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 receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2(-/-) mice assures the physiological importance of SREBP-1 gene induction. IRS-2(-/-) mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2(-/-) mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2(-/-) mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.
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PMID:Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver. 1154 55

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin's beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Here we report that metformin activates AMPK in hepatocytes; as a result, acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed. Activation of AMPK by metformin or an adenosine analogue suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; activity of the AMPK target, ACC, is also reduced. Using a novel AMPK inhibitor, we find that AMPK activation is required for metformin's inhibitory effect on glucose production by hepatocytes. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. Activation of AMPK provides a unified explanation for the pleiotropic beneficial effects of this drug; these results also suggest that alternative means of modulating AMPK should be useful for the treatment of metabolic disorders.
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PMID:Role of AMP-activated protein kinase in mechanism of metformin action. 1160 16

Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA-RH7777 hepatoma cell lines, ethanol induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter via increased levels of mature SREBP-1 protein. This effect of ethanol was blocked by addition of sterols. This effect is likely mediated by acetaldehyde, because the effect was only seen in cell lines expressing alcohol dehydrogenase, and inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect in the hepatoma cells. Furthermore, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells. Consistent with these in vitro findings, feeding mice a low fat diet with ethanol for 4 weeks resulted in a significant increase in steady-state levels of the mature (active) form of SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of hepatic lipogenic genes as well as the accumulation of triglyceride in the livers. These finding suggest that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver.
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PMID:Ethanol induces fatty acid synthesis pathways by activation of sterol regulatory element-binding protein (SREBP). 1203 55

Sterol regulatory element-binding proteins (SREBPs) are a family of membrane-bound transcription factors that regulate cholesterol and fatty acid homeostasis. In mammals, three SREBP isoforms designated SREBP-1a, SREBP-1c, and SREBP-2 have been identified. SREBP-1a and SREBP-1c are derived from the same gene by virtue of alternatively spliced first exons. SREBP-1a has a longer transcriptional activation domain and is a more potent transcriptional activator than SREBP-1c in cultured cells and liver. Here, we describe the physiologic consequences of overexpressing the nuclear form of SREBP-1a (nSREBP-1a) in adipocytes of mice using the adipocyte-specific aP2 promoter (aP2-nSREBP-1a). The transgenic aP2-nSREBP-1a mice developed markedly enlarged white and brown adipocytes that were fully differentiated. Adipocytes isolated from aP2-nSREBP-1a mice had significantly increased rates of fatty acid synthesis and enhanced fatty acid secretion. The increased production and release of fatty acids from adipocytes led, in turn, to a fatty liver. Overexpression of the alternative SREBP-1 isoform, nSREBP-1c, in adipose tissue inhibits adipocyte differentiation; as a result, the transgenic nSREBP-1c mice develop a syndrome resembling human lipodystrophy, which includes a loss of peripheral white adipose tissue, diabetes, and fatty livers (Shimomura, I., Hammer, R. E., Richardson, J. A., Ikemoto, S., Bashmakov, Y., Goldstein, J. L., and Brown, M. S. (1998) Genes Dev. 12, 3182-3194). In striking contrast, nSREBP-1a overexpression in fat resulted in the hypertrophy of fully differentiated adipocytes, no diabetes, and mild hepatic steatosis. These results suggest that nSREBP-1a and nSREBP-1c have distinct roles in adipocyte fat metabolism in vivo.
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PMID:Overexpression of sterol regulatory element-binding protein-1a in mouse adipose tissue produces adipocyte hypertrophy, increased fatty acid secretion, and fatty liver. 1285 91

Akt is critical in insulin-induced metabolism of glucose and lipids. To investigate functions induced by hepatic Akt activation, a constitutively active Akt, NH(2)-terminally myristoylation signal-attached Akt (myr-Akt), was overexpressed in the liver by injecting its adenovirus into mice. Hepatic myr-Akt overexpression resulted in a markedly hypoglycemic, hypoinsulinemic, and hypertriglyceridemic phenotype with fatty liver and hepatomegaly. To elucidate the sterol regulatory element binding protein (SREBP)-1c contribution to these phenotypic features, myr-Akt adenovirus was injected into SREBP-1 knockout mice. myr-Akt overexpression induced hypoglycemia and hepatomegaly with triglyceride accumulation in SREBP-1 knockout mice to a degree similar to that in normal mice, whereas myr-Akt-induced hypertriglyceridemia in knockout mice was milder than that in normal mice. The myr-Akt-induced changes in glucokinase, phosphofructokinase, glucose-6-phosphatase, and PEPCK expressions were not affected by knocking out SREBP-1, whereas stearoyl-CoA desaturase 1 induction was completely inhibited in knockout mice. Constitutively active SREBP-1-overexpressing mice had fatty livers without hepatomegaly, hypoglycemia, or hypertriglyceridemia. Hepatic acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase 1, and glucose-6-phosphate dehydrogenase expressions were significantly increased by overexpressing SREBP-1, whereas glucokinase, phospho-fructokinase, glucose-6-phosphatase, and PEPCK expressions were not or only slightly affected. Thus, SREBP-1 is not absolutely necessary for the hepatic Akt-mediated hypoglycemic effect. In contrast, myr-Akt-induced hypertriglyceridemia and hepatic triglyceride accumulation are mediated by both Akt-induced SREBP-1 expression and a mechanism involving fatty acid synthesis independent of SREBP-1.
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PMID:Hepatic Akt activation induces marked hypoglycemia, hepatomegaly, and hypertriglyceridemia with sterol regulatory element binding protein involvement. 1463 50

Leptin-deficient ob/ob mice show many characteristics of obesity, including excess peripheral adiposity as well as severe hepatic steatosis, at least in part, due to increased hepatic lipogenesis. Polyunsaturated fatty acids (PUFAs) are not only ligands for peroxisome proliferator-activated receptor (PPAR) alpha but are also negative regulators of hepatic lipogenesis, which is thought to be mediated by the repression of sterol regulatory element-binding protein (SREBP)-1. We have previously shown that the disruption of SREBP-1 in ob/ob mice decreased their liver triglyceride storage. To examine whether PUFAs could reduce hepatic triglyceride deposition, we challenged ob/ob mice with dietary PUFA. It is demonstrated that PUFA markedly decreased the mature form of SREBP-1 protein and thereby reduced the expression of lipogenic genes such as fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD1) in the livers of ob/ob mice. Consequently, the liver triglyceride content and plasma alanine aminotransferase (ALT) levels were decreased. Furthermore, both hyperglycemia and hyperinsulinemia in ob/ob mice were improved by PUFA administration, similar to the effect of PPARalpha activators. In conclusion, PUFAs ameliorate obesity-associated symptoms, such as hepatic steatosis and insulin resistance, presumably through both down-regulation of SREBP-1 and activation of PPARalpha.
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PMID:Polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice by SREBP-1 suppression. 1505 26

Dietary fatty acid composition modifies hepatic lipid metabolism. To determine the effects of fatty acids on hepatic triglyceride storage, rats were fed diets enriched in carbohydrates (control), fish oil, or lard. After 4 weeks, the animals were fasted overnight. In the morning, the animals were either sacrificed or fed 8 g of their respective diets before sacrifice. Animals ingested more food calories with diets containing fish oil than with other diets. However, fish oil-fed animals weighed less and had less body fat. In fish oil-fed animals, liver triglyceride was lower by 27% (P <.05) and 73% (P <.01) than in control- and lard-fed animals, respectively. Fish oil altered the postprandial gene expression of hepatic regulators of fatty acid degradation and synthesis. Fish oil feeding blunted the normal postprandial decline in fatty acid degradation genes (PPARalpha, CPT1, and ACO) and blunted the normal postprandial rise in triglyceride synthesis genes (SREBP1-c, FAS, SCD-1). Therefore, the direct postprandial effect of fish oil ingestion decreases the propensity for hepatic triglyceride storage. In conclusion, n-3 polyunsaturated fatty acids decrease total body weight, total body fat, and hepatic steatosis.
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PMID:Dietary n-3 polyunsaturated fatty acids decrease hepatic triglycerides in Fischer 344 rats. 1499 79

Liver X receptors (LXRs) are ligand-activated transcription factors that belong to the nuclear receptor superfamily. LXRs activate transcription of a spectrum of genes that regulate reverse cholesterol transport, including the ATP binding cassette transporter A1 (ABCA1), and raise HDL cholesterol (HDL-C) levels. However, LXR agonists also induce genes that stimulate lipogenesis, including the sterol response element binding protein (SREBP1-c) and fatty acid synthetase (FAS). The induction of these genes in the liver cause increased hepatic triglyceride synthesis, hypertriglyceridemia, and hepatic steatosis. As LXR response elements have been identified in these promoters, it is not clear if these two processes can be separated. Herein, we demonstrate that plasma HDL-C elevation and intestinal ABCA1 induction can occur with relatively little induction of FAS and SREBP1-c in mouse liver via a selective LXR modulator GW3965. This is in contrast to the strong induction of hepatic lipogenic genes by the well-characterized LXR agonist T0901317 (T317). Consistent with the in vivo results, GW3965 is a very weak LXR activator compared with T317 in human hepatoma cells. GW3965-liganded LXR recruits selected coactivators less effectively than T317 and may explain in part the tissue selective gene induction. This demonstration that tissue and gene selective modulation is possible with selective LXR modulators has positive implications for the development of this class of antiatherosclerotic agents.
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PMID:Raising HDL cholesterol without inducing hepatic steatosis and hypertriglyceridemia by a selective LXR modulator. 1514 86

We previously reported a link between ethanol-induced elevation of homocysteine, endoplasmic reticulum (ER) stress, and alcoholic liver injury in the murine model of intragastric ethanol feeding. We studied the role of TNFalpha in this setting by using TNFR1 knockout mice (C57 BL/6). There was a 7.4-fold increase of homocysteine in wild-type and a 6-fold increase in TNFR1 knockout mice with intragastric alcohol exposure for 4 weeks. Plasma TNFalpha increased in the wild-type (18.4 +/- 3.3 pg/mL vs. 8.4 +/- 1.3 pg/mL (control)) and in the knockouts (12.9 +/- 1.4 pg/mL vs. 7.2 +/- 1.6 pg/mL (control)). Similar extent of fatty liver was observed in both types. Increased ALT was observed in both groups. Necroinflammatory foci were increased significantly in ethanol-fed knockouts but not to the same extent as in the ethanol-fed wild type. Increase of hepatic apoptosis and reduction of S-adenosyl-L-methionine was detected in both types of animals fed ethanol. ER stress demonstrated by RT-PCR of mRNA of selective ER stress markers GRP78, CHOP, and SREBP1 was increased equivalently in both types of mice. Betaine administration decreased ER stress in conjunction with attenuation of the elevated plasma homocysteine in both types of animals. Betaine increased hepatic S-adenosyl-L-methionine by 28 fold in the knockouts and by 24-fold in wild type. In conclusion, TNFalpha makes a moderate contribution to the ALT elevation, necroinflammation, apoptosis, a small contribution to the fatty liver and no contribution to hyperhomocysteinemia and ER stress in intragastric alcohol fed mice.
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PMID:Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. 1536 49

AMP-activated protein kinase (AMPK) is a major therapeutic target for the treatment of diabetes. We investigated the effect of a short-term overexpression of AMPK specifically in the liver by adenovirus-mediated transfer of a gene encoding a constitutively active form of AMPKalpha2 (AMPKalpha2-CA). Hepatic AMPKalpha2-CA expression significantly decreased blood glucose levels and gluconeogenic gene expression. Hepatic expression of AMPKalpha2-CA in streptozotocin-induced and ob/ob diabetic mice abolished hyperglycemia and decreased gluconeogenic gene expression. In normal mouse liver, AMPKalpha2-CA considerably decreased the refeeding-induced transcriptional activation of genes encoding proteins involved in glycolysis and lipogenesis and their upstream regulators, SREBP-1 (sterol regulatory element-binding protein-1) and ChREBP (carbohydrate response element-binding protein). This resulted in decreases in hepatic glycogen synthesis and circulating lipid levels. Surprisingly, despite the inhibition of hepatic lipogenesis, expression of AMPKalpha2-CA led to fatty liver due to the accumulation of lipids released from adipose tissue. The relative scarcity of glucose due to AMPKalpha2-CA expression led to an increase in hepatic fatty acid oxidation and ketone bodies production as an alternative source of energy for peripheral tissues. Thus, short-term AMPK activation in the liver reduces blood glucose levels and results in a switch from glucose to fatty acid utilization to supply energy needs.
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PMID:Short-term overexpression of a constitutively active form of AMP-activated protein kinase in the liver leads to mild hypoglycemia and fatty liver. 1585 17


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