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)

In order to obtain some information on how fatty liver arises in geese, we investigated the role of insulin and glucose in triglyceride (TG) accumulation in goose primary hepatocytes. Goose primary hepatocytes were isolated and treated with insulin and glucose. Compared with the control group, 100 and 150 nmol l(-1) insulin increased TG accumulation, acetyl-CoA carboxylase-alpha (ACCalpha) and fatty acid synthase (FAS) activity, and the mRNA levels of sterol regulatory element-binding protein-1 (SREBP-1), FAS and ACCalpha genes. Insulin at 200 nmol l(-1) had an inhibiting effect on TG accumulation and the activity of ACC and FAS, but increased the gene expression of SREBP-1, FAS and ACCalpha. We also found that high glucose (30 mmol l(-1)) increased the TG level, ACC and FAS activity, and the mRNA levels of SREBP-1 and FAS. However, there was no effect of high glucose on ACCalpha mRNA level. In addition, the interaction between insulin and glucose was observed to induce TG accumulation, ACC and FAS activity, and gene expression of SREBP-1, FAS and ACCalpha, and increase SREBP-1 nuclear protein level and binding of nuclear SREBP-1 and the SRE response element of the ACC gene. The result also indicated that the glucose-induced TG accumulation decreased after 96 h when the hepatocytes were cultured with 30 mmol l(-1) glucose. In conclusion, insulin and glucose may affect hepatic lipogenesis by regulating lipogenic gene expression and lipogenic enzyme activity in goose hepatocytes, and SREBP-1 might play an important role in the synergetic activation of lipogenic genes. We propose that the utilization of accumulated TG in hepatocytes is the reason for the reversible phenomenon in goose hepatocellular steatosis.
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PMID:The role of insulin and glucose in goose primary hepatocyte triglyceride accumulation. 1941 49

The pregnane X receptor (PXR) initially isolated as a nuclear receptor regulating xenobiotic and drug metabolism and elimination, seems to play an endobiotic role by affecting lipid homeostasis. In mice, PXR affects lipid homeostasis and increases hepatic deposit of triglycerides. In this study, we show that, in human hepatocyte, PXR activation induces an increase of de novo lipogenesis through the up-regulation of S14. S14 was first identified as a thyroid-responsive gene and is known to transduce hormone-related and nutrient-related signals to genes involved in lipogenesis through a molecular mechanism not yet elucidated. We demonstrate that S14 is a novel transcriptional target of PXR. In addition, we report an increase of fatty acid synthase (FASN) and adenosine triphosphate citrate lyase genes expression after PXR activation in human hepatocyte, leading to an increase of fatty acids accumulation and de novo lipogenesis. RNA interference of the expression of S14 proportionally decreases the FASN induction, whereas S14 overexpression in human hepatic cells provokes an increase of fatty acids accumulation and lipogenesis. These results demonstrate for the first time that xenobiotic or drug-activated PXR promote aberrant hepatic de novo lipogenesis via activation of the nonclassical S14 pathway. In addition, these data suggest that the up-regulation of S14 by PXR may promote aberrant hepatic lipogenesis and hepatic steatosis in human hepatocytes.
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PMID:A novel pregnane X receptor and S14-mediated lipogenic pathway in human hepatocyte. 1943 91

We examined the effects of Rhizoma Dioscoreae Tokoronis extracts (RDTEs) on plasma lipids, body weight, and lipogenic enzymes. Mice were administered a standard chow diet, a 60% high-fat diet, or a high-fat diet with RDTE. Mice that were fed a high-fat diet containing RDTE were found to have lower increases in body and epididymal adipose tissue weights and a lessened occurrence of hepatic steatosis than mice that were fed a high-fat diet. The decreased adiposity that was induced by RDTE accounted for lower plasma levels of tumor necrosis factor-alpha, leptin, and glucose and a higher level of adiponectin. RDTE administration also resulted in a significant decrease in triglyceride, total plasma cholesterol, and low-density lipoprotein-cholesterol when compared to the high-fat group. To identify the mechanism by which RDTE induced its antiobesity effect, we investigated the sterol response element binding protein (SREBP) transcription system, which was induced in mice that were fed the high-fat diet. RDTE was found to suppress the expression of SREBP-1 as well as that of fatty acid synthase in adipose and liver tissues in mice provided the high-fat diet. These findings suggest that the antiobesity action of RDTE in mice that are fed a high-fat diet may occur in response to suppression of the SREBP-1-dependent lipogenic pathway.
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PMID:Antiobesity activity of aqueous extracts of Rhizoma Dioscoreae Tokoronis on high-fat diet-induced obesity in mice. 1945 30

The hypothesis that PDHK4 (pyruvate dehydrogenase kinase isoenzyme 4) has potential as a target for the treatment of type 2 diabetes was tested by feeding wild-type and PDHK4 knockout mice a high saturated fat diet that induces hyperglycemia, hyperinsulinaemia, glucose intolerance, hepatic steatosis and obesity. Previous studies have shown that PDHK4 deficiency lowers blood glucose by limiting the supply of three carbon gluconeogenic substrates to the liver. There is concern, however, that the increase in glucose oxidation caused by less inhibition of the pyruvate dehydrogenase complex by phosphorylation will inhibit fatty acid oxidation, promote ectopic fat accumulation and worsen insulin sensitivity. This was examined by feeding wild-type and PDHK4 knockout mice a high saturated fat diet for 8 months. Fasting blood glucose levels increased gradually in both groups but remained significantly lower in the PDHK4 knockout mice. Hyperinsulinaemia developed in both groups, but glucose tolerance was better and body weight was lower in the PDHK4 knockout mice. At termination, less fat was present in the liver and skeletal muscle of the PDHK4 knockout mice. Higher amounts of PGC-1alpha [PPARgamma (peroxisome proliferator-activated receptor gamma) coactivator 1alpha] and PPARalpha and lower amounts of fatty acid synthase and acetyl-CoA carboxylase isoenzyme 1 were present in the liver of the PDHK4 knockout mice. These findings suggest PDHK4 deficiency creates conditions that alter upstream signalling components involved in the regulation of lipid metabolism. The findings support the hypothesis that PDHK4 is a viable target for the treatment of type 2 diabetes.
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PMID:Pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) deficiency attenuates the long-term negative effects of a high-saturated fat diet. 1962 55

The nuclear receptor PPARalpha is activated by drugs to treat human disorders of lipid metabolism. Its endogenous ligand is unknown. PPARalpha-dependent gene expression is impaired with inactivation of fatty acid synthase (FAS), suggesting that FAS is involved in generation of a PPARalpha ligand. Here we demonstrate the FAS-dependent presence of a phospholipid bound to PPARalpha isolated from mouse liver. Binding was increased under conditions that induce FAS activity and displaced by systemic injection of a PPARalpha agonist. Mass spectrometry identified the species as 1-palmitoyl-2-oleoyl-sn-glycerol-3-phosphocholine (16:0/18:1-GPC). Knockdown of Cept1, required for phosphatidylcholine synthesis, suppressed PPARalpha-dependent gene expression. Interaction of 16:0/18:1-GPC with the PPARalpha ligand-binding domain and coactivator peptide motifs was comparable to PPARalpha agonists, but interactions with PPARdelta were weak and none were detected with PPARgamma. Portal vein infusion of 16:0/18:1-GPC induced PPARalpha-dependent gene expression and decreased hepatic steatosis. These data suggest that 16:0/18:1-GPC is a physiologically relevant endogenous PPARalpha ligand.
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PMID:Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. 1964 43

The susceptibility to development of hepatic steatosis is known to differ between Muscovy and Pekin ducks. Although some experiments were conducted to decipher these differences, few data have been produced to analyse the role of specific genes in this process. For this purpose, expression levels of genes involved in lipid (ATP citrate lyase, malic enzyme 1, fatty acid synthase, stearoyl-CoA desaturase 1, diacylglycerol O-acyl transferase 2, microsomal triglyceride transfer protein, apolipoprotein A1, apolipoprotein B, sterol regulatory element binding factor 1, hepatocyte nuclear factor 4, choline/ethanolamine phosphotransferase 1, carnitine palmitoyl transferase 1A, peroxisome proliferator-activated receptor alpha and sterol O-acyltransferase) and carbohydrate (activating transcription factor 4 or cAMP-response element binding protein, mitochondrial malate dehydrogenase 2 and carbohydrate responsive element binding protein) metabolism and in other functions were analysed in the liver of Pekin and Muscovy ducks fed ad libitum or overfed. A specific positive effect of feeding was observed on the expression of genes involved mainly in fatty acids and TG synthesis and glycolysis, and negative effect on genes involved in beta-oxidation. Interestingly, a strong species effect was also observed on stearoyl-CoA desaturase 1 and to a lesser extent on diacylglycerol O-acyl transferase 2 expression, leading to large differences in expression levels between Pekin and Muscovy overfed ducks, which could explain the difference in lipid metabolism and steatosis ability observed between the two duck species. These results should shed light on gene expression that might underlie susceptibility to hepatic steatosis in humans.
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PMID:Liver gene expression in relation to hepatic steatosis and lipid secretion in two duck species. 1978 Oct 35

We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (approximately 70%); detoxification, steroid, and sulfur metabolism (approximately 65%) as well as cell growth/proliferation and protein synthesis/transformation (approximately 70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-to-cell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7 alpha hydroxylase, cadherin 17, and peroxisome proliferator-activated receptor alpha significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease.
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PMID:A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats. 1978 28

Sauchinone, as an AMP-activated kinase (AMPK)-activating lignan in Saururus chinensis, has been shown to prevent iron-induced oxidative stress and liver injury. Sterol regulatory element binding protein-1c (SREBP-1c) plays a key role in hepatic steatosis, which promotes oxidative stress in obese subjects. Previously, we identified the role of AMPK in liver X receptor-alpha (LXRalpha)-mediated SREBP-1c-dependent lipogenesis. Because sauchinone as an antioxidant has the ability to activate AMPK, this study investigated its effects on SREBP-1c-dependent lipogenesis in hepatocytes and in high-fat diet (HFD)-induced hepatic steatosis and oxidative injury. Sauchinone prevented the ability of an LXRalpha agonist (T0901317) to activate SREBP-1c, repressing transcription of the fatty acid synthase, acetyl-CoA carboxylase, stearoyl-CoA desaturase-1, ATP-binding cassette transporter A1, and LXRalpha genes. Consistent with this, an HFD in mice caused fat accumulation in the liver with SREBP-1c induction, which was attenuated by sauchinone treatment. Also, sauchinone had the ability to inhibit oxidative stress as shown by decreases in thiobarbituric acid-reactive substance formation, nitrotyrosinylation, and 4-hydroxynonenal production. Moreover, it prevented not only the liver injury, but also the AMPK inhibition elicited by HFD feeding. These results demonstrate that sauchinone has the capability to inhibit LXRalpha-mediated SREBP-1c induction and SREBP-1c-dependent hepatic steatosis, thereby protecting hepatocytes from oxidative stress induced by fat accumulation.
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PMID:Inhibition of SREBP-1c-mediated hepatic steatosis and oxidative stress by sauchinone, an AMPK-activating lignan in Saururus chinensis. 2000 44

The objective of this study was to determine the effects of the ethanol extract of two variants of Artemisia princeps Pampanini, Sajabalssuk (SB) and Sajuarissuk (SS), on lipid metabolism in type 2 diabetic animals. Male C57BL/KsJ-db/db mice were divided into control, SB ethanol extract (SBE) (0.171 g/100 g of diet), SS ethanol extract (SSE) (0.154 g/100 g of diet), and rosiglitazone (RG) (0.005 g/100 g of diet) groups. Supplementation of SBE and SSE significantly lowered the plasma levels of free fatty acid, triglyceride, and total cholesterol compared to the control group. The hepatic triglyceride and cholesterol contents and hepatic lipid droplets accumulation were also significantly lower in the SBE- and SSE-supplemented db/db mice than in the control or RG-supplemented db/db mice. Reductions of hepatic triglyceride and cholesterol contents in the SBE and SSE groups were related to the suppression of hepatic lipogenic enzyme activities, fatty acid synthesis (fatty acid synthase and malic enzyme), triglyceride synthesis (phosphatidate phosphohydrolase), and cholesterol synthesis (3-hydroxy-3-methylglutaryl-coenzyme A reductase) and esterification (acyl-coenzyme A:cholesterol acyltransferase). The RG supplement lowered plasma and hepatic lipid levels compared to the control group. However, RG significantly increased the white and brown adipose tissue weight and epididymal adipocyte size, whereas SBE and SSE lowered the brown adipose tissue weight and epididymal adipocyte size compared to the RG group. Together, these data suggest that supplementation of SBE and SSE partly improves lipid dysregulation and fatty liver in db/db mice by suppressing hepatic lipogenic enzyme activities.
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PMID:Antilipogenic and hypolipidemic effects of ethanol extracts from two variants of Artemisia princeps Pampanini in obese diabetic mice. 2004 76

Alcohol intake remains the most important cause of fatty liver throughout the world. The current study was undertaken to determine whether dietary supplementation with Codonopsis lanceolata root water extract attenuates the development of alcoholic fatty liver in rats and to elucidate the molecular mechanism for such an effect. Male Sprague-Dawley rats were fed normal diet (ND), ethanol diet (ED) (36% of total energy from ethanol), or 0.5% C. lanceolata root extract-supplemented ethanol diet (ED+C) for 8 weeks. C. lanceolata root water extract supplemented to rats with chronic alcohol consumption ameliorated the ethanol-induced accumulations of hepatic cholesterol and triglyceride. Chronic alcohol consumption up-regulated the hepatic expression of genes involved in inflammation, fatty acid synthesis, and cholesterol metabolism, including tumor necrosis factor alpha (TNFalpha), liver X receptor alpha (LXRalpha), sterol regulatory element-binding protein (SREBP)-1c, fatty acid synthase, acetyl-coenzyme A carboxylase alpha (ACC), stearoyl-coenzyme A desaturase 1, 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), and low-density lipoprotein receptor (LDLR). The ethanol-induced up-regulations of TNFalpha, LXRalpha, SREBP-1c, HMGR, and LDLR genes in the liver were reversed by feeding C. lanceolata root water extract for 8 weeks. Moreover, ethanol-induced decreases in the ratio of phospho-5'-AMP-activated protein kinase (AMPK) alpha/AMPKalpha and phospho-ACC/ACC protein levels in the liver were significantly restored (135% and 35% increases, respectively, P < .05) by supplementing them with C. lanceolata root water extract. In conclusion, C. lanceolata root water extract appears to be protective against alcoholic fatty liver through the regulation of SREBP-1c, LXRalpha, HMGR, and LDLR genes and by the phosphorylation of AMPKalpha and ACC, which are implicated in lipid metabolism.
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PMID:Protective effect of Codonopsis lanceolata root extract against alcoholic fatty liver in the rat. 2004 84


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