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)

The present study examined the anti-obesity effects of pine needle extract (PNE) in 3T3-L1 preadipocytes and in vivo studies. PNE treatment suppressed both glycerol-3-phosphate dehydrogenase activity and expression of peroxisome proliferator-activated receptor (PPAR) gamma in cultured 3T3-L1 adipocytes. To investigate the effect of PNE on obesity in rats fed high-fat diet, four types of diet, which included a normal diet (ND), high-fat diet (HFD), ND+PNE, and HFD+PNE diets, were fed to the rats ad libitum for 6 weeks. The PNE supplement significantly decreased body weight gain and visceral fat mass compared to the HFD group. The total cholesterol, TG, and leptin levels in the plasma were significantly reduced by PNE supplementation compared with those of the HFD group. Histological findings in liver tissue showed that PNE supplementation alleviated steatosis induced by HFD. In conclusion, PNE treatment suppressed differentiation of 3T-L1 adipocytes, in part by down-regulating expression of PPAPgamma mRNA, and reduced adipose tissue mass, hyperlipidemia, and hepatic steatosis in obese rats fed HFD. Therefore, pine needle water extract may be considered for use in therapy to control obesity.
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PMID:Effects of pine needle extract on differentiation of 3T3-L1 preadipocytes and obesity in high-fat diet fed rats. 1701 60

Adiponectin protects the liver from steatosis caused by obesity or alcohol and therefore the influence of adiponectin on human hepatocytes was analyzed. GeneChip experiments indicated that recombinant adiponectin downregulates aldehyde oxidase 1 (AOX1) expression and this was confirmed by real-time RT-PCR and immunoblot. AOX1 is a xenobiotic metabolizing protein and produces reactive oxygen species (ROS), that promote cell damage and fibrogenesis. Adiponectin and fenofibric acid activate peroxisome proliferator-activated receptor-alpha (PPAR-alpha) and both suppress AOX1 protein and this is blocked by the PPAR-alpha antagonist RU486. Obesity is associated with low adiponectin, reduced hepatic PPAR-alpha activity and fatty liver, and AOX1 was found induced in the liver of rats on a high-fat diet when compared to controls. Free fatty acids and leptin, that are elevated in obesity, failed to upregulate AOX1 in vitro. The current data indicate that adiponectin reduces AOX1 by activating PPAR-alpha whereas fatty liver disease is associated with elevated hepatic AOX1. High AOX1 may be associated with higher ROS well described to induce fibrogenesis in liver tissue but may also influence drug metabolism and activity.
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PMID:Aldehyde oxidase 1 is highly abundant in hepatic steatosis and is downregulated by adiponectin and fenofibric acid in hepatocytes in vitro. 1702 44

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta) has been implicated in important metabolic processes. A mouse lacking PGC-1beta (PGC1betaKO) was generated and phenotyped using physiological, molecular, and bioinformatic approaches. PGC1betaKO mice are generally viable and metabolically healthy. Using systems biology, we identified a general defect in the expression of genes involved in mitochondrial function and, specifically, the electron transport chain. This defect correlated with reduced mitochondrial volume fraction in soleus muscle and heart, but not brown adipose tissue (BAT). Under ambient temperature conditions, PGC-1beta ablation was partially compensated by up-regulation of PGC-1alpha in BAT and white adipose tissue (WAT) that lead to increased thermogenesis, reduced body weight, and reduced fat mass. Despite their decreased fat mass, PGC1betaKO mice had hypertrophic adipocytes in WAT. The thermogenic role of PGC-1beta was identified in thermoneutral and cold-adapted conditions by inadequate responses to norepinephrine injection. Furthermore, PGC1betaKO hearts showed a blunted chronotropic response to dobutamine stimulation, and isolated soleus muscle fibres from PGC1betaKO mice have impaired mitochondrial function. Lack of PGC-1beta also impaired hepatic lipid metabolism in response to acute high fat dietary loads, resulting in hepatic steatosis and reduced lipoprotein-associated triglyceride and cholesterol content. Altogether, our data suggest that PGC-1beta plays a general role in controlling basal mitochondrial function and also participates in tissue-specific adaptive responses during metabolic stress.
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PMID:Ablation of PGC-1beta results in defective mitochondrial activity, thermogenesis, hepatic function, and cardiac performance. 2007 97

Thyroid hormone regulates the balance between lipolysis and lipogenesis. We previously reported that male mice with a dominant-negative P398H mutation introduced into the TRalpha gene have visceral obesity, hyperleptinemia, and reduced catecholamine-stimulated lipolysis in white adipose tissue. Based on our observation of hepatic steatosis in the TRalpha P398H male mice, we used in vitro and in vivo models to investigate the influence of the TRalpha P398H mutant on peroxisome proliferator-activated receptor-alpha (PPARalpha) signaling. Wild-type TRalpha and the P398H mutant significantly reduced PPARalpha-mediated transcription in transient transfection assays. T(3) reversed the inhibition of PPARalpha action by wild-type TRalpha but not the P398H mutant. Chromatin immunoprecipitation assays demonstrated that the P398H mutant reduces PPARalpha binding to peroxisome proliferator receptor elements. In gel shift assays, the P398H mutant directly bound the peroxisome proliferator-activated receptor response element and inhibited PPARalpha binding, which was not reversed by addition of retinoid X receptor. The TRalpha R384C and PV dominant-negative mutants are not associated in vivo with a metabolic phenotype and had reduced (PV) or absent (R384C) PPARalpha inhibition compared with P398H. The metabolic phenotype of the P398H mutant mice is due, in part, to unique properties of the P398H mutant receptor interfering with PPARalpha signaling. The P398H mutant is a potential probe to characterize the physiological role of thyroid hormone receptor/PPARalpha interactions.
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PMID:A mutant thyroid hormone receptor alpha antagonizes peroxisome proliferator-activated receptor alpha signaling in vivo and impairs fatty acid oxidation. 1712 78

1. Fenofibrate and xuezhikang are two types of drugs widely used in the treatment of dyslipidaemia in China. The main purpose of present study was to test the efficacies and explore the potential mechanisms of action of the two lipid-lowering agents on high-fat diet-induced non-alcoholic fatty liver disease (NAFLD). 2. Rats were randomly divided into four groups, with eight rats per group. One group was given normal diet, whereas the other three groups were fed a high-fat diet. Forty-two days later, two of the high-fat diet-fed groups were administered fenofibrate (100 mg/kg, p.o.) and xuezhikang (300 mg/kg, p.o.) for another 42 consecutive days. The other two groups were administered placebo (saline) by gavage. 3. Typical pathological symptoms of NAFLD occurred in the high-fat diet groups. Fenofibrate and xuezhikang treatment markedly improved NAFLD, ameliorating dyslipidaemia and fat accumulation in the liver, improving insulin resistance and ameliorating oxidative stress. Hepatic steatosis, necro-inflammation and collagen deposition were lessened in the drug-treated groups. However, both xuezhikang and fenofibrate failed to reverse hepatomegaly and fenofibrate even aggravated it. Xuezhikang reversed aminotransferase abnormalities, but fenofibrate had less of an effect. 4. The common therapeutic mechanism of action of fenofibate and xuezhikang likely involves inhibition of the hepatic expression of tumour necrosis factor-alpha. Fenofibrate upregulated mRNA levels of peroxisome proliferator-activated receptor (PPAR) alpha in the liver, whereas xuezhikang had no effect on the hepatic expression of PPARalpha and this may explain, in part, their different effects on the NAFLD rats. 5. The results suggest that fenofibrate and xuezhikang may have potential clinical application in the treatment of NAFLD. However, the side-effects of fenofibrate and the underlying constituents of xuezhikang need to be determined and investigated further.
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PMID:Effects of fenofibrate and xuezhikang on high-fat diet-induced non-alcoholic fatty liver disease. 1720 32

The transcriptional coactivator peroxisome proliferator-activated receptor-gamma coactivator 1beta (PGC-1beta) is believed to control mitochondrial oxidative energy metabolism by activating specific target transcription factors including estrogen-related receptors and nuclear respiratory factor 1, yet its physiological role is not yet clearly understood. To define its function in vivo, we generated and characterized mice lacking the functional PGC-1beta protein [PGC-1beta knockout (KO) mice]. PGC-1beta KO mice are viable and fertile and show no overt phenotype under normal laboratory conditions. However, the KO mice displayed an altered expression in a large number of nuclear-encoded genes governing mitochondrial and metabolic functions in multiple tissues including heart, skeletal muscle, brain, brown adipose tissue, and liver. In contrast to PGC-1alpha KO mice that are reportedly hyperactive, PGC-1beta KO mice show greatly decreased activity during the dark cycle. When acutely exposed to cold, the KO mice developed abnormal hypothermia and morbidity. Furthermore, high-fat feeding induced hepatic steatosis and increased serum triglyceride and cholesterol levels in the KO mice. These results suggest that PGC-1beta in mouse plays a nonredundant role in controlling mitochondrial oxidative energy metabolism.
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PMID:PGC-1beta controls mitochondrial metabolism to modulate circadian activity, adaptive thermogenesis, and hepatic steatosis. 1736 Mar 56

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

CCAAT/enhancer-binding protein beta (C/EBPbeta) plays a key role in initiation of adipogenesis in adipose tissue and gluconeogenesis in liver; however, the role of C/EBPbeta in hepatic lipogenesis remains undefined. Here we show that C/EBPbeta inactivation in Lepr(db/db) mice attenuates obesity, fatty liver, and diabetes. In addition to impaired adipogenesis, livers from C/EBPbeta(-/-) x Lepr(db/db) mice had dramatically decreased triglyceride content and reduced lipogenic enzyme activity. C/EBPbeta deletion in Lepr(db/db) mice down-regulated peroxisome proliferator-activated receptor gamma2 (PPARgamma2) and stearoyl-CoA desaturase-1 and up-regulated PPARalpha independent of SREBP1c. Conversely, C/EBPbeta overexpression in wild-type mice increased PPARgamma2 and stearoyl-CoA desaturase-1 mRNA and hepatic triglyceride content. In FAO cells, overexpression of the liver inhibiting form of C/EBPbeta or C/EBPbeta RNA interference attenuated palmitate-induced triglyceride accumulation and reduced PPARgamma2 and triglyceride levels in the liver in vivo. Leptin and the anti-diabetic drug metformin acutely down-regulated C/EBPbeta expression in hepatocytes, whereas fatty acids up-regulate C/EBPbeta expression. These data provide novel evidence linking C/EBPbeta expression to lipogenesis and energy balance with important implications for the treatment of obesity and fatty liver disease.
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PMID:CCAAT/enhancer-binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. 1738 71

The term nonalcoholic steatohepatitis (NASH) has recently been proposed to identify a fatty liver disease accompanied by diffuse fatty infiltration and inflammation. However, no drug therapy has been established for NASH as yet. In the present study, we demonstrate the effect of the angiotensin II type 1 receptor antagonist telmisartan on the development of NASH in a rat model. Telmisartan, but not the angiotensin receptor antagonist valsartan, markedly attenuated hepatic steatosis, inflammation, and fibrosis in these rats. The quantitative parameters of steatosis, inflammation, and fibrosis were also ameliorated by treatment with telmisartan. Compared with telmisartan, the peroxisome proliferator-activated receptor-gamma agonist pioglitazone attenuated hepatic steatosis and fibrosis of the liver to a similar degree. However, telmisartan, but not pioglitazone, dramatically decreased both subcutaneous and visceral fat. In conclusion, these results indicated that telmisartan should be the drug of first choice for the treatment of patients with NASH.
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PMID:Telmisartan, an angiotensin II type 1 receptor blocker, controls progress of nonalcoholic steatohepatitis in rats. 1741 Apr 41

Alcohol-induced fatty liver (steatosis) was believed to result from excessive generation of reducing equivalents from ethanol metabolism, thereby enhancing fat accumulation. Recent findings have revealed a more complex picture in which ethanol oxidation is still required, but specific transcription as well as humoral factors also have important roles. Transcription factors involved include the sterol regulatory element binding protein 1 (SREBP-1) which is activated to induce genes that regulate lipid biosynthesis. Conversely, ethanol consumption causes a general down-regulation of lipid (fatty acid) oxidation, a reflection of inactivation of the peroxisome proliferator-activated receptor-alpha (PPAR-alpha) that regulates genes involved in fatty acid oxidation. A third transcription factor is the early growth response-1 (Egr-1), which is strongly induced prior to the onset of steatosis. The activities of all these factors are governed by that of the principal regulatory enzyme, AMP kinase. Important humoral factors, including adiponectin, and tumor necrosis factor-alpha (TNF-alpha), also regulate alcohol-induced steatosis. Their levels are affected by alcohol consumption and by each other. This review will summarize the actions of these proteins in ethanol-elicited fatty liver. Because steatosis is now regarded as a significant risk factor for advanced liver pathology, an understanding of the molecular mechanisms in its etiology is essential for development of effective therapies.
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PMID:Alcohol-induced steatosis in liver cells. 1785 40


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