showed that (1) duration of protease inhibitor (PI) use was independently associated with myocardial and hepatic triglyceride contents, (2) duration of PI use was independently associated with myocardial triglyceride in cocaine users (p=0.025), but not in cocaine never-users (p=0.84), and (3) duration of PI use was independently associated with hepatic triglyceride in cocaine users, but not in cocaine never-users (p=0.52). Cocaine use may trigger/exacerbate the toxicity of PI in ART-associated myocardial and hepatic steatosis, suggesting that cocaine abstinence/reduced use may retard these ART-associated comorbidities. Clinical trials should be conducted to examine whether reduced cocaine use improves HIV/AIDS-associated myocardial and hepatic steatosis. Copyright © 2017. Published by Elsevier B.V.

Modulation of hepatic steatosis by dietary fatty acids

Science.gov (United States)

Ferramosca, Alessandra; Zara, Vincenzo

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the “case” of olive oil, since several studies have often provided different and⁄or conflicting results in animal models. PMID:24587652

Modulation of hepatic steatosis by dietary fatty acids.

Science.gov (United States)

Ferramosca, Alessandra; Zara, Vincenzo

2014-02-21

Non-alcoholic fatty liver disease (NAFLD) describes a range of conditions caused by fat deposition within liver cells. Liver fat content reflects the equilibrium between several metabolic pathways involved in triglyceride synthesis and disposal, such as lipolysis in adipose tissue and de novo lipogenesis, triglyceride esterification, fatty acid oxidation and very-low-density lipoprotein synthesis/secretion in hepatic tissue. In particular, it has been demonstrated that hepatic de novo lipogenesis plays a significant role in NAFLD pathogenesis. It is widely known that the fatty acid composition of the diet influences hepatic lipogenesis along with other metabolic pathways. Therefore, dietary fat may not only be involved in the pathogenesis of hepatic steatosis, but may also prevent and/or reverse hepatic fat accumulation. In this review, major data from the literature about the role of some dietary fats as a potential cause of hepatic fat accumulation or as a potential treatment for NAFLD are described. Moreover, biochemical mechanisms responsible for an increase or decrease in hepatic lipid content are critically analyzed. It is noteworthy that both quantitative and qualitative aspects of dietary fat influence triglyceride deposition in the liver. A high-fat diet or the dietary administration of conjugated linoleic acids induced hepatic steatosis. In contrast, supplementation of the diet with krill oil or pine nut oil helped in the prevention and/or in the treatment of steatotic liver. Quite interesting is the "case" of olive oil, since several studies have often provided different and/or conflicting results in animal models.

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

Relationship of hepatic lipidosis to health and performance in dairy cattle.

Science.gov (United States)

Gerloff, B J; Herdt, T H; Emery, R S

1986-04-15

In a field study of 80 cows in 9 dairy herds, serial liver biopsies were performed over the peripartum period to determine degree of hepatic lipidosis. Cattle were separated into categories of mild, moderate, and severe hepatic lipidosis on the basis of maximal amounts of hepatic triglyceride that accumulated during this period. Number of cattle with mild, moderate, and severe hepatic lipidosis were 52, 16, and 12, respectively. Cattle with severe hepatic lipidosis had greater concentrations of hepatic triglyceride before calving and after parturition, and greater serum nonesterified fatty acid concentrations and body condition loss after parturition than cattle with mild hepatic lipidosis. Rate of disease and culling and death rate because of disease were greater in cattle with severe hepatic lipidosis. Cattle with severe hepatic lipidosis had reproductive performance equal to clinically normal cattle; however, cattle with moderate hepatic lipidosis had increased days to conception, possibly related to greater milk production.

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

Exendin-4 Inhibits Hepatic Lipogenesis by Increasing β-Catenin Signaling.

Directory of Open Access Journals (Sweden)

Mi Hae Seo

Full Text Available The aim of this study is to investigate whether the beneficial effect of exendin-4 on hepatic steatosis is mediated by β-catenin signaling. After the HepG2 human hepatoma cells were treated with PA for 24 hours, total triglycerides levels were increased in a dose-dependent manner, and the expression levels of perilipin family members were upregulated in cells treated with 400 μM PA. For our in vitro model of hepatic steatosis, HepG2 cells were treated with 400 μM palmitic acid (PA in the presence or absence of 100 nM exendin-4 for 24 hours. PA increased the expression of lipogenic genes, such as sterol regulatory element-binding protein 1c (SREBP-1c, peroxisome proliferator-activated receptor gamma (PPARγ, stearoyl-CoA desaturase 1 (SCD1, fatty acid synthase (FAS, and acetyl-CoA carboxylase (ACC and triglyceride synthesis-involved genes, such as diacylglycerol acyltransferase 1 (DGAT1 and diacylglycerol acyltransferase 2 (DGAT2 in HepG2 cells, whereas exendin-4 treatment significantly prevented the upregulation of SREBP-1c, PPARγ, SCD1, FAS, ACC, DGAT1 and DGAT2. Moreover, exendin-4 treatment increased the expression of phosphorylated glycogen synthase kinase-3 beta (GSK-3β in the cytosolic fraction and the expression of β-catenin and transcription factor 4 (TCF4 in the nuclear fraction. In addition, siRNA-mediated inhibition of β-catenin upregulated the expression of lipogenic transcription factors. The protective effects of exendin-4 on intracellular triglyceride content and total triglyceride levels were not observed in cells treated with the β-catenin inhibitor IWR-1. These data suggest that exendin-4 treatment improves hepatic steatosis by inhibiting lipogenesis via activation of Wnt/β-catenin signaling.

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.

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.

Effect of vildagliptin on hepatic steatosis.

Science.gov (United States)

Macauley, Mavin; Hollingsworth, Kieren G; Smith, Fiona E; Thelwall, Peter E; Al-Mrabeh, Ahmad; Schweizer, Anja; Foley, James E; Taylor, Roy

2015-04-01

Although dipeptidyl-peptidase-4 inhibitors exert their major action via an incretin mechanism, a favorable effect of vildagliptin on lipid metabolism remains unexplained. The objective was to examine hepatic triglyceride levels and insulin sensitivity on vildagliptin. This was a 6-month, randomized, double-blind, placebo-controlled trial. This was an outpatient study at a university clinical research center. Individuals with type 2 diabetes (n = 44) and glycated hemoglobin ≤ 7.6% on stable metformin therapy were included. Intervention was vildagliptin 50 mg twice a day or placebo over 6 months. Main outcome measures were hepatic triglyceride levels and insulin sensitivity. Mean fasting liver triglyceride content decreased by 27% with vildagliptin, from 7.3 ± 1.0% (baseline) to 5.3 ± 0.9% (endpoint). There was no change in the placebo group. The between-group difference in change from baseline was significant (P = .013). Mean fasting plasma glucose concentration decreased over the study period with vildagliptin vs placebo by -1.0 mmol/L (P = .018), and there was a positive correlation between these decrements and liver triglyceride in the vildagliptin group at 3 months (r = 0.47; P = .02) and 6 months (r = 0.44; P = .03). Plasma alanine aminotransferase fell from 27.2 ± 2.8 to 20.3 ± 1.4 IU/L in the vildagliptin group (P = .0007), and there was a correlation between the decrements in alanine aminotransferase and liver triglyceride (r = 0.83; P vildagliptin and placebo groups, respectively (P = .08). This study demonstrates that the dipeptidyl-peptidase-4 inhibitor vildagliptin brings about a clinically significant decrease in hepatic triglyceride levels during 6 months of therapy unrelated to change in body weight. There was no change in peripheral insulin sensitivity.

Methodological approaches to disinfection of human hepatitis B virus.

OpenAIRE

Prince, D L; Prince, H N; Thraenhart, O; Muchmore, E; Bonder, E; Pugh, J

1993-01-01

Three commercial disinfectants (two quaternary formulations and one phenolic) were tested against human hepatitis B virus (HHBV). The treated virus was assayed for infectivity by the chimpanzee assay and for morphological alteration by the Morphological Alteration and Disintegration Test. The same agents were tested against duck hepatitis B virus in a duck hepatocyte infectivity assay. It is apparent that human and duck hepatitis viruses were relatively susceptible to disinfection, becoming n...

[Hepatitis: a longstanding companion in human history].

Science.gov (United States)

Craxi, Lucia

2012-03-01

Hepatitis has gone along with human history since its origins, due to its prompt identifiability linked to jaundice as a symptom. Written evidence of outbreaks of epidemic jaundice can be tracked back a few millenniums before Christ. Unavoidable confusion arises due to the overlap of different sources possibly linked to different aetiologies, identified over time as epidemic jaundice (HAV or HEV hepatitis?) and serum hepatitis (HBV or HCV hepatitis?). The journey that brought to recognize viruses as the main cause of jaundice was long and started midway during the last century, when the infectious hypothesis, which had taken place step by step, was finally confirmed by epidemiological investigations of an outbreak occurring in the US army in 1942, after a yellow fever immunization campaign. Further research identified two clinically different types of hepatitis, called for the first time hepatitis A and hepatitis B.

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

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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.

Brief oral stimulation, but especially oral fat exposure, elevates serum triglycerides in humans

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Mattes, Richard D.

2009-01-01

Oral exposure to dietary fat results in an early initial spike, followed by a prolonged elevation, of serum triglycerides in humans. The physiological and pathophysiological implications remain unknown. This study sought to determine the incidence of the effect, the required fat exposure duration, and its reliability. Thirty-four healthy adults participated in four to six response-driven trials held at least a week apart. They reported to the laboratory after an overnight fast, a catheter was placed in an antecubital vein, and a blood sample was obtained. Participants then ingested 50 g of safflower oil in capsules with 500 ml of water within 15 min to mimic a high fat meal but without oral fat exposure. Blood was collected 0, 10, 20, 30, 40, 50, 60, 120, 240, 360, and 480 min after capsule ingestion with different forms (full fat, nonfat, none) and durations of oral fat exposures (10 s, 5 min, 20 min, and/or 2 h). A triglyceride response (increase of triglyceride >10 mg/dl within 30 min) was observed in 88.2%, 70.5%, and 50% of participants with full-fat, nonfat, and no oral exposure, respectively. Test-retest reliability was 75% with full-fat exposure but only 45.4% with nonfat exposure. Full-fat and nonfat exposures led to comparable significant elevations of triglyceride over no oral stimulation with 10-s exposures, but full fat led to a greater rise than nonfat with 20 min of exposure. These data indicate that nutritionally relevant oral fat exposures reliably elevate serum triglyceride concentrations in most people. PMID:19074638

The G-250A polymorphism in the hepatic lipase gene promoter is associated with changes in hepatic lipase activity and LDL cholesterol: The KANWU Study

DEFF Research Database (Denmark)

Lindi, Virpi; Schwab, Ursula; Louheranta, Anne

2007-01-01

BACKGROUND AND AIMS: Hepatic lipase (HL) catalyzes the hydrolysis of triglycerides and phospholipids from lipoproteins, and promotes the hepatic uptake of lipoproteins. A common G-250A polymorphism in the promoter of the hepatic lipase gene (LIPC) has been described. The aim was to study...

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

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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

Hepatic cholesterol ester hydrolase in human liver disease.

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Simon, J B; Poon, R W

1978-09-01

Human liver contains an acid cholesterol ester hydrolase (CEH) of presumed lysosomal origin, but its significance is unknown. We developed a modified CEH radioassay suitable for needle biopsy specimens and measured hepatic activity of this enzyme in 69 patients undergoing percutaneous liver biopsy. Histologically normal livers hydrolyzed 5.80 +/- 0.78 SEM mumoles of cholesterol ester per hr per g of liver protein (n, 10). Values were similar in alcoholic liver disease (n, 17), obstructive jaundice (n, 9), and miscellaneous hepatic disorders (n, 21). In contrast, mean hepatic CEH activity was more than 3-fold elevated in 12 patients with acute hepatitis, 21.05 +/- 2.45 SEM mumoles per hr per g of protein (P less than 0.01). In 2 patients studied serially, CEH returned to normal as hepatitis resolved. CEH activity in all patients paralleled SGOT levels (r, 0.84; P less than 0.01). There was no correlation with serum levels of free or esterified cholesterol nor with serum activity of lecithin-cholesterol acyltransferase, the enzyme responsible for cholesterol esterification in plasma. These studies confirm the presence of CEH activity in human liver and show markedly increased activity in acute hepatitis. The pathogenesis and clinical significance of altered hepatic CEH activity in liver disease require further study.

Contrasting effects of fish oil and safflower oil on hepatic peroxisomal and tissue lipid content.

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Neschen, Susanne; Moore, Irene; Regittnig, Werner; Yu, Chun Li; Wang, Yanlin; Pypaert, Marc; Petersen, Kitt Falk; Shulman, Gerald I

2002-02-01

To examine the mechanism by which fish oil protects against fat-induced insulin resistance, we studied the effects of control, fish oil, and safflower oil diets on peroxisomal content, fatty acyl-CoA, diacylglycerol, and ceramide content in rat liver and muscle. We found that, in contrast to control and safflower oil-fed rats, fish oil feeding induced a 150% increase in the abundance of peroxisomal acyl-CoA oxidase and 3-ketoacyl-CoA thiolase in liver but lacked similar effects in muscle. This was paralleled by an almost twofold increase in hepatic peroxisome content (both P < 0.002 vs. control and safflower). These changes in the fish oil-fed rats were associated with a more than twofold lower hepatic triglyceride/diacylglycerol, as well as intramuscular triglyceride/fatty acyl-CoA, content. In conclusion, these data strongly support the hypothesis that n-3 fatty acids protect against fat-induced insulin resistance by serving as peroxisome proliferator-activated receptor-alpha ligands and thereby induce hepatic, but not intramuscular, peroxisome proliferation. In turn, an increased hepatic beta-oxidative capacity results in lower hepatic triglyceride/diacylglycerol and intramyocellular triglyceride/fatty acyl-CoA content.

SULF2 strongly prediposes to fasting and postprandial triglycerides in patients with obesity and type 2 diabetes mellitus.

Science.gov (United States)

Hassing, H Carlijne; Surendran, R Preethi; Derudas, Bruno; Verrijken, An; Francque, Sven M; Mooij, Hans L; Bernelot Moens, Sophie J; Hart, Leen M 't; Nijpels, Giel; Dekker, Jacqueline M; Williams, Kevin Jon; Stroes, Erik S G; Van Gaal, Luc F; Staels, Bart; Nieuwdorp, Max; Dallinga-Thie, Geesje M

2014-05-01

Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodeling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here, the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM was investigated. Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1,316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype. Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; P = 0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (P obesity and T2DM. Copyright © 2013 The Obesity Society.

Effect on days of lactation and methionine hydroxy analog on incorporation of plasma fatty acids into plasma triglycerides

International Nuclear Information System (INIS)

Pullen, D.L.; Emergy, R.S.; Palmquist, D.L.

1989-01-01

Methionine hydroxy analog has been proposed to stimulate hepatic lipoprotein synthesis and incorporation of plasma fatty acids into plasma triglyceride. Seven cows were fed diets containing 0 to 30 g analog/d starting 14 d prepartum. At approximately 30 and 60 d postpartum, cows were continuously infused intravenously with 1-[ 14 C]palmitic acid for 160 min to achieve steady-state labeling of plasma fatty acid and triglyceride. Turnover of fatty acid and transfer quotients for triglyceride and CO 2 were 3.3 an 2.7 mmol min -1 ; 13.0 and 10.0%; and 8.0 and 5.0%, for control and analog, respectively. Proportion of fatty acid turnover incorporated into triglyceride and CO 2 were 14.0 and 15.0%; and 21.0 and 18.0, respectively, for control and analog. Analog increased 14 C recovered in milk fat (52 vs. 36%). Plasma concentration of fatty acids, percent oxidized to CO 2 , and percent of CO 2 from fatty acids decreased with increasing lactation days. Milk fat percent and yield fatty acid turnover, and oxidation were positively correlated with concentration of plasma fatty acids, whereas fatty acid incorporated into plasma triglyceride was negatively correlated with fatty acid concentration. The data suggest that hepatic triglyceride secretion is not increased in early lactation; further, no effects of analog on lipid metabolism were detected

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

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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

Potent PPARα activator derived from tomato juice, 13-oxo-9,11-octadecadienoic acid, decreases plasma and hepatic triglyceride in obese diabetic mice.

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Young-il Kim

Full Text Available Dyslipidemia is a major risk factor for development of several obesity-related diseases. The peroxisome proliferator-activated receptor α (PPARα is a ligand-activated transcription factor that regulates energy metabolism. Previously, we reported that 9-oxo-10,12-octadecadienoic acid (9-oxo-ODA is presented in fresh tomato fruits and acts as a PPARα agonist. In addition to 9-oxo-ODA, we developed that 13-oxo-9,11-octadecadienoic acid (13-oxo-ODA, which is an isomer of 9-oxo-ODA, is present only in tomato juice. In this study, we explored the possibility that 13-oxo-ODA acts as a PPARα agonist in vitro and whether its effect ameliorates dyslipidemia and hepatic steatosis in vivo. In vitro luciferase assay experiments revealed that 13-oxo-ODA significantly induced PPARα activation; moreover, the luciferase activity of 13-oxo-ODA was stronger than that of 9-oxo-ODA and conjugated linoleic acid (CLA, which is a precursor of 13-oxo-ODA and is well-known as a potent PPARα activator. In addition to in vitro experiment, treatment with 13-oxo-ODA decreased the levels of plasma and hepatic triglycerides in obese KK-Ay mice fed a high-fat diet. In conclusion, our findings indicate that 13-oxo-ODA act as a potent PPARα agonist, suggesting a possibility to improve obesity-induced dyslipidemia and hepatic steatosis.

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

Hepatitis B, C and Human Immunodeficiency Virus (HIV) Co ...

African Journals Online (AJOL)

TNHJOURNALPH

BACKGROUND. Nigeria which has one of the world's highest burden of children living with. Sickle cell anaemia is also endemic for hepatitis B, C and the Human immunodeficiency virus (HIV). This study set out to determine the prevalence of. Hepatitis B surface antigen (HBsAg), antibodies to Hepatitis C Virus (HCV) and.

Triglycerides

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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 ...

Up-regulation of hepatic Acyl CoA: Diacylglycerol acyltransferase-1 (DGAT-1) expression in nephrotic syndrome.

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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

Four stages of hepatic hematopoiesis in human embryos and fetuses.

Science.gov (United States)

Fanni, D; Angotzi, F; Lai, F; Gerosa, C; Senes, G; Fanos, V; Faa, G

2018-03-01

The liver is a major hematopoietic organ during embryonic and fetal development in humans. Its hematopoietic activity starts during the first weeks of gestation and continues until birth. During this period the liver is colonized by undifferentiated hematopoietic stem cells (HSCs) that gradually differentiate and once mature, enter the circulatory system through the hepatic sinusoids, this process is called hepatic hematopoiesis. The morphology of hepatic hematopoiesis, has been studied in humans through the years, and led to a characterization of all the cell types that make up these phenomena. Studies on murine models also helped to describe the extent of hepatic hematopoiesis at different gestational ages. Using this knowledge, we attempted to describe how hepatic hematopoiesis morphologically evolves as gestation progresses, in human embryos and fetuses. Thus, we observed a total of 32 tissue specimens obtained from the livers of embryos and fetuses at different gestational ages. Basing our observations on the four stages of liver hematopoiesis identified by Sasaki and Sonoda in mice, we also described four consecutive stages of liver hematopoiesis in humans, which resulted to be highly similar to those described in murine models.

Seroprevalence of Hepatitis A virus infection in non-human primates in Assam, India

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B.G. Nath

2013-08-01

Full Text Available The present study investigated 37 serum samples of non-human primates in Assam State Zoo and the Department of Forest and Environment, Govt. of Assam for seroprevalence of hepatitis A virus infection during the period from December, 2007 to November, 2009. Four serum samples were also collected from animal keepers of the zoo to investigate transmission of the disease to the attendants working with these primates. Competitive ELISA was performed using hepatitis A virus ELISA kit (Wanti Hep. AV to detect hepatitis A virus antibody in serum samples. Ten (27.21% of the non-human primate samples and three (75% human samples had detectable anti-hepatitis A virus antibodies. Living status of the non-human primates (Free living was a high potential risk for hepatitis A virus infection. Seroprevalence of hepatitis A virus infection had significant difference between free living non-human primates and captive non-human primates (P less than 0.05. No significant difference (p=0.86 was seen between male and female non-human primates

Mechanisms of triglyceride metabolism in patients with bile acid diarrhea.

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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.

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

Variability of human hepatic UDP-glucuronosyltransferase activity

NARCIS (Netherlands)

Little, JM; Lester, R; Kuipers, F; Vonk, R; Mackenzie, PI; Drake, RR; Frame, L; Radominska-Pandya, A

1999-01-01

The availability of a unique series of liver samples from human subjects, both control patients (9) and those with liver disease (6; biliary atresia (2), retransplant, chronic tyrosinemia type I, tyrosinemia, Wilson's disease) allowed us to characterize human hepatic UDP-glucuronosyltransferases

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

International Nuclear Information System (INIS)

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

2006-01-01

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

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

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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.

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.

2017 George Lyman Duff Memorial Lecture: Fat in the Blood, Fat in the Artery, Fat in the Heart: Triglyceride in Physiology and Disease.

Science.gov (United States)

Goldberg, Ira J

2018-04-01

Cholesterol is not the only lipid that causes heart disease. Triglyceride supplies the heart and skeletal muscles with highly efficient fuel and allows for the storage of excess calories in adipose tissue. Failure to transport, acquire, and use triglyceride leads to energy deficiency and even death. However, overabundance of triglyceride can damage and impair tissues. Circulating lipoprotein-associated triglycerides are lipolyzed by lipoprotein lipase (LpL) and hepatic triglyceride lipase. We inhibited these enzymes and showed that LpL inhibition reduces high-density lipoprotein cholesterol by >50%, and hepatic triglyceride lipase inhibition shifts low-density lipoprotein to larger, more buoyant particles. Genetic variations that reduce LpL activity correlate with increased cardiovascular risk. In contrast, macrophage LpL deficiency reduces macrophage function and atherosclerosis. Therefore, muscle and macrophage LpL have opposite effects on atherosclerosis. With models of atherosclerosis regression that we used to study diabetes mellitus, we are now examining whether triglyceride-rich lipoproteins or their hydrolysis by LpL affect the biology of established plaques. Following our focus on triglyceride metabolism led us to show that heart-specific LpL hydrolysis of triglyceride allows optimal supply of fatty acids to the heart. In contrast, cardiomyocyte LpL overexpression and excess lipid uptake cause lipotoxic heart failure. We are now studying whether interrupting pathways for lipid uptake might prevent or treat some forms of heart failure. © 2018 American Heart Association, Inc.

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.

Prevalence of human immunodeficiency virus, hepatitis C virus ...

African Journals Online (AJOL)

Background. Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and syphilis remain major infections around the world. In Angola, about 166 000 individuals are living with HIV, representing a prevalence of 1.98% in adults between 15 and 49 years of age. In a 2003 study in Luanda, 4.5% ...

Medium-chain, triglyceride-containing lipid emulsions increase human neutrophil beta2 integrin expression, adhesion, and degranulation

NARCIS (Netherlands)

Wanten, G. J.; Geijtenbeek, T. B.; Raymakers, R. A.; van Kooyk, Y.; Roos, D.; Jansen, J. B.; Naber, A. H.

2000-01-01

BACKGROUND: To test the hypothesis that lipid emulsions with different triglyceride structures have distinct immunomodulatory properties, we analyzed human neutrophil adhesion and degranulation after lipid incubation. METHODS: Neutrophils, isolated from the blood of 10 healthy volunteers, were

Calorie restricted high protein diets downregulate lipogenesis and lower intrahepatic triglyceride concentrations in male rats

Science.gov (United States)

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-...

Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia

NARCIS (Netherlands)

Attie, Alan D.; Krauss, Ronald M.; Gray-Keller, Mark P.; Brownlie, Alison; Miyazaki, Makoto; Kastelein, John J.; Lusis, Aldons J.; Stalenhoef, Anton F. H.; Stoehr, Jonathan P.; Hayden, Michael R.; Ntambi, James M.

2002-01-01

Stearoyl-CoA desaturase (SCD) is expressed at high levels in several human tissues and is required for the biosynthesis of oleate (18:1) and palmitoleate (16:1). These monounsaturated fatty acids are the major components of phospholipids, triglycerides, wax esters, and cholesterol esters. Mice with

Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia.

NARCIS (Netherlands)

Attie, A.D.; Krauss, R.M.; Gray-Keller, M.P.; Brownlie, A.; Miyazaki, M.; Kastelein, J.J.P.; Lusis, A.J.; Stalenhoef, A.F.H.; Stoehr, J.P.; Hayden, M.R.; Ntambi, J.M.

2002-01-01

Stearoyl-CoA desaturase (SCD) is expressed at high levels in several human tissues and is required for the biosynthesis of oleate (18:1) and palmitoleate (16:1). These monounsaturated fatty acids are the major components of phospholipids, triglycerides, wax esters, and cholesterol esters. Mice with

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

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

The use of non-human primates as animal models for the study of hepatitis viruses

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C.L. Vitral

1998-08-01

Full Text Available Hepatitis viruses belong to different families and have in common a striking hepatotropism and restrictions for propagation in cell culture. The transmissibility of hepatitis is in great part limited to non-human primates. Enterically transmitted hepatitis viruses (hepatitis A virus and hepatitis E virus can induce hepatitis in a number of Old World and New World monkey species, while the host range of non-human primates susceptible to hepatitis viruses transmitted by the parenteral route (hepatitis B virus, hepatitis C virus and hepatitis delta virus is restricted to few species of Old World monkeys, especially the chimpanzee. Experimental studies on non-human primates have provided an invaluable source of information regarding the biology and pathogenesis of these viruses, and represent a still indispensable tool for vaccine and drug testing.

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

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

Studies on some biochemical parameters in viral hepatitis patients

International Nuclear Information System (INIS)

El-Sherbiny, E.M.

2002-01-01

The present investigation deals with studying liver amino transferases (ALT. AST). Cholesterol and triglycerides. As well as testosterone and protection hormones in blood of Egyptian men infected with hepatitis C virus.hepatitis B virus and mixed B and C viruses. These biochemical parameters were evaluated to be used in diagnosis and prognosis of viral hepatitis. Which considered the most important health problem in Egypt and developing countries. Biochemical analysis were performed using spectrophotometric and radioimmunoassay techniques. All data will be subjected to statistical analysis in order to detect the most suitable biochemical analysis that can be used as specific tests for early diagnosis of viral hepatitis and to detect the parameters that show abnormalities among the different groups of infected patients. The data revealed that AST and ALT levels were increased in all patient groups. Concerning the level of triglycerides, it was increased only in the group of mixed viral hepatitis B and C, while cholesterol showed non-significant changes in all viral hepatitis groups. The sex hormone testosterone was decreased in all infected patients while the prolactin level was increased only in case of patients infected with mixed B and C viruses. However, these abnormal values in such sex hormones play a serious role in male sterility

Antiviral treatment for chronic hepatitis C in patients with human immunodeficiency virus

DEFF Research Database (Denmark)

Iorio, Alfonso; Marchesini, Emanuela; Awad, Tahany

2010-01-01

Antiviral treatment for chronic hepatitis C may be less effective if patients are co-infected with human immunodeficiency virus (HIV).......Antiviral treatment for chronic hepatitis C may be less effective if patients are co-infected with human immunodeficiency virus (HIV)....

Seroprevalence of the Hepatitis B, Hepatitis C, and Human Immunodeficiency Viruses and Treponema pallidum at the Beijing General Hospital from 2010 to 2014: A Cross-Sectional Study.

Directory of Open Access Journals (Sweden)

Shaoxia Xu

Full Text Available The hepatitis B, hepatitis C, human immunodeficiency viruses and Treponema pallidum are important causes of infectious diseases concern to public health.Between 2010 and 2014, we used an automated chemiluminescence microparticle immunoassay to detect the hepatitis B, hepatitis C, and human immunodeficiency viruses as well as Treponema pallidum (the rapid plasma regain test was used in 2010-2011. Positive human immunodeficiency virus tests were confirmed via western blotting.Among 416,130 subjects, the seroprevalences for hepatitis B virus, hepatitis C virus, human immunodeficiency virus, and Treponema pallidum were 5.72%, 1.23%, 0.196%, and 0.76%, respectively. Among 671 patients with positive human immunodeficiency virus results, 392 cases were confirmed via western blotting. Hepatitis B and human immunodeficiency virus infections were more frequent in men (7.78% and 0.26%, respectively than in women (4.45% and 0.021%, respectively. The hepatitis B and C virus seroprevalences decreased from 6.21% and 1.58%, respectively, in 2010, to 5.37% and 0.988%, respectively, in 2014. The human immunodeficiency virus seroprevalence increased from 0.04% in 2010 to 0.17% in 2014, and was elevated in the Infectious Disease (2.65%, Emergency (1.71%, and Dermatology and Sexually Transmitted Diseases (1.12% departments. The specificity of the human immunodeficiency virus screening was 71.4%. The false positive rates for the Treponema pallidum screening tests increased in patients who were 60-70 years old. The co-infection rates for the hepatitis C and human immunodeficiency viruses were 0.47% in hepatitis C virus-positive patients and 7.33% in human immunodeficiency virus-positive patients.During 2010-2014, hepatitis B virus and human immunodeficiency virus infections were more frequent among men at our institution. Although the seroprevalences of hepatitis B and C viruses decreased, the seroprevalence of human immunodeficiency virus infection increased (with

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...

Fractionation of human serum lipoproteins and simultaneous enzymatic determination of cholesterol and triglycerides

International Nuclear Information System (INIS)

Qureshi, Rashid Nazir; Kok, Wim Th.; Schoenmakers, Peter J.

2009-01-01

A method based on Asymmetric Flow Field-Flow Fractionation (AF4) was developed to separate different types of lipoproteins from human serum. The emphasis in the method optimization was on the possibilities to characterize the largest lipoprotein fractions (LDL and VLDL), which is usually not possible with the size-exclusion chromatography methods applied in routine analysis. Different channel geometries and flow programs were tested and compared. The use of a short fractionation channel was shown to give less sample dilution at the same fractionation power compared to a conventional, long channel. Different size selectivities were obtained with an exponential decay and a linear cross flow program. The ratio of the UV absorption signal to the light scattering signal was used to validate the relation between retention time and size of the fractionated particles. An experimental setup was developed for the simultaneous determination of the cholesterol and triglycerides distribution over the lipoprotein fractions, based on enzymatic reactions followed by UV detection at 500 nm. Coiled and knitted PTFE tubing reactors were compared. An improved peak sharpness and sensitivity were observed with the knitted tubing reactor. After optimization of the experimental conditions a satisfactory linearity and precision (2-3% rsd for cholesterol and 5-6% rsd for triglycerides) were obtained. Finally, serum samples, a pooled sample from healthy volunteers and samples of sepsis patients, were analyzed with the method developed. Lipoprotein fractionation and cholesterol and triglyceride distributions could be correlated with the clinical background of the samples.

Fractionation of human serum lipoproteins and simultaneous enzymatic determination of cholesterol and triglycerides

Energy Technology Data Exchange (ETDEWEB)

Qureshi, Rashid Nazir [Polymer-Analysis Group, van' t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018WV Amsterdam (Netherlands); Kok, Wim Th., E-mail: W.Th.Kok@uva.nl [Polymer-Analysis Group, van' t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018WV Amsterdam (Netherlands); Schoenmakers, Peter J. [Polymer-Analysis Group, van' t Hoff Institute for Molecular Sciences, University of Amsterdam, Nieuwe Achtergracht 166, 1018WV Amsterdam (Netherlands)

2009-11-03

A method based on Asymmetric Flow Field-Flow Fractionation (AF4) was developed to separate different types of lipoproteins from human serum. The emphasis in the method optimization was on the possibilities to characterize the largest lipoprotein fractions (LDL and VLDL), which is usually not possible with the size-exclusion chromatography methods applied in routine analysis. Different channel geometries and flow programs were tested and compared. The use of a short fractionation channel was shown to give less sample dilution at the same fractionation power compared to a conventional, long channel. Different size selectivities were obtained with an exponential decay and a linear cross flow program. The ratio of the UV absorption signal to the light scattering signal was used to validate the relation between retention time and size of the fractionated particles. An experimental setup was developed for the simultaneous determination of the cholesterol and triglycerides distribution over the lipoprotein fractions, based on enzymatic reactions followed by UV detection at 500 nm. Coiled and knitted PTFE tubing reactors were compared. An improved peak sharpness and sensitivity were observed with the knitted tubing reactor. After optimization of the experimental conditions a satisfactory linearity and precision (2-3% rsd for cholesterol and 5-6% rsd for triglycerides) were obtained. Finally, serum samples, a pooled sample from healthy volunteers and samples of sepsis patients, were analyzed with the method developed. Lipoprotein fractionation and cholesterol and triglyceride distributions could be correlated with the clinical background of the samples.

Suppression of cytochrome P450 reductase (POR) expression in hepatoma cells replicates the hepatic lipidosis observed in hepatic POR-null mice.

Science.gov (United States)

Porter, Todd D; Banerjee, Subhashis; Stolarczyk, Elzbieta I; Zou, Ling

2011-06-01

Cytochrome P450 reductase (POR) is a microsomal electron transport protein essential to cytochrome P450-mediated drug metabolism and sterol and bile acid synthesis. The conditional deletion of hepatic POR gene expression in mice results in a marked decrease in plasma cholesterol levels counterbalanced by the accumulation of triglycerides in lipid droplets in hepatocytes. To evaluate the role of cholesterol and bile acid synthesis in this hepatic lipidosis, as well as the possible role of lipid transport from peripheral tissues, we developed a stable, small interfering RNA (siRNA)-mediated cell culture model for the suppression of POR. POR mRNA and protein expression were decreased by greater than 50% in McArdle-RH7777 rat hepatoma cells 10 days after transfection with a POR-siRNA expression plasmid, and POR expression was nearly completely extinguished by day 20. Immunofluorescent analysis revealed a marked accumulation of lipid droplets in cells by day 15, accompanied by a nearly 2-fold increase in cellular triglyceride content, replicating the lipidosis seen in hepatic POR-null mouse liver. In contrast, suppression of CYP51A1 (lanosterol demethylase) did not result in lipid accumulation, indicating that loss of cholesterol synthesis is not the basis for this lipidosis. Indeed, addition of cholesterol to the medium appeared to augment the lipidosis in POR-suppressed cells, whereas removal of lipids from the medium reversed the lipidosis. Oxysterols did not accumulate in POR-suppressed cells, discounting a role for liver X receptor in stimulating triglyceride synthesis, but addition of chenodeoxycholate significantly repressed lipid accumulation, suggesting that the absence of bile acids and loss of farnesoid X receptor stimulation lead to excessive triglyceride synthesis.

Plasma apolipoprotein C-III levels, triglycerides, and coronary artery calcification in type 2 diabetics.

Science.gov (United States)

Qamar, Arman; Khetarpal, Sumeet A; Khera, Amit V; Qasim, Atif; Rader, Daniel J; Reilly, Muredach P

2015-08-01

Triglyceride-rich lipoproteins have emerged as causal risk factors for developing coronary heart disease independent of low-density lipoprotein cholesterol levels. Apolipoprotein C-III (ApoC-III) modulates triglyceride-rich lipoprotein metabolism through inhibition of lipoprotein lipase and hepatic uptake of triglyceride-rich lipoproteins. Mutations causing loss-of-function of ApoC-III lower triglycerides and reduce coronary heart disease risk, suggestive of a causal role for ApoC-III. Little data exist about the relationship of ApoC-III, triglycerides, and atherosclerosis in patients with type 2 diabetes mellitus (T2DM). Here, we examined the relationships between plasma ApoC-III, triglycerides, and coronary artery calcification in patients with T2DM. Plasma ApoC-III levels were measured in a cross-sectional study of 1422 subjects with T2DM but without clinically manifest coronary heart disease. ApoC-III levels were positively associated with total cholesterol (Spearman r=0.36), triglycerides (r=0.59), low-density lipoprotein cholesterol (r=0.16), fasting glucose (r=0.16), and glycosylated hemoglobin (r=0.12; Ptriglycerides (Tobit regression ratio, 1.43; 95% confidence interval, 0.94-2.18; P=0.086) and separately for very low-density lipoprotein cholesterol (Tobit regression ratio, 1.14; 95% confidence interval, 0.75-1.71; P=0.53). In persons with T2DM, increased plasma ApoC-III is associated with higher triglycerides, less favorable cardiometabolic phenotypes, and higher coronary artery calcification, a measure of subclinical atherosclerosis. Therapeutic inhibition of ApoC-III may thus be a novel strategy for reducing plasma triglyceride-rich lipoproteins and cardiovascular risk in T2DM. © 2015 American Heart Association, Inc.

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.

The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice.

NARCIS (Netherlands)

Mensenkamp, A.R.; Luyn, M.J.A. van; Havinga, R.; Teusink, B.; Waterman, I.J.; Mann, C.J.; Elzinga, B.M.; Verkade, H.J.; Zammit, V.A.; Havekes, L.M.; Shoulders, C.C.; Kuipers, F.

2004-01-01

BACKGROUND/AIMS: Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and secrete reduced levels of VLDL-TG. METHODS AND RESULTS: We examined the effects of apoE-deficiency on intracellular lipid homeostasis and secretion of triglycerides (TG). We show that intracellular TG turnover and

The transport of triglycerides through the secretory pathway of hepatocytes is impaired in apolipoprotein E deficient mice

NARCIS (Netherlands)

Mensenkamp, AR; van Luyn, MJA; Havinga, R; Teusink, B; Waterman, IJ; Mann, CJ; Elzinga, BM; Verkade, HJ; Zammit, VA; Havekes, LM; Shoulders, CC; Kuipers, F

Background/Aims: Apolipoprotein E (apoE)-deficient mice develop hepatic steatosis and secrete reduced levels of VLDL-TG. Methods and results: We examined the effects of apoE-deficiency on intracellular lipid homeostasis and secretion of triglycerides (TG). We show that intracellular TG turnover and

Evaluation of the Potential Risk of Drugs to Induce Hepatotoxicity in Human—Relationships between Hepatic Steatosis Observed in Non-Clinical Toxicity Study and Hepatotoxicity in Humans-

Science.gov (United States)

Goda, Keisuke; Kobayashi, Akio; Takahashi, Akemi; Takahashi, Tadakazu; Saito, Kosuke; Maekawa, Keiko; Saito, Yoshiro; Sugai, Shoichiro

2017-01-01

In the development of drugs, we sometimes encounter fatty change of the hepatocytes (steatosis) which is not accompanied by degenerative change in the liver in non-clinical toxicity studies. In this study, we investigated the relationships between fatty change of the hepatocytes noted in non-clinical toxicity studies of compound X, a candidate compound in drug development, and mitochondrial dysfunction in order to estimate the potential risk of the compound to induce drug-induced liver injury (DILI) in humans. We conducted in vivo and in vitro exploratory studies for this purpose. In vivo lipidomics analysis was conducted to investigate the relationships between alteration of the hepatic lipids and mitochondrial dysfunction. In the liver of rats treated with compound X, triglycerides containing long-chain fatty acids, which are the main energy source of the mitochondria, accumulated. Accumulation of these triglycerides was considered to be related to the inhibition of mitochondrial respiration based on the results of in vitro mitochondria toxicity studies. In conclusion, fatty change of the hepatocytes (steatosis) in non-clinical toxicity studies of drug candidates can be regarded as a critical finding for the estimation of their potential risk to induce DILI in humans when the fatty change is induced by mitochondrial dysfunction. PMID:28417920

Tribbles-1: a novel regulator of hepatic lipid metabolism in humans.

Science.gov (United States)

Bauer, Robert C; Yenilmez, Batuhan O; Rader, Daniel J

2015-10-01

The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose-dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target. © 2015 Authors; published by Portland Press Limited.

Dietary menhaden oil contributes to hepatic lipidosis in laying hens.

Science.gov (United States)

Van Elswyk, M E; Hargis, B M; Williams, J D; Hargis, P S

1994-05-01

Clinical and epidemiological investigations have indicated that there may be substantial human cardiovascular benefits associated with increased consumption of n-3 fatty acids commonly found in fish oils. Recent studies have indicated that egg yolk n-3 fatty acid content is significantly increased when hens are fed diets enriched with selected fish oils such as menhaden oil (MO). In the present study, reproductively active females but not males exhibited increased hepatic lipidosis following 6 mo of feeding 3% MO. Hens fed 3% animal-vegetable oil (AV) did not exhibit hepatic lipid accumulation. Serum triglyceride and cholesterol concentrations were reduced (P < or = .05) in hens fed MO. Subsequently, yolk and total egg weights of hens fed MO were decreased as compared with those of hens fed AV. A significant interaction of dietary MO and exogenous 17 beta-estradiol was noted among chick liver and gallbladder weights. These data suggest that dietary MO and estradiol may interact in a manner that enhances the lipogenic activity of the liver, thereby inducing hepatic lipidosis in laying hens.

SULF2 Strongly Prediposes to Fasting and Postprandial Triglycerides in Patients with Obesity and Type 2 Diabetes Mellitus

Science.gov (United States)

Hassing, H. Carlijne; Surendran, R. Preethi; Derudas, Bruno; Verrijken, An; Francque, Sven M.; Mooij, Hans L.; Bernelot Moens, Sophie J.; ’t Hart, Leen M.; Nijpels, Giel; Dekker, Jacqueline M.; Williams, Kevin Jon; Stroes, Erik S. G.; Van Gaal, Luc F.; Staels, Bart; Nieuwdorp, Max; Dallinga-Thie, Geesje M.

2014-01-01

Objective Hepatic overexpression of sulfatase-2 (SULF2), a heparan sulfate remodelling enzyme, strongly contributes to high triglyceride (TG) levels in obese, type 2 diabetic (T2DM) db/db mice. Nevertheless, data in humans are lacking. Here we sought to investigate the association of human hepatic SULF2 expression and SULF2 gene variants with TG metabolism in patients with obesity and/or T2DM. Design and Methods Liver biopsies from 121 obese subjects were analyzed for relations between hepatic SULF2 mRNA levels and plasma TG. Associations between seven SULF2 tagSNPs and TG levels were assessed in 210 obese T2DM subjects with dyslipidemia. Replication of positive findings was performed in 1316 independent obese T2DM patients. Postprandial TRL clearance was evaluated in 29 obese T2DM subjects stratified by SULF2 genotype. Results Liver SULF2 expression was significantly associated with fasting plasma TG (r = 0.271; p=0.003) in obese subjects. The SULF2 rs2281279(A>G) SNP was reproducibly associated with lower fasting plasma TG levels in obese T2DM subjects (p<0.05). Carriership of the minor G allele was associated with lower levels of postprandial plasma TG (P<0.05) and retinyl esters (RE) levels (P<0.001). Conclusions These findings implicate SULF2 as potential therapeutic target in the atherogenic dyslipidemia of obesity and T2DM. PMID:24339435

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 ...

ILDR2: an endoplasmic reticulum resident molecule mediating hepatic lipid homeostasis.

Directory of Open Access Journals (Sweden)

Kazuhisa Watanabe

Full Text Available Ildr2, a modifier of diabetes susceptibility in obese mice, is expressed in most organs, including islets and hypothalamus, with reduced levels in livers of diabetes-susceptible B6.DBA mice congenic for a 1.8 Mb interval of Chromosome 1. In hepatoma and neuronal cells, ILDR2 is primarily located in the endoplasmic reticulum membrane. We used adenovirus vectors that express shRNA or are driven by the CMV promoter, respectively, to knockdown or overexpress Ildr2 in livers of wild type and ob/ob mice. Livers in knockdown mice were steatotic, with increased hepatic and circulating triglycerides and total cholesterol. Increased circulating VLDL, without reduction in triglyceride clearance suggests an effect of reduced hepatic ILDR2 on hepatic cholesterol clearance. In animals that overexpress Ildr2, hepatic triglyceride and total cholesterol levels were reduced, and strikingly so in ob/ob mice. There were no significant changes in body weight, energy expenditure or glucose/insulin homeostasis in knockdown or overexpressing mice. Knockdown mice showed reduced expression of genes mediating synthesis and oxidation of hepatic lipids, suggesting secondary suppression in response to increased hepatic lipid content. In Ildr2-overexpressing ob/ob mice, in association with reduced liver fat content, levels of transcripts related to neutral lipid synthesis and cholesterol were increased, suggesting "relief" of the secondary suppression imposed by lipid accumulation. Considering the fixed location of ILDR2 in the endoplasmic reticulum, we investigated the possible participation of ILDR2 in ER stress responses. In general, Ildr2 overexpression was associated with increases, and knockdown with decreases in levels of expression of molecular components of canonical ER stress pathways. We conclude that manipulation of Ildr2 expression in liver affects both lipid homeostasis and ER stress pathways. Given these reciprocal interactions, and the relatively extended time

Valproate induced hepatic steatosis by enhanced fatty acid uptake and triglyceride synthesis.

Science.gov (United States)

Bai, Xupeng; Hong, Weipeng; Cai, Peiheng; Chen, Yibei; Xu, Chuncao; Cao, Di; Yu, Weibang; Zhao, Zhongxiang; Huang, Min; Jin, Jing

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. Copyright © 2017 Elsevier Inc. All rights reserved.

Human Interferon Alpha2a as Anti Hepatitis B and C

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Ratih A. Ningrum

2017-12-01

Full Text Available Hepatitis is an inflammation of the liver mainly caused by hepatitis viruses. There are 5 different types of hepatitis based on the infecting virus; A, B, C, D and E. Hepatitis B and C are chronic diseases that potentially develop into hepatocarcinoma and cirrhosis on unappropriate treatments. World Health Organization (WHO stated that currently 350 million people worldwide are living with chronic hepatitis B and 150 million people are living with Hepatitis C. The mortality rate in the world due to hepatitis is about 1.5 million people per year. The human interferon alpha2a (hIFNα2a is a therapeutic protein used as therapeutic protein for hepatitis B and C. This review discusses the hepatitis B (HBV and C (HCV viruses, mechanisms of hIFNα2a as antivirus through signal transduction pathway and improvement of hIFNα2a properties by protein modification. The application of recombinant hIFNα2a (rhIFNα2a in the treatment of hepatitis B and C that recommended by European Association for The Study of Liver (EASL and the viral resistance mechanism are also included. The status of hepatitis B and C and the development of rhIFNα2a is also described as well.

Hepatic Steatosis as a Marker of Metabolic Dysfunction

Science.gov (United States)

Fabbrini, Elisa; Magkos, Faidon

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is the liver manifestation of the complex metabolic derangements associated with obesity. NAFLD is characterized by excessive deposition of fat in the liver (steatosis) and develops when hepatic fatty acid availability from plasma and de novo synthesis exceeds hepatic fatty acid disposal by oxidation and triglyceride export. Hepatic steatosis is therefore the biochemical result of an imbalance between complex pathways of lipid metabolism, and is associated with an array of adverse changes in glucose, fatty acid, and lipoprotein metabolism across all tissues of the body. Intrahepatic triglyceride (IHTG) content is therefore a very good marker (and in some cases may be the cause) of the presence and the degree of multiple-organ metabolic dysfunction. These metabolic abnormalities are likely responsible for many cardiometabolic risk factors associated with NAFLD, such as insulin resistance, type 2 diabetes mellitus, and dyslipidemia. Understanding the factors involved in the pathogenesis and pathophysiology of NAFLD will lead to a better understanding of the mechanisms responsible for the metabolic complications of obesity, and hopefully to the discovery of novel effective treatments for their reversal. PMID:26102213

Impact of Chronic Hepatitis C Virus Genotype 1b Infection on Triglyceride Concentration in Serum Lipoprotein Fractions

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Tomohisa Nagano

2015-08-01

Full Text Available Reduced low-density lipoprotein (LDL cholesterol level is a characteristic feature of dyslipidemia in chronic hepatitis C virus (HCV infection. However, abnormality in serum triglyceride (TG has not been fully investigated. To clarify the impact of HCV genotype 1b (G1b infection and advanced fibrosis on serum TG profiles, TG concentrations in lipoprotein fractions were examined in fasting sera from 185 subjects with active or cleared HCV infection by high-performance liquid chromatography. Serum lipoproteins were fractionated into four classes: chylomicron, very low-density lipoprotein (VLDL, LDL, and high-density lipoprotein (HDL. Then, the significance of HCV G1b infection on TG levels in each lipoprotein fraction was determined using multiple regression models. We found that active HCV G1b infection was positively associated with high HDL-TG levels and low VLDL-TG levels, independent of other factors included in the regression model. In VLDL sub-fractions, active HCV infection was only found to be associated with low levels of large VLDL-TG. Similarly, advanced liver fibrosis in chronic HCV G1b infection was associated with high levels of LDL-TG, HDL-TG, and small VLDL-TG, independent of other clinical factors. These findings indicate that active HCV G1b infection and advanced fibrosis are closely associated with abnormal serum TG profiles.

Maternal resveratrol intake during lactation attenuates hepatic triglyceride and fatty acid synthesis in adult male rat offspring

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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.

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.

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...

Hepatic differentiation potential of commercially available human mesenchymal stem cells.

Science.gov (United States)

Ong, Shin-Yeu; Dai, Hui; Leong, Kam W

2006-12-01

The ready availability and low immunogenicity of commercially available mesenchymal stem cells (MSC) render them a potential cell source for the development of therapeutic products. With cell source a major bottleneck in hepatic tissue engineering, we investigated whether commercially available human MSC (hMSC) can transdifferentiate into the hepatic lineage. Based on previous studies that find rapid gain of hepatic genes in bone marrow-derived stem cells cocultured with liver tissue, we used a similar approach to drive hepatic differentiation by coculturing the hMSC with rat livers treated or untreated with gadolinium chloride (GdCl(3)). After a 24-hour coculture period with liver tissue injured by GdCl(3) in a Transwell configuration, approximately 34% of the cells differentiated into albumin-expressing cells. Cocultured cells were subsequently maintained with growth factors to complete the hepatic differentiation. Cocultured cells expressed more hepatic gene markers, and had higher metabolic functions and P450 activity than cells that were only differentiated with growth factors. In conclusion, commercially available hMSC do show hepatic differentiation potential, and a liver microenvironment in culture can provide potent cues to accelerate and deepen the differentiation. The ability to generate hepatocyte-like cells from a commercially available cell source would find interesting applications in liver tissue engineering.

Sero-prevalence of Human Immunodeficiency Virus and hepatitis ...

African Journals Online (AJOL)

Sero-prevalence of Human Immunodeficiency Virus and hepatitis viruses and their correlation with CD4 T-cell lymphocyte counts in pregnant women in the Buea Health District of Cameroon. Rebecca Enow Tanjong, Pride Teyim, Henry Lucien Kamga, Edwin Suh Neba, Theresia Nkuo-Akenji ...

Prevalence of hepatitis C Antibody in Human Immunodeficiency ...

African Journals Online (AJOL)

Background: Hepatitis C virus (HCV) is a major public health problem for Human Immunodeficiency virus (HIV) infected population. Both infections share same routes of transmission, and quite often co-exist, with dual infections associated with reciprocal and mutually more rapid progression than either infection alone.

One window-period donation in two years of individual donor-nucleic acid test screening for hepatitis B, hepatitis C and human immunodeficiency virus

Directory of Open Access Journals (Sweden)

Jose Eduardo Levi

2013-06-01

Full Text Available Objective: To describe general data on nucleic acid/serology testing and report the first hepatitis B-nucleic acid testing yield case of an immunized donor in Brazil. Methods: A total of 24,441 donations collected in 2010 and 2011 were submitted to individual nucleic acid testing for hepatitis B, hepatitis C and human immunodeficiency virus using the TaqMan® MPX kit (Roche on the Cobas s201 platform, in addition to routine screening for serological markers. Nucleic acid testing-reactive donations were further evaluated by real-time polymerase chain reaction using Cobas AmpliPrep/Cobas TaqMan hepatitis B virus, hepatitis C virus and human immunodeficiency virus tests. Results: Thirty-two donations were reactive by nucleic acid testing, 31 were also serologically reactive and one first-time donor was identified as having hepatitis B in the window period. Follow-up samples showed increasing titers of anti-HBs rising from 19 UI/mL in the index donation to 109 IU/mL seven months later attributable to his vaccination history. Curiously, this donor was never reactive for HbsAg nor for anti-HBc. In the yield donation, he was concomitantly reactive for syphilis (enzyme immunoassay and fluorescent treponemal antibody-absorption; venereal disease research laboratory non-reactive. Overall, six donors (0.02% were characterized as occult hepatitis B. A total of 35% of the confirmed (recombinant immunoblot assay positive hepatitis C donations were nucleic acid testing non-reactive and no human immunodeficiency virus "elite controller" was identified. Conclusion: The yield rate (1:24,441; 95% confidence interval: 1:9,537 - 1:89,717 contrasts to the North American rate (1:410,540 donations and strongly advocates the adoption of nucleic acid testing for hepatitis B in Brazil despite the increasing rate of anti-HBs reactive subjects due to the successful immunization program.

Radioimmunoassay and some properties of human antibodies to hepatitis B core antigen

Energy Technology Data Exchange (ETDEWEB)

Neurath, A R; Szmuness, W; Stevens, C E; Strick, N; Harley, E J [New York Blood Center, N.Y. (USA)

1978-03-01

A solid-phase radioimmunoassay for antibodies to hepatitis B core antigen (anti-HBsub(c)) is described. Polystyrene beads coated with anti-HBsub(c), hepatitis B core antigen prepared from pooled sera of humans infected with hepatitis B virus (HBV) and /sup 125/I-labelled anti-HBsub(c) were used for the test. Distinct patterns of development and changes of anti-HBsub(c) and their immunological properties are all related to variations of other markers specific for HBV infections. Knowledge concerning the detailed features of the immune response to hepatitis B core antigen may provide deeper insight into the pathogenesis of HBV infections.

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

Energy Technology Data Exchange (ETDEWEB)

Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); Alegret, Marta; Merlos, Manuel; Roglans, Nuria [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); IBUB - Institute of Biomedicine, University of Barcelona, Barcelona (Spain); CIBERobn, [Center for Biomedical Investigation Network in Obesity and Nutrition Physiopathology; Spain; Laguna, Juan C., E-mail: jclagunae@ub.edu [Pharmacology Unit, Department of Pharmacology and Therapeutic Chemistry, School of Pharmacy, University of Barcelona, Barcelona (Spain); IBUB -Institute of Biomedicine, University of Barcelona, Barcelona (Spain); CIBERobn, [Center for Biomedical Investigation Network in Obesity and Nutrition Physiopathology; Spain

2011-02-15

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid {beta}-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid {beta}-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights

Reduction of liver fructokinase expression and improved hepatic inflammation and metabolism in liquid fructose-fed rats after atorvastatin treatment

International Nuclear Information System (INIS)

Vila, Laia; Rebollo, Alba; Adalsteisson, Gunnar S.; Alegret, Marta; Merlos, Manuel; Roglans, Nuria; Laguna, Juan C.

2011-01-01

Consumption of beverages that contain fructose favors the increasing prevalence of metabolic syndrome alterations in humans, including non-alcoholic fatty liver disease (NAFLD). Although the only effective treatment for NAFLD is caloric restriction and weight loss, existing data show that atorvastatin, a hydroxymethyl-glutaryl-CoA reductase inhibitor, can be used safely in patients with NAFLD and improves hepatic histology. To gain further insight into the molecular mechanisms of atorvastatin's therapeutic effect on NAFLD, we used an experimental model that mimics human consumption of fructose-sweetened beverages. Control, fructose (10% w/v solution) and fructose + atorvastatin (30 mg/kg/day) Sprague-Dawley rats were sacrificed after 14 days. Plasma and liver tissue samples were obtained to determine plasma analytes, liver histology, and the expression of liver proteins that are related to fatty acid synthesis and catabolism, and inflammatory processes. Fructose supplementation induced hypertriglyceridemia and hyperleptinemia, hepatic steatosis and necroinflammation, increased the expression of genes related to fatty acid synthesis and decreased fatty acid β-oxidation activity. Atorvastatin treatment completely abolished histological signs of necroinflammation, reducing the hepatic expression of metallothionein-1 and nuclear factor kappa B binding. Furthermore, atorvastatin reduced plasma (x 0.74) and liver triglyceride (x 0.62) concentrations, decreased the liver expression of carbohydrate response element binding protein transcription factor (x0.45) and its target genes, and increased the hepatic activity of the fatty acid β-oxidation system (x 1.15). These effects may be related to the fact that atorvastatin decreased the expression of fructokinase (x 0.6) in livers of fructose-supplemented rats, reducing the metabolic burden on the liver that is imposed by continuous fructose ingestion. - Graphical Abstract: Display Omitted Research Highlights: �

Regulation of energy substrate utilization and hepatic insulin sensitivity by phosphatidylcholine transfer protein/StarD2.

Science.gov (United States)

Scapa, Erez F; Pocai, Alessandro; Wu, Michele K; Gutierrez-Juarez, Roger; Glenz, Lauren; Kanno, Keishi; Li, Hua; Biddinger, Sudha; Jelicks, Linda A; Rossetti, Luciano; Cohen, David E

2008-07-01

Phosphatidylcholine transfer protein (PC-TP, also known as StarD2) is a highly specific intracellular lipid binding protein with accentuated expression in oxidative tissues. Here we show that decreased plasma concentrations of glucose and free fatty acids in fasting PC-TP-deficient (Pctp(-/-)) mice are attributable to increased hepatic insulin sensitivity. In hyperinsulinemic-euglycemic clamp studies, Pctp(-/-) mice exhibited profound reductions in hepatic glucose production, gluconeogenesis, glycogenolysis, and glucose cycling. These changes were explained in part by the lack of PC-TP expression in liver per se and in part by marked alterations in body fat composition. Reduced respiratory quotients in Pctp(-/-) mice were indicative of preferential fatty acid utilization for energy production in oxidative tissues. In the setting of decreased hepatic fatty acid synthesis, increased clearance rates of dietary triglycerides and increased hepatic triglyceride production rates reflected higher turnover in Pctp(-/-) mice. Collectively, these data support a key biological role for PC-TP in the regulation of energy substrate utilization.

Human immunodeficiency virus (HIV) seropositivity and hepatitis B ...

African Journals Online (AJOL)

Method: A total of 130 donors comprising 120 commercial donors and 10 voluntary donors were tested for antibodies to human immunodeficiency virus and hepatitis B surface antigen in Benin city using Immunocomb HIV - 1 and 2 Biospot kit and Quimica Clinica Aplicada direct latex agglutination method respectively.

iPLA2β deficiency attenuates obesity and hepatic steatosis in ob/ob mice through hepatic fatty-acyl phospholipid remodeling.

Science.gov (United States)

Deng, Xiuling; Wang, Jiliang; Jiao, Li; Utaipan, Tanyarath; Tuma-Kellner, Sabine; Schmitz, Gerd; Liebisch, Gerhard; Stremmel, Wolfgang; Chamulitrat, Walee

2016-05-01

PLA2G6 or GVIA calcium-independent PLA2 (iPLA2β) is identified as one of the NAFLD modifier genes in humans, and thought to be a target for NAFLD therapy. iPLA2β is known to play a house-keeping role in phospholipid metabolism and remodeling. However, its role in NAFLD pathogenesis has not been supported by results obtained from high-fat feeding of iPLA2β-null (PKO) mice. Unlike livers of human NAFLD and genetically obese rodents, fatty liver induced by high-fat diet is not associated with depletion of hepatic phospholipids. We therefore tested whether iPLA2β could regulate obesity and hepatic steatosis in leptin-deficient mice by cross-breeding PKO with ob/ob mice to generate ob/ob-PKO mice. Here we observed an improvement in ob/ob-PKO mice with significant reduction in serum enzymes, lipids, glucose, insulin as well as improved glucose tolerance, and reduction in islet hyperplasia. The improvement in hepatic steatosis measured by liver triglycerides, fatty acids and cholesterol esters was associated with decreased expression of PPARγ and de novo lipogenesis genes, and the reversal of β-oxidation gene expression. Notably, ob/ob livers contained depleted levels of lysophospholipids and phospholipids, and iPLA2β deficiency in ob/ob-PKO livers lowers the former, but replenished the latter particularly phosphatidylethanolamine (PE) and phosphatidylcholine (PC) that contained arachidonic (AA) and docosahexaenoic (DHA) acids. Compared with WT livers, PKO livers also contained increased PE and PC containing AA and DHA. Thus, iPLA2β deficiency protected against obesity and ob/ob fatty liver which was associated with hepatic fatty-acyl phospholipid remodeling. Our results support the deleterious role of iPLA2β in severe obesity associated NAFLD. Copyright © 2016 Elsevier B.V. All rights reserved.

Counter-attack on viral hepatitis. [Hepatitis A; Hepatitis B

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Prozesky, O W [Pretoria Univ. (South Africa). Dept. of Medical Virology; Jupp, P G; Joubert, J J; Taylor, M B; Grabow, W O.K.

1985-07-01

The most highly developed radioimmunoassay test system in medical virology is proving of exceptional value in research aimed at controlling and eventually eradicating the scourge of human hepatitis. The use of radioimmunoassay in detecting hepatitis A (HAV) and hepatitis B (HBV) viruses is discussed. The hepatitis A virus is an enterovirus which infects the gastrointestinal tract and is usually transmitted by contaminated food, milk or water. Hepatitis B spreads mainly by the parenteral rate. Bedbugs and ticks are considered as possible transmitters of HBV. Another important contribution of radioimmunoassay is the ability to monitor the immune response of persons at risk who are vaccinated against hepatitis B.

Differential effects of high-carbohydrate and high-fat diets on hepatic lipogenesis in rats.

Science.gov (United States)

Ferramosca, Alessandra; Conte, Annalea; Damiano, Fabrizio; Siculella, Luisa; Zara, Vincenzo

2014-06-01

Hepatic fatty acid synthesis is influenced by several nutritional and hormonal factors. In this study, we have investigated the effects of distinct experimental diets enriched in carbohydrate or in fat on hepatic lipogenesis. Male Wistar rats were divided into four groups and fed distinct experimental diets enriched in carbohydrates (70% w/w) or in fat (20 and 35% w/w). Activity and expression of the mitochondrial citrate carrier and of the cytosolic enzymes acetyl-CoA carboxylase and fatty acid synthetase were analyzed through the study with assessments at 0, 1, 2, 4, and 6 weeks. Liver lipids and plasma levels of lipids, glucose, and insulin were assayed in parallel. Whereas the high-carbohydrate diet moderately stimulated hepatic lipogenesis, a strong inhibition of this anabolic pathway was found in animals fed high-fat diets. This inhibition was time-dependent and concentration-dependent. Moreover, whereas the high-carbohydrate diet induced an increase in plasma triglycerides, the high-fat diets determined an accumulation of triglycerides in liver. An increase in the plasmatic levels of glucose and insulin was observed in all cases. The excess of sucrose in the diet is converted into fat that is distributed by bloodstream in the organism in the form of circulating triglycerides. On the other hand, a high amount of dietary fat caused a strong inhibition of lipogenesis and a concomitant increase in the level of hepatic lipids, thereby highlighting, in these conditions, the role of liver as a reservoir of exogenous fat.

Triglycerides, fatty acids, sterols, mono- and disaccharides and sugar alcohols in human milk and current types of infant formula milk

NARCIS (Netherlands)

Huisman, M; vanBeusekom, CM; Nijeboer, HJ; Muskiet, FAJ; Boersma, ER

Objective: To investigate differences in the fatty acid composition, sterols, minor carbohydrates and sugar alcohols between human and formula milk. Design: We analyzed the concentrations of triglycerides, sterols, di- and monosaccharides and sugar alcohols, as well as the fatty acid composition of

Prevalence of hepatitis C Antibody in Human Immunodeficiency ...

African Journals Online (AJOL)

2015-10-25

Oct 25, 2015 ... Abstract: Background: Hepatitis. C virus (HCV) is a major public health problem for Human Immu- nodeficiency virus (HIV) infected population. Both infections share same routes of transmission, and quite often co-exist, with dual infections associated with recipro- cal and mutually more rapid pro- gression ...

Effects of dietary substitution of mixed amino acids for glucose on the splanchnic metabolism of plasma triglycerides, cholesterol, carbohydrates, and amino acids in conscious fed baboons.

Science.gov (United States)

Wolfe, B M; Redinger, R N; Marliss, E B; Grace, D M

1983-04-01

Splanchnic metabolism was studied in the fed state during prolonged constant intravenous administration of tracer amounts of [9,10]-3H palmitic acid and the calculated isocaloric intraduodenal administration (13 mg/min X kg body wt0.75) of either (1) glucose, (2) 15% mixed amino acids and 85% glucose or (3) 45% mixed amino acids and 55% glucose to conscious, restrained female baboons that had been maintained on a similar diet (supplemented in essential nutrients) for the previous 9 days. Secretion of plasma triglycerides from the splanchnic region was quantified from splanchnic flow and radiochemical measurements of transsplanchnic gradients of 3H-labeled free fatty acids and triglycerides. Mean splanchnic secretion of plasma triglycerides increased significantly as the proportion of dietary calories derived from amino acids was varied from 0 to 15 to 45% (mean values 1.1 +/- 0.1, 2.6 +/- 0.2 and 4.2 +/- 0.3 mumol/min kg body wt0.75, respectively, p less than 0.05). Increased triglyceride secretion was attributable to both significantly higher rates of esterification of free fatty acids taken up in the splanchnic region to triglycerides released into hepatic venous blood plasma (mean values 10 +/- 1, 16 +/- 2 and 34 +/- 5%, respectively) and to significantly higher rates of secretion of triglycerides derived from precursors other than free fatty acids. Higher intake of amino acids was also associated with both higher plasma concentrations of cholesterol and higher values for hepatic oxidation of cholesterol to bile acids.(ABSTRACT TRUNCATED AT 250 WORDS)

Shared genetic effects between hepatic steatosis and fibrosis: A prospective twin study

Science.gov (United States)

Cui, Jeffrey; Chen, Chi-Hua; Lo, Min-Tzu; Schork, Nicholas; Bettencourt, Ricki; Gonzalez, Monica P; Bhatt, Archana; Hooker, Jonathan; Shaffer, Katherine; Nelson, Karen E; Long, Michelle T; Brenner, David A; Sirlin, Claude B; Loomba, Rohit

2016-01-01

Introduction Nonalcoholic fatty liver disease (NAFLD) is associated with metabolic risk factors including hypertension and dyslipidemia, and may progress to liver fibrosis. Previous studies have shown that hepatic steatosis and fibrosis are heritable but whether they have a significant shared gene effect is unknown. This study aimed to examine the shared gene effects between hepatic steatosis, fibrosis, and their associations with metabolic risk factors. Methods This is a cross-sectional analysis of a prospective cohort of well-characterized, community-dwelling twins (45 monozygotic, 20 dizygotic twin pairs, 130 total subjects) from Southern California. Hepatic steatosis was assessed with MRI-proton density fat fraction (MRI-PDFF) and hepatic fibrosis was assessed with magnetic resonance elastography (MRE). A standard bivariate twin AE model was used to estimate the proportion of phenotypic variance between two phenotypes accounted for by additive genetic effects (A) and individual-specific environmental effects (E). Genetic correlations (rG) estimated from this model represent the degree to which the genetic determinants of two phenotypes overlap. Results The mean (±SD) age and BMI were 47.1 (±21.9) years and 26.9 (±6.5) kg/m2, respectively. 20% (26/130) of the cohort had hepatic steatosis (MRI-PDFF ≥5%) and 8.2% (10/122) had hepatic fibrosis (MRE ≥3Kpa). Blood pressure (systolic and diastolic), triglycerides, glucose, homeostatic model assessment of insulin resistance (HOMA-IR), insulin, hemoglobin A1c (HbA1c), and low high-density lipoprotein (HDL) had significant shared gene effects with hepatic steatosis. Triglycerides, glucose, HOMA-IR, insulin, HbA1c, and low HDL had significant shared gene effects with hepatic fibrosis. Hepatic steatosis and fibrosis had a highly significant shared gene effect of 0.756 (95% CI: 0.716–1, psteatosis pathogenesis may also be involved with fibrosis pathogenesis. PMID:27315352

Medium-chain, triglyceride-containing lipid emulsions increase human neutrophil beta2 integrin expression, adhesion, and degranulation.

Science.gov (United States)

Wanten, G J; Geijtenbeek, T B; Raymakers, R A; van Kooyk, Y; Roos, D; Jansen, J B; Naber, A H

2000-01-01

To test the hypothesis that lipid emulsions with different triglyceride structures have distinct immunomodulatory properties, we analyzed human neutrophil adhesion and degranulation after lipid incubation. Neutrophils, isolated from the blood of 10 healthy volunteers, were incubated in medium or physiologic (2.5 mmol/L) emulsions containing long-chain (LCT), medium-chain (MCT), mixed LCT/MCT, or structured (SL) triglycerides. Expression of adhesion molecules and degranulation markers was evaluated by flow cytometry. Also, functional adhesion was investigated by means of a flow cytometric assay using fluorescent beads coated with the integrin ligand intercellular adhesion molecule (ICAM)-1. Although LCT and SL had no effect, LCT/MCT significantly increased expression of the beta2 integrins lymphocyte-function-associated antigen 1 (+18%), macrophage antigen 1 (+387%), p150,95 (+82%), and (alphaDbeta2 (+230%). Degranulation marker expression for azurophilic (CD63, +210%) and specific granules (CD66b, +370%) also significantly increased, whereas L-selectin (CD62L, -70%) decreased. The effects of LCT/MCT were mimicked by the MCT emulsion. ICAM-1 adhesion (% beads bound) was increased by LCT/MCT (34% +/- 4%), whereas LCT (19% +/-3%) and SL (20% +/- 2%) had no effect compared with medium (17% +/- 3%). LCT/MCT and MCT, contrary to LCT and SL emulsions, increased neutrophil beta2 integrin expression, adhesion, and degranulation. Apart from other emulsion constituents, triglyceride chain length might therefore be a key feature in the interaction of lipid emulsions and the phagocyte immune system.

Human Immunodeficiency Virus and Hepatitis C Virus Co-infection ...

African Journals Online (AJOL)

Human Immunodeficiency Virus and Hepatitis C Virus Co-infection in Cameroon: Investigation of the Genetic Diversity and Virulent ... AFRICAN JOURNALS ONLINE (AJOL) · Journals · Advanced Search · USING AJOL · RESOURCES ... DNA sequencing, and bioinformatics tools for sequence management and analysis.

Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress

Science.gov (United States)

Lanaspa, Miguel A.; Sanchez-Lozada, Laura G.; Choi, Yea-Jin; Cicerchi, Christina; Kanbay, Mehmet; Roncal-Jimenez, Carlos A.; Ishimoto, Takuji; Li, Nanxing; Marek, George; Duranay, Murat; Schreiner, George; Rodriguez-Iturbe, Bernardo; Nakagawa, Takahiko; Kang, Duk-Hee; Sautin, Yuri Y.; Johnson, Richard J.

2012-01-01

Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states. PMID:23035112

Long-Term Effects of Docosahexaenoic Acid-Bound Phospholipids and the Combination of Docosahexaenoic Acid-Bound Triglyceride and Egg Yolk Phospholipid on Lipid Metabolism in Mice

Science.gov (United States)

Che, Hongxia; Cui, Jie; Wen, Min; Xu, Jie; Yanagita, Teruyoshi; Wang, Qi; Xue, Changhu; Wang, Yuming

2018-04-01

The bioavailability of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) depends on their chemical forms. This study investigated the long-term effects of DHA-bound triglyceride (TG-DHA), DHA-bound phospholipid (PL-DHA), and the combination of TG-DHA and egg yolk phospholipid (Egg-PL) on lipid metabolism in mice fed with a high-fat diet (fat levels of 22.5%). Male C57BL/6J mice were fed with different formulations containing 0.5% DHA, including TG-DHA, PL-DHA, and the combination of TG-DHA and Egg-PL, for 6 weeks. Serum, hepatic, and cerebral lipid concentrations and the fatty acid compositions of the liver and brain were determined. The concentrations of serum total triglyceride (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), and hepatic TG in the PL-DHA group and the combination group were significantly lower than those in the high-fat (HF) group ( P Egg-PL in decreasing the AI. Long-term dietary supplementation with low amount of DHA (0.5%) may improve hepatic DHA levels, although cerebral DHA levels may not be enhanced.

21 CFR 862.1705 - Triglyceride test system.

Science.gov (United States)

2010-04-01

... diseases involving lipid metabolism, or various endocrine disorders. (b) Classification. Class I (general... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Triglyceride test system. 862.1705 Section 862.1705 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED...

Hepatitis A virus infection and hepatitis A vaccination in human immunodeficiency virus-positive patients: A review.

Science.gov (United States)

Lin, Kuan-Yin; Chen, Guan-Jhou; Lee, Yu-Lin; Huang, Yi-Chia; Cheng, Aristine; Sun, Hsin-Yun; Chang, Sui-Yuan; Liu, Chun-Eng; Hung, Chien-Ching

2017-05-28

Hepatitis A virus (HAV) is one of the most common infectious etiologies of acute hepatitis worldwide. The virus is known to be transmitted fecal-orally, resulting in symptoms ranging from asymptomatic infection to fulminant hepatitis. HAV can also be transmitted through oral-anal sex. Residents from regions of low endemicity for HAV infection often remain susceptible in their adulthood. Therefore, clustered HAV infections or outbreaks of acute hepatitis A among men who have sex with men and injecting drug users have been reported in countries of low endemicity for HAV infection. The duration of HAV viremia and stool shedding of HAV may be longer in human immunodeficiency virus (HIV)-positive individuals compared to HIV-negative individuals with acute hepatitis A. Current guidelines recommend HAV vaccination for individuals with increased risks of exposure to HAV (such as from injecting drug use, oral-anal sex, travel to or residence in endemic areas, frequent clotting factor or blood transfusions) or with increased risks of fulminant disease (such as those with chronic hepatitis). The seroconversion rates following the recommended standard adult dosing schedule (2 doses of HAVRIX 1440 U or VAQTA 50 U administered 6-12 mo apart) are lower among HIV-positive individuals compared to HIV-negative individuals. While the response rates may be augmented by adding a booster dose at week 4 sandwiched between the first dose and the 6-mo dose, the need of booster vaccination remain less clear among HIV-positive individuals who have lost anti-HAV antibodies.

Arginase Inhibition Ameliorates Hepatic Metabolic Abnormalities in Obese Mice

Science.gov (United States)

Moon, Jiyoung; Do, Hyun Ju; Cho, Yoonsu; Shin, Min-Jeong

2014-01-01

Objectives We examined whether arginase inhibition influences hepatic metabolic pathways and whole body adiposity in diet-induced obesity. Methods and Results After obesity induction by a high fat diet (HFD), mice were fed either the HFD or the HFD with an arginase inhibitor, Nω-hydroxy-nor-L-arginine (nor-NOHA). Nor-NOHA significantly prevented HFD-induced increases in body, liver, and visceral fat tissue weight, and ameliorated abnormal lipid profiles. Furthermore, nor-NOHA treatment reduced lipid accumulation in oleic acid-induced hepatic steatosis in vitro. Arginase inhibition increased hepatic nitric oxide (NO) in HFD-fed mice and HepG2 cells, and reversed the elevated mRNA expression of hepatic genes in lipid metabolism. Expression of phosphorylated 5′ AMPK-activated protein kinase α was increased by arginase inhibition in the mouse livers and HepG2 cells. Conclusions Arginase inhibition ameliorated obesity-induced hepatic lipid abnormalities and whole body adiposity, possibly as a result of increased hepatic NO production and subsequent activation of metabolic pathways involved in hepatic triglyceride metabolism and mitochondrial function. PMID:25057910

Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism.

Science.gov (United States)

Almatrafi, Manal Mused; Vergara-Jimenez, Marcela; Murillo, Ana Gabriela; Norris, Gregory H; Blesso, Christopher N; Fernandez, Maria Luz

2017-06-22

To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group ( p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1β and interferon-γ, were lowest in the HM group ( p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls ( p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver.

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

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 ...

Betaine reduces hepatic lipidosis induced by carbon tetrachloride in Sprague-Dawley rats.

Science.gov (United States)

Junnila, M; Barak, A J; Beckenhauer, H C; Rahko, T

1998-10-01

Carbon tetrachloride-injected rats were given liquid diets with and without betaine for 7 d. Hepatic lipidosis was induced by 4 daily injections of carbon tetrachloride (CCl4). Animals were killed and their livers and blood taken for analysis of betaine, S-adenosylmethionine (SAM), betaine homocysteine methyltransferase (BHMT), triglyceride, alanine aminotransferase and aspartate aminotransferase. Liver samples were also processed and stained for histological examination. Supplemental betaine reduced triglyceride in the liver and centrilobular hepatic lipidosis induced by the CCl4 injections. In both the control and experimental groups receiving betaine, liver betaine, BHMT and SAM were significantly higher than in their respective groups not receiving betaine. This study provides evidence that betaine protects the liver against CCl4-induced lipidosis and may be a useful therapeutic and prophylactic agent in ameliorating the harmful effects of CCl4.

Pre‐natal undernutrition and post‐natal overnutrition are associated with permanent changes in hepatic metabolism markers and fatty acid composition in sheep

DEFF Research Database (Denmark)

Hou, L.; Hellgren, Lars; Kongsted, A. H.

2014-01-01

was associated with increased hepatic triglyceride, ceramide and free fatty acid content in adulthood (not observed in lambs), which was accompanied by up‐regulated early‐stage insulin signalling as reflected by increased INSRβ and PI3K‐p110 protein expression. The HCHF diet increased hepatic triglyceride...... content in lambs, associated with down‐regulated expressions of energy‐metabolism‐related genes (GLUT1, PPARα, SREBP1c, PEPCK). These post‐natal effects were not observed in adult HCHF sheep, after they had received a moderate (body‐fat correcting) diet for 1.5 years. Interestingly, pre‐natal LOW...... nutrition induced permanent alterations in hepatic phospholipids’ fatty acid composition. Thus, the amount of linoleic acid (C18 : 2 ∆9,12) was significantly increased and composition of rumen‐derived fatty acids were altered, indicating changed composition of rumenal microbiota. Hepatic insulin signalling...

Bioenergetic Changes during Differentiation of Human Embryonic Stem Cells along the Hepatic Lineage

DEFF Research Database (Denmark)

Hopkinson, Branden M; Madsen, Claus Desler; Kalisz, Mark

2017-01-01

Mitochondrial dysfunction has been demonstrated to result in premature aging due to its effects on stem cells. Nevertheless, a full understanding of the role of mitochondrial bioenergetics through differentiation is still lacking. Here we show the bioenergetics profile of human stem cells...... of embryonic origin differentiating along the hepatic lineage. Our study reveals especially the transition between hepatic specification and hepatic maturation as dependent on mitochondrial respiration and demonstrates that even though differentiating cells are primarily dependent on glycolysis until induction...

Regulation of hepatic PPARγ2 and lipogenic gene expression by melanocortin

International Nuclear Information System (INIS)

Poritsanos, Nicole J.; Wong, Davie; Vrontakis, Maria E.; Mizuno, Tooru M.

2008-01-01

The central melanocortin system regulates hepatic lipid metabolism. Hepatic lipogenic gene expression is regulated by transcription factors including sterol regulatory element-binding protein 1c (SREBP-1c), carbohydrate responsive element-binding protein (ChREBP), and peroxisome proliferator-activated receptor γ2 (PPARγ2). However, it is unclear if central melanocortin signaling regulates hepatic lipogenic gene expression through the activation of these transcription factors. To delineate the molecular mechanisms by which the melanocortin system regulates hepatic lipid metabolism, we examined the effect of intracerebroventricular injection of SHU9119, a melanocortin receptor antagonist, on hepatic expression levels of genes involved in lipid metabolism in mice. SHU9119 treatment increased hepatic triglyceride content and mRNA levels of lipogenic genes, SREBP-1c, and PPARγ2, whereas it did not cause any changes in hepatic ChREBP mRNA levels. These findings suggest that reduced central melanocortin signaling increases hepatic lipid deposition by stimulating hepatic lipogenic gene expression at least partly through the activation of SREBP-1c and PPARγ2

The cyclophilin inhibitor Debio-025 shows potent anti-hepatitis C effect in patients coinfected with hepatitis C and human immunodeficiency virus.

Science.gov (United States)

Flisiak, Robert; Horban, Andrzej; Gallay, Philippe; Bobardt, Michael; Selvarajah, Suganya; Wiercinska-Drapalo, Alicja; Siwak, Ewa; Cielniak, Iwona; Higersberger, Jozef; Kierkus, Jarek; Aeschlimann, Christian; Grosgurin, Pierre; Nicolas-Métral, Valérie; Dumont, Jean-Maurice; Porchet, Hervé; Crabbé, Raf; Scalfaro, Pietro

2008-03-01

Debio-025 is an oral cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus activity in vitro. Its effect on viral load as well as its influence on intracellular Cyp levels was investigated in a randomized, double-blind, placebo-controlled study. Mean hepatitis C viral load decreased significantly by 3.6 log(10) after a 14-day oral treatment with 1200 mg twice daily (P CypB) levels in peripheral blood mononuclear cells decreased from 67 +/- 6 (standard error) ng/mg protein (baseline) to 5 +/- 1 ng/mg protein at day 15 (P CypB levels, coinciding with the decrease in hepatitis C viral load. These are the first preliminary human data supporting the hypothesis that CypB may play an important role in hepatitis C virus replication and that Cyp inhibition is a valid target for the development of anti-hepatitis C drugs.

Epidemiological studies on viral infections and co-infections : Human immunodeficiency virus, hepatitis C virus and human papillomavirus

NARCIS (Netherlands)

van Santen, D.K.

2018-01-01

The research described in this thesis aimed to increase our understanding of the incidence, disease progression and treatment of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and human papillomavirus (HPV) infections and co-infections in key populations. Chapter 1 contains an overview

Prevalence of hepatitis B, hepatitis C and human immunodeficiency ...

African Journals Online (AJOL)

Background. Hepatitis B virus (HBV), hepatitis C virus (HCV) and HIV are common blood-borne infections unevenly distributed across regions in Nigeria. Few population-based prevalence studies have been done in Nigeria. Objective. To determine the prevalence of HBV, HCV and HIV and risk factors for infection with ...

Long-term culture of human liver tissue with advanced hepatic functions.

Science.gov (United States)

Ng, Soon Seng; Xiong, Anming; Nguyen, Khanh; Masek, Marilyn; No, Da Yoon; Elazar, Menashe; Shteyer, Eyal; Winters, Mark A; Voedisch, Amy; Shaw, Kate; Rashid, Sheikh Tamir; Frank, Curtis W; Cho, Nam Joon; Glenn, Jeffrey S

2017-06-02

A major challenge for studying authentic liver cell function and cell replacement therapies is that primary human hepatocytes rapidly lose their advanced function in conventional, 2-dimensional culture platforms. Here, we describe the fabrication of 3-dimensional hexagonally arrayed lobular human liver tissues inspired by the liver's natural architecture. The engineered liver tissues exhibit key features of advanced differentiation, such as human-specific cytochrome P450-mediated drug metabolism and the ability to support efficient infection with patient-derived inoculums of hepatitis C virus. The tissues permit the assessment of antiviral agents and maintain their advanced functions for over 5 months in culture. This extended functionality enabled the prediction of a fatal human-specific hepatotoxicity caused by fialuridine (FIAU), which had escaped detection by preclinical models and short-term clinical studies. The results obtained with the engineered human liver tissue in this study provide proof-of-concept determination of human-specific drug metabolism, demonstrate the ability to support infection with human hepatitis virus derived from an infected patient and subsequent antiviral drug testing against said infection, and facilitate detection of human-specific drug hepatotoxicity associated with late-onset liver failure. Looking forward, the scalability and biocompatibility of the scaffold are also ideal for future cell replacement therapeutic strategies.

Microarray multiplex assay for the simultaneous detection and discrimination of hepatitis B, hepatitis C, and human immunodeficiency type-1 viruses in human blood samples

International Nuclear Information System (INIS)

Hsia, Chu Chieh; Chizhikov, Vladimir E.; Yang, Amy X.; Selvapandiyan, Angamuthu; Hewlett, Indira; Duncan, Robert; Puri, Raj K.; Nakhasi, Hira L.; Kaplan, Gerardo G.

2007-01-01

Hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus type-1 (HIV-1) are transfusion-transmitted human pathogens that have a major impact on blood safety and public health worldwide. We developed a microarray multiplex assay for the simultaneous detection and discrimination of these three viruses. The microarray consists of 16 oligonucleotide probes, immobilized on a silylated glass slide. Amplicons from multiplex PCR were labeled with Cy-5 and hybridized to the microarray. The assay detected 1 International Unit (IU), 10 IU, 20 IU of HBV, HCV, and HIV-1, respectively, in a single multiplex reaction. The assay also detected and discriminated the presence of two or three of these viruses in a single sample. Our data represent a proof-of-concept for the possible use of highly sensitive multiplex microarray assay to screen and confirm the presence of these viruses in blood donors and patients

Committee Opinion No. 655 Summary: Hepatitis B, Hepatitis C, and Human Immunodeficiency Virus Infections in Obstetrician-Gynecologists.

Science.gov (United States)

2016-02-01

To prevent transmission of bloodborne pathogens, it is important that health care providers adhere to standard precautions, follow fundamental infection-control principles, and use appropriate procedural techniques. All obstetrician-gynecologists who provide clinical care should receive the hepatitis B virus vaccine series. The Society for Healthcare Epidemiology of America has established guidelines for the management of health care providers who are infected with hepatitis B virus, hepatitis C virus, or human immunodeficiency virus (HIV). The guidelines categorize representative obstetric and gynecologic procedures according to level of risk of bloodborne pathogen transmission and include recommendations for health care provider clinical activities, based on these categories and viral burden. It is important to note that when no restrictions are recommended, careful supervision should be carried out as highlighted. These recommendations provide a framework within which to consider such cases; however, each case should be independently considered in context by the expert review panel.

VLDL hydrolysis by hepatic lipase regulates PPARδ transcriptional responses.

Directory of Open Access Journals (Sweden)

Jonathan D Brown

Full Text Available PPARs (α,γ,δ are a family of ligand-activated transcription factors that regulate energy balance, including lipid metabolism. Despite these critical functions, the integration between specific pathways of lipid metabolism and distinct PPAR responses remains obscure. Previous work has revealed that lipolytic pathways can activate PPARs. Whether hepatic lipase (HL, an enzyme that regulates VLDL and HDL catabolism, participates in PPAR responses is unknown.Using PPAR ligand binding domain transactivation assays, we found that HL interacted with triglyceride-rich VLDL (>HDL≫LDL, IDL to activate PPARδ preferentially over PPARα or PPARγ, an effect dependent on HL catalytic activity. In cell free ligand displacement assays, VLDL hydrolysis by HL activated PPARδ in a VLDL-concentration dependent manner. Extended further, VLDL stimulation of HL-expressing HUVECs and FAO hepatoma cells increased mRNA expression of canonical PPARδ target genes, including adipocyte differentiation related protein (ADRP, angiopoietin like protein 4 and pyruvate dehydrogenase kinase-4. HL/VLDL regulated ADRP through a PPRE in the promoter region of this gene. In vivo, adenoviral-mediated hepatic HL expression in C57BL/6 mice increased hepatic ADRP mRNA levels by 30%. In ob/ob mice, a model with higher triglycerides than C57BL/6 mice, HL overexpression increased ADRP expression by 70%, demonstrating the importance of triglyceride substrate for HL-mediated PPARδ activation. Global metabolite profiling identified HL/VLDL released fatty acids including oleic acid and palmitoleic acid that were capable of recapitulating PPARδ activation and ADRP gene regulation in vitro.These data define a novel pathway involving HL hydrolysis of VLDL that activates PPARδ through generation of specific monounsaturated fatty acids. These data also demonstrate how integrating cell biology with metabolomic approaches provides insight into specific lipid mediators and pathways of lipid

Hepatitis c and human rights: comparison of legal experience of Ukraine and Georgia.

Science.gov (United States)

Senyuta, Iryna Y

2018-01-01

A comparative legal research of human rights provision in Ukraine and Georgia, in the aspect of combating viral HCV, was conducted. Ukrainian advocacy experience and Georgian strategic litigation experience with regard to human rights and HCV was analyzed. Key international instruments, which lay the conceptual foundations as well as outline the measures, which are directed at human rights in patient care provision and fighting viral hepatitis, were elucidated. Attention was paid to the Global health sector strategy. Viral hepatitis, 2016 - 2021 [1], which, for the first time, defined a global strategy on fighting viral hepatitis, in particular HCV and envisaged the advocacy vectors. The frames of interaction of the human rights in patient care concept and public health, which consists in realization of certain human rights were elucidated and the necessity to embody the human rights in patient care concept into the state policy in the field of public health was determined. It was found out that a common international problem in combating HCV is a deficiency of financial resources, which are necessary for effective fighting the epidemics and guarantee equal access to treatment for every person. The international community outlined five most important spheres, which require investments and will catalyze the measures, which need to be taken in order to fight hepatitis. Analysis of the Ukrainian experience was focused on the issue of donated blood safety and successful advocacy campaigns, which were carried out in order to promote the adoption of programs on prophylactics, diagnostics and treatment of HCV both on national and regional levels. Examples of ensuring the rights of the marginalized groups during HCV treatment, in particular of the people who inject drugs, people living with HIV, participants of the antiterrorist operation were provided. Interesting and important is the experience of Georgia concerning human rights protection in the ECtHR, which has a legal

Predicting Human Clearance of OATP substrates using Cynomolgus monkey: In vitro-in vivo scaling of hepatic uptake clearance.

Science.gov (United States)

de Bruyn, Tom; Ufuk, Ayse; Cantrill, Carina; Kosa, Rachel E; Bi, Yi-An; Niosi, Mark; Modi, Sweta; Rodrigues, A David; Tremaine, Larry M; Varma, Manthena Vs; Galetin, Aleksandra; Houston, J Brian

2018-05-02

This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV, respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a similar range to human parameters and good predictions from respective hepatocyte parameters (with 2.7 and 3.8-fold bias on average, respectively). The use of cross species empirical scaling factors (based on either dataset average or individual drug scaling factor from cynomolgus monkey data) improved prediction (less bias, better concordance) of human hepatic clearance from human hepatocyte data alone. In vitro intracellular binding in hepatocytes also correlated well between species. It is concluded that the minimal species differences observed for the current dataset between cynomolgus monkey and human hepatocyte uptake, both in vitro and in vivo, support future use of this preclinical model to delineate drug hepatic uptake and enable prediction of human in vivo intrinsic hepatic clearance. The American Society for Pharmacology and Experimental Therapeutics.

AMPK Re-Activation Suppresses Hepatic Steatosis but its Downregulation Does Not Promote Fatty Liver Development.

Science.gov (United States)

Boudaba, Nadia; Marion, Allison; Huet, Camille; Pierre, Rémi; Viollet, Benoit; Foretz, Marc

2018-02-01

Nonalcoholic fatty liver disease is a highly prevalent component of disorders associated with disrupted energy homeostasis. Although dysregulation of the energy sensor AMP-activated protein kinase (AMPK) is viewed as a pathogenic factor in the development of fatty liver its role has not been directly demonstrated. Unexpectedly, we show here that liver-specific AMPK KO mice display normal hepatic lipid homeostasis and are not prone to fatty liver development, indicating that the decreases in AMPK activity associated with hepatic steatosis may be a consequence, rather than a cause, of changes in hepatic metabolism. In contrast, we found that pharmacological re-activation of downregulated AMPK in fatty liver is sufficient to normalize hepatic lipid content. Mechanistically, AMPK activation reduces hepatic triglyceride content both by inhibiting lipid synthesis and by stimulating fatty acid oxidation in an LKB1-dependent manner, through a transcription-independent mechanism. Furthermore, the effect of the antidiabetic drug metformin on lipogenesis inhibition and fatty acid oxidation stimulation was enhanced by combination treatment with small-molecule AMPK activators in primary hepatocytes from mice and humans. Overall, these results demonstrate that AMPK downregulation is not a triggering factor in fatty liver development but in contrast, establish the therapeutic impact of pharmacological AMPK re-activation in the treatment of fatty liver disease. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

Science.gov (United States)

Almatrafi, Manal Mused; Vergara-Jimenez, Marcela; Murillo, Ana Gabriela; Norris, Gregory H.; Blesso, Christopher N.; Fernandez, Maria Luz

2017-01-01

To investigate the mechanisms by which Moringa oleifera leaves (ML) modulate hepatic lipids, guinea pigs were allocated to either control (0% ML), 10% Low Moringa (LM) or 15% High Moringa (HM) diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH) and triglyceride (TG) metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG) with the lowest concentrations in the HM group (p < 0.001), consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL)-1β and interferon-γ, were lowest in the HM group (p < 0.005). Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01). This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver. PMID:28640194

Moringa Leaves Prevent Hepatic Lipid Accumulation and Inflammation in Guinea Pigs by Reducing the Expression of Genes Involved in Lipid Metabolism

Directory of Open Access Journals (Sweden)

Manal Mused Almatrafi

2017-06-01

Full Text Available To investigate the mechanisms by which Moringa oleifera leaves (ML modulate hepatic lipids, guinea pigs were allocated to either control (0% ML, 10% Low Moringa (LM or 15% High Moringa (HM diets with 0.25% dietary cholesterol to induce hepatic steatosis. After 6 weeks, guinea pigs were sacrificed and liver and plasma were collected to determine plasma lipids, hepatic lipids, cytokines and the expression of genes involved in hepatic cholesterol (CH and triglyceride (TG metabolism. There were no differences in plasma lipids among groups. A dose-response effect of ML was observed in hepatic lipids (CH and TG with the lowest concentrations in the HM group (p < 0.001, consistent with histological evaluation of lipid droplets. Hepatic gene expression of diglyceride acyltransferase-2 and peroxisome proliferator activated receptor-γ, as well as protein concentrations interleukin (IL-1β and interferon-γ, were lowest in the HM group (p < 0.005. Hepatic gene expression of cluster of differentiation-68 and sterol regulatory element binding protein-1c were 60% lower in both the LM and HM groups compared to controls (p < 0.01. This study demonstrates that ML may prevent hepatic steatosis by affecting gene expression related to hepatic lipids synthesis resulting in lower concentrations of cholesterol and triglycerides and reduced inflammation in the liver.

Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy

Directory of Open Access Journals (Sweden)

Fuyang Zhang

2016-11-01

Full Text Available The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD + BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR, inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA in the HFD + BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte.

Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

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Yi-Chieh Li

Full Text Available Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

Lactoferrin dampens high-fructose corn syrup-induced hepatic manifestations of the metabolic syndrome in a murine model.

Science.gov (United States)

Li, Yi-Chieh; Hsieh, Chang-Chi

2014-01-01

Hepatic manifestations of the metabolic syndrome are related obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease. Here we investigated how the anti-inflammatory properties of lactoferrin can protect against the onset of hepatic manifestations of the metabolic syndrome by using a murine model administered with high-fructose corn syrup. Our results show that a high-fructose diet stimulates intestinal bacterial overgrowth and increases intestinal permeability, leading to the introduction of endotoxin into blood circulation and liver. Immunohistochemical staining of Toll-like receptor-4 and thymic stromal lymphopoietin indicated that lactoferrin can modulate lipopolysaccharide-mediated inflammatory cascade. The important regulatory roles are played by adipokines including interleukin-1β, interleukin-6, tumor necrosis factor-α, monocyte chemotactic protein-1, and adiponectin, ultimately reducing hepatitis and decreasing serum alanine aminotransferase release. These beneficial effects of lactoferrin related to the downregulation of the lipopolysaccharide-induced inflammatory cascade in the liver. Furthermore, lactoferrin reduced serum and hepatic triglycerides to prevent lipid accumulation in the liver, and reduced lipid peroxidation, resulting in 4-hydroxynonenal accumulation. Lactoferrin reduced oral glucose tolerance test and homeostasis model assessment-insulin resistance. Lactoferrin administration thus significantly lowered liver weight, resulting from a decrease in the triglyceride and cholesterol synthesis that activates hepatic steatosis. Taken together, these results suggest that lactoferrin protected against high-fructose corn syrup induced hepatic manifestations of the metabolic syndrome.

Basis of aggravated hepatic lipid metabolism by chronic stress in high-fat diet-fed rat.

Science.gov (United States)

Han, Ying; Lin, Min; Wang, Xiaobin; Guo, Keke; Wang, Shanshan; Sun, Mengfei; Wang, Jiao; Han, Xiaoyu; Fu, Ting; Hu, Yang; Fu, Jihua

2015-03-01

Our previous study has demonstrated that long-term stress, known as chronic stress (CS), can aggravate nonalcoholic fatty liver disease in high-fat diet (HFD)-fed rat. In this study, we tried to figure out which lipid metabolic pathways were impacted by CS in the HFD-fed rat. Male Sprague-Dawley rats (6 weeks of age, n = 8 per group) were fed with either standard diet or HFD with or without CS exposure for 8 weeks. Hepatic lipidosis, biochemical, hormonal, and lipid profile markers in serum and liver, and enzymes involved in de novo lipogenesis (DNL) of fatty acids (FAs) and cholesterol, β-oxidation, FAs uptake, triglycerides synthesis, and very low-density lipoprotein (VLDL) assembly in the liver were detected. CS exposure reduced hepatic lipidosis but further elevated hepatic VLDL content with aggravated dyslipidemia in the HFD-fed rats. There was a synergism between CS and HFD on VLDL production and dyslipidemia. PCR and western blot assays showed that CS exposure significantly promoted hepatic VLDL assembly in rats, especially in the HFD-fed rats, while it had little impact on DNL, β-oxidation, FAs uptake, and triglycerides synthesis in the HFD-fed rats. This phenomenon was in accordance with elevated serum glucocorticoid level. The critical influence of CS exposure on hepatic lipid metabolism in the HFD-fed rats is VLDL assembly which might be regulated by glucocorticoid.

Impaired plasma lipid profiles in acute hepatitis

Directory of Open Access Journals (Sweden)

Wang Yongzhong

2010-01-01

Full Text Available Abstract The present study examined plasma lipid profiles in thirty patients suffered from acute viral hepatitis. Patients' blood samples were collected at both the debut and recovery of diseases. Thirty sex and age matched normal subjects were included as controls. Plasma total triglycerides (TG, total cholesterol, high density lipoprotein cholesterol (HDL-C, low density lipoprotein cholesterol (LDL-C, apolipoprotein AI (ApoAI, apolipoprotein B (ApoB, lipoprotein (a (Lp(a, blood coagulation status including prothrombin complex activity and activated partial tromboplastin time (APTT, and hepatic functions were determined by the automatic biochemical analytical instrument. It demonstrated that plasma levels of total cholesterol, HDL-C and apoAI were significantly lower in the patients at the acute phase of hepatitis than those in normal subjects, whereas plasma levels of TG and LDL-C were obviously higher in the patients than in normal subjects (P

Metabolic and hormonal alterations in cats with hepatic lipidosis.

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Brown, B; Mauldin, G E; Armstrong, J; Moroff, S D; Mauldin, G N

2000-01-01

Hepatic lipidosis in cats is a commonly diagnosed hepatobiliary disease of unknown cause. The purpose of this prospective study was to characterize the blood hormone and lipid status of cats with hepatic lipidosis, and to compare this status to that of cats with other types of liver disease and to control cats. Twenty-three cats with hepatic disease were assigned to 1 of 2 groups on the basis of cytopathologic or histopathologic examination of the liver: group 1, hepatic lipidosis (n = 18); or group 2, cholangiohepatitis (n = 5). Ten healthy young adult cats were used as controls. Food was withheld from control animals for 24 hours before blood collection. Concentrations of plasma glucagon and serum insulin, cortisol, thyroxine, triglycerides, cholesterol, phospholipids, and nonesterified fatty acids (NEFAs) were determined in all cats, in addition to routine hematologic and serum biochemical testing. Cats with hepatic lipidosis had higher serum NEFA concentrations than cats with cholangiohepatitis or control cats (P lipidosis or control cats (P hepatic lipidosis. Serum insulin concentrations were significantly higher in control cats than in diseased cats (P hepatic disease. The high concentration of NEFAs in cats with hepatic lipidosis suggests that at least 1 factor in the pathogenesis of this syndrome may involve the regulation of hormone-sensitive lipase.

Co–inection of hepatitis B and C viruses among human ...

African Journals Online (AJOL)

Introduction: The co–infection of Human immunodeficiency virus (HIV), Hepatitis B and C viruses remains a public health problem particularly in resource limited setting like Nigeria. Studies on these co–infections have been done principally among adult and pregnant women with limited information on the pediatric ...

Hepatitis E Virus Genotype 3 in Humans and Swine, Bolivia

Science.gov (United States)

Cavallo, Annalisa; Gonzales, José Luis; Bonelli, Sara Irene; Valda, Ybar; Pieri, Angela; Segundo, Higinio; Ibañez, Ramón; Mantella, Antonia; Bartalesi, Filippo; Tolari, Francesco; Bartoloni, Alessandro

2011-01-01

We determined the seroprevalence of hepatitis E virus (HEV) in persons in 2 rural communities in southeastern Bolivia and the presence of HEV in human and swine fecal samples. HEV seroprevalence was 6.3%, and HEV genotype 3 strains with high sequence homology were detected. PMID:21801630

Increasing insulin resistance accentuates the effect of triglyceride-associated loci on serum triglycerides during 5 years

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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...

Hepatic fat accumulation and regulation of FAT/CD36: an effect of hepatic irradiation

Science.gov (United States)

Martius, Gesa; Alwahsh, Salamah Mohammad; Rave-Fränk, Margret; Hess, Clemens Friedrich; Christiansen, Hans; Ramadori, Giuliano; Malik, Ihtzaz Ahmed

2014-01-01

Irradiation is known to induce inflammation and affect fat metabolic pathways. The current study investigates hepatic fat accumulation and fatty acid transportation in a rat model of single dose liver irradiation (25-Gy). Rat livers were selectively irradiated in-vivo (25-Gy), sham-irradiated rats served as controls. Hepatic lipids were studied by colorimetric assays in liver and serum. Intracellular lipids, protein and mRNA were studied by Nile red staining, immunohistology, Western Blot analysis and RT-PCR in liver, respectively. Changes in FAT/CD36 expression were studied in-vitro in a human monocyte cell line U937 after irradiation in presence or absence of infliximab (IFX). Nile Red staining of liver cryosections showed a quick (12-48 h) increase in fat droplets. Accordingly, hepatic triglycerides (TG) and free fatty acids (FFA) were elevated. An early increase (3-6 h) in the serum level of HDL-C, TG and cholesterol was measured after single dose irradiation followed by a decrease thereafter. Furthermore, expression of the fat transporter protein FAT/CD36 was increased, immunohistochemistry revealed basolateral and cytoplasmic expression in hepatocytes. Moreover, apolipoprotein-B100, -C3 and enzymes (acetyl-CoA carboxylase, lipoprotein-lipase, carnitine-palmitoyltransferase, malonyl-CoA-decarboxylase) involved in fat metabolism were induced at 12-24 h. Early activation of the NFkβ pathway (IκBα) by TNF-α was seen, followed by a significant elevation of serum markers for liver damage (AST and GLDH). TNF-α blockage by anti-TNF-α in cell culture (U937) prevented the increase of FAT/CD36 caused by irradiation. Selective liver irradiation is a model for rapid induction of steatosis hepatis and fat accumulation could be triggered by irradiation-induced inflammatory mediators (e.g. TNF-α). PMID:25197426

CE: Triglycerides: Do They Matter?

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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.

Branched Chain Amino Acids Cause Liver Injury in Obese/Diabetic Mice by Promoting Adipocyte Lipolysis and Inhibiting Hepatic Autophagy.

Science.gov (United States)

Zhang, Fuyang; Zhao, Shihao; Yan, Wenjun; Xia, Yunlong; Chen, Xiyao; Wang, Wei; Zhang, Jinglong; Gao, Chao; Peng, Cheng; Yan, Feng; Zhao, Huishou; Lian, Kun; Lee, Yan; Zhang, Ling; Lau, Wayne Bond; Ma, Xinliang; Tao, Ling

2016-11-01

The Western meat-rich diet is both high in protein and fat. Although the hazardous effect of a high fat diet (HFD) upon liver structure and function is well recognized, whether the co-presence of high protein intake contributes to, or protects against, HF-induced hepatic injury remains unclear. Increased intake of branched chain amino acids (BCAA, essential amino acids compromising 20% of total protein intake) reduces body weight. However, elevated circulating BCAA is associated with non-alcoholic fatty liver disease and injury. The mechanisms responsible for this quandary remain unknown; the role of BCAA in HF-induced liver injury is unclear. Utilizing HFD or HFD+BCAA models, we demonstrated BCAA supplementation attenuated HFD-induced weight gain, decreased fat mass, activated mammalian target of rapamycin (mTOR), inhibited hepatic lipogenic enzymes, and reduced hepatic triglyceride content. However, BCAA caused significant hepatic damage in HFD mice, evidenced by exacerbated hepatic oxidative stress, increased hepatic apoptosis, and elevated circulation hepatic enzymes. Compared to solely HFD-fed animals, plasma levels of free fatty acids (FFA) in the HFD+BCAA group are significantly further increased, due largely to AMPKα2-mediated adipocyte lipolysis. Lipolysis inhibition normalized plasma FFA levels, and improved insulin sensitivity. Surprisingly, blocking lipolysis failed to abolish BCAA-induced liver injury. Mechanistically, hepatic mTOR activation by BCAA inhibited lipid-induced hepatic autophagy, increased hepatic apoptosis, blocked hepatic FFA/triglyceride conversion, and increased hepatocyte susceptibility to FFA-mediated lipotoxicity. These data demonstrated that BCAA reduces HFD-induced body weight, at the expense of abnormal lipolysis and hyperlipidemia, causing hepatic lipotoxicity. Furthermore, BCAA directly exacerbate hepatic lipotoxicity by reducing lipogenesis and inhibiting autophagy in the hepatocyte. Copyright © 2016. Published by Elsevier

Hepatic-portal oleic acid inhibits feeding more potently than hepatic-portal caprylic acid in rats

NARCIS (Netherlands)

Jambor de Sousa, Ulrike L.; Benthem, Lambertus; Arsenijevic, Denis; Scheurink, Anton J. W.; Langhans, Wolfgang; Geary, Noni; Leonhardt, Monika; Geary, Nori

2006-01-01

In several human and animal studies, medium-chain triglycerides decreased food intake more than did long-chain triglycerides. It is possible that faster uptake and metabolism of medium-chain fatty acids in the liver is responsible for this difference. To test this hypothesis we compared the feeding

Lack of evidence for metabolism of p-phenylenediamine by human hepatic cytochrome P450 enzymes

International Nuclear Information System (INIS)

Stanley, Lesley A.; Skare, Julie A.; Doyle, Edward; Powrie, Robert; D'Angelo, Diane; Elcombe, Clifford R.

2005-01-01

p-Phenylenediamine (PPD) is a widely used ingredient in permanent hair dyes; however, little has been published on its metabolism, especially with respect to hepatic cytochrome P450 (CYP)-mediated oxidation. This is regarded as a key step in the activation of carcinogenic arylamines that ultimately leads to the development of bladder cancer. Most epidemiology studies show no significant association between personal use of hair dyes and bladder cancer, but one recent study reported an increased risk of bladder cancer in women who were frequent users of permanent hair dyes. The aim of the present study was to use intact human hepatocytes, human liver microsomes, and heterologously expressed human CYPs to determine whether PPD is metabolised by hepatic CYPs to form an N-hydroxylamine. p-Phenylenediamine was N-acetylated by human hepatocytes to form N-acetylated metabolites, but there was no evidence for the formation of mono-oxygenated metabolites or for enzyme-mediated covalent binding of 14 C-PPD to microsomal protein. In contrast, 2-aminofluorene underwent CYP-mediated metabolism to ≥4 different hydroxylated metabolites. The lack of evidence for hepatic CYP-mediated metabolism of PPD is inconsistent with the hypothesis that this compound plays a causal role in the development of bladder cancer via a mode of action involving hepatic metabolism to an N-hydroxyarylamine

Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity

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The etiology of type 2 diabetes often involves diet-induced obesity (DIO), which is associated with elevated plasma fatty acids and lipoprotein associated triglycerides. Since aberrant hepatic fatty acid uptake may contribute to this, we investigated whether increased expression of a fatty acid tran...

Hepatitis A Virus and Hepatitis E Virus: Emerging and Re-Emerging Enterically Transmitted Hepatitis Viruses.

Science.gov (United States)

Lemon, Stanley M; Walker, Christopher M

2018-05-07

Over the past two decades, progress in understanding human infections with hepatitis A virus (HAV) and hepatitis E virus (HEV) has been eclipsed by the priority of combating persistent hepatitis B virus (HBV) and hepatitis C virus (HCV) infections. During that time, the global burden of liver disease caused by enteric hepatitis viruses has not abated. Because of vaccines, hepatitis A has become increasingly a disease of adults instead of early childhood in many regions of the world, resulting in an age-related shift toward more severe disease. HEV has remained endemic in many developing countries, and in well-developed, economically advanced countries it is now recognized as a cause of chronic, progressive liver disease in individuals with compromised immunity. The goal of this collection of articles is to review recent progress and to shine a bright light on gaps in our understanding of how these viruses replicate, cause disease, interact with the liver and host immune system, and are transmitted, along with prospects for improved control in human populations. Renewed efforts to study and compare HAV and HEV biology in humans and animal models have high potential to enhance our understanding of host-pathogen balance in the liver, and may contribute ultimately to the control of other infectious diseases of the liver. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Triglyceride-Lowering Effects of Two Probiotics, Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601, in a Rat Model of High-Fat Diet-Induced Hypertriglyceridemia.

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Choi, Il-Dong; Kim, Sung-Hwan; Jeong, Ji-Woong; Lee, Dong Eun; Huh, Chul-Sung; Hong, Seong Soo; Sim, Jae-Hun; Ahn, Young-Tae

2016-03-01

The triglyceride-lowering effect of probiotics Lactobacillus plantarum KY1032 and Lactobacillus curvatus HY7601 were investigated. Male SD Wistar rats were randomly divided into three groups and fed high-fat diet (HFD), HFD and probiotics (5 X 10(9) CFU/day of L. plantarum KY1032 and 5 X 10(9) CFU/day of L. curvatus HY7601), or normal diet for 6 weeks. Probiotic treatment significantly lowered the elevated plasma triglyceride and increased plasma free fatty acid, glycerol, and plasma apolipoprotein A-V (ApoA-V) levels. The probiotic-treated group showed elevated hepatic mRNA expression of PPARα, bile acid receptor (FXR), and ApoA-V. These results demonstrate that L. plantarum KY1032 and L. curvatus HY7601 lower triglycerides in hypertriglyceridemic rats by upregulating ApoA-V, PPARα, and FXR.

Hepatic steatosis in hepatitis B virus infected patients: meta-analysis of risk factors and comparison with hepatitis C infected patients.

Science.gov (United States)

Machado, Mariana V; Oliveira, António G; Cortez-Pinto, Helena

2011-09-01

Although hepatic steatosis (HS) has an association with hepatitis C virus (HCV) infection, an association with hepatitis B virus (HBV) is controversial. We performed a meta-analysis to evaluate HS prevalence and risk factors, in HBV infection. Standard guidelines for performance of meta-analyses were followed. Studies with HS assessed by histology were included. Pooled odd ratios (OR) and standardized mean differences (SMD) were obtained with the random-effects model and DerSimonian-Laid method. Seventeen out of 21 studies were included, comprising 4100 HBV infected patients. Overall HS prevalence was 29.6%. Eight studies also included 945 HCV infected patients, showing decreased risk of HS in HBV versus HCV patients (OR 0.55, 95%CI [0.45-0.67], P SMD 2.17, 95%CI [1.23, 3.11], P SMD 0.84, 95%CI [0.00, 1.67], P = 0.049), triglycerides (SMD 1.18, 95%CI [0.48, 1.89], P = 0.001), cholesterol (SMD 0.88, 95%CI [0.31, 1.45], P = 0.003), moderate alcohol consumption (OR 1.54, 95%CI [1.10-2.15], P = 0.011) and negatively with HBV DNA (SMD -74.12, 95%CI [-82.93, -65.31], P infected patients, relating to metabolic factors but not with hepatic histology severity. A puzzling strong negative association between viral load and HS, may even suggest a protective effect of the virus on HS. © 2011 Journal of Gastroenterology and Hepatology Foundation and Blackwell Publishing Asia Pty Ltd.

Reproducibility of 3.0 Tesla Magnetic Resonance Spectroscopy for Measuring Hepatic Fat Content

NARCIS (Netherlands)

van Werven, Jochem R.; Hoogduin, Johannes M.; Nederveen, Aart J.; van Vliet, Andre A.; Wajs, Ewa; Vandenberk, Petra; Stroes, Erik S. G.; Stoker, Jaap

Purpose: To investigate reproducibility of proton magnetic resonance spectroscopy (H-1-MRS) to measure hepatic triglyceride content (HTGC). Materials and Methods: In 24 subjects, HTGC was evaluated using H-1-MRS at 3.0 Tesla. We studied "between-weeks" reproducibility and reproducibility of H-1-MRS

Hyperlipidemia, hyperlipemia, and hepatic lipidosis in American miniature horses: 23 cases (1990-1994).

Science.gov (United States)

Mogg, T D; Palmer, J E

1995-09-01

The medical records of 23 American Miniature Horses with hyperlipidemia, hyperlipemia, or hepatic lipidosis were reviewed. The most common clinical signs were anorexia and lethargy. The mean duration of clinical signs was 2.4 days. A primary disease was identified in 19 cases. Enterocolitis was the most common primary disease (n = 10). Intentional feed restriction, as part of treatment for colic, resulted in hyperlipemia in 2 horses and hyperlipidemia in 1. Four horses had primary hyperlipemia, 3 of which had signs of hepatoencephalopathy secondary to hepatic lipidosis. Dextrose, heparin, and insulin were the most common treatments. The overall survival was 61% (14/23). All horses with peak serum triglyceride concentrations > 1,200 mg/dl died or were euthanatized, whereas all but 1 with peak serum triglyceride concentrations < 1,200 mg/dl survived. These findings suggest that when American Miniature Horses, like other ponies and donkeys, are in a negative energy balance, they can rapidly develop hyperlipidemia or hyperlipemia. Early detection and treatment may improve survival.

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.

Effects of Fatty Acids at Different Positions in the Triglycerides on Cholesterol Levels

International Nuclear Information System (INIS)

Teh, S.S.; Voon, P.T.; Ng, Y.T.; Ong, S.H.; Augustine, S.H.O.; Choo, Y.M.

2016-01-01

Previous studies established a series of regression equations for predicting the risk factor effects from serum cholesterol concentrations. However, the degree of saturation was solely based on total fatty acid composition in triglycerides. Our article is focused on the relationships between the published human nutrition studies and predicted values of serum cholesterol levels based on total fatty acid compositions and at sn-2 position in triglycerides. Twenty-two published human nutrition studies were chosen to assess the effects of palm olein, olive oil, cocoa butter, sunflower seed oil, corn oil, soyabean oil, grape seed oil, groundnut oil and rice bran oil diets on serum cholesterol levels. There were no statistically significant differences between the predicted values of serum cholesterol levels based on fatty acids at sn-2 position and the published human nutrition studies as proven by the statistical analyses with p values more than 0.05. In contrast, there were statistically significant differences between the predicted values of serum cholesterol levels based on total fatty acids and the published human nutritional studies with p values less than 0.05. Fatty acids at sn-2 position appear to influence the cholesterol levels rather than total fatty acids of the triglyceride. (author)

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

Energy Technology Data Exchange (ETDEWEB)

Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang [Faculty of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016 China (China); Chonan, Ritsu [Koei Kogyo Co., Ltd., Tokyo, 101-0063 Japan (Japan); Yamahara, Johji [Pharmafood Institute, Kyoto, 602-8136 Japan (Japan); Wang, Jianwei, E-mail: wangjianwei1968@gmail.com [Department of Traditional Chinese Medicine, Chongqing Medical University, Chongqing 400016 China (China); Li, Yuhao, E-mail: yuhao@sitcm.edu.au [Endocrinology and Metabolism Group, Sydney Institute of Health Sciences/Sydney Institute of Traditional Chinese Medicine, NSW 2000 Australia (Australia)

2014-10-15

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

Mangiferin treatment inhibits hepatic expression of acyl-coenzyme A:diacylglycerol acyltransferase-2 in fructose-fed spontaneously hypertensive rats: a link to amelioration of fatty liver

International Nuclear Information System (INIS)

Xing, Xiaomang; Li, Danyang; Chen, Dilong; Zhou, Liang; Chonan, Ritsu; Yamahara, Johji; Wang, Jianwei; Li, Yuhao

2014-01-01

Mangiferin, a xanthone glucoside, and its associated traditional herbs have been demonstrated to improve abnormalities of lipid metabolism. However, its underlying mechanisms remain largely unclear. This study investigated the anti-steatotic effect of mangiferin in fructose-fed spontaneously hypertensive rat (SHR)s that have a mutation in sterol regulatory element binding protein (SREBP)-1. The results showed that co-administration of mangiferin (15 mg/kg, once daily, by oral gavage) over 7 weeks dramatically diminished fructose-induced increases in hepatic triglyceride content and Oil Red O-stained area in SHRs. However, blood pressure, fructose and chow intakes, white adipose tissue weight and metabolic parameters (plasma concentrations of glucose, insulin, triglyceride, total cholesterol and non-esterified fatty acids) were unaffected by mangiferin treatment. Mechanistically, mangiferin treatment suppressed acyl-coenzyme A:diacylglycerol acyltransferase (DGAT)-2 expression at the mRNA and protein levels in the liver. In contrast, mangiferin treatment was without effect on hepatic mRNA and/or protein expression of SREBP-1/1c, carbohydrate response element binding protein, liver pyruvate kinase, fatty acid synthase, acetyl-CoA carboxylase-1, stearoyl-CoA desaturase-1, DGAT-1, monoacyglycerol acyltransferase-2, microsomal triglyceride transfer protein, peroxisome proliferator-activated receptor-alpha, carnitine palmitoyltransferase-1 and acyl-CoA oxidase. Collectively, our results suggest that mangiferin treatment ameliorates fatty liver in fructose-fed SHRs by inhibiting hepatic DGAT-2 that catalyzes the final step in triglyceride biosynthesis. The anti-steatotic effect of mangiferin may occur independently of the hepatic signals associated with de novo fatty acid synthesis and oxidation. - Highlights: • We investigated the anti-steatotic effect of mangiferin (MA) in fructose-fed SHR. • MA (15 mg/kg/day for 7 weeks) ameliorated fructose-induced fatty liver in

Human gamma interferon production by cytotoxic T lymphocytes sensitized during hepatitis A virus infection

International Nuclear Information System (INIS)

Maier, K.; Gabriel, P.; Koscielniak, E.; Stierhof, Y.D.; Wiedmann, K.H.; Flehmig, B.; Vallbracht, A.

1988-01-01

The production of interferon (IFN) during a chromium-51 release assay with hepatitis A virus (HAV)-infected fibroblasts and autologous peripheral blood lymphocytes from patients with acute HAV infection was studied to determine whether IFN plays a role in immunopathogenesis of hepatitis A infection in humans. Skin fibroblasts of eight patients after acute HAV infection and from two control persons without history of current of past HAV infection were infected with HAV. Peripheral blood lymphocytes were collected at different times after the onset of icterus and tested in a chromium-51 release assay against autologous HAV-infected skin fibroblasts for their cytolytic and IFN-producing activity. The IFN produced during the assay was characterized and found to have the properties of human gamma IFN. Cytotoxicity and gamma IFN release were virus specific. The cell types responsible for both functions were characterized and found to be in the HLA-dependent T8 + lymphocyte subset. Considering that gamma IFN has an antiviral effect on persistent HAV infection in vitro and that it probably accounts for stimulation of HLA class I antigen expression on hepatocytes, these experimental results presented here demonstrate that human gamma IFN produced by HAV-specific T cells may participate in pathogenesis of hepatitis A infection in humans

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.

Hepatitis C virus infection in the human immunodeficiency virus infected patient

DEFF Research Database (Denmark)

Clausen, Louise Nygaard; Lundbo, Lene Fogt; Benfield, Thomas

2014-01-01

Human immunodeficiency virus (HIV) and hepatitis C virus (HCV) share the same transmission routes; therefore, coinfection is frequent. An estimated 5-10 million individuals alone in the western world are infected with both viruses. The majority of people acquire HCV by injection drug use and...

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.

Age dependent in vitro metabolism of bifenthrin in rat and human hepatic microsomes.

Science.gov (United States)

Nallani, Gopinath C; Chandrasekaran, Appavu; Kassahun, Kelem; Shen, Li; ElNaggar, Shaaban F; Liu, Zhiwei

2018-01-01

Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CL int ) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean V max (±SD) for the formation of 4'-OH-BIF in juvenile rat hepatic microsomes was 25.0±1.5pmol/min/mg which was significantly lower (pbifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CL int values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0±7.2 and 166.7±20.5μl/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0±4.0 and 21.3±1.2μl/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes. Copyright © 2017 Elsevier Inc. All rights reserved.

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

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Fukuda, N; Ontko, J A

1984-08-01

triglyceride produced from both de novo fatty acid synthesis and from infused free fatty acid substrate. These observations suggest the following chain of events in the liver following TOFA treatment: inhibition of fatty acid and cholesterol synthesis; increased fatty acid oxidation and ketogenesis; decreased triglyceride synthesis as a result of inhibition of fatty acid synthesis, stimulation of fatty acid oxidation, and altered partition of diglyceride between triglyceride and phospholipid synthesis; and decreased production of VLDL. These comparative rat liver perfusion experiments indicate that free fatty acids provide the major source of substrate for the hepatic production of triglyceri

Genetic Polymorphisms in Organic Cation Transporter 1 Attenuates Hepatic Metformin Exposure in Humans

DEFF Research Database (Denmark)

Sundelin, E. I.O.; Gormsen, Lars C; Jensen, J. B.

2017-01-01

the transporter protein OCT1, affect the hepatic distribution of metformin in humans. We performed noninvasive 11C-metformin positron emission tomography (PET)/computed tomography (CT) to determine hepatic exposure in 12 subjects genotyped for variants in SLC22A1. Hepatic distribution of metformin...... was significantly reduced after oral intake in carriers of M420del and R61C variants in SLC22A1 without being associated with changes in circulating levels of metformin. Our data show that genetic polymorphisms in transporter proteins cause variation in hepatic exposure to metformin, and it demonstrates......Metformin has been used successfully to treat type 2 diabetes for decades. However, the efficacy of the drug varies considerably from patient to patient and this may in part be due to its pharmacokinetic properties. The aim of this study was to examine if common polymorphisms in SLC22A1, encoding...

Dietary sea cucumber cerebroside alleviates orotic acid-induced excess hepatic adipopexis in rats

Science.gov (United States)

2012-01-01

Background Nonalcoholic fatty liver disease (NAFLD) is a prevalent chronic liver disease in industrialized countries. The present study was undertaken to explore the preventive effect of dietary sea cucumber cerebroside (SCC) extracted from Acaudina molpadioides in fatty liver rats. Methods Male Wistar rats were randomly divided into four groups including normal control group, NAFLD model group, and two SCC-treated groups with SCC at 0.006% and 0.03% respectively. The fatty liver model was established by administration of 1% orotic acid (OA) to the rats. After 10d, serum and hepatic lipid levels were detected. And the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities were also determined. Besides, to gain the potential mechanism, the changes of key enzymes and gene expressions related to the hepatic lipid metabolism were measured. Results Dietary SCC at the level of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats. SCC administration elevated the serum triglyceride (TG) level and the ALT, AST activities in OA-fed rats. The activities of hepatic lipogenic enzymes including fatty acid synthase (FAS), malic enzyme (ME) and glucose-6-phosphatedehydrogenase (G6PDH) were inhibited by SCC treatment. And the gene expressions of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c) were also reduced in rats fed SCC. However, dietary SCC didn't affect the activity and mRNA expression of carnitine palmitoyltransferase (CPT) in liver. Besides, suppression of microsomal triglyceride transfer protein (MTP) activity was observed in SCC-feeding rats. Conclusions These results suggested that dietary SCC could attenuate hepatic steatosis due to its inhibition of hepatic lipogenic gene expression and enzyme activity and the enhancement of TG secretion from liver. PMID:22569330

Dietary sea cucumber cerebroside alleviates orotic acid-induced excess hepatic adipopexis in rats

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Zhang Bei

2012-05-01

Full Text Available Abstract Background Nonalcoholic fatty liver disease (NAFLD is a prevalent chronic liver disease in industrialized countries. The present study was undertaken to explore the preventive effect of dietary sea cucumber cerebroside (SCC extracted from Acaudina molpadioides in fatty liver rats. Methods Male Wistar rats were randomly divided into four groups including normal control group, NAFLD model group, and two SCC-treated groups with SCC at 0.006% and 0.03% respectively. The fatty liver model was established by administration of 1% orotic acid (OA to the rats. After 10d, serum and hepatic lipid levels were detected. And the serum alanine aminotransferase (ALT and aspartate aminotransferase (AST activities were also determined. Besides, to gain the potential mechanism, the changes of key enzymes and gene expressions related to the hepatic lipid metabolism were measured. Results Dietary SCC at the level of 0.006% and 0.03% ameliorated the hepatic lipid accumulation in fatty liver rats. SCC administration elevated the serum triglyceride (TG level and the ALT, AST activities in OA-fed rats. The activities of hepatic lipogenic enzymes including fatty acid synthase (FAS, malic enzyme (ME and glucose-6-phosphatedehydrogenase (G6PDH were inhibited by SCC treatment. And the gene expressions of FAS, ME, G6PDH and sterol-regulatory element binding protein (SREBP-1c were also reduced in rats fed SCC. However, dietary SCC didn't affect the activity and mRNA expression of carnitine palmitoyltransferase (CPT in liver. Besides, suppression of microsomal triglyceride transfer protein (MTP activity was observed in SCC-feeding rats. Conclusions These results suggested that dietary SCC could attenuate hepatic steatosis due to its inhibition of hepatic lipogenic gene expression and enzyme activity and the enhancement of TG secretion from liver.

Fasting time and lipid parameters: association with hepatic steatosis — data from a random population sample

Science.gov (United States)

2014-01-01

Background Current guidelines recommend measuring plasma lipids in fasting patients. Recent studies, however, suggest that variation in plasma lipid concentrations secondary to fasting time may be minimal. Objective of the present study was to investigate the impact of fasting time on plasma lipid concentrations (total cholesterol, HDL and LDL cholesterol, triglycerides). A second objective was to determine the effect of non-alcoholic fatty liver disease exerted on the above-mentioned lipid levels. Method Subjects participating in a population-based cross-sectional study (2,445 subjects; 51.7% females) were questioned at time of phlebotomy regarding duration of pre-phlebotomy fasting. Total cholesterol, LDL and HDL cholesterol, and triglycerides were determined and correlated with length of fasting. An upper abdominal ultrasonographic examination was performed and body-mass index (BMI) and waist-to-hip ratio (WHR) were calculated. Subjects were divided into three groups based on their reported fasting periods of 1–4 h, 4–8 h and > 8 h. After application of the exclusion criteria, a total of 1,195 subjects (52.4% females) were included in the study collective. The Kruskal-Wallis test was used for continuous variables and the chi-square test for categorical variables. The effects of age, BMI, WHR, alcohol consumption, fasting time and hepatic steatosis on the respective lipid variables were analyzed using multivariate logistic regression. Results At multivariate analysis, fasting time was associated with elevated triglycerides (p = 0.0047 for 1–4 h and p = 0.0147 for 4–8 h among females; p fasting period. LDL cholesterol and triglycerides exhibit highly significant variability; the greatest impact is seen with the triglycerides. Fasting time represents an independent factor for reduced LDL cholesterol and elevated triglyceride concentrations. There is a close association between elevated lipids and hepatic steatosis. PMID:24447492

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

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

2016-01-15

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

Inhibition of Intracellular Triglyceride Lipolysis Suppresses Cold-Induced Brown Adipose Tissue Metabolism and Increases Shivering in Humans.

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Blondin, Denis P; Frisch, Frédérique; Phoenix, Serge; Guérin, Brigitte; Turcotte, Éric E; Haman, François; Richard, Denis; Carpentier, André C

2017-02-07

Indirect evidence from human studies suggests that brown adipose tissue (BAT) thermogenesis is fueled predominantly by fatty acids hydrolyzed from intracellular triglycerides (TGs). However, no direct experimental evidence to support this assumption currently exists in humans. The aim of this study was to determine the role of intracellular TG in BAT thermogenesis, in cold-exposed men. Using positron emission tomography with 11 C-acetate and 18 F-fluorodeoxyglucose, we showed that oral nicotinic acid (NiAc) administration, an inhibitor of intracellular TG lipolysis, suppressed the cold-induced increase in BAT oxidative metabolism and glucose uptake, despite no difference in BAT blood flow. There was a commensurate increase in shivering intensity and shift toward a greater reliance on glycolytic muscle fibers without modifying total heat production. Together, these findings show that intracellular TG lipolysis is critical for BAT thermogenesis and provides experimental evidence for a reciprocal role of BAT thermogenesis and shivering in cold-induced thermogenesis in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

Non-invasive assessment of hepatic fat accumulation in chronic hepatitis C by {sup 1}H magnetic resonance spectroscopy

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Krssak, Martin [Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna (Austria); Hofer, Harald [Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna (Austria); Wrba, Fritz [Department of Clinical Pathology, Medical University of Vienna (Austria); Meyerspeer, Martin [MR Centre-of-Excellence, Department of Radiodiagnostics, Medical University of Vienna (Austria); Center for Biomedical Engineering and Physics, Medical University of Vienna (Austria); Brehm, Attila [Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna (Austria); Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center of Diabetes Research and Department of Medicine/Metabolic Diseases, Heinrich Heine University, Duesseldorf (Germany); Lohninger, Alfred [Department of Medical Chemistry, Center for Physiology and Pathophysiology, Medical University of Vienna (Austria); Steindl-Munda, Petra [Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna (Austria); MR Centre-of-Excellence, Department of Radiodiagnostics, Medical University of Vienna (Austria); Moser, Ewald [MR Centre-of-Excellence, Department of Radiodiagnostics, Medical University of Vienna (Austria); Center for Biomedical Engineering and Physics, Medical University of Vienna (Austria); Ferenci, Peter [Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna (Austria); Roden, Michael, E-mail: michael.roden@ddz.uni-duesseldorf.d [Department of Internal Medicine III, Division of Endocrinology and Metabolism, Medical University of Vienna (Austria); Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center of Diabetes Research and Department of Medicine/Metabolic Diseases, Heinrich Heine University, Duesseldorf (Germany)

2010-06-15

Background: Liver biopsy is the standard method for diagnosis of hepatic steatosis, but is invasive and carries some risk of morbidity. Aims and methods: Quantification of hepatocellular lipid content (HCL) with non-invasive single voxel {sup 1}H magnetic resonance spectroscopy (MRS) at 3 T was compared with histological grading and biochemical analysis of liver biopsies in 29 patients with chronic hepatitis C. Body mass index, indices of insulin resistance (homeostasis model assessment index, HOMA-IR), serum lipids and serum liver transaminases were also quantified. Results: HCL as assessed by {sup 1}H MRS linearly correlated (r = 0.70, p < 0.001) with histological evaluation of liver biopsies and was in agreement with histological steatosis staging in 65% of the patients. Biochemically assessed hepatic triglyceride contents correlated with HCL measured with {sup 1}H MRS (r = 0.63, p < 0.03) and allowed discriminating between none or mild steatosis versus moderate or severe steatosis. Patients infected with hepatitis C virus genotype 3 had a higher prevalence of steatosis (62%) which was not explained by differences in body mass or whole body insulin resistance. When these patients were excluded from correlation analysis, hepatic fat accumulation positively correlated with insulin resistance in the remaining hepatitis C patients (HCL vs. HOMA-IR, r = 0.559, p < 0.020, n = 17). Conclusion: Localized {sup 1}H MRS is a valid and useful method for quantification of HCL content in patients with chronic hepatitis C and can be easily applied to non-invasively monitoring of steatosis during repeated follow-up measurements in a clinical setting.

Dried blood spots, valid screening for viral hepatitis and human immunodeficiency virus in real-life

DEFF Research Database (Denmark)

Mössner, Belinda K; Staugaard, Benjamin; Jensen, Janne

2016-01-01

AIM: To detect chronic hepatitis B (CHB), chronic hepatitis C (CHC) and human immunodeficiency virus (HIV) infections in dried blood spot (DBS) and compare these samples to venous blood sampling in real-life. METHODS: We included prospective patients with known viral infections from drug treatment......, but correctly classified 95% of the anti-HCV-positive patients with chronic and past infections. Anti-HBc and anti-HBS showed low sensitivity in DBS (68% and 42%). CONCLUSION: DBS sampling, combined with an automated analysis system, is a feasible screening method to diagnose chronic viral hepatitis and HIV...

Profile of Inflammation-associated genes during Hepatic Differentiation of Human Pluripotent Stem Cells

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Joseph Ignatius Irudayam

2015-12-01

Full Text Available Expression of genes associated with inflammation was analyzed during differentiation of human pluripotent stem cells (PSCs to hepatic cells. Messenger RNA transcript profiles of differentiated endoderm (day 5, hepatoblast (day 15 and hepatocyte-like cells (day 21 were obtained by RNA sequencing analysis. When compared to endoderm cells an immature cell type, the hepatic cells (days 15 and 21 had significantly higher expression of acute phase protein genes including complement factors, coagulation factors, serum amyloid A and serpins. Furthermore, hepatic phase of cells expressed proinflammatory cytokines IL18 and IL32 as well as cytokine receptors IL18R1, IL1R1, IL1RAP, IL2RG, IL6R, IL6ST and IL10RB. These cells also produced CCL14, CCL15, and CXCL- 1, 2, 3, 16 and 17 chemokines. Endoderm cells had higher levels of chemokine receptors, CXCR4 and CXCR7, than that of hepatic cells. Sirtuin family of genes involved in aging, inflammation and metabolism were differentially regulated in endoderm and hepatic phase cells. Ligands and receptors of the tumor necrosis factor (TNF family as well as downstream signaling factors TRAF2, TRAF4, FADD, NFKB1 and NFKBIB were differentially expressed during hepatic differentiation.

Triglycerides Test

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... 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 ...

Improved hepatic lipid composition following short-term exercise in nonalcoholic fatty liver disease

DEFF Research Database (Denmark)

Haus, Jacob M; Solomon, Thomas; Kelly, Karen R

2013-01-01

measures included hepatic triglyceride content, and a lipid saturation index and polyunsaturated lipid index (PUI) of the liver, obtained by 1H magnetic resonance spectroscopy (N = 14). Insulin sensitivity was estimated from an oral glucose tolerance test (OGTT), and mononuclear cells were isolated...... to assess reactive oxygen species production during the OGTT. Circulating glucose, insulin, and high molecular weight (HMW) adiponectin were determined from plasma. Main Outcome: Short-term aerobic exercise training improved hepatic lipid composition in patients with NAFLD. Results: Exercise training...... resulted in an increase in liver PUI (P Index: P

Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.

OpenAIRE

Zanger, U M; Hauri, H P; Loeper, J; Homberg, J C; Meyer, U A

1988-01-01

In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems...

An improved reference measurement procedure for triglycerides and total glycerides in human serum by isotope dilution gas chromatography-mass spectrometry.

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Chen, Yizhao; Liu, Qinde; Yong, Sharon; Teo, Hui Ling; Lee, Tong Kooi

2014-01-20

Triglycerides are widely tested in clinical laboratories using enzymatic methods for lipid profiling. As enzymatic methods can be affected by interferences from biological samples, this together with the non-specific nature of triglycerides measurement makes it necessary to verify the accuracy of the test results with a reference measurement procedure. Several such measurement procedures had been published. These procedures generally involved lengthy and laborious sample preparation steps. In this paper, an improved reference measurement procedure for triglycerides and total glycerides was reported which simplifies the sample preparation steps and greatly shortens the time taken. The procedure was based on isotope dilution gas chromatography-mass spectrometry (IDGC-MS)with tripalmitin as the calibration standard. Serum samples were first spiked with isotope-labeled tripalmitin. For the measurement of triglycerides, the serum samples were subjected to lipid extraction followed by separation of triglycerides from diglycerides and monoglycerides. Triglycerides were then hydrolyzed to glycerol, derivatized and injected into the GC–MS for quantification. For the measurement of total glycerides, the serum samples were hydrolyzed directly and derivatized before injection into the GC-MS for quantification. All measurement results showed good precision with CV triglycerides and total glycerides were well within the certified ranges of the CRM, with deviation triglycerides and total glycerides.

Effect of sulfonylureas on hepatic fatty acid oxidation

International Nuclear Information System (INIS)

Patel, T.B.

1986-01-01

In isolated rat livers perfused with oleic acid (0.1 mM), infusion of tolbutamide or glyburide decreased the rate of ketogenesis in a dose-dependent manner. The inhibition of fatty acid oxidation was maximal at 2.0 mM and 10 μM concentrations of tolbutamide and glyburide, respectively. Neither tolbutamide nor glyburide inhibited ketogenesis in livers perfused with octanoate. The inhibition of hepatic ketogenesis by sulfonylureas was independent of perfusate oleic acid concentration. Additionally, in rat livers perfused with oleic acid in the presence of L-(-)-carnitine (10 mM), submaximal concentrations of tolbutamide and glyburide did not inhibit hepatic ketogenesis. Finally, glyburide infusion into livers perfused with [U- 1 $C]oleic acid (0.1 mM) increased the rate of 14 C label incorporation into hepatic triglycerides by 2.5-fold. These data suggest that both tolbutamide and glyburide inhibit long-chain fatty acid oxidation by inhibition the key regulatory enzyme, carnitine palmitoyltransferase I, most probably by competing with L-(-)-carnitine

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

What Are High Blood Cholesterol and Triglycerides?

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... 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 ...

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

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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.

Three-Dimensional Culture of Human Embryonic Stem Cell Derived Hepatic Endoderm and Its Role in Bioartificial Liver Construction

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Ruchi Sharma

2010-01-01

Full Text Available The liver carries out a range of functions essential for bodily homeostasis. The impairment of liver functions has serious implications and is responsible for high rates of patient morbidity and mortality. Presently, liver transplantation remains the only effective treatment, but donor availability is a major limitation. Therefore, artificial and bioartificial liver devices have been developed to bridge patients to liver transplantation. Existing support devices improve hepatic encephalopathy to a certain extent; however their usage is associated with side effects. The major hindrance in the development of bioartificial liver devices and cellular therapies is the limited availability of human hepatocytes. Moreover, primary hepatocytes are difficult to maintain and lose hepatic identity and function over time even with sophisticated tissue culture media. To overcome this limitation, renewable cell sources are being explored. Human embryonic stem cells are one such cellular resource and have been shown to generate a reliable and reproducible supply of human hepatic endoderm. Therefore, the use of human embryonic stem cell-derived hepatic endoderm in combination with tissue engineering has the potential to pave the way for the development of novel bioartificial liver devices and predictive drug toxicity assays.

Coinfection of Hepatic Cell Lines with Human Immunodeficiency Virus and Hepatitis B Virus Leads to an Increase in Intracellular Hepatitis B Surface Antigen▿

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Iser, David M.; Warner, Nadia; Revill, Peter A.; Solomon, Ajantha; Wightman, Fiona; Saleh, Suha; Crane, Megan; Cameron, Paul U.; Bowden, Scott; Nguyen, Tin; Pereira, Cândida F.; Desmond, Paul V.; Locarnini, Stephen A.; Lewin, Sharon R.

2010-01-01

Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV. We infected human hepatic cell lines expressing HBV (Hep3B and AD38 cells) or not expressing HBV (Huh7, HepG2, and AD43 cells) with laboratory strains of HIV (NL4-3 and AD8), as well as a vesicular stomatitis virus (VSV)-pseudotyped HIV expressing enhanced green fluorescent protein (EGFP). Following HIV infection with NL4-3 or AD8 in hepatic cell lines, we observed a significant increase in HIV reverse transcriptase activity which was infectious. Despite no detection of surface CD4, CCR5, and CXCR4 by flow cytometry, AD8 infection of AD38 cells was inhibited by maraviroc and NL4-3 was inhibited by AMD3100, demonstrating that HIV enters AD38 hepatic cell lines via CCR5 or CXCR4. High-level infection of AD38 cells (50%) was achieved using VSV-pseudotyped HIV. Coinfection of the AD38 cell line with HIV did not alter the HBV DNA amount or species as determined by Southern blotting or nucleic acid signal amplification. However, coinfection with HIV was associated with a significant increase in intracellular HBsAg when measured by Western blotting, quantitative HBsAg, and fluorescence microscopy. We conclude that HIV infection of HBV-infected hepatic cell lines significantly increased intracellular HBsAg but not HBV DNA synthesis and that increased intrahepatic HBsAg secondary to direct infection by HIV may contribute to accelerated liver disease in HIV-HBV-coinfected individuals. PMID:20357083

Coinfection of hepatic cell lines with human immunodeficiency virus and hepatitis B virus leads to an increase in intracellular hepatitis B surface antigen.

Science.gov (United States)

Iser, David M; Warner, Nadia; Revill, Peter A; Solomon, Ajantha; Wightman, Fiona; Saleh, Suha; Crane, Megan; Cameron, Paul U; Bowden, Scott; Nguyen, Tin; Pereira, Cândida F; Desmond, Paul V; Locarnini, Stephen A; Lewin, Sharon R

2010-06-01

Liver-related mortality is increased in the setting of HIV-hepatitis B virus (HBV) coinfection. However, interactions between HIV and HBV to explain this observation have not been described. We hypothesized that HIV infection of hepatocytes directly affects the life cycle of HBV. We infected human hepatic cell lines expressing HBV (Hep3B and AD38 cells) or not expressing HBV (Huh7, HepG2, and AD43 cells) with laboratory strains of HIV (NL4-3 and AD8), as well as a vesicular stomatitis virus (VSV)-pseudotyped HIV expressing enhanced green fluorescent protein (EGFP). Following HIV infection with NL4-3 or AD8 in hepatic cell lines, we observed a significant increase in HIV reverse transcriptase activity which was infectious. Despite no detection of surface CD4, CCR5, and CXCR4 by flow cytometry, AD8 infection of AD38 cells was inhibited by maraviroc and NL4-3 was inhibited by AMD3100, demonstrating that HIV enters AD38 hepatic cell lines via CCR5 or CXCR4. High-level infection of AD38 cells (50%) was achieved using VSV-pseudotyped HIV. Coinfection of the AD38 cell line with HIV did not alter the HBV DNA amount or species as determined by Southern blotting or nucleic acid signal amplification. However, coinfection with HIV was associated with a significant increase in intracellular HBsAg when measured by Western blotting, quantitative HBsAg, and fluorescence microscopy. We conclude that HIV infection of HBV-infected hepatic cell lines significantly increased intracellular HBsAg but not HBV DNA synthesis and that increased intrahepatic HBsAg secondary to direct infection by HIV may contribute to accelerated liver disease in HIV-HBV-coinfected individuals.

Hepatic Fatty Acid Oxidation Restrains Systemic Catabolism during Starvation

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Jieun Lee

2016-06-01

Full Text Available The liver is critical for maintaining systemic energy balance during starvation. To understand the role of hepatic fatty acid β-oxidation on this process, we generated mice with a liver-specific knockout of carnitine palmitoyltransferase 2 (Cpt2L−/−, an obligate step in mitochondrial long-chain fatty acid β-oxidation. Fasting induced hepatic steatosis and serum dyslipidemia with an absence of circulating ketones, while blood glucose remained normal. Systemic energy homeostasis was largely maintained in fasting Cpt2L−/− mice by adaptations in hepatic and systemic oxidative gene expression mediated in part by Pparα target genes including procatabolic hepatokines Fgf21, Gdf15, and Igfbp1. Feeding a ketogenic diet to Cpt2L−/− mice resulted in severe hepatomegaly, liver damage, and death with a complete absence of adipose triglyceride stores. These data show that hepatic fatty acid oxidation is not required for survival during acute food deprivation but essential for constraining adipocyte lipolysis and regulating systemic catabolism when glucose is limiting.

Hepatitis C Virus, Cholesterol and Lipoproteins — Impact for the Viral Life Cycle and Pathogenesis of Liver Disease

Science.gov (United States)

Felmlee, Daniel J.; Hafirassou, Mohamed Lamine; Lefevre, Mathieu; Baumert, Thomas F.; Schuster, Catherine

2013-01-01

Hepatitis C virus (HCV) is a leading cause of chronic liver disease, including chronic hepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. Hepatitis C infection associates with lipid and lipoprotein metabolism disorders such as hepatic steatosis, hypobetalipoproteinemia, and hypocholesterolemia. Furthermore, virus production is dependent on hepatic very-low-density lipoprotein (VLDL) assembly, and circulating virions are physically associated with lipoproteins in complexes termed lipoviral particles. Evidence has indicated several functional roles for the formation of these complexes, including co-opting of lipoprotein receptors for attachment and entry, concealing epitopes to facilitate immune escape, and hijacking host factors for HCV maturation and secretion. Here, we review the evidence surrounding pathogenesis of the hepatitis C infection regarding lipoprotein engagement, cholesterol and triglyceride regulation, and the molecular mechanisms underlying these effects. PMID:23698400

Comparative Pathology of Hepatitis A Virus and Hepatitis E Virus Infection.

Science.gov (United States)

Cullen, John M; Lemon, Stanley M

2018-04-30

Hepatitis A virus (HAV) and hepatitis E virus (HEV) cause acute, self-limiting hepatic infections that are usually spread by the fecal-oral route in humans. Naturally occurring and experimental infections are possible in a variety of nonhuman primates and, in the case of HEV, a number of other species. Many advances in understanding the pathogenesis of these viruses have come from studies in experimental animals. In general, animals infected with these viruses recapitulate the histologic lesions seen in infected humans, but typically with less severe clinical and histopathological manifestations. This review describes the histopathologic changes associated with HAV and HEV infection in humans and experimental animals. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Occurrence of water-borne enteric viruses in two settlements based in Eastern Chad: analysis of hepatitis E virus, hepatitis A virus and human adenovirus in water sources.

Science.gov (United States)

Guerrero-Latorre, Laura; Carratala, Anna; Rodriguez-Manzano, Jesus; Calgua, Byron; Hundesa, Ayalkibet; Girones, Rosina

2011-09-01

Hepatitis E virus (HEV) is a common cause of water-borne acute hepatitis in areas with poor sanitation. In 2004 an outbreak of HEV infection affected around 2,000 people in Eastern Chad (Dar Sila). This paper describes the decrease in the incidence of acute jaundice syndrome (AJS) from 2004 until 2009 when a mean incidence of 0.48 cases/1,000 people/year was recorded in the region. Outbreaks of AJS were identified in some of the camps in 2007 and 2008. Moreover, water samples from drinking water sources were screened for human adenoviruses considered as viral indicators and for hepatitis A virus and HEV. Screening of faecal samples from donkeys for HEV gave negative results. Some of the samples were also analysed for faecal coliforms showing values before disinfection treatment between 3 and >50 colony forming units per 100 mL. All water samples tested were negative for HEV and HAV; however, the presence of low levels of human adenoviruses in 4 out of 16 samples analysed indicates possible human faecal contamination of groundwater. Consequently, breakdowns in the treatment of drinking water and/or increased excretion of hepatitis viruses, which could be related to the arrival of a new population, could spread future outbreaks through drinking water.

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

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

Hepatic Aryl hydrocarbon Receptor Nuclear Translocator (ARNT regulates metabolism in mice.

Directory of Open Access Journals (Sweden)

Christopher H Scott

Full Text Available Aryl hydrocarbon Receptor Nuclear Translocator (ARNT and its partners hypoxia-inducible factors (HIF-1α and HIF-2α are candidate factors for the well-known link between the liver, metabolic dysfunction and elevation in circulating lipids and glucose. Methods: Hepatocyte-specific ARNT-null (LARNT, HIF-1α-null (LHIF1α and HIF-2α-null (LHIF2α mice were created.LARNT mice had increased fasting glucose, impaired glucose tolerance, increased glucose production, raised post-prandial serum triglycerides (TG and markedly lower hepatic ATP versus littermate controls. There was increased expression of G6Pase, Chrebp, Fas and Scd-1 mRNAs in LARNT animals. Surprisingly, LHIF1α and LHIF2α mice exhibited no alterations in any metabolic parameter assessed.These results provide convincing evidence that reduced hepatic ARNT can contribute to inappropriate hepatic glucose production and post-prandial dyslipidaemia. Hepatic ARNT may be a novel therapeutic target for improving post-prandial hypertriglyceridemia and glucose homeostasis.

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...

Human hepatic carbohydrate metabolism. Dynamic observation using 13C MRS without proton decoupling

International Nuclear Information System (INIS)

Ikehira, H.; Obata, T.; Koga, M.; Yoshida, K.

1997-01-01

Purpose: Dynamic natural-abundance 13 C MR spectroscopy (MRS) studies without proton decoupling were performed in the human liver using commercial 1.5 T MR equipment. Material and methods: A single tuned custom-made circular surface coil with an OD of 20 cm operating at 16.04 MHz was used for the 13 C study. Seventy-five grams of glucose dissolved in water was administered for the natural-abundance 13 C-MRS dynamic study which lasted for approximately 40 to 60 min. Data acquisition was broken into 20-min and 1.7-min blocks. Localized proton shimming with a whole-body coil was performed with sufficient volume to include the observing area of the surface coil; the line width of the water signal was less than 20 Hz. Results and Conclusion: The glucose and glycogen spectra were clearly visible at 80 to 120 ppm after oral administration of the glucose solution. These data demonstrate that dynamic hepatic carbohydrate metabolism can be observed with commercially available MR equipment. Given that the human hepatic glycogen pool reaches maximum level within less than 10 min, this technique should provide a direct diagnosis of hepatic carbohydrate metabolic disorders. (orig.)

Recent Advances in the Assessment of Hepatic Steatosis

Directory of Open Access Journals (Sweden)

V.I. Didenko

2015-09-01

Full Text Available The article deals with a review of scientific works on the issue of hepatic steatosis verification. Nowadays, the problem of timely detection and treatment of chronic diffuse liver diseases, in the pathogenesis of which fibrosis and hepatic steatosis play key role, becomes more and more important. It is recognized that hepatic steatosis is characterized by the accumulation of lipids in hepatocytes exceeding 5 % of the liver mass. In recent years, special attention is paid to the methods for verification of hepatic steatosis, which can be divided into invasive, minimally invasive and non-invasive. Invasive methods are still relevant, they include liver core needle biopsy — the gold standard. Minimally invasive methods for hepatic steatosis verification are based on the biochemical study of venous blood. Minimally invasive methods can be conditionally divided into routine — triglycerides, total cholesterol, high density lipoproteins etc., and calculated coefficients: SteatoTest and others. Their results are calculated on the basis of several indicators. Non-invasive methods of verification include: ultrasound, computed tomography, magnetic resonance imaging, elastometry with CAP™function (Fibroscan, model 502. In our opinion, for verification of hepatic steatosis, it is promising to use the ultrasound with the option of measuring the parameters of arterial stiffness in the WТrack mode. Among the non-invasive methods of hepatic steatosis verification, liver elastometry using FibroScan-502-touch device with CAP™ function made a breakthrough in some specific sense. Opening possibilities for early detection of hepatic steatosis enable to place on timely preventive and therapeutic measures and to create the conditions for stopping the progression, and possibly for the regression of hepatic steatosis.

Hepatic Disposition of Gemfibrozil and Its Major Metabolite Gemfibrozil 1-O-β-Glucuronide.

Science.gov (United States)

Kimoto, Emi; Li, Rui; Scialis, Renato J; Lai, Yurong; Varma, Manthena V S

2015-11-02

Gemfibrozil (GEM), which decreases serum triglycerides and low density lipoprotein, perpetrates drug-drug interactions (DDIs) with several drugs. These DDIs are primarily attributed to the inhibition of drug transporters and metabolic enzymes, particularly cytochrome P450 (CYP) 2C8 by the major circulating metabolite gemfibrozil 1-O-β-glucuronide (GG). Here, we characterized the transporter-mediated hepatic disposition of GEM and GG using sandwich-cultured human hepatocytes (SCHH) and transporter-transfect systems. Significant active uptake was noted in SCHH for the metabolite. GG, but not GEM, showed substrate affinity to organic anion transporting polypeptide (OATP) 1B1, 1B3, and 2B1. In SCHH, glucuronidation was characterized affinity constants (Km) of 7.9 and 61.4 μM, and biliary excretion of GG was observed. Furthermore, GG showed active basolateral efflux from preloaded SCHH and ATP-dependent uptake into membrane vesicles overexpressing multidrug resistance-associated protein (MRP) 2, MRP3, and MRP4. A mathematical model was developed to estimate hepatic uptake and efflux kinetics of GEM and GG based on SCHH studies. Collectively, the hepatic transporters play a key role in the disposition and thus determine the local concentrations of GEM and more so for GG, which is the predominant inhibitory species against CYP2C8 and OATP1B1.

Kupffer cells promote hepatic steatosis via interleukin-1-dependent suppression of peroxisome proliferator-activated receptor activity

NARCIS (Netherlands)

Stienstra, R.; Saudale, F.; Duval, C.N.C.; Keshtkar, S.; Groener, C.; Rooijen, van N.; Staels, B.; Kersten, A.H.; Müller, M.R.

2010-01-01

Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to

Prevalence of nucleic acid sequences specific for human parvoviruses, hepatitis A and hepatitis E viruses in coagulation factor concentrates.

Science.gov (United States)

Modrow, S; Wenzel, J J; Schimanski, S; Schwarzbeck, J; Rothe, U; Oldenburg, J; Jilg, W; Eis-Hübinger, A M

2011-05-01

Due to their high resistance to inactivation procedures, nonenveloped viruses such as parvovirus B19, human bocavirus (HBoV), human parvovirus 4 (PARV4), hepatitis A (HAV) and hepatitis E virus (HEV) pose a particular threat to blood products. Virus transmission to patients treated with blood products presents an additional burden to disease. We determined the frequency and the amount of nucleic acid specific for nonenveloped viruses in recently manufactured preparations of commercial coagulation factor concentrates. At least three different batches of each of 13 different plasma-derived and recombinant coagulation factor products were tested for the presence and the amount of nucleic acid for parvovirus B19, HBoV, human parvovirus 4, hepatitis A virus and HEV by using quantitative polymerase chain reaction. Whereas none of the recombinant products tested positive for any of these viruses, parvovirus B19 DNA with amounts ranging between 2×10(1) and 1.3×10(3) genome equivalents/ml was detected in five plasma-derived products. In addition to parvovirus B19 genotype 1, genotypes 2 and 3 were observed in two batches of a factor VIII/von-Willebrand factor product. In two products (one factor VIII concentrate and one activated prothrombin complex concentrate), a combination of both genotypes 1 and 2 of parvovirus B19 was detected. The data show that nucleic acids from several relevant nonenveloped viruses are not found at detectable levels in coagulation factor concentrates. In some cases, parvovirus B19 DNA was detectable at low levels. Testing of the plasma pools for the full range of parvovirus genotypes is advocated for ensuring product safety. © 2010 The Author(s). Vox Sanguinis © 2010 International Society of Blood Transfusion.

Effect of neoadjuvant chemotherapy in hepatic steatosis.

Science.gov (United States)

Jiménez, Raúl; Hijona, Elizabeth; Emparanza, José; Alústiza, Jose M; Hijona, Lander; Macarulla, Maria T; Portillo, Maria P; Herreros-Villanueva, Marta; Beguiristain, Adolfo; Arenas, Juan; Bujanda, Luis

2012-01-01

Chemotherapy drugs often produce side effects in the liver. In recent years, there has been speculation about the ability to produce hepatic steatosis in patients treated with 5-fluorouracil and oxaliplatin. This prospective study examines whether these drugs can produce steatosis in patients with neoadjuvant treatment who were operated on for liver tumors. Our objective was to assess the effect of neoadjuvant chemotherapy (NAC) on the development of hepatic steatosis in the healthy liver. This was a prospective study based on 32 patients divided into two groups. The presence of steatosis was assessed using a histological score (Kleiner classification) and a biochemical method (Folch method) for patients from both groups. A total of 14 patients (44%) had hepatic steatosis and half of these were in each group. The steatosis was moderate to severe (grades 2-3) in 4 patients (13%), 2 in each group. The mean levels of triglycerides in the liver were 33.38 and 29.94 mg/g in group I and group II, respectively, with the difference not being statistically significant. Almost half of the patients treated with NAC for liver neoplasia developed steatosis. Nevertheless, NAC does not seem to increase the risk of hepatic steatosis. Copyright © 2012 S. Karger AG, Basel.

Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease

Science.gov (United States)

2014-01-01

Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (Ptriglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.) PMID:24941081

Correlation between the dielectric properties and biological activities of human ex vivo hepatic tissue

International Nuclear Information System (INIS)

Wang, Hang; You, Fusheng; Fu, Feng; Dong, Xiuzhen; Shi, Xuetao; He, Yong; Yang, Min; Yan, Qingguo

2015-01-01

Dielectric properties are vital biophysical features of biological tissues, and biological activity is an index to ascertain the active state of tissues. This study investigated the potential correlation between the dielectric properties and biological activities of human hepatic tissue with prolonged ex vivo time through correlation and regression analyses. The dielectric properties of 26 cases of normal human hepatic tissue at 10 Hz to 100 MHz were measured from 15 min after isolation to 24 h at 37 °C with 90% humidity. Cell morphologies, including nucleus area (NA) and alteration rate of intercellular area (ICAR), were analyzed as indicators of biological activities. Conductivity, complex resistivity, and NA exhibited opposing changes 1 h after isolation. Relative permittivity and ex vivo time were not closely correlated (p > 0.05). The dielectric properties measured at low frequencies (i.e. <1 MHz) were more sensitive than those measured at high frequencies in reflecting the biological activity of ex vivo tissue. Highly significant correlations were found between conductivity, resistivity and the ex vivo time (p < 0.05) as well as conductivity and the cell morphology (p < 0.05). The findings indicated that establishing the correlation between the dielectric properties and biological activities of human hepatic tissue is of great significance for promoting the role of dielectric properties in biological science, particularly in human biology. (paper)

Using Bovine Viral Diarrhea Virus (BVDV) As Surrogate for Human Hepatitis C Virus

Science.gov (United States)

This test is designed to validate virucidal effectiveness claims for a product to be registered as a virucide. It determines the potential of the test agent to disinfect hard surfaces contaminated with human Hepatitis C virus (HCV).

PGC-1α in the exercise training-mediated regulation of hepatic UPR in mice

DEFF Research Database (Denmark)

Maag Kristensen, Caroline

not be elucidated, because exercise training only had minor effects in the control mice. Study II demonstrated that aging mice had elevated hepatic triglyceride content, a tendency for increased BiP protein, decreased PERK protein content as well as increased IRE1α and cleaved ATF6 protein level in the liver...

Antibodies against human cytochrome P-450db1 in autoimmune hepatitis type II.

Science.gov (United States)

Zanger, U M; Hauri, H P; Loeper, J; Homberg, J C; Meyer, U A

1988-11-01

In a subgroup of children with chronic active hepatitis, circulating autoantibodies occur that bind to liver and kidney endoplasmic reticulum (anti-liver/kidney microsome antibody type I or anti-LKM1). Anti-LKM1 titers follow the severity of the disease and the presence of these antibodies serves as a diagnostic marker for this autoimmune hepatitis type II. We demonstrate that anti-LKM1 IgGs specifically inhibit the hydroxylation of bufuralol in human liver microsomes. Using two assay systems with different selectivity for the two cytochrome P-450 isozymes catalyzing bufuralol metabolism in human liver, we show that anti-LKM1 exclusively recognizes cytochrome P-450db1. Immunopurification of the LKM1 antigen from solubilized human liver microsomes resulted in an electrophoretically homogenous protein that had the same molecular mass (50 kDa) as purified P-450db1 and an identical N-terminal amino acid sequence. Recognition of both purified P-450db1 and the immunoisolated protein on western blots by several monoclonal antibodies confirmed the identity of the LKM1 antigen with cytochrome P-450db1. Cytochrome P-450db1 has been identified as the target of a common genetic polymorphism of drug oxidation. However, the relationship between the polymorphic cytochrome P-450db1 and the appearance of anti-LKM1 autoantibodies as well as their role in the pathogenesis of chronic active hepatitis remains speculative.

Human Sterol Regulatory Element-Binding Protein 1a Contributes Significantly to Hepatic Lipogenic Gene Expression

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Andreas Bitter

2015-01-01

Full Text Available Background/Aims: Sterol regulatory element-binding protein (SREBP 1, the master regulator of lipogenesis, was shown to be associated with non-alcoholic fatty liver disease, which is attributed to its major isoform SREBP1c. Based on studies in mice, the minor isoform SREBP1a is regarded as negligible for hepatic lipogenesis. This study aims to elucidate the expression and functional role of SREBP1a in human liver. Methods: mRNA expression of both isoforms was quantified in cohorts of human livers and primary human hepatocytes. Hepatocytes were treated with PF-429242 to inhibit the proteolytic activation of SREBP precursor protein. SREBP1a-specifc and pan-SREBP1 knock-down were performed by transfection of respective siRNAs. Lipogenic SREBP-target gene expression was analyzed by real-time RT-PCR. Results: In human liver, SREBP1a accounts for up to half of the total SREBP1 pool. Treatment with PF-429242 indicated SREBP-dependent auto-regulation of SREBP1a, which however was much weaker than of SREBP1c. SREBP1a-specifc knock-down also reduced significantly the expression of SREBP1c and of SREBP-target genes. Regarding most SREBP-target genes, simultaneous knock-down of both isoforms resulted in effects of only similar extent as SREBP1a-specific knock-down. Conclusion: We here showed that SREBP1a is significantly contributing to the human hepatic SREBP1 pool and has a share in human hepatic lipogenic gene expression.

Whole-Body and Hepatic Insulin Resistance in Obese Children

Science.gov (United States)

Ibarra-Reynoso, Lorena del Rocío; Pisarchyk, Liudmila; Pérez-Luque, Elva Leticia; Garay-Sevilla, Ma. Eugenia; Malacara, Juan Manuel

2014-01-01

Background Insulin resistance may be assessed as whole body or hepatic. Objective To study factors associated with both types of insulin resistance. Methods Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother's BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver. Conclusion In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance. PMID:25411786

Peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus

DEFF Research Database (Denmark)

Gluud, Lise Lotte; Marchesini, Emanuela; Iorio, Alfonso

2009-01-01

OBJECTIVES: The aim of this study was to assess the effects of peginterferon plus ribavirin for chronic hepatitis C in patients with human immunodeficiency virus (HIV). METHODS: Trials were identified through manual and electronic searches. Randomized trials comparing peginterferon plus ribavirin...... with other antiviral treatments for patients with chronic hepatitis C and HIV were included. The primary outcome measure was virological response at the end of treatment and after > or =6 months (sustained). Intention-to-treat meta-analyses including data on all patients who were randomized were carried out....... RESULTS: Seven randomized trials were eligible for inclusion. The patients included had chronic hepatitis C and stable HIV and were not previously treated with interferon or ribavirin (treatment naive). The mean dosages were 180 or 1.5 microg/kg once weekly for peginterferon and 800 mg daily for ribavirin...

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...

Association Between Serum Triglycerides and Cerebral Amyloidosis in Cognitively Normal Elderly.

Science.gov (United States)

Choi, Hyo Jung; Byun, Min Soo; Yi, Dahyun; Choe, Young Min; Sohn, Bo Kyung; Baek, Hye Won; Lee, Jun Ho; Kim, Hyun Jung; Han, Ji Young; Yoon, Eun Jin; Kim, Yu Kyeong; Woo, Jong Inn; Lee, Dong Young

2016-08-01

Although many preclinical studies have suggested the possible linkage between dyslipidemia and cerebral amyloid deposition, the association between serum lipid measures and cerebral amyloid-beta (Aβ) deposition in human brain is still poorly known. We aimed to investigate the association in cognitively normal (CN) elderly individuals. Cross-sectional study. University hospital dementia clinic. 59 CN elderly. The study measures included comprehensive clinical and neuropsychological assessment based on the CERAD protocol, magnetic resonance imaging and (11)C-labelled Pittsburgh Compound B positron emission tomography scans, and quantification for serum lipid biomarkers. Multiple linear regression analyses showed that a higher serum triglycerides level was associated with heavier global cerebral Aβ deposition even after controlling age, sex, and apolipoprotein E ε4 genotype. Serum apolipoprotein B also showed significant positive association with global cerebral Aβ deposition, but the significance disappeared after controlling serum triglycerides level. No association was found between other lipid measures and global cerebral Aβ deposition. The findings suggest that serum triglycerides are closely associated with cerebral amyloidosis, although population-based prospective studies are needed to provide further evidence of the causative effect of triglycerides on cerebral amyloidosis. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

Peroxisomal abnormalities in the immortalized human hepatocyte (IHH) cell line.

Science.gov (United States)

Klouwer, Femke C C; Koster, Janet; Ferdinandusse, Sacha; Waterham, Hans R

2017-04-01

The immortalized human hepatocyte (IHH) cell line is increasingly used for studies related to liver metabolism, including hepatic glucose, lipid, lipoprotein and triglyceride metabolism, and the effect of therapeutic interventions. To determine whether the IHH cell line is a good model to investigate hepatic peroxisomal metabolism, we measured several peroxisomal parameters in IHH cells and, for comparison, HepG2 cells and primary skin fibroblasts. This revealed a marked plasmalogen deficiency and a deficient fatty acid α-oxidation in the IHH cells, due to a defect of PEX7, a cytosolic receptor protein required for peroxisomal import of a subset of peroxisomal proteins. These abnormalities have consequences for the lipid homeostasis of these cells and thus should be taken into account for the interpretation of data previously generated by using this cell line and when considering using this cell line for future research.

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 ...

Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

International Nuclear Information System (INIS)

Winkler, Sandra; Borkham-Kamphorst, Erawan; Stock, Peggy; Brückner, Sandra; Dollinger, Matthias; Weiskirchen, Ralf; Christ, Bruno

2014-01-01

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH

Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

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Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de [Department for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig (Germany)

2014-08-15

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.

Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

Science.gov (United States)

Softic, Samir; Gupta, Manoj K; Wang, Guo-Xiao; Fujisaka, Shiho; O'Neill, Brian T; Rao, Tata Nageswara; Willoughby, Jennifer; Harbison, Carole; Fitzgerald, Kevin; Ilkayeva, Olga; Newgard, Christopher B; Cohen, David E; Kahn, C Ronald

2017-11-01

Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

Calorie Restricted High Protein Diets Downregulate Lipogenesis and Lower Intrahepatic Triglyceride Concentrations in Male Rats

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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.

Therapeutic role of niacin in the prevention and regression of hepatic steatosis in rat model of nonalcoholic fatty liver disease.

Science.gov (United States)

Ganji, Shobha H; Kukes, Gary D; Lambrecht, Nils; Kashyap, Moti L; Kamanna, Vaijinath S

2014-02-15

Nonalcoholic fatty liver disease (NAFLD), a leading cause of liver damage, comprises a spectrum of liver abnormalities including the early fat deposition in the liver (hepatic steatosis) and advanced nonalcoholic steatohepatitis. Niacin decreases plasma triglycerides, but its effect on hepatic steatosis is elusive. To examine the effect of niacin on steatosis, rats were fed either a rodent normal chow, chow containing high fat (HF), or HF containing 0.5% or 1.0% niacin in the diet for 4 wk. For regression studies, rats were first fed the HF diet for 6 wk to induce hepatic steatosis and were then treated with niacin (0.5% in the diet) while on the HF diet for 6 wk. The findings indicated that inclusion of niacin at 0.5% and 1.0% doses in the HF diet significantly decreased liver fat content, liver weight, hepatic oxidative products, and prevented hepatic steatosis. Niacin treatment to rats with preexisting hepatic steatosis induced by the HF diet significantly regressed steatosis. Niacin had no effect on the mRNA expression of fatty acid synthesis or oxidation genes (including sterol-regulatory element-binding protein 1, acetyl-CoA carboxylase 1, fatty acid synthase, and carnitine palmitoyltransferase 1) but significantly inhibited mRNA levels, protein expression, and activity of diacylglycerol acyltrasferase 2, a key enzyme in triglyceride synthesis. These novel findings suggest that niacin effectively prevents and causes the regression of experimental hepatic steatosis. Approved niacin formulation(s) for other indications or niacin analogs may offer a very cost-effective opportunity for the clinical development of niacin for treating NAFLD and fatty liver disease.

PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

DEFF Research Database (Denmark)

Bezy, Olivier; Tran, Thien T; Pihlajamäki, Jussi

2011-01-01

C57BL/6J and 129S6/Sv (B6 and 129) mice differ dramatically in their susceptibility to developing diabetes in response to diet- or genetically induced insulin resistance. A major locus contributing to this difference has been mapped to a region on mouse chromosome 14 that contains the gene encoding...... tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation...... of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome....

Changes of very low-density lipoprotein concentration in hepatic blood from cows with fasting-induced hepatic lipidosis.

Science.gov (United States)

Oikawa, Shin; Mizunuma, Yuko; Iwasaki, Yukari; Tharwat, Mohamed

2010-10-01

The purpose of this study was to evaluate changes of very low-density lipoprotein (VLDL) components in hepatic blood (HB) from 5 nonlactating nonpregnant cows fasted from days 0 to 3 and subsequently refed to day 10 and, in addition, to assess those of other lipoproteins. Increased phospholipid concentrations in each lipoprotein after the start of fasting suggested their availability for the surface lipids of lipoproteins. Although the VLDL-triglyceride (TG) concentration in HB from all cows increased on day 1, the value on day 4 became similar to that on day 0. However, the concentration on day 10 was significantly increased. In all cows, the decreased ratio of the VLDL-TG concentration in HB to the non-esterified fatty acids (NEFA) concentration in portal blood (PB) on day 4 appeared to reflect relatively decreased secretion of TG as VLDL by NEFA excessively mobilized to the liver via PB. The markedly increased ratio on day 10 was considered to contribute to the improvement of hepatic lipidosis.

ABHD5/CGI-58, the Chanarin-Dorfman Syndrome Protein, Mobilises Lipid Stores for Hepatitis C Virus Production.

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Gabrielle Vieyres

2016-04-01

Full Text Available Hepatitis C virus (HCV particles closely mimic human very-low-density lipoproteins (VLDL to evade humoral immunity and to facilitate cell entry. However, the principles that govern HCV association with VLDL components are poorly defined. Using an siRNA screen, we identified ABHD5 (α/β hydrolase domain containing protein 5, also known as CGI-58 as a new host factor promoting both virus assembly and release. ABHD5 associated with lipid droplets and triggered their hydrolysis. Importantly, ABHD5 Chanarin-Dorfman syndrome mutants responsible for a rare lipid storage disorder in humans were mislocalised, and unable to consume lipid droplets or support HCV production. Additional ABHD5 mutagenesis revealed a novel tribasic motif that does not influence subcellular localization but determines both ABHD5 lipolytic and proviral properties. These results indicate that HCV taps into the lipid droplet triglyceride reservoir usurping ABHD5 lipase cofactor function. They also suggest that the resulting lipid flux, normally devoted to VLDL synthesis, also participates in the assembly and release of the HCV lipo-viro-particle. Altogether, our study provides the first association between the Chanarin-Dorfman syndrome protein and an infectious disease and sheds light on the hepatic manifestations of this rare genetic disorder as well as on HCV morphogenesis.

Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

International Nuclear Information System (INIS)

Pols, Thijs W.H.; Ottenhoff, Roelof; Vos, Mariska; Levels, Johannes H.M.; Quax, Paul H.A.; Meijers, Joost C.M.; Pannekoek, Hans; Groen, Albert K.; Vries, Carlie J.M. de

2008-01-01

NR4A nuclear receptors are induced in the liver upon fasting and regulate hepatic gluconeogenesis. Here, we studied the role of nuclear receptor Nur77 (NR4A1) in hepatic lipid metabolism. We generated mice expressing hepatic Nur77 using adenoviral vectors, and demonstrate that these mice exhibit a modulation of the plasma lipid profile and a reduction in hepatic triglyceride. Expression analysis of >25 key genes involved in lipid metabolism revealed that Nur77 inhibits SREBP1c expression. This results in decreased SREBP1c activity as is illustrated by reduced expression of its target genes stearoyl-coA desaturase-1, mitochondrial glycerol-3-phosphate acyltransferase, fatty acid synthase and the LDL receptor, and provides a mechanism for the physiological changes observed in response to Nur77. Expression of LXR target genes Abcg5 and Abcg8 is reduced by Nur77, and may suggest involvement of LXR in the inhibitory action of Nur77 on SREBP1c expression. Taken together, our study demonstrates that Nur77 modulates hepatic lipid metabolism through suppression of SREBP1c activity

Kupffer cells promote hepatic steatosis via interleukin-1beta-dependent suppression of peroxisome proliferator-activated receptor alpha activity

NARCIS (Netherlands)

Stienstra, Rinke; Saudale, Fredy; Duval, Caroline; Keshtkar, Shohreh; Groener, Johanna E. M.; van Rooijen, Nico; Staels, Bart; Kersten, Sander; Müller, Michael

2010-01-01

Kupffer cells have been implicated in the pathogenesis of various liver diseases. However, their involvement in metabolic disorders of the liver, including fatty liver disease, remains unclear. The present study sought to determine the impact of Kupffer cells on hepatic triglyceride storage and to

Lipids in hepatic glycogen storage diseases: pathophysiology, monitoring of dietary management and future directions.

Science.gov (United States)

Derks, Terry G J; van Rijn, Margreet

2015-05-01

Hepatic glycogen storage diseases (GSD) underscore the intimate relationship between carbohydrate and lipid metabolism. The hyperlipidemias in hepatic GSD reflect perturbed intracellular metabolism, providing biomarkers in blood to monitor dietary management. In different types of GSD, hyperlipidemias are of a different origin. Hypertriglyceridemia is most prominent in GSD type Ia and associated with long-term outcome morbidity, like pancreatitis and hepatic adenomas. In the ketotic subtypes of GSD, hypertriglyceridemia reflects the age-dependent fasting intolerance, secondary lipolysis and increased mitochondrial fatty acid oxidation. The role of high protein diets is established for ketotic types of GSD, but non-traditional dietary interventions (like medium-chain triglycerides and the ketogenic diet) in hepatic GSD are still controversial and necessitate further studies. Patients with these rare inherited disorders of carbohydrate metabolism meet several criteria of the metabolic syndrome, therefore close monitoring for cardiovascular diseases in ageing GSD patients may be justified.

Clinical significance of measurement of plasma homocysteine (Hcy) levels in patients with hepatic cirrhosis

International Nuclear Information System (INIS)

Wu Jiaming

2006-01-01

Objective: To investigate the correlationship between the plasma homocysteine (Hcy) levels and development of hepatic cirrhosis as well as the diagnostic value of plasma Hcy determination. Method: Plasma Hcy levels were measured with ELISA in: (1) 64 patients with post-hepatitis cirrhosis (2) 42 patients with various types of hepatitis but no cirrhosis and (3) 60 controls. Results: The plasma levels of Hcy in patients with cirrhosis were significantly higher than those in the other two groups (P<0.01). The plasma Hcy levels in cirrhotic patients were well correlated with the levels of other hepatic fibrosis markers such as hyaluronic acid and laminin (r=0.87 and r=0.88 respectively, P<0.01), but were not correlated with cholesterol, triglyceride and HDL levels. Conclusion: Plasma Hcy levels was markedly elevated in cirrhotic patients and might be taken as a diagnostic marker. (authors)

Transfusion-associated hepatitis before the screening of blood for hepatitis risk factors

DEFF Research Database (Denmark)

Engle, Ronald E; Bukh, Jens; Alter, Harvey J

2014-01-01

%) with HBV alone, and one (3%) with both viruses. Overall, 100% of patients with hepatitis and 39% of those without hepatitis were infected with HBV and/or HCV; one patient was also infected with hepatitis E virus. The donor carrier rate for HBV and/or HCV was estimated to be more than 6%; contemporaneously......%) developed biochemical evidence of hepatitis; of these, 20 (67%) were infected with hepatitis C virus (HCV) alone, four (13%) with hepatitis B virus (HBV) alone, and six (20%) with both viruses. Among the 36 patients who did not develop hepatitis, four (11%) were newly infected with HCV alone, nine (25...... prepared pooled normal human plasma was also contaminated with multiple hepatitis viruses. CONCLUSION: TAH virus infections were a larger problem than perceived 50 years ago and HCV was the predominant agent transmitted. All hepatitis cases could be attributed to HCV and/or HBV and hence...

[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...

The participation of human hepatic P450 isoforms, flavin-containing monooxygenases and aldehyde oxidase in the biotransformation of the insecticide fenthion

International Nuclear Information System (INIS)

Leoni, Claudia; Buratti, Franca M.; Testai, Emanuela

2008-01-01

Although fenthion (FEN) is widely used as a broad spectrum insecticide on various crops in many countries, very scant data are available on its biotransformation in humans. In this study the in vitro human hepatic FEN biotransformation was characterized, identifying the relative contributions of cytochrome P450 (CYPs) and/or flavin-containing monooxygenase (FMOs) by using single c-DNA expressed human enzymes, human liver microsomes and cytosol and CYP/FMO-specific inhibitors. Two major metabolites, FEN-sulfoxide and FEN-oxon (FOX), are formed by some CYPs although at very different levels, depending on the relative CYP hepatic content. Formation of further oxidation products and the reduction of FEN-sulfoxide back to FEN by the cytosolic aldehyde oxidase enzyme were ruled out. Comparing intrinsic clearance values, FOX formation seemed to be favored and at low FEN concentrations CYP2B6 and 1A2 are mainly involved in its formation. At higher levels, a more widespread CYP involvement was evident, as in the case of FEN-sulfoxide, although a higher efficiency of CYP2C family was suggested. Hepatic FMOs were able to catalyze only sulfoxide formation, but at low FEN concentrations hepatic FEN sulfoxidation is predominantly P450-driven. Indeed, the contribution of the hepatic isoforms FMO 3 and FMO 5 was generally negligible, although at high FEN concentrations FMO's showed activities comparable to the active CYPs, accounting for up to 30% of total sulfoxidation. Recombinant FMO 1 showed the highest efficiency with respect to CYPs and the other FMOs, but it is not expressed in the adult human liver. This suggests that FMO 1 -catalysed sulfoxidation may represent the major extra-hepatic pathway of FEN biotransformation

Hepatic mTORC1 controls locomotor activity, body temperature, and lipid metabolism through FGF21

Science.gov (United States)

Cornu, Marion; Oppliger, Wolfgang; Albert, Verena; Robitaille, Aaron M.; Trapani, Francesca; Quagliata, Luca; Fuhrer, Tobias; Sauer, Uwe; Terracciano, Luigi; Hall, Michael N.

2014-01-01

The liver is a key metabolic organ that controls whole-body physiology in response to nutrient availability. Mammalian target of rapamycin (mTOR) is a nutrient-activated kinase and central controller of growth and metabolism that is negatively regulated by the tumor suppressor tuberous sclerosis complex 1 (TSC1). To investigate the role of hepatic mTOR complex 1 (mTORC1) in whole-body physiology, we generated liver-specific Tsc1 (L-Tsc1 KO) knockout mice. L-Tsc1 KO mice displayed reduced locomotor activity, body temperature, and hepatic triglyceride content in a rapamycin-sensitive manner. Ectopic activation of mTORC1 also caused depletion of hepatic and plasma glutamine, leading to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α)–dependent fibroblast growth factor 21 (FGF21) expression in the liver. Injection of glutamine or knockdown of PGC-1α or FGF21 in the liver suppressed the behavioral and metabolic defects due to mTORC1 activation. Thus, mTORC1 in the liver controls whole-body physiology through PGC-1α and FGF21. Finally, mTORC1 signaling correlated with FGF21 expression in human liver tumors, suggesting that treatment of glutamine-addicted cancers with mTOR inhibitors might have beneficial effects at both the tumor and whole-body level. PMID:25082895

Maternal chocolate and sucrose soft drink intake induces hepatic steatosis in rat offspring associated with altered lipid gene expression profile

DEFF Research Database (Denmark)

Kjærgaard, Maj; Nilsson, C.; Rosendal, A.

2014-01-01

weight gain and adiposity in offspring born to chow-fed dams. Conclusion: Our results suggest that supplementation of chocolate and soft drink during gestation and lactation contributes to early onset of hepatic steatosis associated with changes in hepatic gene expression and lipid handling....... until weaning, giving four dietary groups. Results: At postnatal day 1, offspring from high-fat/high-sucrose-fed dams were heavier and had increased hepatic triglycerides (TG), hepatic glycogen, blood glucose and plasma insulin compared with offspring from chow-fed dams. Hepatic genes involved in lipid...... oxidation, VLDL transport and insulin receptor were down-regulated, whereas FGF21 expression was up-regulated. Independent of postnatal litter size, offspring from high-fat/high-sucrose-fed dams aged 21 days had still increased hepatic TG and up-regulated FGF21 expression, while plasma insulin started...

Integration-deficient lentivectors: an effective strategy to purify and differentiate human embryonic stem cell-derived hepatic progenitors.

Science.gov (United States)

Yang, Guanghua; Si-Tayeb, Karim; Corbineau, Sébastien; Vernet, Rémi; Gayon, Régis; Dianat, Noushin; Martinet, Clémence; Clay, Denis; Goulinet-Mainot, Sylvie; Tachdjian, Gérard; Tachdjian, Gérard; Burks, Deborah; Vallier, Ludovic; Bouillé, Pascale; Dubart-Kupperschmitt, Anne; Weber, Anne

2013-07-19

Human pluripotent stem cells (hPSCs) hold great promise for applications in regenerative medicine. However, the safety of cell therapy using differentiated hPSC derivatives must be improved through methods that will permit the transplantation of homogenous populations of a specific cell type. To date, purification of progenitors and mature cells generated from either embryonic or induced pluripotent stem cells remains challenging with use of conventional methods. We used lentivectors encoding green fluorescent protein (GFP) driven by the liver-specific apoliprotein A-II (APOA-II) promoter to purify human hepatic progenitors. We evaluated both integrating and integration-defective lentivectors in combination with an HIV integrase inhibitor. A human embryonic stem cell line was differentiated into hepatic progenitors using a chemically defined protocol. Subsequently, cells were transduced and sorted at day 16 of differentiation to obtain a cell population enriched in hepatic progenitor cells. After sorting, more than 99% of these APOA-II-GFP-positive cells expressed hepatoblast markers such as α-fetoprotein and cytokeratin 19. When further cultured for 16 days, these cells underwent differentiation into more mature cells and exhibited hepatocyte properties such as albumin secretion. Moreover, they were devoid of vector DNA integration. We have developed an effective strategy to purify human hepatic cells from cultures of differentiating hPSCs, producing a novel tool that could be used not only for cell therapy but also for in vitro applications such as drug screening. The present strategy should also be suitable for the purification of a broad range of cell types derived from either pluripotent or adult stem cells.

Senescence marker protein-30/superoxide dismutase 1 double knockout mice exhibit increased oxidative stress and hepatic steatosis

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Yoshitaka Kondo

2014-01-01

Full Text Available Superoxide dismutase 1 (SOD1 is an antioxidant enzyme that converts superoxide anion radicals into hydrogen peroxide and molecular oxygen. The senescence marker protein-30 (SMP30 is a gluconolactonase that functions as an antioxidant protein in mammals due to its involvement in ascorbic acid (AA biosynthesis. SMP30 also participates in Ca2+ efflux by activating the calmodulin-dependent Ca2+-pump. To reveal the role of oxidative stress in lipid metabolism defects occurring in non-alcoholic fatty liver disease pathogenesis, we generated SMP30/SOD1-double knockout (SMP30/SOD1-DKO mice and investigated their survival curves, plasma and hepatic lipid profiles, amounts of hepatic oxidative stress, and hepatic protein levels expressed by genes related to lipid metabolism. While SMP30/SOD1-DKO pups had no growth retardation by 14 days of age, they did have low plasma and hepatic AA levels. Thereafter, 39% and 53% of male and female pups died by 15–24 and 89 days of age, respectively. Compared to wild type, SMP30-KO and SOD1-KO mice, by 14 days SMP30/SOD1-DKO mice exhibited: (1 higher plasma levels of triglyceride and aspartate aminotransferase; (2 severe accumulation of hepatic triglyceride and total cholesterol; (3 higher levels of superoxide anion radicals and thiobarbituric acid reactive substances in livers; and (4 decreased mRNA and protein levels of Apolipoprotein B (ApoB in livers – ApoB is an essential component of VLDL secretion. These results suggest that high levels of oxidative stress due to concomitant deficiency of SMP30 and/or AA, and SOD1 cause abnormal plasma lipid metabolism, hepatic lipid accumulation and premature death resulting from impaired VLDL secretion.

Hepatitis E virus and fulminant hepatitis--a virus or host-specific pathology?

Science.gov (United States)

Smith, Donald B; Simmonds, Peter

2015-04-01

Fulminant hepatitis is a rare outcome of infection with hepatitis E virus. Several recent reports suggest that virus variation is an important determinant of disease progression. To critically examine the evidence that virus-specific factors underlie the development of fulminant hepatitis following hepatitis E virus infection. Published sequence information of hepatitis E virus isolates from patients with and without fulminant hepatitis was collected and analysed using statistical tests to identify associations between virus polymorphisms and disease outcome. Fulminant hepatitis has been reported following infection with all four hepatitis E virus genotypes that infect humans comprising multiple phylogenetic lineages within genotypes 1, 3 and 4. Analysis of virus sequences from individuals infected by a common source did not detect any common substitutions associated with progression to fulminant hepatitis. Re-analysis of previously reported associations between virus substitutions and fulminant hepatitis suggests that these were probably the result of sampling biases. Host-specific factors rather than virus genotype, variants or specific substitutions appear to be responsible for the development of fulminant hepatitis. © 2014 The Authors. Liver International Published by John Wiley & Sons Ltd.

Acute central neuropeptide Y administration increases food intake but does not affect hepatic very low-density lipoprotein (VLDL) production in mice

NARCIS (Netherlands)

Geerling, Janine J.; Wang, Yanan; Havekes, Louis M.; Romijn, Johannes A.; Rensen, Patrick C. N.

2013-01-01

Central neuropeptide Y (NPY) administration stimulates food intake in rodents. In addition, acute modulation of central NPY signaling increases hepatic production of very low-density lipoprotein (VLDL)-triglyceride (TG) in rats. As hypertriglyceridemia is an important risk factor for

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...

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...

Reduction of VLDL secretion decreases cholesterol excretion in niemann-pick C1-like 1 hepatic transgenic mice.

Directory of Open Access Journals (Sweden)

Stephanie M Marshall

Full Text Available An effective way to reduce LDL cholesterol, the primary risk factor of atherosclerotic cardiovascular disease, is to increase cholesterol excretion from the body. Our group and others have recently found that cholesterol excretion can be facilitated by both hepatobiliary and transintestinal pathways. However, the lipoprotein that moves cholesterol through the plasma to the small intestine for transintestinal cholesterol efflux (TICE is unknown. To test the hypothesis that hepatic very low-density lipoproteins (VLDL support TICE, antisense oligonucleotides (ASO were used to knockdown hepatic expression of microsomal triglyceride transfer protein (MTP, which is necessary for VLDL assembly. While maintained on a high cholesterol diet, Niemann-Pick C1-like 1 hepatic transgenic (L1Tg mice, which predominantly excrete cholesterol via TICE, and wild type (WT littermates were treated with control ASO or MTP ASO. In both WT and L1Tg mice, MTP ASO decreased VLDL triglyceride (TG and cholesterol secretion. Regardless of treatment, L1Tg mice had reduced biliary cholesterol compared to WT mice. However, only L1Tg mice treated with MTP ASO had reduced fecal cholesterol excretion. Based upon these findings, we conclude that VLDL or a byproduct such as LDL can move cholesterol from the liver to the small intestine for TICE.

Meta-analysis of structured triglyceride versus other lipid emulsions for parenteral nutrition.

Science.gov (United States)

Zhu, Mengbai; Li, Xueliang

2013-06-01

Structured triglyceride (STG) is a new emulsion synthesized from long-chain fatty acids and medium-chain fatty acids bound to the same glycerol backbone. We performed a meta-analysis to examine the safety, efficacy, and tolerability of STG for parenteral nutrition. We searched MEDLINE, EMBASE, and the Chinese Biomedicine Database, with the last search done in May 2012. Only randomized controlled trials in humans published in Chinese or English were included. Search terms included structured triglyceride and structural lipid. Methodologic quality was evaluated using the Jadad Scale. Meta-analysis was conducted using Review Manager 5.0.24 to calculate the weighted mean difference (WMD) and standardized mean difference (SMD) with 95% confidence intervals. Twenty-one studies (833 participants) published in English or Chinese were included in the analysis. STG significantly affected plasma triglycerides (WMD = -0.15; 95% confidence interval [CI], -0.29 to -0.01; P = 0.04), plasma glycerol (WMD = 0.21; 95% CI, 0.01-0.41; P = 0.04), free fatty acids (WMD = 0.21; 95% CI, 0.03-0.39; P = 0.02), nitrogen balance (SMD = 1.13; 95% CI, 0.26-1.99; P = 0.01), AST (WMD = -5.97; 95% CI, -7.17 to -4.76; P triglycerides. Copyright © 2013 Elsevier Inc. All rights reserved.

Gene expression data from acetaminophen-induced toxicity in human hepatic in vitro systems and clinical liver samples

Directory of Open Access Journals (Sweden)

Robim M. Rodrigues

2016-06-01

Full Text Available This data set is composed of transcriptomics analyses of (i liver samples from patients suffering from acetaminophen-induced acute liver failure (ALF and (ii hepatic cell systems exposed to acetaminophen and their respective controls. The in vitro systems include widely employed cell lines i.e. HepaRG and HepG2 cells as well as a novel stem cell-derived model i.e. human skin-precursors-derived hepatocyte-like cells (hSKP-HPC. Data from primary human hepatocytes was also added to the data set “Open TG-GATEs: a large-scale toxicogenomics database” (Igarashi et al., 2015 [1]. Changes in gene expression due to acetaminophen intoxication as well as comparative information between human in vivo and in vitro samples are provided. The microarray data have been deposited in NCBI׳s Gene Expression Omnibus and are accessible through GEO Series accession number GEO: GSE74000. The provided data is used to evaluate the predictive capacity of each hepatic in vitro system and can be directly compared with large-scale publically available toxicogenomics databases. Further interpretation and discussion of these data feature in the corresponding research article “Toxicogenomics-based prediction of acetaminophen-induced liver injury using human hepatic cell systems” (Rodrigues et al., 2016 [2].

Acute Central Neuropeptide Y Administration Increases Food Intake but Does Not Affect Hepatic Very Low-Density Lipoprotein (Vldl) Production in Mice

NARCIS (Netherlands)

Geerling, J.J.; Wang, Y.; Havekes, L.M.; Romijn, J.A.; Rensen, P.C.N.

2013-01-01

Objective: Central neuropeptide Y (NPY) administration stimulates food intake in rodents. In addition, acute modulation of central NPY signaling increases hepatic production of very low-density lipoprotein (VLDL)-triglyceride (TG) in rats. As hypertriglyceridemia is an important risk factor for

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...

The effect of bacterial sepsis severity on triglyceride value

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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.

Delayed clearance of triglyceride-rich lipoproteins in young, healthy obese subjects.

Science.gov (United States)

Larsen, M A; Goll, R; Lekahl, S; Moen, O S; Florholmen, J

2015-12-01

Obesity is associated with the metabolic syndrome. The aims were, first, to study the postprandial triglyceride clearance in young, healthy obese subjects and, second, to investigate if fasting triglycerides can predict delayed postprandial triglyceride clearance. Eighteen apparently healthy, obese subjects with no clinical signs of metabolic disturbances participated. Controls were age- and sex-matched, healthy, normal weight subjects. Subclinical markers of metabolic disturbances were assessed by measuring postprandial triglycerides in serum and in chylomicrons by oral fat tolerance test. Postprandial triglyceride clearance for 8 h was assessed indirectly as removal of the lipid from serum during the oral fat tolerance test. Insulin resistance was measured by the homeostasis model assessment of insulin resistance (HOMA-IR). Twelve (66%) of the apparently healthy obese individuals had insulin resistance measured by HOMA-IR. There was a delayed clearance of serum triglycerides and chylomicron triglycerides at 6 h when compared with the control group, while, at 8 h, the differences were only detected for the chylomicron triglyceride clearance. Triglyceride response was significantly greater in the obese subjects. Fasting triglycerides in upper normal level predicted a delayed postprandial triglyceride clearance and insulin resistance. In young, apparently healthy obese subjects early metabolic disturbances including insulin resistance and delayed postprandial triglyceride clearance can be detected. Fasting serum triglyceride in upper normal level predicted delayed postprandial triglyceride clearance and insulin resistance. © 2015 World Obesity.

Fracture Simulation of Highly Crosslinked Polymer Networks: Triglyceride-Based Adhesives

Science.gov (United States)

Lorenz, Christian; Stevens, Mark; Wool, Richard

2003-03-01

The ACRES program at the U. of Delaware has shown that triglyceride oils derived from plants are a favorable alternative to the traditional adhesives. The triglyceride networks are formed from an initial mixture of styrene monomers, free-radical initiators and triglycerides. We have performed simulations to study the effect of physical composition and physical characteristics of the triglyceride network on the strength of triglyceride network. A coarse-grained, bead-spring model of the triglyceride system is used. The average triglyceride consists of 6 beads per chain, the styrenes are represented as a single bead and the initiators are two bead chains. The polymer network is formed using an off-lattice 3D Monte Carlo simulation, in which the initiators activate the styrene and triglyceride reactive sites and then bonds are randomly formed between the styrene and active triglyceride monomers producing a highly crosslinked polymer network. Molecular dynamics simulations of the network under tensile and shear strains were performed to determine the strength as a function of the network composition. The relationship between the network structure and its strength will also be discussed.

Low trans structured fat from flaxseed oil improves plasma and hepatic lipid metabolism in apo E(-/-) mice.

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Cho, Yun-Young; Kwon, Eun-Young; Kim, Hye-Jin; Park, Yong-Bok; Lee, Ki-Teak; Park, Taesun; Choi, Myung-Sook

2009-07-01

The objective of this study was to explicate the effects of feeding low trans structured fat from flaxseed oil (LF) on plasma and hepatic lipid metabolism involved in apo E(-/-) mice. The animals were fed a commercial shortening (CS), commercial low trans fat (CL) and LF diet based on AIN-76 diet (10% fat) for 12 weeks. LF supplementation exerted a significant suppression in hepatic lipid accumulation with the concomitant decrease in liver weight. The LF significantly lowered plasma total cholesterol and free fatty acid whereas it significantly increased HDL-C concentration and the HDL-C/total-C ratio compared to the CS group. Reduction of hepatic lipid levels in the LF group was related with the suppression of hepatic enzyme activities for fatty acid and triglyceride synthesis, and cholesterol regulating enzyme activity compared to the CS and CL groups. Accordingly, low trans structured fat from flaxseed oil is highly effective for improving hyperlipidemia and hepatic lipid accumulation in apo E(-/-) mice.

Fasting and nonfasting triglycerides in cardiovascular and other diseases.

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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.

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.

Lipase H, a new member of the triglyceride lipase family synthesized by the intestine

NARCIS (Netherlands)

Jin, Weijun; Broedl, Uli C.; Monajemi, Houshang; Glick, Jane M.; Rader, Daniel J.

2002-01-01

We report here the molecular cloning of a novel member of the triglyceride lipase family, a 2.4-kb cDNA encoding human lipase H (LIPH) and the mouse ortholog (Liph). The human LIPH cDNA encodes a 451-amino-acid protein with a lipase domain. Mouse Liph shows 85% amino acid identity and 75% nucleotide

p38 MAPK protects human monocytes from postprandial triglyceride-rich lipoprotein-induced toxicity.

Science.gov (United States)

Lopez, Sergio; Jaramillo, Sara; Varela, Lourdes M; Ortega, Almudena; Bermudez, Beatriz; Abia, Rocio; Muriana, Francisco J G

2013-05-01

Postprandial triglyceride (TG)-rich lipoproteins (TRLs) transport dietary fatty acids through the circulatory system to satisfy the energy and structural needs of the tissues. However, fatty acids are also able to modulate gene expression and/or induce cell death. We investigated the underlying mechanism by which postprandial TRLs of different fatty acid compositions can induce cell death in human monocytes. Three types of dietary fat [refined olive oil (ROO), high-palmitic sunflower oil (HPSO), and butter] with progressively increasing SFA:MUFA ratios (0.18, 0.41, and 2.08, respectively) were used as a source of postprandial TRLs (TRL-ROO, TRL-HPSO, and TRL-BUTTER) from healthy men. The monocytic cell line THP-1 was used as a model for this study. We demonstrated that postprandial TRLs increased intracellular lipid accumulation (31-106%), reactive oxygen species production (268-349%), DNA damage (133-1467%), poly(ADP-ribose) polymerase 1 (800-1710%) and caspase-3 (696-1244%) activities, and phosphorylation of c-Jun NH2-terminal kinase (JNK) (54 kDa, 141-288%) and p38 (24-92%). These effects were significantly greater with TRL-BUTTER, and TRL-ROO did not induce DNA damage, DNA fragmentation, or p38 phosphorylation. In addition, blockade of p38, but not of JNK, significantly decreased intracellular lipid accumulation and increased cell death in postprandial TRL-treated cells. These results suggest that in human monocytes, p38 is involved in survival signaling pathways that protect against the lipid-mediated cytotoxicity induced by postprandial TRLs that are abundant in saturated fatty acids.

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.

Alkannin Inhibited Hepatic Inflammation in Diabetic Db/Db Mice

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Wenhua Xue

2018-03-01

Full Text Available Background/Aims: The current study was designed to investigate the protective role of alkannin (ALK on liver injury in diabetic C57BL/KsJ-db/db mice and explore its potential mechanisms. Methods: An oral glucose tolerance test (OGTT was performed. The levels of insulin, alanine aminotransferase (ALT, aspartate aminotransaminase (AST, total cholesterol (TC and triglyceride (TG were determined by commercial kits. The pro-inflammatory cytokines interleukin (IL-1β, IL-6 and tumour necrosis factor (TNF-α were determined by ELISA. The levels of the ROCK/NF-κB pathway were determined by Western blotting. Results: The contents of pro-inflammatory cytokines interleukin (IL-1β, IL-6 and tumour necrosis factor (TNF-α were inhibited by ALK, metformin or fasudil in diabetic db/db mice. Further, Western blotting analysis showed that the expression of Rho, ROCK1, ROCK2, p-NF-κBp65, and p-IκBα was significantly reversed by ALK treatment. In human hepatic HepG2 cells, the hepatoprotective effects of ALK were further characterized. With response to palmitic acid-challenge, increased amounts of insulin, ALT, AST, TG, and TC were observed, whereas ALK pretreatment significantly inhibited their leakage in HepG2 cells without appreciable cytotoxic effects. The inflammation condition was recovered with ALK treatment as shown by changes of IL-1β, IL-6 and TNF-α. Further, Western blotting analysis also suggested that ALK improves hepatic inflammation in a Rho-kinase pathway. Conclusion: The present study successfully investigated the role of Rho-kinase signalling in diabetic liver injury. ALK exhibited hepatoprotective effects in diabetic db/db mice, and it might act through improving hepatic inflammation through the Rho-kinase pathway.

Hepatic drug clearance following traumatic injury.

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Slaughter, R L; Hassett, J M

1985-11-01

Trauma is a complex disease state associated with physiologic changes that have the potential to alter hepatic drug clearance mechanisms. These responses include alterations in hepatic blood flow, reduction in hepatic microsomal activity, reduction in hepatic excretion processes, and changes in protein binding. Hepatic blood flow is influenced by sympathomimetic activity. Both animal and human studies demonstrate an initial reduction and subsequent increase in hepatic blood flow, which coincides with an observed increase and subsequent return to normal in serum catecholamine concentrations. Unfortunately, there are no human studies that address the importance these findings may have to the clearance processes of high intrinsic clearance compounds. Animal studies of trauma indicate that hepatic microsomal activity is depressed during the post-traumatic period. Reduction in the hepatic clearance of antipyrine, a model low intrinsic compound, has also been demonstrated in animal models of trauma. In addition to these effects, hepatic excretion of substances such as indocyanine green and bilirubin have been demonstrated to be impaired in both traumatized animals and humans. Finally, substantial increases in the serum concentration of the binding protein alpha 1-acid glycoprotein occur in trauma patients. This has been reported to be associated with subsequent decreases in the free fraction of lidocaine and quinidine. In addition to changing serum drug concentration/response relationships, the pharmacokinetic behavior of drugs bound to alpha 1-acid glycoprotein should also change. Preliminary observations in our laboratory in a dog model of surgically-induced trauma have shown a reduction in the total clearance of lidocaine and reduction in free lidocaine concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitochondria-targeted antioxidant mitoquinone deactivates human and rat hepatic stellate cells and reduces portal hypertension in cirrhotic rats.

Science.gov (United States)

Vilaseca, Marina; García-Calderó, Héctor; Lafoz, Erica; Ruart, Maria; López-Sanjurjo, Cristina Isabel; Murphy, Michael P; Deulofeu, Ramon; Bosch, Jaume; Hernández-Gea, Virginia; Gracia-Sancho, Jordi; García-Pagán, Juan Carlos

2017-07-01

In cirrhosis, activated hepatic stellate cells (HSC) play a major role in increasing intrahepatic vascular resistance and developing portal hypertension. We have shown that cirrhotic livers have increased reactive oxygen species (ROS), and that antioxidant therapy decreases portal pressure. Considering that mitochondria produce many of these ROS, our aim was to assess the effects of the oral mitochondria-targeted antioxidant mitoquinone on hepatic oxidative stress, HSC phenotype, liver fibrosis and portal hypertension. Ex vivo: Hepatic stellate cells phenotype was analysed in human precision-cut liver slices in response to mitoquinone or vehicle. In vitro: Mitochondrial oxidative stress was analysed in different cell type of livers from control and cirrhotic rats. HSC phenotype, proliferation and viability were assessed in LX2, and in primary human and rat HSC treated with mitoquinone or vehicle. In vivo: CCl 4 - and thioacetamide-cirrhotic rats were treated with mitoquinone (5 mg/kg/day) or the vehicle compound, DecylTPP, for 2 weeks, followed by measurement of oxidative stress, systemic and hepatic haemodynamic, liver fibrosis, HSC phenotype and liver inflammation. Mitoquinone deactivated human and rat HSC, decreased their proliferation but with no effects on viability. In CCl 4 -cirrhotic rats, mitoquinone decreased hepatic oxidative stress, improved HSC phenotype, reduced intrahepatic vascular resistance and diminished liver fibrosis. These effects were associated with a significant reduction in portal pressure without changes in arterial pressure. These results were further confirmed in the thioacetamide-cirrhotic model. We propose mitochondria-targeted antioxidants as a novel treatment approach against portal hypertension and cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes

Energy Technology Data Exchange (ETDEWEB)

Ohhira, Shuji; Watanabe, Masatomo; Matsui, Hisao [Department of Hygiene, Dokkyo University School of Medicine, Mibu-machi, 321-0293, Tochigi (Japan)

2003-03-01

Tributyltin and triphenyltin are metabolized by cytochrome P-450 system enzymes, and their metabolic fate may contribute to the toxicity of the chemicals. In the current study, the in vitro metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes was investigated to elucidate the metabolic competence for these compounds in humans. The metabolic reaction using microsome-NADPH system that is usually conducted was not applicable to in vitro metabolism of organotins, especially triphenyltin. We therefore examined the effects of dithiothreitol (DTT), one of the antioxidants for sulfhydryl groups, to determine the in vitro metabolism of tributyltin and triphenyltin. As a result, the treatment with 0.1 mM DTT in vitro increased the activity of the microsomal monooxygenase system for metabolism of tributyltin as well as triphenyltin; the total yield of tributyltin and triphenyltin metabolites as tin increased, respectively, by approximately 1.8 and 8.9 times for rat, 2.1 and 1.2 times for hamster, and 1.6 and 1.5 times for human. It is suggested that the organotins directly inactivate cytochrome P-450 because of the interaction with critical sulfhydryl groups of the hemoprotein. We confirmed the utility of this in vitro metabolic system using DTT in the hepatic microsomes of phenobarbital (PB)-pretreated and untreated hamsters. Thus, the in vitro metabolic system described here was applied to a comparative study of the metabolism of organotins in rats, hamsters and humans. Tributyltin was metabolized more readily than triphenyltin in all the species. In humans, the in vitro metabolic pattern resembled that of hamsters, which were susceptible to in vivo triphenyltin toxicity because of incompetent metabolism. It is possible that the hamster is a qualitatively and quantitatively suitable animal model for exploring the influence of tributyltin and triphenyltin in humans. (orig.)

Prevalence of human immunodeficiency virus, syphilis, hepatitis B and C in blood donations in Namibia.

Science.gov (United States)

Mavenyengwa, Rooyen T; Mukesi, Munyaradzi; Chipare, Israel; Shoombe, Esra

2014-05-05

Transfusion Transmissible Infections (TTIs) such as Human Immunodeficiency Virus (HIV), syphilis, hepatitis B virus (HBV) and hepatitis C virus (HCV) are infections which are common in some communities in Southern Africa. It is important to screen blood donations for these infections. This is a retrospective study which involved reviewing of previous blood donation records for the year 2012 in Namibia. The records were analyzed to determine the prevalence of HIV, syphilis, Hepatitis B and C among blood donations with regard to gender, age and geographical region of the donors. The findings indicated a significantly low prevalence of HIV, syphilis, HBsAg and anti-Hepatitis C among the blood donations. A low infection rate of 1.3% by any of the four tested TTIs was found among the blood donations given by the donor population in Namibia in 2012. The blood donations given by the donor population in Namibia has a low infection rate with the HIV, syphilis, HBsAg and anti-HCV. A strict screening regime must continue to be used as the infections are still present albeit in small numbers.

Counter-attack on virol hepatitis

International Nuclear Information System (INIS)

Prozesky, O.W.; Jupp, P.G.; Joubert, J.J.; Taylor, M.B.; Grabow, W.O.K.

1985-01-01

The most highly developed radioimmunoassay test system in medical virology is proving of exceptional value in research aimed at controlling and eventually eradicating the scourge of human hepatitis. The use of radioimmunoassay in detecting hepatitis A (HAV) and hepatitis B (HBV) viruses is discussed. The hepatitis A virus is an enterovirus which infects the gastrointestinal tract and is usually transmitted by contaminated food, milk or water. Hepatitis B spreads mainly by the parenteral rate. Bedbugs and ticks are considered as possible transmitters of HBV. Another important contribution of radioimmunoassay is the ability to monitor the immune response of persons at risk who are vaccinated against hepatitis B

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

Obesity-driven prepartal hepatic lipid accumulation in dairy cows is associated with increased CD36 and SREBP-1 expression.

Science.gov (United States)

Prodanović, Radiša; Korićanac, Goran; Vujanac, Ivan; Djordjević, Ana; Pantelić, Marija; Romić, Snježana; Stanimirović, Zoran; Kirovski, Danijela

2016-08-01

We investigated the hypothesis that obesity in dairy cows enhanced expression of proteins involved in hepatic fatty acid uptake and metabolism. Sixteen Holstein-Friesian close-up cows were divided into 2 equal groups based on their body condition score (BCS) as optimal (3.25≤BCS≤3.5) and high (4.0≤BCS≤4.25). Intravenous glucose tolerance test (GTT) and liver biopsies were carried out at day 10 before calving. Blood samples were collected before (basal) and after glucose infusion, and glucose, insulin and non-esterified fatty acid (NEFA) levels were determined at each sample point. In addition, β-hydroxybutyrate and triglycerides levels were measured in the basal samples. The liver biopsies were analyzed for total lipid content and protein expression of insulin receptor beta (IRβ), fatty acid translocase (FAT/CD36) and sterol regulatory element-binding protein-1 (SREBP-1). Basal glucose and insulin were higher in high-BCS cows, which coincided with higher circulating triglycerides and hepatic lipid content. Clearance rate and AUC for NEFA during GTT were higher in optimal-BCS cows. The development of insulin resistance and fatty liver in obese cows was paralleled by increased hepatic expression of the IRβ, CD36 and SREBP-1. These results suggest that increased expression of hepatic CD36 and SREBP-1 is relevant in the obesity-driven lipid accumulation in the liver of dairy cows during late gestation. Copyright © 2016 Elsevier Ltd. All rights reserved.

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.

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.

A preliminary discussion of angiographic anatomy and variations of rabbit hepatic vessels and catheterization methods of hepatic artery

International Nuclear Information System (INIS)

Wang Diaodong; Yang Renjie; Zhang Hongzhi; Sun Hongliang

2006-01-01

Objective: To study the normal angiographic anatomy and variations of rabbit hepatic vessels, and explore the optimal method for hepatic artery catheterization. Methods: 30 rabbits were divided into two groups randomly. Modified surgical method and interventional method were used to catheterize hepatic artery respectively, and followed by angiography to demonstrate the normal anatomy and variations of rabbit celiac artery, hepatic artery and portal vein. Results: The route and distribution of rabbit celiac artery and hepatic artery were very different from human's. The commonly seen variation showed the differences in branching bifurcation of hepatic-gastric artery, with the incidence of 13.3%. The rates of successfully hepatic artery catheterization with surgical and interventional methods were 86.6%(13/15) and 80%(12/15) respectively (P>0.05). The surgical method will not be successful, whenever there's variation. Conclusion: The normal anatomy and variation of rabbit celiac artery and hepatic artery are quite different from human's. Both surgical and interventional catheterizations could be rather successful but possessing advantages and disadvantages of each its own. (authors)

Increased hepatic cholesterol esterification with essential fatty acid deficiency (EFAD): relationship to plasma lipoprotein (LP) cholesterol content

International Nuclear Information System (INIS)

Ney, D.M.; Ziboh, V.A.; Schneeman, B.O.

1986-01-01

EFAD in the rat is associated with hepatic accumulation of esterified cholesterol and altered distribution of cholesterol between plasma and hepatic tissue. Little is known regarding the impact of EFAD on LP composition. To determine the relationship between hepatic cholesterol esterification and plasma lP composition in control (C) and EFAD male Wistar rats, the authors induced EFAD with continuous intragastric (IG) infusion of EFA-free solutions containing 3.5% of calories as triolein for 7 and 14 days. C animals received IG infusion of solutions containing 3.5% of calories as linoleic acid. Data in the EFAD groups reveal: (i) marked decreases in hepatic EFAs and increases in monoenoic acids; (ii) progressive increases in hepatic content of triglyceride and esterified cholesterol with 7 and 14 days of feeding; (iii) assay of acyl CoA:cholesterol acyltransferase activity in hepatic tissue using 14 C-cholesterol demonstrates an increase in hepatic cholesterol esterification when compared to C animals. Increased hepatic cholesterol esterification correlates with elevated levels of esterified cholesterol in plasma VLDL and HDL particles. These data indicate that the elevated levels of cholesterol esters in LP particles is due, at least in part, to increased hepatic cholesterol esterification with EFAD

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

[History of viral hepatitis].

Science.gov (United States)

Fonseca, José Carlos Ferraz da

2010-01-01

The history of viral hepatitis goes back thousands of years and is a fascinating one. When humans were first infected by such agents, a natural repetitive cycle began, with the capacity to infect billions of humans, thus decimating the population and causing sequelae in thousands of lives. This article reviews the available scientific information on the history of viral hepatitis. All the information was obtained through extensive bibliographic review, including original and review articles and consultations on the internet. There are reports on outbreaks of jaundice epidemics in China 5,000 years ago and in Babylon more than 2,500 years ago. The catastrophic history of great jaundice epidemics and pandemics is well known and generally associated with major wars. In the American Civil War, 40,000 cases occurred among Union troops. In 1885, an outbreak of catarrhal jaundice affected 191 workers at the Bremen shipyard (Germany) after vaccination against smallpox. In 1942, 28,585 soldiers became infected with hepatitis after inoculation with the yellow fever vaccine. The number of cases of hepatitis during the Second World War was estimated to be 16 million. Only in the twentieth century were the main agents causing viral hepatitis identified. The hepatitis B virus was the first to be discovered. In this paper, through reviewing the history of major epidemics caused by hepatitis viruses and the history of discovery of these agents, singular peculiarities were revealed. Examples of this include the accidental or chance discovery of the hepatitis B and D viruses.

Effects of parenteral infusion with medium-chain triglycerides and safflower oil emulsions on hepatic lipids, plasma amino acids and inflammatory mediators in septic rats.

Science.gov (United States)

Yeh, S; Chao, C; Lin, M; Chen, W

2000-04-01

This study was designed to investigate the effects of preinfusion with total parenteral nutrition (TPN) using medium-chain triglycerides (MCT) versus safflower oil (SO) emulsion as fat sources on hepatic lipids, plasma amino acid profiles, and inflammatory-related mediators in septic rats. Normal rats, with internal jugular catheters, were divided into two groups and received TPN. TPN provided 300kcal/kg/day with 40% of the non-protein energy provided as fat. All TPN solutions were isonitrogenous and identical in nutrient composition except for the fat emulsion, which was made of SO or a mixture of MCT and soybean oil (9:1) (MO). After receiving TPN for 6 days, each group of rats was further divided into control and sepsis subgroups. Sepsis was induced by cecal ligation and puncture, whereas control rats received sham operation. All rats were classified into four groups as follows: MCT control group (MOC, n= 8), MCT sepsis group (MOS, n= 8), safflower oil control group (SOC, n= 8), and safflower oil sepsis group (SOS, n= 11). The results of the study demonstrated that the MOS group had lower hepatic lipids than did the SOS group. Plasma leucine and isoleucine levels were significantly lower in the SOS than in the SOC group, but no differences in these two amino acids were observed between the MOC and MOS groups. Plasma arginine levels were significantly lower in septic groups than in those without sepsis despite whether MCT or safflower oil was infused. Plasma glutamine and alanine levels, however, did not differ between septic and non-septic groups either in the SO or MO groups. No differences in interleukin-1b, interleukin-6, tumor necrosis factor-alpha, and leukotriene B(4)concentrations in peritoneal lavage fluid were observed between the two septic groups. These results suggest that catabolic reaction is septic rats preinfused MCT is not as obvious as those preinfused safflower oil. Compared with safflower oil, TPN with MCT administration has better effects on

Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation

International Nuclear Information System (INIS)

Yu, Jung Hwan; Lee, Yoo Jeong; Kim, Hyo Jung; Choi, Hyeonjin; Choi, Yoonjeong; Seok, Jo Woon; Kim, Jae-woo

2015-01-01

Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor γ (PPARγ), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARγ overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARγ by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARγ overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARγ, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans. - Highlights: • PPARγ promotes MGAT1 expression in human primary hepatocytes. • PPARγ directly regulates MGAT1 promoter activity. • Human MGAT1 promoter has at least two PPARγ-binding elements. • Inhibition of MGAT1 expression attenuates hepatic lipid accumulation in humans

Monoacylglycerol O-acyltransferase 1 is regulated by peroxisome proliferator-activated receptor γ in human hepatocytes and increases lipid accumulation

Energy Technology Data Exchange (ETDEWEB)

Yu, Jung Hwan [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); Lee, Yoo Jeong [Division of Metabolic Disease, Center for Biomedical Sciences, National Institutes of Health, Cheongwon-gun, Chungbuk 363-951 (Korea, Republic of); Kim, Hyo Jung; Choi, Hyeonjin [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); Choi, Yoonjeong; Seok, Jo Woon [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); Kim, Jae-woo, E-mail: japol13@yuhs.ac [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); Severance Biomedical Science Institute, Yonsei University College of Medicine, Seoul 120-752 (Korea, Republic of)

2015-05-08

Monoacylglycerol O-acyltransferase (MGAT) is an enzyme that is involved in triglyceride synthesis by catalyzing the formation of diacylglycerol from monoacylglycerol and fatty acyl CoAs. Recently, we reported that MGAT1 has a critical role in hepatic TG accumulation and that its suppression ameliorates hepatic steatosis in a mouse model. However, the function of MGAT enzymes in hepatic lipid accumulation has not been investigated in humans. Unlike in rodents, MGAT3 as well as MGAT1 and MGAT2 are present in humans. In this study, we evaluated the differences between MGAT subtypes and their association with peroxisome proliferator-activated receptor γ (PPARγ), a regulator of mouse MGAT1 expression. In human primary hepatocytes, basal expression of MGAT1 was lower than that of MGAT2 or MGAT3, but was strongly induced by PPARγ overexpression. A luciferase assay as well as an electromobility shift assay revealed that human MGAT1 promoter activity is driven by PPARγ by direct binding to at least two regions of the promoter in 293T and HepG2 cells. Moreover, siRNA-mediated suppression of MGAT1 expression significantly attenuated lipid accumulation by PPARγ overexpression in HepG2 cells, as evidenced by oil-red-O staining. These results suggest that human MGAT1 has an important role in fatty liver formation as a target gene of PPARγ, and blocking MGAT1 activity could be an efficient therapeutic way to reduce nonalcoholic fatty liver diseases in humans. - Highlights: • PPARγ promotes MGAT1 expression in human primary hepatocytes. • PPARγ directly regulates MGAT1 promoter activity. • Human MGAT1 promoter has at least two PPARγ-binding elements. • Inhibition of MGAT1 expression attenuates hepatic lipid accumulation in humans.

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

The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes

DEFF Research Database (Denmark)

Perry, Rachel J; Samuel, Varman T.; Petersen, Kitt Mia Falck

2014-01-01

Non-alcoholic fatty liver disease and its downstream sequelae, hepatic insulin resistance and type 2 diabetes, are rapidly growing epidemics, which lead to increased morbidity and mortality rates, and soaring health-care costs. Developing interventions requires a comprehensive understanding...... of the mechanisms by which excess hepatic lipid develops and causes hepatic insulin resistance and type 2 diabetes. Proposed mechanisms implicate various lipid species, inflammatory signalling and other cellular modifications. Studies in mice and humans have elucidated a key role for hepatic diacylglycerol...... activation of protein kinase Cε in triggering hepatic insulin resistance. Therapeutic approaches based on this mechanism could alleviate the related epidemics of non-alcoholic fatty liver disease and type 2 diabetes....

Scoring system in cirrhotics due to viral hepatitis

International Nuclear Information System (INIS)

Abbasi, A.; Bhutto, A.R.; Butt, N.; Lal, K.; Munir, S.M.

2012-01-01

Objective: To determine the association of serum cholesterol levels with Child-Pugh class in patients with decompensated chronic liver disease due to viral hepatitis. Methodology: Consecutive patients attending outpatient department or admitted in medical unit III were eligible if they had a diagnosis of cirrhosis secondary to viral hepatitis. Patients were excluded if alcoholic, diabetic, hypertensive, or with non-alcoholic fatty liver disease, autoimmune, metabolic, cardiovascular, cerebrovascular or kidney diseases and recent use of lipid-regulating drugs. Serum lipid profile was determined after an overnight fast of 12 hours. On the basis of serum total cholesterol, patients were divided into four groups; Group I with serum total cholesterol = 100 mg/dl, Group II with level of 101-150 mg/dl, Group III with level of 151-200 mg/dl and Group IV with serum total cholesterol level of > 200 mg/dl. Hepatic dysfunction was categorized according to Child-Pugh scoring system. Chi-square and Spearman's correlation testing with p < 0.05 was accepted as significant. Results: One hundred and fourteen patients met the inclusion criteria with a mean age of 40.32 +- 13.59 years. Among these 32 were females (28.1%) while 82 were males (71.9%). According to Child-Pugh class; 34 patients (29.8%) presented with Child-Pugh class A, 34 (29.8%) in class B and 46 (40.4%) were in class C. Serum cholesterol (total) and triglycerides had significant association with Child-Pugh class (p = 0.0001 and p = 0.004 respectively) suggesting that as severity of liver dysfunction increases; serum cholesterol and triglycerides levels decrease. Results also revealed that males were significantly more hypocholesterolemic than females (p = 0.006). Conclusion: Hypocholesterolemia is a common finding in decompensated chronic liver disease and has got significant association with Child-Pugh class. It may increase the reliability of Child-Pugh classification in assessment of severity and prognosis in

Mitochondrial and bioenergetic dysfunction in human hepatic cells infected with dengue 2 virus

OpenAIRE

El-Bacha , Tatiana; Midlej , Victor; Silva , Ana Paula Pereira Da; Costa , Leandro Silva Da; Benchimol , Marlene; Galina , Antonio; Poian , Andrea T. Da

2007-01-01

Mitochondrial and bioenergetic dysfunction in human hepatic cells infected with dengue 2 virus correspondence: Corresponding author. Fax: +55 21 22708647. (El-Bacha, Tatiana) (El-Bacha, Tatiana) Laboratorio de Bioquimica de Virus, Instituto de Bioquimica Medica, Universidade Federal do Rio de Janeiro - RJ-Brasil--> , Av. Bauhinia n? 400 ? CCS Bloco H 2? andar--> , sala 22. Ilha do Governador--> ...

Effects of medium-chain triglycerides on gluconeogenesis and ureagenesis in weaned rats fed a high fat diet

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Chitose Sugiyama

2015-12-01

Full Text Available We explored the effects of Medium-chain triglycerides (MCT on gluconeogenesis and ureagenesis in the liver of weaned male rats fed high fat, carbohydrate-free diets. The rats of three experimental groups and control were fed for 10 days. The diets were high fat, carbohydrate-free diets consisting either of a corn oil or MCT, and high protein carbohydrate-free diet and a control (high carbohydrate diet. The hepatic glucose-6-phosphatase (G6Pase activity increased in the experimental groups. Despite the elevated G6Pase activity in these groups, hepatic activities of glutamic alanine transaminase (GAT, pyruvate carboxylase (PC and arginase differed among the experimental groups. The HF-corn oil rats showed elevation of PC activity, but no elevation of GAT activity, and the lowest arginase activity among the three groups. The HF-MCT diet-fed rats showed higher GAT and arginase activities than the HF-corn oil group. In the HP diet-fed rats, GAT and arginase activities enhanced, PC did not.

A krill oil supplemented diet suppresses hepatic steatosis in high-fat fed rats.

Science.gov (United States)

Ferramosca, Alessandra; Conte, Annalea; Burri, Lena; Berge, Kjetil; De Nuccio, Francesco; Giudetti, Anna Maria; Zara, Vincenzo

2012-01-01

Krill oil (KO) is a dietary source of n-3 polyunsaturated fatty acids, mainly represented by eicosapentaenoic acid and docosahexaenoic acid bound to phospholipids. The supplementation of a high-fat diet with 2.5% KO efficiently prevented triglyceride and cholesterol accumulation in liver of treated rats. This effect was accompanied by a parallel reduction of the plasma levels of triglycerides and glucose and by the prevention of a plasma insulin increase. The investigation of the molecular mechanisms of KO action in high-fat fed animals revealed a strong decrease in the activities of the mitochondrial citrate carrier and of the cytosolic acetyl-CoA carboxylase and fatty acid synthetase, which are both involved in hepatic de novo lipogenesis. In these animals a significant increase in the activity of carnitine palmitoyl-transferase I and in the levels of carnitine was also observed, suggesting a concomitant stimulation of hepatic fatty acid oxidation. The KO supplemented animals also retained an efficient mitochondrial oxidative phosphorylation, most probably as a consequence of a KO-induced arrest of the uncoupling effects of a high-fat diet. Lastly, the KO supplementation prevented an increase in body weight, as well as oxidative damage of lipids and proteins, which is often found in high-fat fed animals.

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.

Unanticipated increases in hepatic steatosis among human immunodeficiency virus patients receiving mineralocorticoid receptor antagonist eplerenone for non-alcoholic fatty liver disease.

Science.gov (United States)

Chaudhury, Chloe S; Purdy, Julia B; Liu, Chia-Ying; Morse, Caryn G; Stanley, Takara L; Kleiner, David; Hadigan, Colleen

2018-05-01

Non-alcoholic fatty liver disease is common in human immunodeficiency virus, but there are no approved therapies. The aim of this open-label proof-of-concept study was to determine the effect of the mineralocorticoid receptor antagonist eplerenone on hepatic fat in human immunodeficiency virus-infected patients with hepatic fat ≥5% by magnetic resonance spectroscopy. Five subjects received eplerenone (25 mg daily × 1 week followed by 50 mg daily × 23 weeks). Laboratory tests were done at each visit, and the primary endpoint, change in hepatic fat content, was determined by MRI spectroscopy at baseline and week 24. The study was stopped early after observing unexpected significant increases in hepatic fat at week 24 (mean increase 13.0 ± 7.3%, P = .02). The increases in steatosis were accompanied by a tendency for transaminase values to decrease (alanine aminotransferase mean change -14 ± 16 IU/L, P = .14). There were no consistent changes in other metabolic parameters or blood pressure. Repeat assessment of hepatic steatosis 1-2 months after stopping study medication revealed improvements in steatosis towards baseline values. The unexpected observation of increased hepatic steatosis with the administration of eplerenone led to early termination of the investigation. While limited because of the small number of participants and the open-label design, this study provides data to suggest that mineralocorticoid receptor antagonism with eplerenone may not be an effective approach to treat hepatic steatosis in human immunodeficiency virus or the general population. Additional research is needed to determine the pathophysiological mechanism behind these unanticipated observations. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.

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Alexander Wehr

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH, fibrosis and eventually cirrhosis. Modulating inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20, confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4- and chronic methionine-choline-deficient (MCD diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.

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

Impairments of hepatic gluconeogenesis and ketogenesis in PPARα-deficient neonatal mice.

Science.gov (United States)

Cotter, David G; Ercal, Baris; d'Avignon, D André; Dietzen, Dennis J; Crawford, Peter A

2014-07-15

Peroxisome proliferator activated receptor-α (PPARα) is a master transcriptional regulator of hepatic metabolism and mediates the adaptive response to fasting. Here, we demonstrate the roles for PPARα in hepatic metabolic adaptations to birth. Like fasting, nutrient supply is abruptly altered at birth when a transplacental source of carbohydrates is replaced by a high-fat, low-carbohydrate milk diet. PPARα-knockout (KO) neonatal mice exhibit relative hypoglycemia due to impaired conversion of glycerol to glucose. Although hepatic expression of fatty acyl-CoA dehydrogenases is imparied in PPARα neonates, these animals exhibit normal blood acylcarnitine profiles. Furthermore, quantitative metabolic fate mapping of the medium-chain fatty acid [(13)C]octanoate in neonatal mouse livers revealed normal contribution of this fatty acid to the hepatic TCA cycle. Interestingly, octanoate-derived carbon labeled glucose uniquely in livers of PPARα-KO neonates. Relative hypoketonemia in newborn PPARα-KO animals could be mechanistically linked to a 50% decrease in de novo hepatic ketogenesis from labeled octanoate. Decreased ketogenesis was associated with diminished mRNA and protein abundance of the fate-committing ketogenic enzyme mitochondrial 3-hydroxymethylglutaryl-CoA synthase (HMGCS2) and decreased protein abundance of the ketogenic enzyme β-hydroxybutyrate dehydrogenase 1 (BDH1). Finally, hepatic triglyceride and free fatty acid concentrations were increased 6.9- and 2.7-fold, respectively, in suckling PPARα-KO neonates. Together, these findings indicate a primary defect of gluconeogenesis from glycerol and an important role for PPARα-dependent ketogenesis in the disposal of hepatic fatty acids during the neonatal period. Copyright © 2014 the American Physiological Society.

Discovery of an Orally Bioavailable Benzimidazole Diacylglycerol Acyltransferase 1 (DGAT1) Inhibitor That Suppresses Body Weight Gain in Diet-Induced Obese Dogs and Postprandial Triglycerides in Humans.

Science.gov (United States)

Nakajima, Katsumasa; Chatelain, Ricardo; Clairmont, Kevin B; Commerford, Renee; Coppola, Gary M; Daniels, Thomas; Forster, Cornelia J; Gilmore, Thomas A; Gong, Yongjin; Jain, Monish; Kanter, Aaron; Kwak, Youngshin; Li, Jingzhou; Meyers, Charles D; Neubert, Alan D; Szklennik, Paul; Tedesco, Vivienne; Thompson, James; Truong, David; Yang, Qing; Hubbard, Brian K; Serrano-Wu, Michael H

2017-06-08

Modification of a gut restricted class of benzimidazole DGAT1 inhibitor 1 led to 9 with good oral bioavailability. The key structural changes to 1 include bioisosteric replacement of the amide with oxadiazole and α,α-dimethylation of the carboxylic acid, improving DGAT1 potency and gut permeability. Since DGAT1 is expressed in the small intestine, both 1 and 9 can suppress postprandial triglycerides during acute oral lipid challenges in rats and dogs. Interestingly, only 9 was found to be effective in suppressing body weight gain relative to control in a diet-induced obese dog model, suggesting the importance of systemic inhibition of DGAT1 for body weight control. 9 has advanced to clinical investigation and successfully suppressed postprandial triglycerides during an acute meal challenge in humans.

Age-Dependent Human Hepatic Carboxylesterase 1 (Ces1) and Carboxylesterase 2 (Ces2) Postnatal Ontogeny

Science.gov (United States)

Human hepatic carboxylesterase 1 and 2 (CES1 and CES2) are important for ester- and amide- bond containing pharmaceutical and environmental chemical disposition. Despite concern regarding juvenile sensitivity to such compounds, CES1 and CES2 ontogeny has not been well characteriz...

Profiling of hepatic gene expression in rats treated with fibric acid analogs

International Nuclear Information System (INIS)

Cornwell, Paul D.; Souza, Angus T. de; Ulrich, Roger G.

2004-01-01

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal β-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPARα activation, although signaling through other receptors (e.g. PPARγ, RXR) or through non-receptor pathways cannot be excluded

Seroprevalence of hepatitis and human immuno-deficiency virus in multitransfused patients from a pediatric hematology clinic

Directory of Open Access Journals (Sweden)

Suar Çakı Kılıç

2008-12-01

Full Text Available OBJECTIVE: Transfusion transmitted hepatitis has been a severe problem in Turkey in pediatric cancer patients and in chronic congenital anemia. The aim of the present study was to investigate the prevalence of hepatitis B, hepatitis C and human immunodeficiency virus infections in these patients in a University Hospital. METHODS: Multi-transfused 66 children (59 acute leukemia, 6 thalassemia major, 1 severe hereditary spherocytosis diagnosed and followed-up between May, 2000 and December, 2006 were evaluated. Screening of all the patients for HbsAg, anti-HBs, anti-HBc, anti-HCV and anti-HIV was performed at presentation and during the last follow-up. Serologic studies of leukemic patients were also repeated at the end of the chemotherapy. Hepatitis B vaccination was administered to unvaccinated patients with anemia. All blood products were provided by Blood Bank of the Center. RESULTS: No patient was found HBsAg, anti-HCV or anti-HIV positive at diagnosis and at the end of the therapy. There was history of hepatitis B vaccination in only 42% of the patients at diagnosis due to administration of this vaccine to newborns since 1998. At the beginning of the study, 45 % (n=27 of the leukemic patients were immune for hepatitis B, but after completion of the intensive chemotherapy seropositivity persisted in only 28.8 % (n=17. CONCLUSION: Transmission of these viruses is no longer a real problem even in multitransfused immunosuppressed children in Pediatric Hematology Units as a result of the improvements in screening of voluntary blood donors, administration of disposable material in clinics and vaccination by hepatitis B.

Optical diagnostic of hepatitis B (HBV) and C (HCV) from human blood serum using Raman spectroscopy

International Nuclear Information System (INIS)

Anwar, Shahzad; Firdous, Shamaraz

2015-01-01

Hepatitis is the second most common disease worldwide with half of the cases arising in the developing world. The mortality associated with hepatitis B and C can be reduced if the disease is detected at the early stages of development. The aim of this study was to investigate the potential of Raman spectroscopy as a diagnostic tool to detect biochemical changes accompanying hepatitis progression. Raman spectra were acquired from 20 individuals with six hepatitis B infected patients, six hepatitis C infected patients and eight healthy patients in order to gain an insight into the determination of biochemical changes for early diagnostic. The human blood serum was examined at a 532 nm excitation laser source. Raman characteristic peaks were observed in normal sera at 1006, 1157 and 1513 cm −1 , while in the case of hepatitis B and C these peaks were found to be blue shifted with decreased intensity. New Raman peaks appeared in HBV and HCV infected sera at 1194, 1302, 844, 905, 1065 and 1303 cm −1 respectively. A Mat lab subroutine and frequency domain filter program is developed and applied to signal processing of Raman scattering data. The algorithms have been successfully applied to remove the signal noise found in experimental scattering signals. The results show that Raman spectroscopy displays a high sensitivity to biochemical changes in blood sera during disease progression resulting in exceptional prediction accuracy when discriminating between normal and malignant. Raman spectroscopy shows enormous clinical potential as a rapid non-invasive diagnostic tool for hepatitis and other infectious diseases. (letter)

Optical diagnostic of hepatitis B (HBV) and C (HCV) from human blood serum using Raman spectroscopy

Science.gov (United States)

Anwar, Shahzad; Firdous, Shamaraz

2015-06-01

Hepatitis is the second most common disease worldwide with half of the cases arising in the developing world. The mortality associated with hepatitis B and C can be reduced if the disease is detected at the early stages of development. The aim of this study was to investigate the potential of Raman spectroscopy as a diagnostic tool to detect biochemical changes accompanying hepatitis progression. Raman spectra were acquired from 20 individuals with six hepatitis B infected patients, six hepatitis C infected patients and eight healthy patients in order to gain an insight into the determination of biochemical changes for early diagnostic. The human blood serum was examined at a 532 nm excitation laser source. Raman characteristic peaks were observed in normal sera at 1006, 1157 and 1513 cm-1, while in the case of hepatitis B and C these peaks were found to be blue shifted with decreased intensity. New Raman peaks appeared in HBV and HCV infected sera at 1194, 1302, 844, 905, 1065 and 1303 cm-1 respectively. A Mat lab subroutine and frequency domain filter program is developed and applied to signal processing of Raman scattering data. The algorithms have been successfully applied to remove the signal noise found in experimental scattering signals. The results show that Raman spectroscopy displays a high sensitivity to biochemical changes in blood sera during disease progression resulting in exceptional prediction accuracy when discriminating between normal and malignant. Raman spectroscopy shows enormous clinical potential as a rapid non-invasive diagnostic tool for hepatitis and other infectious diseases.

Hypolipidemic effect of dietary pea proteins: Impact on genes regulating hepatic lipid metabolism.

Science.gov (United States)

Rigamonti, Elena; Parolini, Cinzia; Marchesi, Marta; Diani, Erika; Brambilla, Stefano; Sirtori, Cesare R; Chiesa, Giulia

2010-05-01

Controversial data on the lipid-lowering effect of dietary pea proteins have been provided and the mechanisms behind this effect are not completely understood. The aim of the study was to evaluate a possible hypolipidemic activity of a pea protein isolate and to determine whether pea proteins could affect the hepatic lipid metabolism through regulation of genes involved in cholesterol and fatty acid homeostasis. Rats were fed Nath's hypercholesterolemic diets for 28 days, the protein sources being casein or a pea protein isolate from Pisum sativum. After 14 and 28 days of dietary treatment, rats fed pea proteins had markedly lower plasma cholesterol and triglyceride levels than rats fed casein (pPea protein-fed rats displayed higher hepatic mRNA levels of LDL receptor versus those fed casein (ppea protein-fed rats than in rats fed casein (ppea proteins in rats. Moreover, pea proteins appear to affect cellular lipid homeostasis by upregulating genes involved in hepatic cholesterol uptake and by downregulating fatty acid synthesis genes.

Hepatitis B and C virus co-infections in human immunodeficiency virus positive North Indian patients

Science.gov (United States)

Gupta, Swati; Singh, Sarman

2006-01-01

AIM: To determine the prevalence of hepatitis B and C virus infections in human immunodeficiency virus (HIV) -positive patients at a tertiary care hospital in New Delhi, India. METHODS: Serum samples from 451 HIV positive patients were analyzed for HBsAg and HCV antibodies during three years (Jan 2003-Dec 2005). The control group comprised of apparently healthy bone-marrow and renal donors. RESULTS: The study population comprised essentially of heterosexually transmitted HIV infection. The prevalence rate of HBsAg in this population was 5.3% as compared to 1.4% in apparently healthy donors (P < 0.001). Though prevalence of HCV co-infection (2.43%) was lower than HBV in this group of HIV positive patients, the prevalence was significantly higher (P < 0.05) than controls (0.7%). Triple infection of HIV, HBV and HCV was not detected in any patient. CONCLUSION: Our study shows a significantly high prevalence of hepatitis virus infections in HIV infected patients. Hepatitis viruses in HIV may lead to faster progression to liver cirrhosis and a higher risk of antiretroviral therapy induced hepatotoxicity. Therefore, it would be advisable to detect hepatitis virus co-infections in these patients at the earliest. PMID:17106941

Triglycerides and carotid intima-media thickness in ischemic stroke patients.

Science.gov (United States)

Batluk, Jana; Leonards, Christopher O; Grittner, Ulrike; Lange, Kristin Sophie; Schreiber, Stephan J; Endres, Matthias; Ebinger, Martin

2015-11-01

Common carotid artery intima-media thickness (CCA-IMT) is an established marker for atherosclerosis. The role of triglycerides in CCA-IMT remains controversial. We sought to determine if elevated fasting and post-challenge triglycerides are associated with CCA-IMT. All acute ischemic stroke patients who participated in the Berlin "Cream & Sugar" study in the Charité Virchow and Charité Mitte Campuses between January 2009 and January 2014 and underwent carotid artery ultrasound studies were eligible for inclusion. A combined oral glucose and triglyceride tolerance test was performed 3-7 days after first ever ischemic stroke. Patients were classified according to triglyceride metabolism-namely, (1) patients reaching a maximum triglyceride levels 3 h post-challenge ("fast metabolizers," n = 37), (2) patients with increasing triglycerides 4 (medium metabolizers, n = 64), and (3) 5 h post-challenge ("slow metabolizers," n = 44; 13 missing). We included 158 patients (34% female; mean age 63 years, SD 14). Absolute non-fasting triglyceride levels were positively associated with CCA-IMT. A final multiple regression model revealed that older age, more severe strokes, and higher levels of fasting triglycerides were significantly and independently associated with higher mean CCA-IMT. Older age, higher waist-to-hip ratio, and higher levels of thyroid-stimulating hormone were independently associated with higher maximum CCA-IMT. Fasting triglycerides but not post-challenge triglycerides associate with CCA-IMT. An oral fat challenge may not add information on atherosclerotic status in ischemic stroke patients. The Berlin "Cream & Sugar" study is registered with EudraCT (2009-010356-97) and clinicaltrials.gov (NCT 01378468). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Lipase-nanoporous gold biocomposite modified electrode for reliable detection of triglycerides.

Science.gov (United States)

Wu, Chao; Liu, Xueying; Li, Yufei; Du, Xiaoyu; Wang, Xia; Xu, Ping

2014-03-15

For triglycerides biosensor design, protein immobilization is necessary to create the interface between the enzyme and the electrode. In this study, a glassy carbon electrode (GCE) was modified with lipase-nanoporous gold (NPG) biocomposite (denoted as lipase/NPG/GCE). Due to highly conductive, porous, and biocompatible three-dimensional structure, NPG is suitable for enzyme immobilization. In cyclic voltammetry experiments, the lipase/NPG/GCE bioelectrode displayed surface-confined reaction in a phosphate buffer solution. Linear responses were obtained for tributyrin concentrations ranging from 50 to 250 mg dl(-1) and olive oil concentrations ranging from 10 to 200 mg dl(-1). The value of apparent Michaelis-Menten constant for tributyrin was 10.67 mg dl(-1) and the detection limit was 2.68 mg dl(-1). Further, the lipase/NPG/GCE bioelectrode had strong anti-interference ability against urea, glucose, cholesterol, and uric acid as well as a long shelf-life. For the detection of triglycerides in human serum, the values given by the lipase/NPG/GCE bioelectrode were in good agreement with those of an automatic biochemical analyzer. These properties along with a long self-life make the lipase/NPG/GCE bioelectrode an excellent choice for the construction of triglycerides biosensor. © 2013 Elsevier B.V. All rights reserved.

A murine model of type 2 autoimmune hepatitis: Xenoimmunization with human antigens.

Science.gov (United States)

Lapierre, Pascal; Djilali-Saiah, Idriss; Vitozzi, Susana; Alvarez, Fernando

2004-04-01

Autoimmune hepatitis (AIH) is characterized by an immune-mediated injury of the hepatic parenchyma of unknown pathogenesis. Type 2 AIH is identified by the presence of anti-liver-kidney microsomes type 1 (anti-LKM1) and anti-liver cytosol type 1 (anti-LC1) autoantibodies. The current study shows that a murine model of AIH can be generated by DNA immunization against type 2 AIH self-antigens (P450 2D6 and formiminotransferase-cyclodeaminase). A pCMV plasmid containing the N-terminal region of mouse CTLA-4 and the antigenic region of human CYP2D6 (672-1,377 bp) and human formiminotransferase cyclodeaminase (FTCD; 1,232-1,668 bp) was used for DNA immunization of C57BL/6 female mice. Immunized mice showed elevated levels of alanine aminotransferase (ALT), with peaks at 4 and 7 months postinjection. Periportal, portal, and intralobular liver inflammatory infiltrates were observed at histology. Mainly CD4+ lymphocytes, but also CD8+ and B lymphocytes, were found in the liver. Cytotoxic-specific T cells were found in both the liver and spleen of these animals. Mice developed anti-LKM1 and anti-LC1 antibodies of immunoglobulin G2 (IgG2) subclass, against specific mouse autoantigens. The ALT levels correlated with both the presence of anti-LKM1/anti-LC1 antibodies and the presence of liver necroinflammation. In conclusion, in mice, DNA immunization against human autoantigens breaks tolerance and induces an autoimmune liver disease. Molecular mimicry between foreign and self-antigens explains the liver injury. This model of AIH resembles human type 2 AIH and will be helpful for the study of its pathogenesis.

In vivo activity of a mixture of two human monoclonal antibodies (anti-HBs) in a chronic hepatitis B virus carrier chimpanzee

NARCIS (Netherlands)

R. Heijtink; W. Paulij; P.A.C. van Bergen (Patrick); M.H. van Roosmalen (Mark); D. Rohm; B. Eichentopf (Bertram); E. Muchmore; A.D.M.E. Osterhaus (Albert); R.A. de Man (Robert)

1999-01-01

textabstractA 35-year-old female hepatitis B virus carrier chimpanzee was infused with one dose of a mixture of human monoclonal antibodies 9H9 and 4-7B (antibodies against hepatitis B virus surface antigen; HBsAg). Blood samples were taken before and up to 3 weeks

Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice.

Science.gov (United States)

Tsuchida, Takuma; Shiraishi, Muneshige; Ohta, Tetsuya; Sakai, Kaoru; Ishii, Shinichi

2012-07-01

Type 2 diabetes mellitus is frequently accompanied by fatty liver/nonalcoholic fatty liver disease. Hence, accumulation of lipids in the liver is considered to be one of the risk factors for insulin resistance and metabolic syndrome. Ursodeoxycholic acid (UDCA) is widely used for the treatment of liver dysfunction. We investigated the therapeutic effects of UDCA on type 2 diabetes mellitus exacerbating hepatic steatosis and the underlying mechanisms of its action using KK-A(y) mice fed a high-fat diet. KK-A(y) mice were prefed a high-fat diet; and 50, 150, and 450 mg/kg of UDCA was orally administered for 2 or 3 weeks. Administration of UDCA decreased fasting hyperglycemia and hyperinsulinemia. Hyperinsulinemic-euglycemic clamp analyses showed that UDCA improved hepatic (but not peripheral) insulin resistance. Hepatic triglyceride and cholesterol contents were significantly reduced by treatment with UDCA, although the genes involved in the synthesis of fatty acids and cholesterol, including fatty acid synthase and 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase, were upregulated. Fecal levels of bile acids, neutral sterols, fatty acids, and phospholipids were significantly increased by UDCA treatment. The gene expression levels and protein phosphorylation levels of endoplasmic reticulum stress markers were not changed by UDCA treatment. These results indicate that UDCA ameliorates hyperglycemia and hyperinsulinemia by improving hepatic insulin resistance and steatosis in high-fat diet-fed KK-A(y) mice. Reduction of hepatic lipids might be due to their excretion in feces, followed by enhanced utilization of glucose for the synthesis of fatty acids and cholesterol. Ursodeoxycholic acid should be effective for the treatment of type 2 diabetes mellitus accompanying hepatic steatosis. Copyright © 2012 Elsevier Inc. All rights reserved.

Acute Effects of Morning Light on Plasma Glucose and Triglycerides in Healthy Men and Men with Type 2 Diabetes

Science.gov (United States)

Versteeg, Ruth I.; Stenvers, Dirk J.; Visintainer, Dana; Linnenbank, Andre; Tanck, Michael W.; Zwanenburg, Gooitzen; Smilde, Age K.; Fliers, Eric; Kalsbeek, Andries; Serlie, Mireille J.; la Fleur, Susanne E.; Bisschop, Peter H.

2017-01-01

Ambient light intensity is signaled directly to hypothalamic areas that regulate energy metabolism. Observational studies have shown associations between ambient light intensity and plasma glucose and lipid levels, but human data on the acute metabolic effects of light are scarce. Since light is the main signal indicating the onset of the diurnal phase of physical activity and food intake in humans, we hypothesized that bright light would affect glucose and lipid metabolism. Therefore, we determined the acute effects of bright light on plasma glucose and lipid concentrations in 2 randomized crossover trials: (1) in 8 healthy lean men and (2) in 8 obese men with type 2 diabetes. From 0730 h, subjects were exposed to either bright light (4000 lux) or dim light (10 lux) for 5 h. After 1 h of light exposure, subjects consumed a 600-kcal mixed meal. Primary endpoints were fasting and postprandial plasma glucose levels. In healthy men, bright light did not affect fasting or postprandial plasma glucose levels. However, bright light increased fasting and postprandial plasma triglycerides. In men with type 2 diabetes, bright light increased fasting and postprandial glucose levels. In men with type 2 diabetes, bright light did not affect fasting triglyceride levels but increased postprandial triglyceride levels. We show that ambient light intensity acutely affects human plasma glucose and triglyceride levels. Our findings warrant further research into the consequences of the metabolic effects of light for the diagnosis and prevention of hyperglycemia and dyslipidemia. PMID:28470119

Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

Science.gov (United States)

Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

2016-02-01

Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition

Hepatitis C Virus Core Protein Decreases Lipid Droplet Turnover

Science.gov (United States)

Harris, Charles; Herker, Eva; Farese, Robert V.; Ott, Melanie

2011-01-01

Steatosis is a frequent complication of hepatitis C virus infection. In mice, this condition is recapitulated by the expression of a single viral protein, the nucleocapsid core. Core localizes to the surface of lipid droplets (LDs) in infected liver cells through a process dependent on host diacylglycerol acyltransferase 1 (DGAT1), an enzyme that synthesizes triglycerides in the endoplasmic reticulum. Whether DGAT1 also plays a role in core-induced steatosis is uncertain. Here, we show that mouse embryonic fibroblasts isolated from DGAT1−/− mice are protected from core-induced steatosis, as are livers of DGAT1−/− mice expressing core, demonstrating that the steatosis is DGAT1-dependent. Surprisingly, core expression did not increase DGAT1 activity or triglyceride synthesis, thus excluding the possibility that core activates DGAT1 to cause steatosis. Instead, we find that DGAT1-dependent localization of core to LDs is a prerequisite for the steatogenic properties of the core. Using biochemical and immunofluorescence microscopy techniques, we show that the turnover of lipids in core-coated droplets is decreased, providing a physiological mechanism for core-induced steatosis. Our results support a bipartite model in which core first requires DGAT1 to gain access to LDs, and then LD-localized core interferes with triglyceride turnover, thus stabilizing lipid droplets and leading to steatosis. PMID:21984835

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

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

Changes in distribution of hepatic blood flow induced by intra-arterial infusion of angiotensin II in human hepatic cancer

International Nuclear Information System (INIS)

Sasaki, Y.; Imaoka, S.; Hasegawa, Y.

1985-01-01

Changes in the distribution of the hepatic blood flow induced by intra-arterial infusion of angiotensin II (AT-II) were studied in human hepatic cancers using extremely short-lived radioisotope (RI) (krypton 81 m [/sup 81m/Kr]; half-life, 13 seconds). After the start of continuous infusion of AT-II, the radioactivity of the tumor showed about a two-fold increase, whereas that of the nontumor region decreased to about one half as much as the level before the infusion. Consequently, the mean ratio of the arterial blood flow in the tumor region to that in the nontumor region (T/N ratio) increased to 3.30 (P less than 0.001). The T/N ratio showed a peak before the peripheral blood pressure reached the maximum, and thereafter tended to decrease. Intra-arterial infusion of AT-II raised the T/N ratio more obviously than did intravenous infusion of the drug, with less rise in the peripheral blood pressure. It is believed that intra-arterial infusion chemotherapy with local use of AT-II enables better accessibility of chemotherapeutic drugs to tumors

2-heptyl-formononetin increases cholesterol and induces hepatic steatosis in mice

DEFF Research Database (Denmark)

Andersen, Charlotte; Schjoldager, Janne Gram; Tortzen, Christian

2013-01-01

Consumption of isoflavones may prevent adiposity, hepatic steatosis, and dyslipidaemia. However, studies in the area are few and primarily with genistein. This study investigated the effects of formononetin and its synthetic analogue, 2-heptyl-formononetin (C7F), on lipid and cholesterol metabolism...... in C57BL/6J mice. The mice were fed a cholesterol-enriched diet for five weeks to induce hypercholesterolemia and were then fed either the cholesterol-enriched diet or the cholesterol-enriched diet-supplemented formononetin or C7F for three weeks. Body weight and composition, glucose homeostasis......, and plasma lipids were compared. In another experiment, mice were fed the above diets for five weeks, and hepatic triglyceride accumulation and gene expression and histology of adipose tissue and liver were examined. Supplementation with C7F increased plasma HDL-cholesterol thereby increasing the plasma...

Natural history and treatment of hepatitis B virus and hepatitis C virus coinfection

Directory of Open Access Journals (Sweden)

Keeffe Emmet B

2005-09-01

Full Text Available Abstract Hepatitis B virus (HBV and hepatitis C virus (HCV coinfection is not uncommon as a result of similar routes of infection. Patients who are coinfected represent a unique group with diverse serologic profiles. Combined chronic hepatitis B and C leads to more severe liver disease and an increased risk of hepatocellular carcinoma. Furthermore, coinfected patients represent a treatment challenge. No standard recommendations exist for treatment of viral hepatitis due to dual HBV/HCV infection, and therefore treatment must be individualized based on patient variables such as serologic and virologic profiles, patient's prior exposure to antiviral treatment, and the presence of other parenterally transmitted viruses such as hepatitis D virus and human immunodeficiency virus. The natural history and treatment of patients with HBV and HCV coinfection is reviewed.

Detection of Osteopontin in the pericyst of human hepatic Echinococcus granulosus.

Science.gov (United States)

Peng, Xinyu; Li, Jianhui; Wu, Xiangwei; Zhang, Shijie; Niu, Jianhua; Chen, Xiaoping; Yao, Jin; Sun, Hong

2006-12-01

It aims at investigating the expression and distribution of the Osteopontin (OPN) in the pericyst of human hepatic Echinococcus granulosus and their related significances. Sixty pericysts excised by "sub-adventitial cystectomy" were studied. OPN was detected in 80% (48/60) of cysts by Western blotting and distributed in the side of "exocyst" layer directing to the parasite, also macrophages were identified in the vicinity of OPN by immunohistochemistry staining. The coexpression of OPN and CD68 was observed by immunofluorescence double labeling and analyzed by Image-Pro Plus 5.1; with special stain techniques, variable degrees of calcium deposits were observed in 80% (48/60) cysts, and the calcium deposits concurrencely found with the OPN expression. The selective distribution of OPN, calcium in the "exocyst" provides a new pathological evidence for the "sub-adventitial cystectomy" we developed. The pericyst of hepatic E. granulosus consists of two detachable layers with different formative mechanisms: the "exocyst" layer directing towards the cyst of parasite was the result of granulomatous reaction; also the results suggest OPN is one regulator in the granulomatous reaction and calcification of "exocyst".

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....

Giving It Our Best Shot? Human Papillomavirus and Hepatitis B Virus Immunization Among Refugees, Massachusetts, 2011-2013.

Science.gov (United States)

Berman, Rachel Stein; Smock, Laura; Bair-Merritt, Megan H; Cochran, Jennifer; Geltman, Paul L

2017-06-22

The receipt rate of hepatitis B virus vaccine among adolescents in the United States is high, while the receipt rate of human papillomavirus vaccine is low. Rates have not been closely studied among refugees, whose home countries have high rates of disease caused by these viruses. We examined human papillomavirus and hepatitis B virus immunization rates among 2,269 refugees aged 9 to 26 years who resettled in Massachusetts from 2011 through 2013. This was a secondary analysis of data from their medical screenings. We used binary logistic regression to assess characteristics associated with immunization and bivariate analyses to compare refugee immunization rates with those of the general US population. Forty-five percent of US adolescents aged 13 to 17 years received 1 dose of human papillomavirus vaccine, compared with 68% of similarly aged refugees. Males (adjusted odds ratio [aOR], 0.62; 95% confidence interval [CI], 0.52-0.74), refugees older than 13 years (aOR, 0.74; 95% CI, 0.60-0.93), and refugees not from Sub-Saharan Africa (aOR, 0.74; 95% CI, 0.59-0.92) were less likely to receive human papillomavirus vaccine, while arrivals in 2012 through 2013 were more likely (aOR, 1.6; 95% CI, 1.3-1.9) than those arriving in 2011. Refugees older than 13 years were less likely to receive 2 doses of hepatitis B virus vaccine (aOR, 0.49; 95% CI, 0.37-0.63) than older refugees. Specialized post-arrival health assessment may improve refugees' immunization rates.

Hypercholesterolemia and hepatic steatosis in mice fed on low-cost high-fat diet - doi: 10.4025/actascihealthsci.v35i1.10871

Directory of Open Access Journals (Sweden)

Lívia Bracht

2013-03-01

Full Text Available To verify whether high-fat diet prepared from commercial diet plus chocolate, roasted peanuts and corn cookies induces hypercholesterolemia in mice and whether there is any hepatic involvement in this type of animal testing. Swiss mice received a high-fat diet for 15 and 30 days; plasma cholesterol, triglycerides and glucose rates were determined. Hepatic impairment was evaluated by histopathological analysis. Cholesterol levels increased 43% in animals treated with high-fat diet for 30 days. Further, histopathological analysis revealed that treatment of animals for 15 and 30 days produced hepatic steatosis and steatohepatitis, respectively. Experimental model is suitable for assessing the action of anti-hypercholesterolemia and the treatment of steatohepatitis.  

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

Early Life Exposure to Fructose Alters Maternal, Fetal and Neonatal Hepatic Gene Expression and Leads to Sex-Dependent Changes in Lipid Metabolism in Rat Offspring

Science.gov (United States)

Clayton, Zoe E.; Vickers, Mark H.; Bernal, Angelica; Yap, Cassandra; Sloboda, Deborah M.

2015-01-01

Aim Fructose consumption is associated with altered hepatic function and metabolic compromise and not surprisingly has become a focus for perinatal studies. We have previously shown that maternal fructose intake results in sex specific changes in fetal, placental and neonatal outcomes. In this follow-up study we investigated effects on maternal, fetal and neonatal hepatic fatty acid metabolism and immune modulation. Methods Pregnant rats were randomised to either control (CON) or high-fructose (FR) diets. Fructose was given in solution and comprised 20% of total caloric intake. Blood and liver samples were collected at embryonic day 21 (E21) and postnatal day (P)10. Maternal liver samples were also collected at E21 and P10. Liver triglyceride and glycogen content was measured with standard assays. Hepatic gene expression was measured with qPCR. Results Maternal fructose intake during pregnancy resulted in maternal hepatic ER stress, hepatocellular injury and increased levels of genes that favour lipogenesis. These changes were associated with a reduction in the NLRP3 inflammasome. Fetuses of mothers fed a high fructose diet displayed increased hepatic fructose transporter and reduced fructokinase mRNA levels and by 10 days of postnatal age, also have hepatic ER stress, and elevated IL1β mRNA levels. At P10, FR neonates demonstrated increased hepatic triglyceride content and particularly in males, associated changes in the expression of genes regulating beta oxidation and the NLRP3 inflammasome. Further, prenatal fructose results in sex-dependant changes in levels of key clock genes. Conclusions Maternal fructose intake results in age and sex-specific alterations in maternal fetal and neonatal free fatty acid metabolism, which may be associated in disruptions in core clock gene machinery. How these changes are associated with hepatic inflammatory processes is still unclear, although suppression of the hepatic inflammasome, as least in mothers and male neonates may

Randomized Trial: Immunogenicity and Safety of Coadministered Human Papillomavirus-16/18 AS04-Adjuvanted Vaccine and Combined Hepatitis A and B Vaccine in Girls

DEFF Research Database (Denmark)

Pedersen, Court; Breindahl, Morten; Aggarwal, Naresh

2012-01-01

This randomized, open, controlled, multicenter study (110886/NCT00578227) evaluated human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine (HPV-16/18 vaccine) coadministered with inactivated hepatitis A and B (HAB) vaccine. Coprimary objectives were to demonstrate noninferiority of hepatitis A......, hepatitis B, and HPV-16/18 immune responses at month 7 when vaccines were coadministered, compared with the same vaccines administered alone....

Human immunodeficiency virus (HIV) seropositivity and hepatitis B surface antigenemia (HBSAG) among blood donors in Benin city, Edo state, Nigeria.

Science.gov (United States)

Umolu, Patience Idia; Okoror, Lawrence Ehis; Orhue, Philip

2005-03-01

Human Immunodeficiency Virus and Hepatitis B virus are blood borne pathogens that can be transmitted through blood transfusion and could pose a huge problem in areas where mechanisms of ensuring blood safety are suspect. This study became necessary in a population where most of the blood for transfusion is from commercial blood donors. A total of 130 donors comprising 120 commercial donors and 10 voluntary donors were tested for antibodies to human immunodeficiency virus and hepatitis B surface antigen in Benin city using Immunocomb HIV - 1 and 2 Biospot kit and Quimica Clinica Aplicada direct latex agglutination method respectively. Thirteen (10%) samples were HIV seropositive and 7(5.8%) were HBsAg positive. The age bracket 18 - 25years had the highest numbers of donors and also had the highest number of HBsAg positive cases (7.8%) while the age group 29 - 38years had highest number of HIV seropositive cases. High prevalence of HIV antibodies and Hepatitis B surface antigen was found among commercial blood donors. Appropriate and compulsory screening of blood donors using sensitive methods, must be ensured to prevent post transfusion hepatitis and HIV.

[Progress in research of the mechanisms related with the hepatic steatosis in the nonalcoholic fatty liver disease].

Science.gov (United States)

Shi, Li-Juan; Song, Guang-Yao

2013-12-01

With the increased morbidity of Nonalcoholic fatty liver disease, the pathogenesis of which has become one of the focuses for researchers. Many details need to be clarified. The hepatic steatosis has been taken as the clinical pathological characters and the "golden standard of diagnosis" for the nonalcoholic fatty liver disease. More and more studies have shown that the hepatic steatosis (mainly as triglycerides) is the consequence of hepatic lipid metabolism disequilibrium. Generally, the related metabolism pathways including lipid input, lipid uptake, de novo lipogenesis, fatty acid oxidation, fatty acid reesterification, and lipid secretion etc. In this review, we focused on the progress of some key enzymes involved in these pathways in order to clarify the possible molecular mechanisms and the effective targets so that to broad our vision about the prevention and treatment of non-alcoholic fatty liver disease.

Human leukocyte antigen-e alleles are associated with hepatitis c virus, torque teno virus, and toxoplasma co-infections but are not associated with hepatitis b virus, hepatitis d virus, and GB virus c co-infections in human immunodeficiency virus patients

Directory of Open Access Journals (Sweden)

Afiono Agung Prasetyo

2016-01-01

Full Text Available Context: Data regarding the distribution of Human Leukocyte Antigen (HLA-E alleles and their association with blood-borne pathogen infections/co-infections are limited for many populations, including Indonesia. Aims: The aim of this study was to analyze the association between HLA-E allelic variants and infection with blood-borne pathogens such as hepatitis B virus (HBV, hepatitis C virus (HCV, hepatitis D virus (HDV, torque teno virus (TTV, GB virus C (GBV-C, and Toxoplasma gondii (T. gondii in Indonesian Javanese human immunodeficiency virus (HIV patients. Settings and Design: A total of 320 anti-HIV-positive blood samples were analyzed for HBV, HCV, HDV, TTV, GBV-C, and T. gondii infection status and its association with HLA-E allelic variants. Materials and Methods: Nucleic acid was extracted from plasma samples and used for the molecular detection of HBV DNA, HCV RNA, HDV RNA, TTV DNA, and GBV-C RNA, whereas hepatitis B surface antigen, anti-HCV, immunoglobulin M and G (IgM and IgG anti-T. gondii were detected through serological testing. The blood samples were genotyped for HLA-E loci using a sequence-specific primer-polymerase chain reaction. Statistical Analysis Used: Either the Chi-square or Fisher′s exact test was performed to analyze the frequency of HLA-E alleles and blood-borne pathogen infections in the population. Odds ratios (ORs were calculated to measure the association between the antibodies found and the participants′ possible risk behaviors. A logistic regression analysis was used to assess the associations. Results: HLA-EFNx010101/0101 was associated with HCV/TTV co-infection (adjusted OR [aOR]: 3.5; 95% confidence interval [CI]: 1.156-10.734; P = 0.027 and IgM/IgG anti-Toxo positivity (aOR: 27.0; 95% CI: 3.626-200.472; P = 0.001. HLA-EFNx010103/0103 was associated with TTV co-infection (aOR: 2.7; 95% CI: 1.509-4.796; P = 0.001. Conclusions: HLA-E alleles in Indonesian Javanese HIV patients were found to be associated

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)

Antilipogenic and Anti-Inflammatory Activities of Codonopsis lanceolata in Mice Hepatic Tissues after Chronic Ethanol Feeding

Directory of Open Access Journals (Sweden)

Areum Cha

2012-01-01

Full Text Available This study evaluated the antilipogenic and anti-inflammatory effects of Codonopsis lanceolata (C. lanceolata root extract in mice with alcohol-induced fatty liver and elucidated its underlying molecular mechanisms. Ethanol was introduced into the liquid diet by mixing it with distilled water at 5% (wt/v, providing 36% of the energy, for nine weeks. Among the three different fractions prepared from the C. lanceolata root, the C. lanceolata methanol extract (CME exhibited the most remarkable attenuation of alcohol-induced fatty liver with respect to various parameters such as hepatic free fatty acid concentration, body weight loss, and hepatic accumulations of triglyceride and cholesterol. The hepatic gene and protein expression levels were analysed via RT-PCR and Western blotting, respectively. CME feeding significantly restored the ethanol-induced downregulation of the adiponectin receptor (adipoR 1 and of adipoR2, along with their downstream molecules. Furthermore, the study data showed that CME feeding dramatically reversed ethanol-induced hepatic upregulation of toll-like receptor- (TLR- mediated signaling cascade molecules. These results indicate that the beneficial effects of CME against alcoholic fatty livers of mice appear to be with adenosine- and adiponectin-mediated regulation of hepatic steatosis and TLR-mediated modulation of hepatic proinflammatory responses.

Current Knowledge on Hepatitis E.

Science.gov (United States)

Pérez-Gracia, María Teresa; García, Mario; Suay, Beatriz; Mateos-Lindemann, María Luisa

2015-06-28

Although only a single serotype of hepatitis E virus (HEV), the causative agent of hepatitis E, has been identified, there is great genetic variation among the different HEV isolates reported. There are at least four major recognized genotypes of HEV: genotypes 1 and 2 are mainly restricted to humans and linked to epidemic outbreaks in nonindustrialized countries, whereas genotypes 3 and 4 are zoonotic in both developing and industrialized countries. Besides human strains, genotype 3 and 4 strains of HEV have been genetically characterized from swine, sika deer, mongooses, sheep, and rabbits. Currently, there are approximately 11,000 human and animal sequences of HEV available at the International Nucleotide Sequence Database Collaboration. HEV is the major cause of waterborne outbreaks of hepatitis in areas of poor sanitation. Additionally, it is responsible for sporadic cases of viral hepatitis in not only endemic but industrialized countries as well. Transmission of HEV occurs predominantly by the fecal-oral route, although parenteral and perinatal routes have been reported. HEV infection develops in most individuals as a self-limiting, acute, icteric hepatitis; with mortality rates around 1%. However, some affected individuals will develop fulminant hepatic failure, a serious condition that is frequently fatal without a liver transplant. This complication is particularly common when the infection occurs in pregnant women, where mortality rates rise dramatically to up to 25%. Among the preventive measures available to avoid HEV infection, two separate subunit vaccines containing recombinant truncated capsid proteins of HEV have been shown to be highly effective in the prevention of disease. One of them, HEV 239, was approved in China, and its commercialization by Innovax began in November 2012 under the name Hecolin(®).

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...

Gene expression variability in human hepatic drug metabolizing enzymes and transporters.

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Lun Yang

Full Text Available Interindividual variability in the expression of drug-metabolizing enzymes and transporters (DMETs in human liver may contribute to interindividual differences in drug efficacy and adverse reactions. Published studies that analyzed variability in the expression of DMET genes were limited by sample sizes and the number of genes profiled. We systematically analyzed the expression of 374 DMETs from a microarray data set consisting of gene expression profiles derived from 427 human liver samples. The standard deviation of interindividual expression for DMET genes was much higher than that for non-DMET genes. The 20 DMET genes with the largest variability in the expression provided examples of the interindividual variation. Gene expression data were also analyzed using network analysis methods, which delineates the similarities of biological functionalities and regulation mechanisms for these highly variable DMET genes. Expression variability of human hepatic DMET genes may affect drug-gene interactions and disease susceptibility, with concomitant clinical implications.

Hepatic steatosis in transgenic mice overexpressing human histone deacetylase 1

International Nuclear Information System (INIS)

Wang, Ai-Guo; Seo, Sang-Beom; Moon, Hyung-Bae; Shin, Hye-Jun; Kim, Dong Hoon; Kim, Jin-Man; Lee, Tae-Hoon; Kwon, Ho Jeong; Yu, Dae-Yeul; Lee, Dong-Seok

2005-01-01

It is generally thought that histone deacetylases (HDACs) play important roles in the transcriptional regulation of genes. However, little information is available concerning the specific functions of individual HDACs in disease states. In this study, two transgenic mice lines were established which harbored the human HDAC1 gene. Overexpressed HDAC1 was detected in the nuclei of transgenic liver cells, and HDAC1 enzymatic activity was significantly higher in the transgenic mice than in control littermates. The HDAC1 transgenic mice exhibited a high incidence of hepatic steatosis and nuclear pleomorphism. Molecular studies showed that HDAC1 may contribute to nuclear pleomorphism through the p53/p21 signaling pathway

Common variants associated with plasma triglycerides and risk for coronary artery disease.

Science.gov (United States)

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

2013-11-01

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 variants recently mapped for plasma lipids (P triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.

Sensitive genotyping of foodborne-associated human noroviruses and hepatitis A virus using an array-based platform

Science.gov (United States)

The viral pathogens, human norovirus (NoV) and hepatitis A virus (HAV), are significant contributors of foodborne associated outbreaks. To develop a typing tool for foodborne viruses, a focused, low-density DNA microarray was developed in conjunction with a rapid and high-throughput fluorescent meth...

Is there any relationship between coronary artery disease and postprandial triglyceride levels?

Science.gov (United States)

Atar, Inci Aslı; Atar, Ilyas; Aydınalp, Alp; Ertan, Cağatay; Bozbaş, Hüseyin; Ozin, Bülent; Yıldırır, Aylin; Müderrisoğlu, Haldun

2011-05-01

We aimed to evaluate the relationship between postprandial triglyceride (PPTG) levels and coronary artery disease (CAD). A total of 80 patients were included in this prospective cohort study. Oral lipid loading was used in order to measure PPTG levels. In the fasting state and after the high fat breakfast, triglyceride levels were measured by enzymatic methods at 2nd, 4th, 6th and 8th hours. We made subgroup analysis to show the effects of lipid loading on triglyceride levels in patients with and without fasting hypertriglyceridemia. We evaluated triglyceride levels and changes of triglyceride levels in percentages after lipid loading using a general linear model for repeated measures. Sample size analysis was performed. Baseline clinical, demographic and laboratory characteristics of both groups were similar. The peak triglyceride levels were seen at the 4th hour in both groups. Triglyceride levels were significantly increased after lipid-rich-breakfast loading compared to baseline levels in both groups (p<0.001) but these changes were not significant (p=0.279). In patients with elevated fasting triglyceride levels, the area under the plasma triglyceride concentration curve was significantly larger in CAD group than control group (334±103 vs. 233±58 mg/dl, p=0.02). Our data show that in patients who have a high fasting triglyceride level, high levels of PPTG may be related to CAD, however high PPTG levels are not related to CAD in patients with normal fasting levels of triglyceride.

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

Science.gov (United States)

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

2014-07-01

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

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

Science.gov (United States)

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

2012-01-01

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

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

Directory of Open Access Journals (Sweden)

Yuki Ito

2012-01-01

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

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.

Cocoa butter and safflower oil elicit different effects on hepatic gene expression and lipid metabolism in rats.

Science.gov (United States)

Gustavsson, Carolina; Parini, Paolo; Ostojic, Jovanca; Cheung, Louisa; Hu, Jin; Zadjali, Fahad; Tahir, Faheem; Brismar, Kerstin; Norstedt, Gunnar; Tollet-Egnell, Petra

2009-11-01

The aim of this study was to compare the effects of cocoa butter and safflower oil on hepatic transcript profiles, lipid metabolism and insulin sensitivity in healthy rats. Cocoa butter-based high-fat feeding for 3 days did not affect plasma total triglyceride (TG) levels or TG-rich VLDL particles or hepatic insulin sensitivity, but changes in hepatic gene expression were induced that might lead to increased lipid synthesis, lipotoxicity, inflammation and insulin resistance if maintained. Safflower oil increased hepatic beta-oxidation, was beneficial in terms of circulating TG-rich VLDL particles, but led to reduced hepatic insulin sensitivity. The effects of safflower oil on hepatic gene expression were partly overlapping with those exerted by cocoa butter, but fewer transcripts from anabolic pathways were altered. Increased hepatic cholesterol levels and increased expression of hepatic CYP7A1 and ABCG5 mRNA, important gene products in bile acid production and cholesterol excretion, were specific effects elicited by safflower oil only. Common effects on gene expression included increased levels of p8, DIG-1 IGFBP-1 and FGF21, and reduced levels of SCD-1 and SCD-2. This indicates that a lipid-induced program for hepatic lipid disposal and cell survival was induced by 3 days of high-fat feeding, independent on the lipid source. Based on the results, we speculate that hepatic TG infiltration leads to reduced expression of SCD-1, which might mediate either neutral, beneficial or unfavorable effects on hepatic metabolism upon high-fat feeding, depending on which fatty acids were provided by the diet.

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

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.)

Engineering E. coli for triglyceride accumulation through native and heterologous metabolic reactions.

Science.gov (United States)

Rucker, Joanna; Paul, Julie; Pfeifer, Blaine A; Lee, Kyongbum

2013-03-01

Triglycerides, traditionally sourced from plant oils, are heavily used in both industrial and healthcare applications. Commercially significant products produced from triglycerides include biodiesel, lubricants, moisturizers, and oils for cooking and dietary supplements. The need to rely upon plant-based production, however, raises concerns of increasing demand and sustainability. The reliance on crop yields and a strong demand for triglycerides provides motivation to engineer production from a robust microbial platform. In this study, Escherichia coli was engineered to synthesize and accumulate triglycerides. Triglycerides were produced from cell wall phospholipid precursors through engineered expression of two enzymes, phosphatidic acid phosphatase (PAP) and diacylglycerol acyltransferase (DGAT). A liquid chromatography-mass spectrometry (LC-MS) method was developed to analyze the production of triglycerides by the engineered E. coli strains. This proof-of-concept study demonstrated a yield of 1.1 mg/L triglycerides (2 g/L dry cell weight) in lysogeny broth medium containing 5 g/L glucose at 8 h following induction of PAP and DGAT expression. LC-MS results also demonstrated that the intracellular triglyceride composition of E. coli was highly conserved. Triglycerides containing the fatty acid distributions 16:0/16:0/16:1, 16:0/16:0/18:1, and 18:1/16:0/16:1 were found in highest concentrations and represent ∼70 % of triglycerides observed.

Hepatitis B Virus X Protein Induces Hepatic Steatosis by Enhancing the Expression of Liver Fatty Acid Binding Protein.

Science.gov (United States)

Wu, Yun-Li; Peng, Xian-E; Zhu, Yi-Bing; Yan, Xiao-Li; Chen, Wan-Nan; Lin, Xu

2016-02-15

Hepatitis B virus (HBV) has been implicated as a potential trigger of hepatic steatosis although molecular mechanisms involved in the pathogenesis of HBV-associated hepatic steatosis still remain elusive. Our prior work has revealed that the expression level of liver fatty acid binding protein 1 (FABP1), a key regulator of hepatic lipid metabolism, was elevated in HBV-producing hepatoma cells. In this study, the effects of HBV X protein (HBx) mediated FABP1 regulation on hepatic steatosis and the underlying mechanism were determined. mRNA and protein levels of FABP1 were measured by quantitative RT-PCR (qPCR) and Western blotting. HBx-mediated FABP1 regulation was evaluated by luciferase assay, coimmunoprecipitation, and chromatin immunoprecipitation. Hepatic lipid accumulation was measured by using Oil-Red-O staining and the triglyceride level. It was found that expression of FABP1 was increased in HBV-producing hepatoma cells, the sera of HBV-infected patients, and the sera and liver tissues of HBV-transgenic mice. Ectopic overexpression of HBx resulted in upregulation of FABP1 in HBx-expressing hepatoma cells, whereas HBx abolishment reduced FABP1 expression. Mechanistically, HBx activated the FABP1 promoter in an HNF3β-, C/EBPα-, and PPARα-dependent manner, in which HBx increased the gene expression of HNF3β and physically interacted with C/EBPα and PPARα. On the other hand, knockdown of FABP1 remarkably blocked lipid accumulation both in long-chain free fatty acids treated HBx-expressing HepG2 cells and in a high-fat diet-fed HBx-transgenic mice. Therefore, FABP1 is a key driver gene in HBx-induced hepatic lipid accumulation via regulation of HNF3β, C/EBPα, and PPARα. FABP1 may represent a novel target for treatment of HBV-associated hepatic steatosis. Accumulating evidence from epidemiological and experimental studies has indicated that chronic HBV infection is associated with hepatic steatosis. However, the molecular mechanism underlying HBV

The role of fasting versus nonfasting triglycerides in ischemicstroke: a systematic review

Directory of Open Access Journals (Sweden)

Christopher Leonards

2010-10-01

Full Text Available Objective: To synthesize results from pertinent studies and determine if fasting and/or nonfasting triglycerides are a risk factor for ischemic stroke. Method: We performed two independent systematic literature searches using the PubMed and ScienceDirect databases to identify studies examining the relationship between fasting and nonfasting triglyceride concentrations and ischemic stroke risk. A meta-analysis was performed using ischemic stroke as a primary endpoint. Results: Twenty-five reports were identified, including 13 prospective cohort and 12 case-control studies. Baseline characteristics, study samples, methods, and primary outcomes varied. Of 13 prospective cohort studies, 9 assessed triglyceride concentrations in the fasting state. Seven of these identified triglycerides as an independent risk factor for ischemic stroke risk (n=1624 ischemic cases. Three prospective cohort studies identified a positive association between elevated nonfasting triglyceride concentrations and ischemic stroke risk (n=2050 ischemic cases. One prospective cohort study that compared fasting and nonfasting triglycerides identified only nonfasting triglycerides as an independent risk factor for ischemic stroke. Of 12 case-control studies identified, 5 identified a positive relationship between ischemic stroke risk and elevated fasting triglycerides (n=838 cases. Seven case-control studies were included in the metaanalysis (n=1996 ischemic stroke cases, revealing an odds ratio of 1.15 (95% CI, 1.08 to 1.21. Conclusions: The available data are inconsistent. The relationship between triglyceride levels and ischemic stroke needs further investigation under standardized conditions. We recommend a standardized triglyceride tolerance test to further investigate the associations between fasting versus nonfasting triglyceride levels and ischemic stroke.

Profiling of hepatic gene expression in rats treated with fibric acid analogs

Energy Technology Data Exchange (ETDEWEB)

Cornwell, Paul D.; Souza, Angus T. de; Ulrich, Roger G

2004-05-18

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors whose ligands include fatty acids, eicosanoids and the fibrate class of drugs. In humans, fibrates are used to treat dyslipidemias. In rodents, fibrates cause peroxisome proliferation, a change that might explain the observed hepatomegaly. In this study, rats were treated with multiple dose levels of six fibric acid analogs (including fenofibrate) for up to two weeks. Pathological analysis identified hepatocellular hypertrophy as the only sign of hepatotoxicity, and only one compound at the highest dose caused any significant increase in serum ALT or AST activity. RNA profiling revealed that the expression of 1288 genes was related to dose or length of treatment and correlated with hepatocellular hypertrophy. This gene list included expression changes that were consistent with increased mitochondrial and peroxisomal {beta}-oxidation, increased fatty acid transport, increased hepatic uptake of LDL-cholesterol, decreased hepatic uptake of glucose, decreased gluconeogenesis and decreased glycolysis. These changes are likely linked to many of the clinical benefits of fibrate drugs, including decreased serum triglycerides, decreased serum LDL-cholesterol and increased serum HDL-cholesterol. In light of the fact that all six compounds stimulated similar or identical changes in the expression of this set of 1288 genes, these results indicate that hepatomegaly is due to PPAR{alpha} activation, although signaling through other receptors (e.g. PPAR{gamma}, RXR) or through non-receptor pathways cannot be excluded.

Structured medium and long chain triglycerides show short-term increases in fat oxidation, but no changes in adiposity in men.

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Roynette, Catherine E; Rudkowska, Iwona; Nakhasi, Dilip K; Jones, Peter J H

2008-05-01

Medium chain triglycerides (MCT) have been suggested as modulators of human energy expenditure (EE) and thus may influence total and regional body fat distribution. To investigate in overweight men the effects of structured medium and long chain triglycerides on EE, substrate oxidation and body adiposity, compared to extra virgin olive oil (OO). In a 6 week single-blind crossover study, 23 overweight men were randomly assigned to consume a standard high-fat diet of which 75% total fat was provided as either structured medium and long chain triglycerides referred to as structured oil (StO), or OO. EE and body composition were measured using indirect calorimetry and magnetic resonance imaging, respectively, at weeks 1 and 6 of each phase. Body weight decreased (pstructured medium and long chain triglyceride oil increases short-term fat oxidation but fails to modulate body weight or adiposity through a change in EE.

Polymerized and functionalized triglycerides

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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 ...

Drug-binding ability of human serum albumin at children with chronic virus hepatitis radiochemical definition method

International Nuclear Information System (INIS)

Kim, A.A.; Dadakhanov, J.A.; Djuraeva, G.T.; Shukurov, B.V.; Mavlyanov, I.R.

2006-01-01

Full text: The chronic virus hepatitis produces numerous abnormalities of liver function. The viruses of B, C, D, F and G hepatitis possess the ability to cause chronically proceeding diseases. Earlier we have found that binding ability of serum albumin at patients with acute forms of virus hepatitis is authentically reduced in comparison with the given parameters of control group. At an acute virus hepatitis B with middle severity the reducing of binding ability of serum albumin was observed at 70 % of patients. At an acute virus hepatitis A the reduce of binding ability of serum albumin is less expressed than at acute virus hepatitis B. At of chronic virus intoxication in human organism there is a formation and accumulation of toxic compounds in the excessive concentrations, which are not inherent to a normal metabolism. One of universal mechanisms of reaction of an organism on the increasing concentration of metabolism products is formation of complexes of various compounds with blood plasma proteins. The formation in an organism of endo- and exotoxins excessive concentrations results in blocking the binding centers of albumin molecule that causes the change of its complexing ability. The purpose of the present research: investigation of binding ability of serum albumin with use of radiochemical method at children with a chronic virus hepatitis B and C. Materials and methods. Under clinical observation there were 52 children in the age from 3 till 14 years. From them at 32 the chronic virus hepatitis B was confirmed, at 20 chronic virus - hepatitis C. Etiological diagnostics was carried out by definition of specific markers of a hepatitis B and C method IFA and PCR. Binding ability of serum albumin was defined by radiochemical method with use of the tritium labeled no-spa (drotaverine hydrochloride). The control group consists from 10 conditionally health children of similar age. Results and their discussion. The results of investigation have shown, that at a

[Epidemiologic aspects of human immunodeficiency virus and hepatitis virus infections].

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Diarra, M; Konate, A; Minta, D; Sounko, A; Dembele, M; Toure, C S; Kalle, A; Traore, H H; Maiga, M Y

2006-01-01

In order to determinate the prevalence of hepatitis B virus and hepatitis C virus among patients infected by the HIV, We realized a transverse survey case--control in hepato-gastro-enterological ward and serology unity of National Institute of Research in Public health (INRSP). Our sample was constituted with 100 patients HIV positive compared to 100 controls HIV negative. The viral markers research has been made by methods immuno-enzymatiqueses of ELISA 3rd generation. Tests permitted to get the following results: Hepatitis B surface antigen (HBs Ag) was positive among 21% with patients HIV positive versus 23% among control (p = 0,732); Antibody to hepatitis C virus (anti-HCV ab) was present among 23% with patients HIV positive versus 0% among control (p <0,05). Female was predominant among co-infections patient, but without statistic link (p = 0,9 and p = 0,45); The co-infection HBV- HCV was significatively linked to age beyond 40 years (p = 0,0005). Co-infections with HIV infection and hepatitis virus are not rare and deserve to be investigated.

Internalisation of hepatitis C virus core protein by human conjunctival fibroblasts.

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Rajalakshmy, A R; Malathi, J; Madhavan, H N; Bhaskar, S; Iyer, G K

2016-01-01

Recent studies indicate that hepatitis C virus (HCV) proteins can mediate innate immune response and inflammation in conjunctival fibroblasts which contributes to the pathology of dry eye condition associated with chronic HCV infection. The present study investigates the phagocytic potential of human conjunctival fibroblasts (HCFj) for HCV core protein. HCFj cells were incubated with HCV core antigen for different periods of time, and fluorescent micrographs were taken to observe protein internalisation. HCFj cells were capable of internalising HCV core antigen within 1 h; this gives an insight into another molecular mechanism which may contribute towards HCV-associated conjunctival inflammation.

A snapshot of the hepatic transcriptome: ad libitum alcohol intake suppresses expression of cholesterol synthesis genes in alcohol-preferring (P rats.

Directory of Open Access Journals (Sweden)

Jonathon D Klein

Full Text Available Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (∼ 7.43 g ethanol/kg/day in inbred alcohol-preferring (iP10a rats. Chronic consumption led to down-regulation of nine genes in the cholesterol biosynthesis pathway, including HMG-CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake.

A snapshot of the hepatic transcriptome: ad libitum alcohol intake suppresses expression of cholesterol synthesis genes in alcohol-preferring (P) rats.

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Klein, Jonathon D; Sherrill, Jeremy B; Morello, Gabriella M; San Miguel, Phillip J; Ding, Zhenming; Liangpunsakul, Suthat; Liang, Tiebing; Muir, William M; Lumeng, Lawrence; Lossie, Amy C

2014-01-01

Research is uncovering the genetic and biochemical effects of consuming large quantities of alcohol. One prime example is the J- or U-shaped relationship between the levels of alcohol consumption and the risk of atherosclerotic cardiovascular disease. Moderate alcohol consumption in humans (about 30 g ethanol/d) is associated with reduced risk of coronary heart disease, while abstinence and heavier alcohol intake is linked to increased risk. However, the hepatic consequences of moderate alcohol drinking are largely unknown. Previous data from alcohol-preferring (P) rats showed that chronic consumption does not produce significant hepatic steatosis in this well-established model. Therefore, free-choice alcohol drinking in P rats may mimic low risk or nonhazardous drinking in humans, and chronic exposure in P animals can illuminate the molecular underpinnings of free-choice drinking in the liver. To address this gap, we captured the global, steady-state liver transcriptome following a 23 week free-choice, moderate alcohol consumption regimen (∼ 7.43 g ethanol/kg/day) in inbred alcohol-preferring (iP10a) rats. Chronic consumption led to down-regulation of nine genes in the cholesterol biosynthesis pathway, including HMG-CoA reductase, the rate-limiting step for cholesterol synthesis. These findings corroborate our phenotypic analyses, which indicate that this paradigm produced animals whose hepatic triglyceride levels, cholesterol levels and liver histology were indistinguishable from controls. These findings explain, at least in part, the J- or U-shaped relationship between cardiovascular risk and alcohol intake, and provide outstanding candidates for future studies aimed at understanding the mechanisms that underlie the salutary cardiovascular benefits of chronic low risk and nonhazardous alcohol intake.

High density lipoprotein is an inappropriate substrate for hepatic lipase in postmenopausal women.

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Zago, Valeria; Miksztowicz, Verónica; Cacciagiú, Leonardo; Basilio, Francisco; Berg, Gabriela; Schreier, Laura

2012-12-24

HDL antiatherogenic effects would not only depend on its concentration but also on its biological quality. Hepatic lipase (HL) action on HDL acts in one of the last steps of reverse cholesterol transport. Cardiovascular risk increases after menopause, however HDL does not decrease even when HL is increased. We evaluated HDL capacity as a substrate of HL in healthy postmenopausal women (PMW). We studied 20 PMW (51-60 y) and 20 premenopausal (PreMW) (26-40 y). In fasting serum, lipid-lipoprotein profile and HDL composition were assessed. Optimal assay conditions for HDL/HL ex vivo incubation were established. Increasing HDL-triglyceride concentrations (0.015 to 0.20 mmol/l) were incubated with post-heparin plasma obtained from a single healthy donor as a source of HL. Free fatty acids were measured and kinetic parameters calculated: K(m)(app), inverse to enzyme affinity, and V(max). HDL composition in PMW exhibits triglyceride enrichment (p<0.001). Kinetic analysis revealed higher K(m)(app) in PMW [130 (40-380) vs 45 (20-91) mmol/l, p<0.0001)] correlating directly with HDL-triglycerides (r=0.7, p=0.0001). Catalytic efficiency, V(max)/K(m)(app) was reduced when compared to controls (p=0.0001). Triglyceride-enriched HDL from PMW constitutes a poor substrate for HL suggesting that this particle may not exert efficiently its antiatherogenic function, regardless of plasma concentration. Copyright © 2012 Elsevier B.V. All rights reserved.

Links between human LINE-1 retrotransposons and hepatitis virus-related hepatocellular carcinoma

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Honda, Tomoyuki

2016-05-01

Hepatocellular carcinoma (HCC) accounts for approximately 80% of liver cancers, the third most frequent cause of cancer mortality. The most prevalent risk factors for HCC are infections by hepatitis B or hepatitis C virus. Findings suggest that hepatitis virus-related HCC might be a cancer in which LINE-1 retrotransposons, often termed L1, activity plays a potential role. Firstly, hepatitis viruses can suppress host defense factors that also control L1 mobilization. Secondly, many recent studies also have indicated that hypomethylation of L1 affects the prognosis of HCC patients. Thirdly, endogenous L1 retrotransposition was demonstrated to activate oncogenic pathways in HCC. Fourthly, several L1 chimeric transcripts with host or viral genes are found in hepatitis virus-related HCC. Such lines of evidence suggest a linkage between L1 retrotransposons and hepatitis virus-related HCC. Here, I briefly summarize current understandings of the association between hepatitis virus-related HCC and L1. Then, I discuss potential mechanisms of how hepatitis viruses drive the development of HCC via L1 retrotransposons. An increased understanding of the contribution of L1 to hepatitis virus-related HCC may provide unique insights related to the development of novel therapeutics for this disease.

The occurrence of triglycerides in Namibian Shelf diatomaceous ooze

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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.

Discovery of a novel hepatovirus (Phopivirus of seals) related to human Hepatitis A Virus

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Anthony. S.J.,; St. Leger, J.A; Liang, E.; Hicks, A.L.; Sanchez-Leon, M.D; Ip, Hon S.; Jain, K.; Lefkowitch, J. H.; Navarrete-Macias, I.; Knowles, N.; Goldstein, T.; Pugliares, K.; Rowles, T.; Lipkin, W.I.

2015-01-01

Describing the viral diversity of wildlife can provide interesting and useful insights into the natural history of established human pathogens. In this study, we describe a previously unknown picornavirus in harbor seals (tentatively named phopivirus) that is related to human hepatitis A virus (HAV). We show that phopivirus shares several genetic and phenotypic characteristics with HAV, including phylogenetic relatedness across the genome, a specific and seemingly quiescent tropism for hepatocytes, structural conservation in a key functional region of the type III internal ribosomal entry site (IRES), and a codon usage bias consistent with that of HAV.

Factors in enhancing blood safety by nucleic acid technology testing for human immunodeficiency virus, hepatitis C virus and hepatitis B virus.

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Shyamala, Venkatakrishna

2014-01-01

In the last few decades through an awareness of transfusion transmitted infections (TTI), a majority of countries have mandated serology based blood screening assays for Human immunodeficiency virus (HIV), Hepatitis C virus (HCV), and Hepatitis B virus (HBV). However, despite improved serology assays, the transfusion transmission of HIV, HCV, and HBV continues, primarily due to release of serology negative units that are infectious because of the window period (WP) and occult HBV infections (OBI). Effective mode of nucleic acid technology (NAT) testing of the viruses can be used to minimize the risk of TTIs. This review compiles the examples of NAT testing failures for all three viruses; analyzes the causes for failure, and the suggestions from retrospective studies to minimize such failures. The results suggest the safest path to be individual donation testing (ID) format for highest sensitivity, and detection of multiple regions for rapidly mutating and recombining viruses. The role of blood screening in the context of the donation and transfusion practices in India, the donor population, and the epidemiology is also discussed. World wide, as the public awareness of TTIs increases, as the recipient rights for safe blood are legally upheld, as the possibility to manage diseases such as hepatitis through expensive and prolonged treatment becomes accessible, and the societal responsibility to shoulder the health costs as in the case for HIV becomes routine, there is much to gain by preventing infections than treating diseases.

Factors in enhancing blood safety by nucleic acid technology testing for human immunodeficiency virus, hepatitis C virus and hepatitis B virus

Directory of Open Access Journals (Sweden)

Venkatakrishna Shyamala

2014-01-01

Full Text Available In the last few decades through an awareness of transfusion transmitted infections (TTI, a majority of countries have mandated serology based blood screening assays for Human immunodeficiency virus (HIV, Hepatitis C virus (HCV, and Hepatitis B virus (HBV. However, despite improved serology assays, the transfusion transmission of HIV, HCV, and HBV continues, primarily due to release of serology negative units that are infectious because of the window period (WP and occult HBV infections (OBI. Effective mode of nucleic acid technology (NAT testing of the viruses can be used to minimize the risk of TTIs. This review compiles the examples of NAT testing failures for all three viruses; analyzes the causes for failure, and the suggestions from retrospective studies to minimize such failures. The results suggest the safest path to be individual donation testing (ID format for highest sensitivity, and detection of multiple regions for rapidly mutating and recombining viruses. The role of blood screening in the context of the donation and transfusion practices in India, the donor population, and the epidemiology is also discussed. World wide, as the public awareness of TTIs increases, as the recipient rights for safe blood are legally upheld, as the possibility to manage diseases such as hepatitis through expensive and prolonged treatment becomes accessible, and the societal responsibility to shoulder the health costs as in the case for HIV becomes routine, there is much to gain by preventing infections than treating diseases.

Exercise and Omega-3 Polyunsaturated Fatty Acid Supplementation for the Treatment of Hepatic Steatosis in Hyperphagic OLETF Rats

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Sarah J. Borengasser

2012-01-01

Full Text Available Background and Aims. This study examined if exercise and omega-3 fatty acid (n3PUFA supplementation is an effective treatment for hepatic steatosis in obese, hyperphagic Otsuka Long-Evans Tokushima Fatty (OLETF rats. Methods. Male OLETF rats were divided into 4 groups (n=8/group: (1 remained sedentary (SED, (2 access to running wheels; (EX (3 a diet supplemented with 3% of energy from fish oil (n3PUFA-SED; and (4 n3PUFA supplementation plus EX (n3PUFA+EX. The 8 week treatments began at 13 weeks, when hepatic steatosis is present in OLETF-SED rats. Results. EX alone lowered hepatic triglyceride (TAG while, in contrast, n3PUFAs failed to lower hepatic TAG and blunted the ability of EX to decrease hepatic TAG levels in n3PUFAs+EX. Insulin sensitivity was improved in EX animals, to a lesser extent in n3PUFA+EX rats, and did not differ between n3PUFA-SED and SED rats. Only the EX group displayed higher complete hepatic fatty acid oxidation (FAO to CO2 and carnitine palmitoyl transferase-1 activity. EX also lowered hepatic fatty acid synthase protein while both EX and n3PUFA+EX decreased stearoyl CoA desaturase-1 protein. Conclusions. Exercise lowers hepatic steatosis through increased complete hepatic FAO, insulin sensitivity, and reduced expression of de novo fatty acid synthesis proteins while n3PUFAs had no effect.

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome*

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Libby, Andrew E.; Bales, Elise; Orlicky, David J.; McManaman, James L.

2016-01-01

Perilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in ω-3 and ω-6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease. PMID:27679530

Perilipin-2 Deletion Impairs Hepatic Lipid Accumulation by Interfering with Sterol Regulatory Element-binding Protein (SREBP) Activation and Altering the Hepatic Lipidome.

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Libby, Andrew E; Bales, Elise; Orlicky, David J; McManaman, James L

2016-11-11

Perilipin-2 (PLIN2) is a constitutively associated cytoplasmic lipid droplet coat protein that has been implicated in fatty liver formation in non-alcoholic fatty liver disease. Mice with or without whole-body deletion of perilipin-2 (Plin2-null) were fed either Western or control diets for 30 weeks. Perilipin-2 deletion prevents obesity and insulin resistance in Western diet-fed mice and dramatically reduces hepatic triglyceride and cholesterol levels in mice fed Western or control diets. Gene and protein expression studies reveal that PLIN2 deletion suppressed SREBP-1 and SREBP-2 target genes involved in de novo lipogenesis and cholesterol biosynthetic pathways in livers of mice on either diet. GC-MS lipidomics demonstrate that this reduction correlated with profound alterations in the hepatic lipidome with significant reductions in both desaturation and elongation of hepatic neutral lipid species. To examine the possibility that lipidomic actions of PLIN2 deletion contribute to suppression of SREBP activation, we isolated endoplasmic reticulum membrane fractions from long-term Western diet-fed wild type (WT) and Plin2-null mice. Lipidomic analyses reveal that endoplasmic reticulum membranes from Plin2-null mice are markedly enriched in ω-3 and ω-6 long-chain polyunsaturated fatty acids, which others have shown inhibit SREBP activation and de novo lipogenesis. Our results identify PLIN2 as a determinant of global changes in the hepatic lipidome and suggest the hypothesis that these actions contribute to SREBP-regulated de novo lipogenesis involved in non-alcoholic fatty liver disease. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

One-Hour Postload Hyperglycemia Confers Higher Risk of Hepatic Steatosis to HbA1c-Defined Prediabetic Subjects.

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Fiorentino, Teresa Vanessa; Andreozzi, Francesco; Mannino, Gaia Chiara; Pedace, Elisabetta; Perticone, Maria; Sciacqua, Angela; Perticone, Francesco; Sesti, Giorgio

2016-11-01

Individuals with glycated hemoglobin (HbA1c)-defined prediabetes (HbA1c value of 5.7-6.4%) and 1-hour plasma glucose ≥155 mg/dL during an oral glucose tolerance test have an increased risk of developing type 2 diabetes. To evaluate the degree to which HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL individually and jointly associate with hepatic steatosis and related biomarkers. A cross-sectional analysis was performed on 1108 White individuals. Ambulatory care. Anthropometric and metabolic characteristics including hepatic steatosis assessed by ultrasonography. Compared with the normal group (HbA1c prediabetic and diabetic individuals exhibit higher values of fasting, 1-hour, and 2-hour postload glucose; fasting and 2-hour postload insulin; triglycerides; uric acid; homeostasis model of assessment for insulin resistance; liver insulin resistance index; liver enzymes; and inflammatory biomarkers; and lower levels of high-density lipoprotein cholesterol and IGF-1. Prediabetic and diabetic subjects have increased risk of hepatic steatosis (1.5- and 2.46-fold, respectively). Stratifying participants according to HbA1c and 1-hour postload glucose, we found that individuals with HbA1c-defined prediabetes and 1-hour postload glucose ≥155 mg/dL have significantly higher risk of hepatic steatosis as compared with individuals with HbA1c-defined prediabetes but 1-hour postload glucose prediabetes and 1-hour postload glucose ≥155 mg/dL exhibit higher values of liver enzymes; fasting, 1-hour, and 2-hour postload glucose; insulin; triglycerides; uric acid; and inflammatory biomarkers; and lower levels of high-density lipoprotein and IGF-1. These data suggest that a value of 1-hour postload glucose ≥155 mg/dL may be helpful to identify a subset of individuals within HbA1c-defined glycemic categories at higher risk of hepatic steatosis.

Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis.

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Koh, Hong; Kim, Seung; Kim, Myung-Joon; Kim, Hyun Gi; Shin, Hyun Joo; Lee, Mi-Jung

2015-09-07

To evaluate the possibility of treatment effect monitoring using hepatic fat quantification magnetic resonance (MR) in pediatric nonalcoholic steatohepatitis (NASH). We retrospectively reviewed the medical records of patients who received educational recommendations and vitamin E for NASH and underwent hepatic fat quantification MR from 2011 to 2013. Hepatic fat fraction (%) was measured using dual- and triple-echo gradient-recalled-echo sequences at 3T. The compliant and non-compliant groups were compared clinically, biochemically, and radiologically. Twenty seven patients (M:F = 24:3; mean age: 12 ± 2.3 years) were included (compliant group = 22, non-compliant = 5). None of the baseline findings differed between the 2 groups, except for triglyceride level (compliant vs non-compliant, 167.7 mg/dL vs 74.2 mg/dL, P = 0.001). In the compliant group, high-density lipoprotein increased and all other parameters decreased after 1-year follow-up. However, there were various changes in the non-compliant group. Dual-echo fat fraction (-19.2% vs 4.6, P fat fraction (-13.4% vs 3.5, P fat fraction showed a positive correlation (ρ = 0.418, P = 0.030). Hepatic fat quantification MR can be a non-invasive, quantitative and useful tool for monitoring treatment effects in pediatric NASH.

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

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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.

Structured triglycerides were well tolerated and induced increased whole body fat oxidation compared with long-chain triglycerides in postoperative patients.

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Sandström, R; Hyltander, A; Körner, U; Lundholm, K

1995-01-01

It has been proposed, on the basis of animal experiments, that medium-chain triglycerides (MCT) may exert more favorable effects on whole body metabolism of injured animals than long-chain triglycerides (LCT). Therefore, the present study was designed to evaluate whether structured triglycerides are associated with increased whole body fat oxidation without promotion of ketogenesis in postoperative patients. A structured lipid emulsion (73403 Pharmacia, Sweden) containing medium- and long-chain fatty acids, esterified randomly to glycerol in a triglyceride structure, was used. Whole body fat oxidation was determined by indirect calorimetry in the postoperative period. Patients were randomized to receive structured lipids 1 day followed by LCT (Intralipid, Pharmacia) the next day or vice versa during 6 postoperative days. In part 1 of the study patients received fat at 1.0 g/kg per day in the presence of 80% of the basal requirement of nonprotein calories. In part 2 patients received fat at 1.5 g/kg per day in the presence of 120% of the nonprotein caloric requirement. Amino acids were always provided at 0.15 g N/kg per day. Structured lipids were not associated with any side effects, were rapidly cleared from the plasma compartment, and were rapidly oxidized without any significant hyperlipidemia or ketosis. Provision of structured lipids in the presence of excess of nonprotein calories (part 2) caused a significantly higher whole body fat oxidation (2.4 +/- 0.05 g/kg per day) compared with LCT provision (1.9 +/- 0.06 g/kg per day) (p structured triglycerides were associated with increased whole body fat oxidation in stressed postoperative patients, which is in line with the original metabolic and biochemical concept for structured triglycerides. The study provided evidence to support that structured lipids may represent a next generation of IV fat emulsions that may be clinically advantageous compared with conventional LCT emulsions in certain clinical conditions.

Gamma radiation-induced structural changes in triglyceride molecules in pork fat

International Nuclear Information System (INIS)

Salkova, Z.; Koman, V.

1976-01-01

In the structure of associated and individual triglyceride pork fat molecules, some changes take place under the effect of ionizing radiation. Due to the irradiation of the fat the amount of the di- and tri-unsaturated (UUU, UUS, USU) triglyceride molecules decreases. The occurrence of the unsatured fatty acids on sites 1,3 decreases and the percentage of the individual triglyceride molecules having on their extreme sites C-1,3 unsaturated fatty acids decreases in all combinations. It can be assumed that hydrogenation and pre-esterification occurs in the triglyceride molecules. (author)

A consensus for occupational health management of healthcare workers infected with human immunodeficiency virus, hepatitis B virus, and / or hepatitis C virus.

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Ishimaru, Tomohiro; Wada, Koji; Smith, Derek R

2017-05-25

Occupational health management plays an important role in the prevention of provider-to-patient transmission in healthcare workers infected with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and/or hepatitis C virus (HCV). Therefore, the Japan Society for Occupational Health's Research Group on Occupational Health for Health Care Workers has proposed a consensus for the management of healthcare workers infected with HIV, HBV, and/or HCV based on recent evidence for each concerned group. The consensus recommends that: (1) employers in medical institutions should establish a policy of respecting the human rights of healthcare workers, management strategies for occupational blood exposure, and occupational health consultation; (2) occupational health staff should appropriately assess the risk of provider-to-patient transmission of HIV, HBV, and/or HCV infection and rearrange their tasks if necessary. When conducting risk assessment, occupational health staff should obtain informed consent and then cooperate with the physician in charge as well as infection control experts in the workplace; (3) healthcare workers infected with HIV, HBV, and/or HCV should disclose their employment to their treating physician and consult with their doctor regarding the need for special considerations at work; and (4) supervisors and colleagues in medical institutions should correctly understand the risks of HIV, HBV, and HCV infection and should not engage in any behavior that leads to discrimination against colleagues infected with HIV, HBV, and/or HCV.

Aberrant hepatic lipid storage and metabolism in canine portosystemic shunts.

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Van den Bossche, Lindsay; Schoonenberg, Vivien A C; Burgener, Iwan A; Penning, Louis C; Schrall, Ingrid M; Kruitwagen, Hedwig S; van Wolferen, Monique E; Grinwis, Guy C M; Kummeling, Anne; Rothuizen, Jan; van Velzen, Jeroen F; Stathonikos, Nikolas; Molenaar, Martijn R; Helms, Bernd J; Brouwers, Jos F H M; Spee, Bart; van Steenbeek, Frank G

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is a poorly understood multifactorial pandemic disorder. One of the hallmarks of NAFLD, hepatic steatosis, is a common feature in canine congenital portosystemic shunts. The aim of this study was to gain detailed insight into the pathogenesis of steatosis in this large animal model. Hepatic lipid accumulation, gene-expression analysis and HPLC-MS of neutral lipids and phospholipids in extrahepatic (EHPSS) and intrahepatic portosystemic shunts (IHPSS) was compared to healthy control dogs. Liver organoids of diseased dogs and healthy control dogs were incubated with palmitic- and oleic-acid, and lipid accumulation was quantified using LD540. In histological slides of shunt livers, a 12-fold increase of lipid content was detected compared to the control dogs (EHPSS Plipid-related genes to steatosis in portosystemic shunting was corroborated using gene-expression profiling. Lipid analysis demonstrated different triglyceride composition and a shift towards short chain and omega-3 fatty acids in shunt versus healthy dogs, with no difference in lipid species composition between shunt types. All organoids showed a similar increase in triacylglycerols after free fatty acids enrichment. This study demonstrates that steatosis is probably secondary to canine portosystemic shunts. Unravelling the pathogenesis of this hepatic steatosis might contribute to a better understanding of steatosis in NAFLD.

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.

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

International Nuclear Information System (INIS)

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

2011-01-01

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

Seroprevalence of Hepatitis B surface antigen, antibodies to the Hepatitis C virus, and human immunodeficiency virus in a hospital-based population in Jaipur, Rajasthan

Directory of Open Access Journals (Sweden)

Sood Smita

2010-01-01

Full Text Available Background: Hepatitis B, hepatitis C, and HIV infections are a serious global and public health problem. To assess the magnitude and dynamics of disease transmission and for its prevention and control, the study of its seroprevalence is important. A private hospital catering to the needs of a large population represents an important center for serological surveys. Available data, at Rajasthan state level, on the seroprevalence of these bloodborne pathogens is also very limited. Objective: A study was undertaken to estimate the seroprevalence of hepatitis B surface antigen (HBsAg and antibodies to hepatitis C (anti-HCV Ab and human immunodeficiency virus (anti-HIV Ab in both the sexes and different age groups in a hospital-based population in Jaipur, Rajasthan. Materials and Methods: Serum samples collected over a period of 14 months from patients attending OPDs and admitted to various IPDs of Fortis Escorts Hospital, Jaipur, were subjected within the hospital-based lab for the detection of HBsAg and anti-HCV Ab and anti-HIV Ab using rapid card tests. This was followed by further confirmation of all reactive samples by a microparticle enzyme immunoassay (Abbott AxSYM at Super Religare Laboratories (formerly SRL Ranbaxy Reference Lab, Mumbai. Results: The seroprevalence of HBsAg was found to be 0.87%, of anti-HCV Ab as 0.28%, and of anti-HIV Ab as 0.35%. Conclusion: The study throws light on the magnitude of viral transmission in the community in the state of Rajasthan and provides a reference for future studies.

Hepatitis B virus, hepatitis C virus and human immunodeficiency virus infection in undocumented migrants and refugees in southern Italy, January 2012 to June 2013.

Science.gov (United States)

Coppola, Nicola; Alessio, Loredana; Gualdieri, Luciano; Pisaturo, Mariantonietta; Sagnelli, Caterina; Caprio, Nunzio; Maffei, Rita; Starace, Mario; Angelillo, Italo Francesco; Pasquale, Giuseppe; Sagnelli, Evangelista

2015-01-01

Screening of undocumented migrants or refugees for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections has been offered free of charge and free from bureaucratic procedures since 2012 at four primary-level clinical centres in Naples and Caserta, Italy. Of 926 undocumented migrants and refugees visiting one of the primary-level clinical centres from January 2012 to June 2013, 882 (95%) were screened for hepatitis B surface antigen (HBsAg), total hepatitis B core antibody (anti-HBc) and antibodies against HCV and HIV. Of the 882 individuals enrolled, 78 (9%) were HBsAg positive, 35 (4%) anti-HCV positive and 11 (1%) anti-HIV positive (single infections); seven (1%) had more than one infection (three were HBsAg positive). Of the 801 HBsAg-negative patients, 373 (47%) were anti-HBc positive. The HBsAg-positivity rate was high (14%; 62/444) in individuals from sub-Saharan Africa and intermediate in those from eastern Europe (6%; 12/198), northern Africa (2%; 2/80) and Bangladesh, India, Pakistan and Sri Lanka (the 'India-Pakistan area') (3%; 4/126). Anti-HCV was detected in 9/126 (7%) individuals originating from the India-Pakistan area, in 12/198 (6%) from eastern Europe, in 17/444 (4%) from sub-Saharan and in 2/80 (2%) from northern Africa. The HBV, HCV and HIV infections in the undocumented migrants and refugees screened serve as a reminder to the Italian healthcare authorities to carry out extensive screening and educational programmes for these populations.

Postprandial triglyceride-rich lipoproteins promote lipid accumulation and apolipoprotein B-48 receptor transcriptional activity in human circulating and murine bone marrow neutrophils in a fatty acid-dependent manner.

Science.gov (United States)

Ortega-Gómez, Almudena; Varela, Lourdes M; López, Sergio; Montserrat de la Paz, Sergio; Sánchez, Rosario; Muriana, Francisco J G; Bermúdez, Beatriz; Abia, Rocío

2017-09-01

Postprandial triglyceride-rich lipoproteins (TRLs) promote atherosclerosis. Recent research points the bone marrow (BM) as a primary site in atherosclerosis. We elucidated how the acute administration of monounsaturated fatty acids (MUFAs) MUFAs, omega-3 polyunsaturated fatty acids (PUFAs) PUFAs and saturated fatty acids (SFAs) affects human circulating and murine BM neutrophil lipid accumulation and functionality. Postprandial hypertriglyceridemia was induced in healthy subjects and Apoe -/- mice by the acute administration of dietary fats enriched in MUFAs, PUFAs, or SFAs. Postprandial hypertriglyceridemia increased apolipoprotein-B48 receptor (ApoB48R) transcriptional activity that was linearly correlated with intracellular triglycerides (TGs) TGs accumulation in human circulating and murine BM neutrophils. MUFA and omega-3 PUFAs attenuated ApoB48R gene expression and intracellular TG accumulation compared to SFAs. TRLs induced apoB48R-dependent TG accumulation in human neutrophils ex vivo. Murine BM neutrophils showed a decrease in surface L-selectin and an increase in TNF-α and IL-1β mRNA expressions only after SFAs administration. TRLs enriched in SFAs induced BM neutrophil degranulation ex vivo suggesting cell priming/activation. Postprandial TRLs disrupts the normal biology and function of circulating and BM neutrophils. MUFA- and omega-3 PUFA-rich dietary fats such as virgin olive oil or fish oil has the potential to prevent excessive neutrophil lipid accumulation and activation by targeting the fatty acid composition of TRLs. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Obesity resistance and multiple mechanisms of triglyceride synthesis in mice lacking Dgat.

Science.gov (United States)

Smith, S J; Cases, S; Jensen, D R; Chen, H C; Sande, E; Tow, B; Sanan, D A; Raber, J; Eckel, R H; Farese, R V

2000-05-01

Triglycerides (or triacylglycerols) represent the major form of stored energy in eukaryotes. Triglyceride synthesis has been assumed to occur primarily through acyl CoA:diacylglycerol transferase (Dgat), a microsomal enzyme that catalyses the final and only committed step in the glycerol phosphate pathway. Therefore, Dgat has been considered necessary for adipose tissue formation and essential for survival. Here we show that Dgat-deficient (Dgat-/-) mice are viable and can still synthesize triglycerides. Moreover, these mice are lean and resistant to diet-induced obesity. The obesity resistance involves increased energy expenditure and increased activity. Dgat deficiency also alters triglyceride metabolism in other tissues, including the mammary gland, where lactation is defective in Dgat-/- females. Our findings indicate that multiple mechanisms exist for triglyceride synthesis and suggest that the selective inhibition of Dgat-mediated triglyceride synthesis may be useful for treating obesity.

Rapid and sensitive enzymatic-radiochemical assay for the determination of triglycerides

International Nuclear Information System (INIS)

Khoo, J.C.; Miller, E.; Goldberg, D.I.

1987-01-01

An enzymatic-radiochemical method suitable for the determination of triglyceride levels of cells in culture is described. The method is based on the enzymatic hydrolysis of triglycerides to free fatty acids which then complex with 63 Ni. The method is rapid, accurate, and inexpensive. The procedure extends the sensitivity of triglyceride measurement to as low as 0.25 nanomoles

Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

Energy Technology Data Exchange (ETDEWEB)

Lynch, Caitlin; Pan, Yongmei; Li, Linhao [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Heyward, Scott; Moeller, Timothy [Bioreclamation In Vitro Technologies, Baltimore, MD 21227 (United States); Swaan, Peter W. [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States); Wang, Hongbing, E-mail: hwang@rx.umaryland.edu [Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, MD 21201 (United States)

2014-08-15

Objective: Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods: Ligand-based structure–activity models were used for virtual screening of the Specs database ( (www.specs.net)) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH. Results: Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion: Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. - Highlights: • Novel hCAR activators were identified by computational and biological approaches. • The role

Activation of the constitutive androstane receptor inhibits gluconeogenesis without affecting lipogenesis or fatty acid synthesis in human hepatocytes

International Nuclear Information System (INIS)

Lynch, Caitlin; Pan, Yongmei; Li, Linhao; Heyward, Scott; Moeller, Timothy; Swaan, Peter W.; Wang, Hongbing

2014-01-01

Objective: Accumulating evidence suggests that activation of mouse constitutive androstane receptor (mCAR) alleviates type 2 diabetes and obesity by inhibiting hepatic gluconeogenesis, lipogenesis, and fatty acid synthesis. However, the role of human (h) CAR in energy metabolism is largely unknown. The present study aims to investigate the effects of selective hCAR activators on hepatic energy metabolism in human primary hepatocytes (HPH). Methods: Ligand-based structure–activity models were used for virtual screening of the Specs database ( (www.specs.net)) followed by biological validation in cell-based luciferase assays. The effects of two novel hCAR activators (UM104 and UM145) on hepatic energy metabolism were evaluated in HPH. Results: Real-time PCR and Western blotting analyses reveal that activation of hCAR by UM104 and UM145 significantly repressed the expression of glucose-6-phosphatase and phosphoenolpyruvate carboxykinase, two pivotal gluconeogenic enzymes, while exerting negligible effects on the expression of genes associated with lipogenesis and fatty acid synthesis. Functional experiments show that UM104 and UM145 markedly inhibit hepatic synthesis of glucose but not triglycerides in HPH. In contrast, activation of mCAR by 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene, a selective mCAR activator, repressed the expression of genes associated with gluconeogenesis, lipogenesis, and fatty acid synthesis in mouse primary hepatocytes, which were consistent with previous observations in mouse model in vivo. Conclusion: Our findings uncover an important species difference between hCAR and mCAR in hepatic energy metabolism, where hCAR selectively inhibits gluconeogenesis without suppressing fatty acid synthesis. Implications: Such species selectivity should be considered when exploring CAR as a potential therapeutic target for metabolic disorders. - Highlights: • Novel hCAR activators were identified by computational and biological approaches. • The role

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...

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

Effect of P/S ratio (0.5 vs 0.9) on hepatic LDL transport at three levels of dietary cholesterol in cynomolgus macaques

International Nuclear Information System (INIS)

Hunt, C.E.; Funk, G.M.; Turley, S.D.; Spady, D.K.; Dietschy, J.M.

1990-01-01

Interaction between dietary polyunsaturated to saturated (P/S) fatty acid ratio and cholesterol (C) was studied in 6 groups of male cynomolgus macaques fed diets (oleic acid constant) for 72 weeks as follows (C mg/Cal-P/S): (1), 0.06 - 0.5; (2), 0.06-0.9, (3), 0.28-0.5; (4), 0.28-0.9; (5), 2,35-0.5; (6), 2,35-0.9. Plasma C was proportional to dietary C and was affected significantly by P/S in 1 and 2 only. Mean plasma C (mg/dl) at 72 weeks was: (1) 158; (2) 117; (3) 320; (4) 284; (5) 602; (6) 601. LDL-C was significantly higher in (1) than in (2) (90 vs 65 mg/dl). In vivo LDL turnover studies showed that LDL clearance was suppressed by excess dietary C and by saturated fats in low C diets. Receptor-independent clearance was relatively constant. Hepatic LDL transport was determined after injection of 125I-cellobiose-LDL. Hepatic LDL-C uptake was greater in (2) than in (1). LDL-C synthesis was reduced in (4) and (6) compared to (3) and (5), respectively. The authors conclude that (i) hepatic LDL receptor activity is altered by degree of saturation in dietary triglycerides when dietary C is minimal and (ii) saturated triglycerides enhance LDL-C synthesis when dietary C is ample in this model

An implantable vascularized protein gel construct that supports human fetal hepatoblast survival and infection by hepatitis C virus in mice.

Directory of Open Access Journals (Sweden)

Martha J Harding

2010-04-01

Full Text Available Widely accessible small animal models suitable for the study of hepatitis C virus (HCV in vivo are lacking, primarily because rodent hepatocytes cannot be productively infected and because human hepatocytes are not easily engrafted in immunodeficient mice.We report here on a novel approach for human hepatocyte engraftment that involves subcutaneous implantation of primary human fetal hepatoblasts (HFH within a vascularized rat collagen type I/human fibronectin (rCI/hFN gel containing Bcl-2-transduced human umbilical vein endothelial cells (Bcl-2-HUVEC in severe combined immunodeficient X beige (SCID/bg mice. Maturing hepatic epithelial cells in HFH/Bcl-2-HUVEC co-implants displayed endocytotic activity at the basolateral surface, canalicular microvilli and apical tight junctions between adjacent cells assessed by transmission electron microscopy. Some primary HFH, but not Huh-7.5 hepatoma cells, appeared to differentiate towards a cholangiocyte lineage within the gels, based on histological appearance and cytokeratin 7 (CK7 mRNA and protein expression. Levels of human albumin and hepatic nuclear factor 4alpha (HNF4alpha mRNA expression in gel implants and plasma human albumin levels in mice engrafted with HFH and Bcl-2-HUVEC were somewhat enhanced by including murine liver-like basement membrane (mLBM components and/or hepatocyte growth factor (HGF-HUVEC within the gel matrix. Following ex vivo viral adsorption, both HFH/Bcl-2-HUVEC and Huh-7.5/Bcl-2-HUVEC co-implants sustained HCV Jc1 infection for at least 2 weeks in vivo, based on qRT-PCR and immunoelectron microscopic (IEM analyses of gel tissue.The system described here thus provides the basis for a simple and robust small animal model of HFH engraftment that is applicable to the study of HCV infections in vivo.

Studies on the propagation in cell culture and the infectivity for baboons of human hepatitis A virus

International Nuclear Information System (INIS)

Taylor, M.B.

1985-05-01

Current aspects of hepatitis A and hepatitis A virus (HAV) research and the techniques used for the propagation and monitoring of HAV and HAV antigen (HA Ag) production in vitro and HAV infection in vivo, and its sequelae are reviewed. Radioimmunoassay, immunofluorescence and electron microscopic techniques for the demonstration of HA Ag were adapted for this investigation. The cell-adapted strain of HAV(MBB) was successfully propagated in the human hepatoma cell line PLC/PRF/5 at 32 degrees Celsius. A crystalline structure was demonstrated in the cytoplasm of HAV-infected cells by thin-section electron microscopy. The origin and significance of this structure is uncertain. A possible temperature variant of HAV (strain MBB) or an HAV-related baboon virus was detected in PLC/PRF/5 cells maintained at 37 degrees Celsius after infection with a faecal extract prepared from baboons which had been infected with the cell-cultured HAV. Baboons, both free-ranging and in captivity, were found to have antibodies to HAV, which suggests susceptibility to human HAV or another cross-reacting virus. The experimental infection of the Cape baboon orally, intravenously or by both routes with HAV were investigated. The results of the study suggest reasons for the presence of anti-HAV antibodies in certain baboon populations and show that the baboon is not an ideal model for hepatitis A investigations

Studies on the propagation in cell culture and the infectivity for baboons of human hepatitis A virus

Energy Technology Data Exchange (ETDEWEB)

Taylor, M B

1985-01-01

Current aspects of hepatitis A and hepatitis A virus (HAV) research and the techniques used for the propagation and monitoring of HAV and HAV antigen (HA Ag) production in vitro and HAV infection in vivo, and its sequelae are reviewed. Radioimmunoassay, immunofluorescence and electron microscopic techniques for the demonstration of HA Ag were adapted for this investigation. The cell-adapted strain of HAV(MBB) was successfully propagated in the human hepatoma cell line PLC/PRF/5 at 32 degrees Celsius. A crystalline structure was demonstrated in the cytoplasm of HAV-infected cells by thin-section electron microscopy. The origin and significance of this structure is uncertain. A possible temperature variant of HAV (strain MBB) or an HAV-related baboon virus was detected in PLC/PRF/5 cells maintained at 37 degrees Celsius after infection with a faecal extract prepared from baboons which had been infected with the cell-cultured HAV. Baboons, both free-ranging and in captivity, were found to have antibodies to HAV, which suggests susceptibility to human HAV or another cross-reacting virus. The experimental infection of the Cape baboon orally, intravenously or by both routes with HAV were investigated. The results of the study suggest reasons for the presence of anti-HAV antibodies in certain baboon populations and show that the baboon is not an ideal model for hepatitis A investigations.

Hepatic and biochemical repercussions of a polyunsaturated fat-rich hypercaloric and hyperlipidic diet in Wistar rats

Directory of Open Access Journals (Sweden)

Idália M. B. Burlamaqui

2011-06-01

Full Text Available CONTEXT: Non-alcoholic fatty liver disease is characterized by lipid deposits in the hepatocytes and has been associated with obesity, dyslipidemia and type-2 diabetes. It is considered a hepatic manifestation of the metabolic syndrome, of which the main component is insulin resistance leading to hyperinsulinemia and increased production of inflammatory cytokines. Saturated fat promotes hypertriglyceridemia and hyperinsulinemia, reduces levels of high-density cholesterol and increases levels of low-density cholesterol, while polyunsaturated fat is associated with hypolipidemic, antiinflammatory and imunoregulating action. OBJECTIVE: To evaluate the hepatic and biochemical repercussions of a polyunsaturated fat-rich diet in Wistar rats. METHODS: Twenty-two rats were distributed equally in two groups: GI - standard diet (Biobase Bio-tec Ratos e Camundongos® providing 3.000 kcal/kg and GII - hypercaloric and hyperlipidic diet providing 4.250 kcal/kg (ω-6:ω-3 = 3:1. The animals were euthanized after 23 weeks of experiment. The weight, biochemical parameters and hepatohistological changes were registered. RESULTS: Findings were submitted to variance analysis with the level of statistical significance at 5%. The average weight did not differ significantly between the groups at baseline (P = 0.711, but was greater in Group II by the end of the experiment (P = 0.000. The levels of triglycerides (P = 0.039, total cholesterol (P = 0.015 and HDL (P = 0.005 were higher in Group I than in Group II. Macrovesicular steatosis was significantly more common in Group II than in Group I (P = 0.03. CONCLUSION: Hypercaloric and hyperlipidic diet rich in polyunsaturated fat promotes weight gain and favors the development of hepatic steatosis while reducing serum levels of triglycerides, total cholesterol and HDL.