Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Liver fatty acid-binding protein (L-FABP) and acyl-CoA-binding protein (ACBP) are involved in the intracellular trafficking and compartmentalization of fatty acids and fatty acyl-CoA esters, respectively, in the liver. Both proteins are induced in rat liver by the potent peroxisome proliferator perfluorodecanoic acid (PFDA). While it is believed that the peroxisome proliferator-activated receptor may mediate the responses to peroxisome proliferators by inducing responsive genes, the ligand(s) of this receptor remains unknown. We hypothesized that induction of L-FABP and ACBP in rat liver by PFDA is secondary to accumulation of long-chain acyl-CoA esters. However, neither dose-response nor time-course effects of PFDA on hepatic long-chain acyl-CoA, L-FABP, or ACBP concentrations confirmed this hypothesis. In a dose-response study, PFDA increased hepatic long-chain acyl-CoA concentrations (7 days after treatment) over the dose range of 20-50 mg/kg, whereas it increased ACBP and L-FABP over the wider dose range of 20-65 mg/kg. In the time-course study, PFDA treatment (50 mg/kg) elevated long-chain acyl-CoA esters in the liver beginning on day 3 post-treatment, yet hepatic L-FABP concentrations were increased earlier beginning on day 2 and ACBP was not induced until day 7. To determine if this dissociation of increases in hepatic long-chain acyl-CoA concentrations from increases in hepatic L-FABP and ACBP concentrations could be demonstrated under other conditions, control rats fasted for 24-48 hr were used. Fasting increased hepatic long-chain acyl-CoA levels to a greater extent than PFDA treatment, yet neither L-FABP nor ACBP was induced. We conclude that elevated concentrations of hepatic long-chain acyl-CoAs in PFDA-treated rats are not a major contributor to the induction of L-FABP or ACBP by peroxisome proliferators. A more plausible mechanism is that PFDA induces L-FABP and ACBP by activating the peroxisome proliferator receptor directly rather than indirectly through long-chain acyl-CoA esters.
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PMID:Induction of hepatic acyl-CoA-binding protein and liver fatty acid-binding protein by perfluorodecanoic acid in rats. Lack of correlation with hepatic long-chain acyl-CoA levels. 809 8

Liver fatty acid-binding protein (L-FABP) expression is modulated by developmental, hormonal, dietary, and pharmacological factors. The most pronounced induction is seen after treatment with peroxisome proliferators, which induce L-FABP coordinately with microsomal cytochrome P-450 4A1 and the enzymes of peroxisomal fatty acid beta-oxidation. These effects of peroxisome proliferators may be mediated by a receptor which has been shown to be activated by peroxisome proliferators in mammalian cell transfection studies. However, the peroxisome proliferators tested thus far do not bind to this receptor, known as the peroxisome proliferator-activated receptor (PPAR), and its endogenous ligand(s) also remain unknown. Peroxisome proliferators inhibit mitochondrial beta-oxidation, and one hypothesis is that the dicarboxylic fatty acid metabolites of accumulated LCFA, formed via the P-450 4A1 omega-oxidation pathway, serve as primary inducers of L-FABP and peroxisomal beta-oxidation. We have tested this hypothesis in primary hepatocyte cultures exposed to clofibrate (CF). Inhibition of P-450 4A1 markedly diminished, via a pre-translational mechanism, the CF induction of L-FABP and peroxisomal beta-oxidation. In further experiments, long-chain dicarboxylic acids, the final products of the P-450 4A1 omega-oxidation pathway, but not LCFA, induced L-FABP and peroxisomal beta-oxidation pre-translationally. These results suggest a role, in part, for long-chain dicarboxylic acids in mediating the peroxisome proliferator induction of L-FABP and peroxisomal beta-oxidation. We also found that LCFA, which undergo rapid hepatocellular metabolism, could become inducers of L-FABP and peroxisomal beta-oxidation under conditions where their metabolism was inhibited.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mechanisms of regulation of liver fatty acid-binding protein. 823 72

Glucose and fatty acid metabolism (oxidation versus esterification) has been measured in hepatocytes isolated from 24 h starved peroxisome proliferator-activated receptor-alpha (PPARalpha) null and wild-type mice. In PPARalpha null mice, the development of hypoglycemia during starvation was due to a reduced capacity for hepatic gluconeogenesis secondary to a 70% lower rate of fatty acid oxidation. This was not due to inappropriate expression of the hepatic CPT I gene, which was similar in both genotypes, but to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression in the PPARalpha null mouse liver. We also demonstrate that hepatic steatosis of fasting PPARalpha null mice was not due to enhanced triglyceride synthesis.
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PMID:Reduced hepatic fatty acid oxidation in fasting PPARalpha null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. 1086 48

The definable causes of nonalcoholic steatohepatitis (NASH) include jejunoileal bypass surgery (JIB), other causes of rapid and profound weight loss in obese subjects, total parenteral nutrition, drugs, industrial toxins, copper toxicity, and disorders characterized by extreme insulin resistance. However, the etiopathogenesis in most cases of NASH appears multifactorial. Obesity, type 2 diabetes, and hypertriglyceridemia are often associated with hepatic steatosis, and although this does not invariably lead to NASH, the fatty liver is vulnerable to hepatocellular injury initiated by reactive oxygen species (ROS). It is critical to understand not only the triggers for hepatitis (injury and inflammation) in NASH but also how this is perpetuated as chronic liver disease. The present focus is on whether the biochemical processes that generate oxidative stress lead to hepatocyte injury and secondary recruitment of inflammation or whether inflammation is the primary mediator of liver cell injury. Insulin resistance is a reproducible pathogenic factor in NASH. It favors accumulation of free fatty acids in the liver and predisposes to oxidative stress by stimulating microsomal lipid peroxidases and by the direct effects of high insulin levels in decreasing mitochondrial beta-oxidation. CYP2E1 is normally suppressed by insulin but is invariably increased in the livers of patients with NASH. In rodent dietary models of steatohepatitis, CYP2E1 is the catalyst of microsomal lipid peroxidation, while in Cyp 2e1 nullizygous mice, CYP4A proteins are induced and function as alternative microsomal lipid peroxidases. Other studies implicate activation of peroxisome proliferator-activated receptor-alpha (PPAR alpha) as leading to NASH; PPAR alpha is a transcription factor that governs both microsomal (via CYP4A) and peroxisomal (beta-oxidation) pathways of lipid oxidation and ultimately production of ROS. Increased lipid peroxidation is a crucial difference between the livers of rodents with experimental NASH and those of ob/ob genetically obese mice that have uncomplicated steatosis. Administration of endotoxin, through the release of tumor necrosis factor-alpha (TNF-alpha), provokes liver inflammation with hepatocyte injury in the steatotic liver. This may be particularly relevant in JIB and has been suggested as a pathogenic mechanism in primary NASH. It has been proposed that inheriting one or more copies of the hemochromatosis gene, C282Y, promotes fibrotic progression in NASH because of increased hepatic iron deposition, but recent studies have failed to confirm this. The relationship between the severity of hepatitis in NASH and progression to cirrhosis implies that products of the inflammatory infiltrate play a role in fibrogenesis. In summary, NASH can be regarded as the hepatic consequence of the metabolic syndrome (or syndrome X). Attention should now shift from steatosis, a generally benign process that is less evident in the advanced stages of cirrhosis, to the mechanisms for hepatocellular injury, inflammation, and hepatic fibrosis. In particular, the genetic, molecular, and cellular factors that ordain and moderate fibrosis in the context of steatohepatitis will be of greatest relevance to effective therapy and clinical outcome.
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PMID:Etiopathogenesis of nonalcoholic steatohepatitis. 1129 94

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Recently, aromatase-deficient (ArKO, Ar-/-) mice lacking intrinsic estrogen was developed and the molecular mechanism involved in progression of massive hepatic steatosis in estrogen-deficiency was elucidated; impairment in hepatic fatty acid beta-oxidation of peroxisomes, microsomes and mitochondria. This impairment is latent, but is potentially serious, because hepatic energy supply depends greatly on fatty acid beta-oxidation. Therefore in the present study, we tried to conquer impaired hepatic fatty acid beta-oxidation by administrating bezafibrate, a potent peroxisome proliferator, to Ar-/- mice through activating fatty acid beta-oxidation via the peroxisome proliferator activated receptor-alpha mediated signaling pathway. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase in mitochondria, essential enzymes in fatty acid beta-oxidation by administration of bezafibrate. Severe hepatic steatosis observed in Ar-/- mice regressed dramatically. Consistent findings were obtained in the in vitro assays of fatty acid beta-oxidation activity. These findings demonstrate that bezafibrate is capable of restoring impaired fatty acid beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha mediated signaling pathway and is potent enough to regress severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Aromatase-deficient (ArKO) mice are retrieved from severe hepatic steatosis by peroxisome proliferator administration. 1192 13

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice. 1288 Jan 7

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

Alcoholic liver disease is associated with a state of hepatic fatty acid overload. We examined the effect of ethanol and different types of dietary fat on the expression of mRNA for liver fatty acid binding protein (L-FABP), peroxisome proliferator-activated receptor-alpha (PPARalpha), and peroxisomal fatty acyl CoA oxidase (FACO). Four groups of rats (n = 5) were fed intragastrically, a liquid diet with or without ethanol (10-16 g/kg/day) for 4 weeks. Pair-fed controls received isocaloric amounts of dextrose. The source of fat was either corn oil or fish oil. Ethanolfed rats developed fatty liver, necrosis, and inflammation; the changes were more severe in the fish oil-ethanol (FE) rats. PPARalpha mRNA levels were not different between groups, although there was a trend toward increased levels in ethanol-fed rats. We calculated L-FABP/PPARalpha and FACO/PPARalpha ratios as a measure of FACO and L-FABP up-regulation relative to PPARalpha expression. Both FACO/PPARalpha and L-FABP/PPARalpha ratios were significantly decreased in FE rats. However, only L-FABP/PPARalpha was decreased in corn oil plus ethanol rats. Also, the level of L-FABP/mRNA correlated inversely with the degree of fatty liver in ethanol-fed rats. Since expression of PPARalpha response genes was impaired in ethanol-fed rats, we determined whether activation of PPARalpha would normalize the PPARalpha response and prevent the pathological changes in ethanol-fed rats. Treatment with clofibrate, a PPARalpha-activating ligand, led to a marked decrease in fatty liver and complete abrogation of necroinflammatory changes in FE rats. Also, nuclear factor kappaB activation and up-regulation of tumor necrosis factor-alpha and cyclooxygenase-2 was also abolished in clofibrate-treated rats. We conclude that adaptive gene regulation of FACO and L-FABP by PPARalpha is impaired in ethanol-fed rats and that treatment with clofibrate, a PPARalpha ligand, prevents alcohol-induced pathological liver injury, possibly by reversing the above changes.
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PMID:Alcoholic liver injury in the rat is associated with reduced expression of peroxisome proliferator-alpha (PPARalpha)-regulated genes and is ameliorated by PPARalpha activation. 1501 35

We recently identified mutations in the lipin gene, Lpin1, as the cause of lipodystrophy in the fatty liver dystrophy (fld) mouse. Here we identify impaired adipocyte differentiation as the basis for lipodystrophy in lipin-deficient mice and demonstrate that lipin is required for normal induction of the adipogenic gene transcription program. We found that the reduced adiposity in chow fed fld mice and resistance to obesity in fld mice fed a high-fat diet is associated with reduced adipogenic gene expression. Using primary mouse embryonic fibroblasts isolated from fld mice, we confirmed that lipin deficiency prevents normal lipid accumulation and induction of key adipogenic genes, including peroxisome proliferator-activated receptor (PPAR)gamma and CCAAT enhancer-binding protein (C/EBP)alpha. However, our previous studies of daily gene expression in differentiating 3T3-L1 preadipocytes indicated that lipin expression is undetectable until about day 3 of differentiation, at a point after PPARgamma and C/EBPalpha gene expression is established. This paradox was resolved by examining gene expression at 10-h intervals during 3T3-L1 cell differentiation, leading to detection of transient lipin expression at 10 h into the differentiation program, prior to the induction of PPARgamma and C/EBPalpha. Consistent with a requirement for lipin expression upstream of PPARgamma, differentiation of lipin-deficient mouse embryonic fibroblasts could be rescued by ectopic expression of PPARgamma. Thus, we conclude that lipin expression is required prior to PPARgamma during adipocyte differentiation.
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PMID:Lipin expression preceding peroxisome proliferator-activated receptor-gamma is critical for adipogenesis in vivo and in vitro. 1512 8

Stearoyl-CoA desaturase catalyzes the rate-limiting step in the biosynthesis of monounsaturated fatty acids, which are required for normal rates of synthesis of triglycerides, cholesterol esters, and phospholipids. Mice with a targeted disruption of the stearoyl-CoA desaturase 1 (SCD1) isoform are protected against diet and leptin deficiency-induced adiposity, have increased energy expenditure, and have up-regulated expression of hepatic genes encoding enzymes of fatty acid beta-oxidation. Because peroxisome proliferator-activated receptor-alpha (PPARalpha) is a key transcription factor that induces the transcription of fatty acid beta-oxidation and thermogenic genes, we hypothesized that the increased fatty acid oxidation observed in SCD1 deficiency is dependent on activation of the PPARalpha pathway. Here we show that mice nullizygous for SCD1 and PPARalpha are still protected against adiposity, have increased energy expenditure, and maintain high expression of PPARalpha target genes in the liver and brown adipose tissue. The SCD1 deficiency rescued hepatic steatosis of the PPARalpha(-/-) mice. The SCD1 mutation increased the phosphorylation of both AMP-activated protein kinase and acetyl-CoA carboxylase, thereby increasing CPT activity and stimulating the oxidation of liver palmitoyl-CoA in the PPARalpha null mice. The findings indicate that the reduced adiposity, reduced liver steatosis, increased energy expenditure, and increased expression of PPARalpha target genes associated with SCD1 deficiency are independent of activation of the PPARalpha pathway.
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PMID:Reduced adiposity and liver steatosis by stearoyl-CoA desaturase deficiency are independent of peroxisome proliferator-activated receptor-alpha. 1518 Sep 99


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