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 fed diets containing trans 10, cis 12 (t10, c12)-conjugated linoleic acid (CLA) develop fatty livers and the role of the hepatic fatty acid oxidation enzymes in this development is not well defined. We examined the effects of dietary cis 9, trans 11-CLA (c9, t11-CLA) and t10, c12-CLA on the expression of hepatic genes for fatty acid metabolism. Female mice, 8 weeks old, (six animals per group) were fed either a control diet or diets supplemented with 0.5% c9, t11- or c12-CLA for 8 weeks. DNA microarray analysis showed that t10, c12-CLA increased the expression of 278 hepatic genes and decreased those of 121 genes (>2 fold); c9, t11-CLA increased expression of twenty-two genes and decreased those of nine. Real-time PCR confirmed that t10, c12-CLA reduced by the expression of fatty acid oxidation genes including flavin monooxygenase (FMO)-3 95%, cytochrome P450 (cyt p450) 69%, carnitine palmitoyl transferase 1a 77%, acetyl CoA oxidase (ACOX) 50% and PPARalpha 65%: it increased the expression of fatty acid synthase by 3.5-fold (P<0.05 for all genes, except ACOX P=0.08). It also reduced the enzymatic activity of hepatic microsomal FMO by 40% and the FMO3 specific protein by 67%. c9, t11-CLA reduced FMO3 and cyt P450 expression by 61% (P=0.001) and 38% (P=0.06) and increased steoryl CoA desaturase transcription by 5.9-fold (P=0.07). Both decreased fatty acid oxidation and increased fatty acid synthesis seem to contribute to the CLA-induced fatty liver. Since FMO and cyt P450 are also involved in drug detoxification, suppression of the transcription of these genes by CLA may have other health consequences besides development of fatty liver.
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PMID:Dietary trans 10, cis 12-conjugated linoleic acid reduces the expression of fatty acid oxidation and drug detoxification enzymes in mouse liver. 1721 60

Obesity and type 2 diabetes are worldwide health issues. The present paper investigates prenatal and postnatal pathways to obesity, identifying different metabolic outcomes with different effects on insulin sensitivity and different underlying mechanisms involving key components of insulin receptor signaling pathways. Pregnant Wistar rats either were fed chow ad libitum or were undernourished throughout pregnancy, generating either control or intrauterine growth restricted (IUGR) offspring. Male offspring were fed either standard chow or a high-fat diet from weaning. At 260 d of age, whole-body insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and other metabolic parameters were measured. As expected, high-fat feeding caused diet-induced obesity (DIO) and insulin resistance. Importantly, the insulin sensitivity of IUGR offspring was similar to that of control offspring, despite fasting insulin hypersecretion and increased adiposity, irrespective of postnatal nutrition. Real-time PCR and Western blot analyses of key markers of insulin sensitivity and metabolic regulation showed that IUGR offspring had increased hepatic levels of atypical protein kinase C zeta (PKC zeta) and increased expression of fatty acid synthase mRNA. In contrast, DIO led to decreased expression of fatty acid synthase mRNA and hepatic steatosis. The decrease in hepatic PKC zeta with DIO may explain, at least in part, the insulin resistance. Our data suggest that the mechanisms of obesity induced by prenatal events are fundamentally different from those of obesity induced by postnatal high-fat nutrition. The origin of insulin hypersecretion in IUGR offspring may be independent of the mechanistic events that trigger the insulin resistance commonly observed in DIO.
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PMID:Prenatal and postnatal pathways to obesity: different underlying mechanisms, different metabolic outcomes. 1727 92

Metabolic adaptation is required to cope with episodes of protein deprivation and malnutrition. GCN2 eIF2alpha kinase, a sensor of amino acid deficiency, plays a key role in yeast and mammals in modulating amino acid metabolism as part of adaptation to nutrient deprivation. The role of GCN2 in adaptation to long-term amino acid deprivation in mammals, however, is poorly understood. We found that expression of lipogenic genes and the activity of fatty acid synthase (FAS) in the liver are repressed and lipid stores in adipose tissue are mobilized in wild-type mice upon leucine deprivation. In contrast, GCN2-deficient mice developed liver steatosis and exhibited reduced lipid mobilization. Liver steatosis in Gcn2(-/-) mice was found to be caused by unrepressed expression of lipogenic genes, including Srebp-1c and Fas. Thus, our study identifies a novel function of GCN2 in regulating lipid metabolism during leucine deprivation in addition to regulating amino acid metabolism.
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PMID:The GCN2 eIF2alpha kinase regulates fatty-acid homeostasis in the liver during deprivation of an essential amino acid. 1727 50

Although tamoxifen can trigger steatohepatitis, the mechanism of steatosis is unclear. We hypothesized that this DNA-intercalating, cationic amphiphilic drug could accumulate within mitochondria to impair fatty acid oxidation, respiration, and mitochondrial DNA relaxation and synthesis. We studied the in vitro effects of tamoxifen on topoisomerases and mouse liver mitochondria and its in vivo hepatic effects in mice treated for 1 to 28 days with a daily dose of tamoxifen reproducing the plasma concentrations observed in humans. In vitro, tamoxifen inhibited topoisomerase-mediated plasmid DNA relaxation. It accumulated 40-fold inside mitochondria and inhibited both respiration and fatty acid oxidation. In vivo, a single dose of tamoxifen inhibited palmitic acid oxidation and hepatic lipoprotein secretion. Tamoxifen administration also decreased mitochondrial DNA synthesis and progressively depleted hepatic mitochondrial DNA, down to 40% of control values at 28 days. The decrease in mitochondrial DNA-encoded respiratory complexes sensitized mitochondria to the inhibitory effects of tamoxifen on mitochondrial respiration. Hepatic steatosis was absent at 5 days, mild at 12 days, and moderate at 28 days. The fatty acid synthase protein was normally expressed at 12 days but was decreased by 52% at 28 days. In conclusion, tamoxifen decreases hepatic triglyceride secretion, and it accumulates electrophoretically in mitochondria, where it impairs beta-oxidation and respiration. Tamoxifen also inhibits topoisomerases and mitochondrial DNA synthesis and progressively depletes hepatic mitochondrial DNA in vivo. These combined effects could decrease fat removal from the liver, thus causing hepatic steatosis despite a secondary down-regulation of hepatic fatty acid synthase expression.
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PMID:Tamoxifen inhibits topoisomerases, depletes mitochondrial DNA, and triggers steatosis in mouse liver. 1727 97

Dysfunctional cross talk between adipose tissue and liver tissue results in metabolic and inflammatory disorders. As an insulin sensitizer, rosiglitazone (Rosi) improves insulin resistance yet causes increased adipose mass and weight gain in mice and humans. Conjugated linoleic acid (CLA) reduces adipose mass and body weight gain but induces hepatic steatosis in mice. We examined the combined effects of Rosi and CLA on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed male C57Bl/6 mice. CLA alone suppressed weight gain and adipose mass but caused hepatic steatosis. Addition of Rosi attenuated CLA-induced insulin resistance and dysregulation of adipocytokines. In adipose, CLA significantly suppressed lipoprotein lipase and fatty acid translocase (FAT/CD36) mRNA, suggesting inhibition of fatty acid uptake into adipose; addition of Rosi completely rescued this effect. In addition, CLA alone increased markers of macrophage infiltration, F4/80, and CD68 mRNA levels, without inducing TNF-alpha in epididymal adipose tissue. The ratio of Bax to Bcl2, a marker of apoptosis, was significantly increased in adipose of the CLA-alone group and was partially prevented by treatment of Rosi. Immunohistochemistry of F4/80 demonstrates a proinflammatory response induced by CLA in epididymal adipose. In the liver, CLA alone induced microsteatotic liver but surprisingly increased the rate of very-low-density lipoprotein-triglyceride production without inducing inflammatory mediator-TNF-alpha and markers of macrophage infiltration. These changes were accompanied by significantly increased mRNA levels of stearoyl-CoA desaturase, FAT/CD36, and fatty acid synthase. The combined administration of CLA and Rosi reduced hepatic liver triglyceride content as well as lipogenic gene expression compared with CLA alone. In summary, dietary CLA prevented weight gain in Rosi-treated mice without attenuating the beneficial effects of Rosi on insulin sensitivity. Rosi ameliorated CLA-induced lipodystrophic disorders that occurred in parallel with rescued expression of adipocytokine and adipocytes-abundant genes.
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PMID:Combined effects of rosiglitazone and conjugated linoleic acid on adiposity, insulin sensitivity, and hepatic steatosis in high-fat-fed mice. 1732 64

The dietary fatty acid conjugated linoleic acid (CLA) reduces hepatic lipid accumulation in some rodent models for obesity and hepatic steatosis. However, these effects are variable and complex due to differences in isomer responses and degree and sensitivity to changes in adiposity. Here, we hypothesized that CLA decreases hepatic steatosis in a diet-induced model of obesity in rats which are resistant to the adipose-lowering effects of CLA. To investigate this, we fed male Wistar rats a high-fat (20%) diet for 4 weeks to induce obesity and hepatic steatosis followed by low-fat (6.5%) experimental diets containing either 6.5% soybean oil (CON) or 1.5% CLA triglyceride mix plus 5% soybean oil (CLA). Dietary CLA significantly lowered hepatic triglycerides without changing weight, adiposity or adipokines, and was associated with significantly lower hepatic fatty acid synthase and stearoyl CoA desaturase-1 (SCD-1) mRNA levels and SCD-1 index along with significantly lower sterol regulatory element binding protein-1 mRNA, a transcription factor that regulates lipogenesis. Furthermore, the lower lipogenesis was associated with significantly higher mRNA expression of lipid oxidation gene peroxisome proliferator-activated receptor-alpha and acetyl CoA oxidase in the livers of rats fed dietary CLA. The lipid-lowering effects of CLA in the liver were observed in the absence of changes in adipose tissue and body weight. Thus, we conclude that in the Wistar rat model, where adipose levels remain static after feeding dietary CLA, hepatic lipid accumulation is reduced and these effects are not due to an improvement in overall adiposity.
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PMID:Conjugated linoleic acid does not reduce body fat but decreases hepatic steatosis in adult Wistar rats. 1736 79

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

Non-alcoholic fatty liver disease is tightly associated with insulin resistance, type 2 diabetes and obesity, but the molecular links between hepatic fat accumulation and insulin resistance are not fully identified. Excessive accumulation of triglycerides (TG) is one the main characteristics of non-alcoholic fatty liver disease and fatty acids utilized for the synthesis of TG in liver are available from the plasma non-esterified fatty acid pool but also from fatty acids newly synthesized through hepatic de novo lipogenesis. Recently, the transcription factor ChREBP (carbohydrate responsive element binding protein) has emerged as a central determinant of lipid synthesis in liver through its transcriptional control of key genes of the lipogenic pathway, including fatty acid synthase and acetyl CoA carboxylase. In this mini-review, we will focus on the importance of ChREBP in the physiopathology of hepatic steatosis and insulin resistance by discussing the physiological and metabolic consequences of ChREBP knockdown in liver of ob/ob mice.
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PMID:Role of ChREBP in hepatic steatosis and insulin resistance. 1771 60

Exercise training is commonly prescribed for treatment of nonalcoholic fatty liver disease (NAFLD). We sought to determine whether exercise training prevents the development of NAFLD in Otsuka Long-Evans Tokushima Fatty (OLETF) rats and to elucidate the molecular mechanisms underlying the effects of exercise on hepatic steatosis. Four-week-old OLETF rats were randomly assigned to either a sedentary control group (Sed) or a group given access to voluntary running wheels for 16 wk (Ex). Wheels were locked 2 days before euthanasia in the Ex animals, and both groups were euthanized at 20 wk old. Voluntary wheel running attenuated weight gain and reduced serum glucose, insulin, free fatty acids, and triglycerides in Ex animals compared with Sed (P < 0.001). Ex animals exhibited significantly reduced hepatic triglyceride levels and displayed fewer lipid droplets (Oil Red O staining) and reduced lipid droplet size compared with Sed. Wheel running increased by threefold the percent of palmitate oxidized completely to CO(2) in the Ex animals but did not alter AMP-activated protein kinase-alpha (AMPKalpha) or AMPK phosphorylation status. However, fatty acid synthase and acetyl-coenzyme A carboxylase (ACC) content were significantly reduced (approximately 70 and approximately 35%, respectively), and ACC phosphorylation and cytochrome c content were significantly elevated (approximately 35 and approximately 30%, respectively) in the Ex animals. These results unequivocally demonstrate that daily physical activity attenuates hepatic steatosis and NAFLD in an obese rodent model and suggest that this effect is likely mediated, in part, through enhancement of hepatic fatty acid oxidation and reductions in key protein intermediates of fatty acid synthesis.
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PMID:Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima Fatty rats. 1817 72

Obesity has become a prevailing epidemic throughout the globe. Effective therapies for obesity become attracting. Food components with beneficial effects on "weight loss" have caught increasing attentions. Conjugated linoleic acid (CLA), docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA) belong to different families of polyunsaturated fatty acids (PUFA). However, they have similar effects on alleviating obesity and/or preventing from obesity. They influence the balance between energy intake and expenditure; and reduce body weight and/or fat deposition in animal models, but show little effect in healthy human subjects. They inhibit key enzymes responsible for lipid synthesis, such as fatty acid synthase and stearoyl-CoA desaturase-1, enhance lipid oxidation and thermogenesis, and prevent free fatty acids from entering adipocytes for lipogenesis. PUFA also exert suppressive effects on several key factors involved in adipocyte differentiation and fat storage. Despite their similar effects and shared mechanisms, they display differences in the regulation of lipid metabolism. Moreover, DHA and EPA exhibit "anti-obesity" effect as well as improving insulin sensitivity, while CLA induces insulin resistance and fatty liver in most cases. A deeper and more detailed investigation into the complex network of anti-obesity regulatory pathways by different PUFA will improve our understanding of the mechanisms of body weight control and reduce the prevalence of obesity.
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PMID:Anti-obesity effects of conjugated linoleic acid, docosahexaenoic acid, and eicosapentaenoic acid. 1830 30


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