Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015695 (fatty liver)
 13,941 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mice were fed with control or high fat diet containing approximately 10% or 80% cholesterol, respectively. Macroscopic and microscopic findings demonstrated that lipid accumulation in the liver was observed as early as 2 weeks after high fat diet and that high fat diet for 12 weeks developed a fatty liver phenotype, establishing a novel model of diet-induced liver steatosis. PPARgamma and its targeted gene, CD36 mRNA expression were specifically up-regulated in the liver by high fat diet for 2 weeks. Immunohistochemical study revealed that PPARgamma protein expression is increased in the nuclei of hepatocytes by high fat diet. These results suggest that PPARgamma signaling pathway may be involved in the high fat diet-induced liver steatosis.
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PMID:[Increased expression of PPargamma in fatty liver induced by high fat diet]. 1676 9

Perturbations in hepatic lipid homeostasis are linked to the development of obesity-related steatohepatitis. Mutations in the gene encoding lipin 1 cause hepatic steatosis in fld mice, a genetic model of lipodystrophy. However, the molecular function of lipin 1 is unclear. Herein, we demonstrate that the expression of lipin 1 is induced by peroxisome proliferator-activated receptor gamma (PPARgamma) coactivator 1alpha (PGC-1alpha), a transcriptional coactivator controlling several key hepatic metabolic pathways. Gain-of-function and loss-of-function strategies demonstrated that lipin selectively activates a subset of PGC-1alpha target pathways, including fatty acid oxidation and mitochondrial oxidative phosphorylation, while suppressing the lipogenic program and lowering circulating lipid levels. Lipin activates mitochondrial fatty acid oxidative metabolism by inducing expression of the nuclear receptor PPARalpha, a known PGC-1alpha target, and via direct physical interactions with PPARalpha and PGC-1alpha. These results identify lipin 1 as a selective physiological amplifier of the PGC-1alpha/PPARalpha-mediated control of hepatic lipid metabolism.
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PMID:Lipin 1 is an inducible amplifier of the hepatic PGC-1alpha/PPARalpha regulatory pathway. 1695 Jan 37

Insulin-resistant apoB/BATless mice have hypertriglyceridemia because of increased assembly and secretion of very low density apolipoprotein B (apoB) and triglycerides compared with mice expressing only apoB (Siri, P., Candela, N., Ko, C., Zhang, Y., Eusufzai, S., Ginsberg, H. N., and Huang, L. S. (2001) J. Biol. Chem. 276, 46064-46072). Despite increased very low density lipoprotein secretion, apoB/BATless mice have fatty livers. We found that hepatic mRNA levels of key lipogenic enzymes, acetyl-CoA carboxylase, fatty-acid synthase, and stearoyl-CoA desaturase-1 were increased in apoB/BATless mice compared with levels in apoB mice, suggesting increased lipogenesis in apoB/BATless mice. This was confirmed by determining incorporation of tritiated water into fatty acids. Neither the hepatic mRNA of the lipogenic transcription factor, SREBP-1c (sterol-response element-binding protein 1c), nor the nuclear levels of the mature form of SREBP-1 protein were elevated in apoB/BATless mice. By contrast, hepatic levels of peroxisomal proliferator-activated receptor 2 (PPARgamma2) mRNA and protein were specifically increased in apoB/BATless mice, as were hepatic mRNA levels of two targets of PPARgamma, CD36 and aP2. Treatment of apoB/BATless mice for 4 weeks with intraperitoneal injections of a PPARgamma antisense oligonucleotide resulted in dramatic reductions of both PPARgamma1 and PPARgamma2 mRNA, PPARgamma2 protein, and mRNA levels of fatty-acid synthase and acetyl-CoA carboxylase. These changes were associated with decreased hepatic de novo lipogenesis and hepatic triglyceride concentrations. We conclude that hepatic steatosis in apoB/BATless mice is associated with elevated rates of hepatic lipogenesis that are linked directly to increased hepatic expression of PPARgamma2. The mechanism whereby hepatic Ppargamma2 gene expression is increased and how PPARgamma2 stimulates lipogenesis is under investigation.
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PMID:Aberrant hepatic expression of PPARgamma2 stimulates hepatic lipogenesis in a mouse model of obesity, insulin resistance, dyslipidemia, and hepatic steatosis. 1697 90

Nonalcoholic fatty liver disease (NAFLD) is a frequent and potentially progressive chronic liver disease that occurs in subjects who do not abuse alcohol. NAFLD is often associated with obesity, metabolic syndrome and insulin resistance and its more aggressive form, nonalcoholic steatohepatitis (NASH) is a major cause of cryptogenic cirrhosis. NAFLD/NASH are commonly detected because of elevated serum aminotransferase levels, ultrasonographic fatty liver and, at liver histology, steatosis, inflammation, and occasionally fibrosis that may progress to cirrhosis. No established treatment exists for this potentially serious disorder. Current management of NAFLD/NASH is largely conservative and includes diet regimen, aerobic exercise, and interventions towards the associated metabolic abnormalities. The main concern is therefore to decrease liver steatosis and its progression toward steatohepatitis and fibrosis, and the risk of "cryptogenic" cirrhosis. Among the most promising medications, weight reducing drugs, insulin sensitizers and lipid-lowering agents, antioxidants, bile salts, co-factors increasing the mitochondrial transport of fatty acids are being considered. Among them, thiazolidinediones are the most promising drug family that act by activating PPARgamma nuclear receptors and by regulating both microsomal and peroxisomal lipid oxidative pathways. Pharmacological treatment of obesity and probiotics should be considered as potential therapeutic options. In this review, after summarizing the general background on fatty liver, the most current and attractive pharmacological approaches to the problem of NAFLD/NASH are discussed.
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PMID:Current pharmacological treatment of nonalcoholic fatty liver. 1707 35

Hepatic insulin resistance is associated with hepatic steatosis and is thought to play an important role in the pathogenesis of steatohepatitis. Using a murine model of steatohepatitis (mice fed a diet deficient in methionine and choline-MCD diet), we tested the effects of the insulin-sensitising, PPARgamma agonist drug pioglitazone (PGZ) on systemic and intrahepatic insulin sensitivity and on liver pathology. Compared to controls, mice fed the MCD diet develop a significant steatohepatitis, have enhanced glucose tolerance and enhanced systemic response to insulin. PGZ did not affect the systemic insulin sensitivity in control or MCD-fed mice as assessed in vivo by intraperitoneal glucose or insulin dynamic tests. However, PGZ prevented hepatic fat accumulation and steatohepatitis induced by the MCD diet. This effect was associated with an increased mass of adipose tissue and increased expression and release of adiponectin, while hepatic acyl co-enzyme A oxidase and acyl-co-enzyme A carboxylase, regulating hepatic beta-oxidation of fatty acid, remained unchanged. Steatohepatitis in MCD-diet-fed mice was associated with intrahepatic insulin resistance as shown by a reduced phosphorylation of hepatic insulin receptor, and Akt in response to an insulin stimulus. PGZ to MCD-fed mice restored the activation of the insulin receptor and of the Akt pathway in response to insulin. In conclusion, PGZ alleviates steatosis and steatohepatitis induced by the MCD diet, an effect associated with correction of intrahepatic insulin resistance.
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PMID:Intrahepatic insulin resistance in a murine model of steatohepatitis: effect of PPARgamma agonist pioglitazone. 1707 77

The nutritional environment encountered during fetal life is strongly implicated as a determinant of lifelong metabolic capacity and risk of disease. Pregnant rats were fed a control or low-protein (LP) diet, targeted to early (LPE), mid-(LPM), or late (LPL) pregnancy, or throughout gestation (LPA). The offspring were studied at 1, 9, and 18 mo of age. All LP-exposed groups had similar plasma triglyceride, cholesterol, glucose, and insulin concentrations to those of controls at 1 and 9 mo of age, but by 18 mo there was evidence of LP-programmed hypertriglyceridemia and insulin resistance. All LP-exposed groups exhibited histological evidence of hepatic steatosis and were found to have two- to threefold more hepatic triglyceride than control animals. These phenotypic changes were accompanied by age-related changes in mRNA and protein expression of the transcription factors SREBP-1c, ChREBP, PPARgamma, and PPARalpha and their respective downstream target genes ACC1, FAS, L-PK, and MCAD. At 9 mo of age, the LP groups exhibited suppression of the SREBP-1c-related lipogenic pathway but between 9 and 18 mo underwent a switch to increased lipogenic capacity with a lower expression of PPARgamma and MCAD, consistent with reduced lipid oxidation. The findings indicate that prenatal protein restriction programs development of a metabolic syndrome-like phenotype that develops only with senescence. The data implicate altered expression of SREBP-1c and ChREBP as key mediators of the programmed phenotype, but the basis of the switch in metabolic status that occurred between 9 and 18 mo of age is, as yet, unidentified.
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PMID:Prenatal exposure to a low-protein diet programs disordered regulation of lipid metabolism in the aging rat. 1729 84

Hepatic steatosis is a common feature in patients with chronic hepatitis C virus (HCV) infection. HCV core protein plays an important role in the development of hepatic steatosis in HCV infection. Because SREBP1 (sterol regulatory element binding protein 1) and PPARgamma (peroxisome proliferators-activated receptor gamma) are involved in the regulation of lipid metabolism of hepatocyte, we sought to determine whether HCV core protein may impair the expression and activity of SREBP1 and PPARgamma. In this study, it was demonstrated that HCV core protein increases the gene expression of SREBP1 not only in Chang liver, Huh7, and HepG2 cells transiently transfected with HCV core protein expression plasmid, but also in Chang liver-core stable cells. Furthermore, HCV core protein enhanced the transcriptional activity of SREBP1. In addition, HCV core protein elevated PPARgamma transcriptional activity. However, HCV core protein had no effect on PPARgamma gene expression. Finally, we showed that HCV core protein stimulates the genes expression of lipogenic enzyme and fatty acid uptake associated protein. Therefore, our finding provides a new insight into the mechanism of hepatic steatosis by HCV infection.
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PMID:HCV core protein induces hepatic lipid accumulation by activating SREBP1 and PPARgamma. 1733 64

Mitochondrial dysfunction is involved in the three stages of the transition from lack of exercise and excessive food intake to insulin resistance, diabetes and non-alcoholic steatohepatitis (NASH). In muscle, lack of exercise, a fat-rich diet, a polymorphism in peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1), and possibly age-related mitochondrial DNA (mtDNA) mutations may variously combine their effects to decrease PGC-1 expression, mitochondrial biogenesis and fat oxidation. Together with excessive food intake, insufficient fat oxidation causes fat accumulation and cellular stress in myocytes. The activation of Jun N-terminal kinase and protein kinase C-theta triggers the serine phosphorylation and inactivation of the insulin receptor substrate, and hampers the insulin-mediated translocation of glucose transporter-4 to the plasma membrane. Initially, the trend for increased blood glucose increases insulin secretion by pancreatic beta-cells. High plasma insulin levels compensate for insulin resistance in muscle and maintain normal blood glucose levels. Eventually, however, increased uncoupling protein-2 expression and possibly acquired mtDNA mutations in pancreatic beta-cells can blunt glucose-mediated adenosine triphosphate (ATP) formation and insulin secretion, to cause diabetes in some patients. High plasma glucose and/or insulin levels induce hepatic lipogenesis and cause hepatic steatosis. In fat-engorged hepatocytes, several vicious cycles involving tumor necrosis factor-alpha, reactive oxygen species (ROS), peroxynitrite, and lipid peroxidation products alter respiratory chain polypeptides and mtDNA, thus partially blocking the flow of electrons in the respiratory chain. The overreduction of upstream respiratory chain complexes increases mitochondrial ROS and peroxynitrite formation. Oxidative stress increases the release of lipid peroxidation products and cytokines, which together trigger the liver lesions of NASH.
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PMID:Role of mitochondria in non-alcoholic fatty liver disease. 1756 59

Effects of buckwheat germinated for 48 h in suppressing fatty liver were investigated using an animal study. Concentration of rutin was increased more than 10 times, with production of quercitrin and one newly formed flavonoid during 48 h germination. When an ethanol extract of germinated buckwheat was fed daily to C57BL/6 mice at 100 or 200 mg/kg body wt, along with a high-fat diet, oral administration of germinated buckwheat caused significant reductions in TG and TC levels in the liver after 8 weeks. Oral administration of germinated buckwheat also down-regulated mRNA expressions of PPARgamma and C/EBPalpha in hepatocytes, in a dose-dependent manner. These results suggest that germinated buckwheat has potent anti-fatty liver activities caused partially by suppressing the gene expression of certain adipogenic transcription factors like PPARgamma and C/EBPalpha in hepatocytes.
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PMID:Suppressive effects of germinated buckwheat on development of fatty liver in mice fed with high-fat diet. 1760 14

Although the epidemic of obesity has been accompanied by an increase in the prevalence of the metabolic syndrome, not all obese develop the syndrome and even lean individuals can be insulin resistant. Both lean and obese insulin resistant individuals have an excess of fat in the liver which is not attributable to alcohol or other known causes of liver disease, a condition defined as nonalcoholic fatty liver disease (NAFLD) by gastroenterologists. The fatty liver is insulin resistant. Liver fat is highly significantly and linearly correlated with all components of the metabolic syndrome independent of obesity. Overproduction of glucose, VLDL, CRP, and coagulation factors by the fatty liver could contribute to the excess risk of cardiovascular disease associated with the metabolic syndrome and NAFLD. Both of the latter conditions also increase the risk of type 2 diabetes and advanced liver disease. The reason why some deposit fat in the liver whereas others do not is poorly understood. Individuals with a fatty liver are more likely to have excess intraabdominal fat and inflammatory changes in adipose tissue. Intervention studies have shown that liver fat can be decreased by weight loss, PPARgamma agonists, and insulin therapy.
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PMID:Fatty liver: a novel component of the metabolic syndrome. 1769 Mar 17


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