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)

Insulin resistance-related obesity and diabetes mellitus are the predominant causes of fatty liver disease. Here we examine the effects of dietary diacylglycerol (DG), which is a minor component of plant oils, on lipid accumulation and the expression of genes involved in lipid metabolism in the liver. The animals were fed diets containing either 10% triacylglycerol (TG), 10% TG + 4% alpha-linolenic acid-rich TG (ALATG) or 10% TG + 4% alpha-linolenic acid-rich diacylglycerol (ALADG) for a period of 1 month. Supplementation with ALADG significantly inhibited hepatic triglyceride accumulation; this was accompanied by the up-regulation of beta-oxidation activity, and acyl-CoA oxidase (ACO) and medium-chain acyl-CoA dehydrogenase (MCAD) mRNA levels. By contrast, no significant changes were observed in the levels of peroxisome proliferator-activated receptor-alpha (PPARalpha) and sterol regulatory element-binding protein-1 (SREBP-1) mRNAs. These results indicate that ALADG might be useful in the prevention of fatty liver formation; this effect could be closely related to the stimulation of lipid catabolism in the liver. In addition, our findings suggest that both acylglycerol structure (that is, the structural difference between TG and DG) and fatty-acid species affect the nutritional behaviour of dietary lipids.
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PMID:Supplementation with alpha-linolenic acid-rich diacylglycerol suppresses fatty liver formation accompanied by an up-regulation of beta-oxidation in Zucker fatty rats. 1586 69

Central role of suppressors of cytokine signaling proteins in hepatic steatosis, insulin resistance, and the metabolic syndrome in the mouse. Ueki K, Kondo T, Tseng YH, Kahn CR. Insulin resistance, obesity, diabetes, dyslipidemia, and nonalcoholic fatty liver are components of the metabolic syndrome, a disease complex that is increasing at epidemic rates in westernized countries. Although proinflammatory cytokines have been suggested to contribute to the development of these disorders, the molecular mechanism is poorly understood. Here we show that overexpression of suppressors of cytokine signaling (SOCS)-1 and SOCS-3 in liver causes insulin resistance and an increase in the key regulator of fatty acid synthesis in liver, sterol regulatory element-binding protein (SREBP)-1c. Conversely, inhibition of SOCS-1 and -3 in obese diabetic mice improves insulin sensitivity, normalizes the increased expression of SREBP-1c, and dramatically ameliorates hepatic steatosis and hypertriglyceridemia. In obese animals, increased SOCS proteins enhance SREBP-1c expression by antagonizing STAT3-mediated inhibition of SREBP-1c promoter activity. Thus, SOCS proteins play an important role in pathogenesis of the metabolic syndrome by concordantly modulating insulin signaling and cytokine signaling. [Abstract reproduced by permission of Proc Natl Acad Sci USA 2004;101:10422-7].
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PMID:Signalling links in the liver: knitting SOCS with fat and inflammation. 1591 29

Obstructive sleep apnea (OSA), a condition tightly linked to obesity, leads to chronic intermittent hypoxia (CIH) during sleep. There is emerging evidence that OSA is independently associated with insulin resistance and fatty liver disease, suggesting that OSA may affect hepatic lipid metabolism. To test this hypothesis, leptin-deficient obese (ob/ob) mice were exposed to CIH during the light phase (9 AM-9 PM) for 12 wk. Liver lipid content and gene expression profile in the liver (Affymetrix 430 GeneChip with real-time PCR validation) were determined on completion of the exposure. CIH caused a 30% increase in triglyceride and phospholipid liver content (P < 0.05), whereas liver cholesterol content was unchanged. Gene expression analysis showed that CIH upregulated multiple genes controlling 1) cholesterol and fatty acid biosynthesis [malic enzyme and acetyl coenzyme A (CoA) synthetase], 2) predominantly fatty acid biosynthesis (acetyl-CoA carboxylase and stearoyl-CoA desaturases 1 and 2), and 3) triglyceride and phospholipid biosynthesis (mitochondrial glycerol-3-phosphate acyltransferase). A majority of overexpressed genes were transcriptionally regulated by sterol regulatory element-binding protein (SREBP) 1, a master regulator of lipogenesis. A 2.8-fold increase in SREBP-1 gene expression in CIH was confirmed by real-time PCR (P = 0.001). Expression of major genes of cholesterol biosynthesis, SREBP-2 and 3-hydroxy-3-methylglutaryl-CoA reductase, was unchanged. In conclusion, we have shown that CIH may exacerbate preexisting fatty liver of obesity via upregulation of the pathways of lipid biosynthesis in the liver.
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PMID:Chronic intermittent hypoxia upregulates genes of lipid biosynthesis in obese mice. 1622 56

Although CCAAT/enhancer-binding protein alpha (C/EBPalpha) is essential for initiating or sustaining several metabolic processes during the perinatal period, the consequences of total ablation of C/EBPalpha during postnatal development have not been investigated. We have created a conditional knock-out model in which the administration of poly(I:C) caused a virtually total deletion of c/ebpalpha (C/EBPalpha(Delta/-) mice) in the liver, spleen, white and brown adipose tissues, pancreas, lung, and kidney of the mice. C/EBPalpha itself was completely ablated in the liver by day 4 after the injection of poly(I:C). There was no noticeable change in phenotype during the first 15 days after the injection. The mice maintained a normal level of fasting blood glucose and responded to the diabetogenic action of streptozotocin. From day 16 onward, the mice developed hypophagia, exhibited severe weight loss, lost triglyceride in white but not brown adipose tissue, became hypoglycemic and hypoinsulinemic, depleted their hepatic glycogen, and developed fatty liver. They also exhibited lowered plasma levels of free fatty acid, triglyceride, and cholesterol, as well as marked changes in hepatic mRNA for C/EBPdelta, peroxisome proliferator-activated receptor alpha, sterol regulatory element-binding protein 1, hydroxymethylglutaryl-coenzyme A reductase, and apolipoproteins. Although basal levels of hepatic mRNA for the cytosolic isoform of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase were reduced, transcription of the genes for these enzymes was inducible by dibutyryl cyclic AMP in C/EBPalpha(Delta/-) mice. The animals died about 1 month after the injection of poly(I:C). These findings demonstrate that C/EBPalpha is essential for the survival of animals during postnatal life and that its ablation leads to distinct biphasic change in metabolic processes.
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PMID:Metabolic response of mice to a postnatal ablation of CCAAT/enhancer-binding protein alpha. 1616 91

Intragastric ethanol feeding in mice induces expression of unfolded protein response/endoplasmic reticulum (UPR/ER) stress response genes. The proximate cause appears to be hyperhomocysteinemia, a well-known cause of ER stress in other contexts. Hyperhomocysteinemia appears to be due to downregulation of methionine synthase. The importance of homocysteine and ER stress in the pathogenesis of liver disease was suggested by the prevention of the alcohol-induced changes by feeding sufficient betaine to lower homocysteine via betaine homocysteine methyl transferase. The ER stress, via CHOP, causes apoptosis and CHOP null mice exhibit no apoptosis. Alcohol-induced ER stress can activate sterol regulatory element-binding protein (SREBP)-1c and SREBP-2, which contribute to the accumulation of triglyceride and cholesterol. Hyperhomocysteinemia, ER stress and pathological changes of alcohol were minimally affected by absence of tumor necrosis factor receptor 1 (TNFR1) and the effect of betaine was also independent of TNF signaling. At present ER stress as an important factor in the pathogenesis of alcoholic liver disease is an exciting new hypothesis and ongoing research will need to further clarify its contribution. Among the issues in need of further elucidation are the role of ER stress induced by alcohol in SREBP regulation and fatty liver, as well as the precise mechanism of protection by betaine: decreased homocysteine, decreased S-adenosylhomocysteine, or increased S-adenosylmethionine.
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PMID:Unfolding new mechanisms of alcoholic liver disease in the endoplasmic reticulum. 1695 78

Nonalcoholic steatohepatitis (NASH) is one of the life-threatening hepatic diseases associated with insulin resistance. Here we report that nuclear sterol regulatory element-binding protein 1c (nSREBP-1c) transgenic mice, an inherited lipodystrophic model with severe insulin resistance, spontaneously develop steatohepatitis. The animal had marked fatty liver accompanied by hyperglycemia, hypoleptinemia, and hypoadiponectinemia. Liver histology similar to NASH, that is, mononuclear cell infiltration, pericellular fibrosis, ballooning degeneration, and Mallory hyaline body formation were seen in the livers from transgenic mice 20 weeks or older. In contrast, no liver histologic abnormalities were noted in wild-type mice aged 30 weeks. Immunoreactive 8-hydroxy-2'-deoxyguanosine was observed in the nuclei of livers from transgenic mice, suggesting that in addition to insulin resistance, oxidative stress may be involved in the development of the NASH-like lesion. Thus, the nSREBP-1c transgenic mouse may serve as a unique model of spontaneously occurring NASH.
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PMID:Transgenic mice expressing nuclear sterol regulatory element-binding protein 1c in adipose tissue exhibit liver histology similar to nonalcoholic steatohepatitis. 1737 3

The worldwide increase in degenerative diseases is in part due to modifications in the lifestyle including the diet. Epidemiological, clinical, and experimental evidence shows that soy protein may prevent lipotoxicity in non-adipose tissues during obesity. The molecular mechanism by which soy protein prevents lipotoxicity involves a reduction in the insulin/glucagon ratio, resulting in a down-regulation of lipogenic genes mediated by the transcription factor sterol regulatory element-binding protein (SREBP)-1, and up-regulation of SREBP-2 to reduce serum cholesterol. In addition, soy protein maintains the functionality of adipose tissue-liver axis to prevent hepatic steatosis during the development of obesity.
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PMID:The role of dietary protein on lipotoxicity. 1760 16

Ethanol induces cumulative liver damage including steatosis, steatohepatitis and cirrhosis. The aim of this study is to investigate the global intrahepatic gene expression profile in the mouse liver treated with ethanol. A single oral dose of 0.5 or 5 g/kg ethanol was administered to male ICR mice, and liver samples were obtained after 6, 24 and 72 h. Histopathological evaluation showed typical fatty livers in the high-dose group at 24 h. Microarray analysis identified 28 genes as being ethanol responsive (two-way ANOVA; p<0.05), after adjustment by the Benjamini-Hochberg multiple testing correction; these genes displayed >or=2-fold induction or repression. The expression of genes that are known to be involved in fatty acid synthesis was examined. The transcript for lipogenic transcription factor, sterol regulatory element (SRE)-binding factor 1 (Srebf1), was upregulated by acute ethanol exposure. Of the genes known to contain SRE or SRE-like sequences and to be regulated by SRE-binding protein 1 (SREBP1), those encoding malic enzyme (Mod1), ATP-citrate lyase (Acly), fatty acid synthase (Fasn) and stearyl-CoA desaturase (Scd1) were induced by ethanol. Quantitative real-time PCR confirmed the changes in the expression levels of the selected genes. The change in the Srebf1 mRNA level correlates well with that of the SREBP1 protein expression as well as its binding to the promoters of the target genes. The present study identifies differentially expressed genes that can be applied to the biomarkers for alcohol-binge-induced fatty liver. These results support the hypothesis by which ethanol-induced steatosis in mice is mediated by the fatty acid synthetic pathway regulated by SREBP1.
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PMID:Differential gene expression and lipid metabolism in fatty liver induced by acute ethanol treatment in mice. 1765

PXR was isolated as a "xenobiotic receptor" that regulates drug-metabolizing enzymes and transporters, whereas LXR is known to promote hepatic lipogenesis by activating the lipogenic transcriptional factor sterol regulatory element-binding protein (SREBP). We have recently shown that PXR can mediate a SREBP-independent lipogenic pathway by activating the free fatty acid (FFA) uptake transporter CD36, PPARgamma, and several accessory lipogenic enzymes, such as stearoyl CoA desaturase-1 (SCD-1) and long-chain free fatty acid elongase (FAE). More recently, we found activation of LXR also induced the expression of CD36. Promoter analysis established CD36 as a novel transcriptional target of LXRalpha. Moreover, the steatotic effect of LXR agonists was largely abolished in CD36 null mice, suggesting an essential role for CD36 and FFA uptake in LXR-mediated steatosis. We also showed that PPARgamma, a positive regulator of CD36, is also a transcriptional target of PXR. Thus, PXR can regulate CD36 directly or through its activation of PPARgamma. Interestingly, PXR- and LXR-mediated CD36 activation and PXR-mediated PPARgamma activation are all liver-specific. We conclude that CD36 is a shared target of LXR, PXR, and PPARgamma. The network of CD36 regulation controlled by LXR, PXR, and PPARgamma establishes this FFA transporter as a common target of orphan nuclear receptors in their mediation of hepatic steatosis. It is hoped that the nuclear receptor-mediated CD36 regulation may offer novel targets for the therapeutic management of alcoholic and nonalcoholic steatosis.
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PMID:PXR and LXR in hepatic steatosis: a new dog and an old dog with new tricks. 1807 48

This study aimed to clarify the molecular mechanisms of age-specific hepatic lipid accumulation accompanying hyperinsulinemia in a peroxisome proliferator-activated receptor alpha (PPARalpha) (+/-):low-density lipoprotein receptor (LDLR) (+/-) mouse line. The hepatic fat content, protein amounts, and mRNA levels of genes involved in hepatic lipid metabolism were analyzed in 25-, 50-, 75- and 100-week-old mice. Severe fatty liver was confirmed only in 50- and 75-week-old mice. The hepatic expression of proteins that function in lipid transport and catabolism did not differ among the groups. In contrast, the mRNA levels and protein amounts of lipogenic enzymes, including acetyl-coenzyme A carboxylase-1, fatty acid synthase, and glycerol-3-phosphate acyltransferase, enhanced in the mice with fatty liver. Elevated mRNA and protein levels of lipoprotein lipase and fatty acid translocase, which are involved in hepatic lipid uptake, were also detected in mice with fatty liver. Moreover, both protein and mRNA levels of sterol regulatory element-binding protein-1 (SREBP-1), a transcription factor regulating lipid synthesis, had age-specific patterns similar to those of the proteins described above. Therefore, the age-specific fatty liver found in the PPARalpha (+/-):LDLR (+/-) mouse line is probably caused by age-specific expression of SREBP-1 and its downstream lipogenic genes, coordinated by the increased uptake of lipids. All of these factors might be affected by age-specific changes in serum insulin concentration.
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PMID:Molecular mechanism of age-specific hepatic lipid accumulation in PPARalpha (+/-):LDLR (+/-) mice, an obese mouse model. 1833 69


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