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)

It is well established that chronic ethanol ingestion enhances lipid peroxidation in the liver in vivo and in vitro. The relationship of lipid peroxidation and protein adduct formation to morphologically assessed liver damage remains problematic. To help determine if a relationship exists between lipid peroxidation and liver pathology rats were fed ethanol and a high fat diet by continuous intragastric tube feeding for 72 days, maintaining the blood alcohol levels above 200 mg/dl. This model induced a fatty liver with focal necrosis and fibrosis. This pathology was associated with an increased total cytochrome P450, an increased cytochrome P450 2E1 isoenzyme (CYP2E1), a decrease in the NADPH-cytochrome P450 reductase activity, an increased rate of NADPH oxidation and an increased NADPH-dependent lipid peroxidation in liver microsomes compared to controls. Serum protein adducts with malondialdehyde 4-hydroxynonenal were significantly increased. Thus, the alcohol-induced liver pathology was associated with the induction of CYP2EI, lipid peroxidation, and protein adduct formation. When isoniazid (INH) in therapeutic doses was fed to rats with ethanol these parameters were changed in that central-central bridging fibrosis was increased, as was lipid peroxidation, whereas INH reduced the ethanol-induced decrease in the reductase, the increase in total P450 and CYP2EI, as well as the NADPH oxidation rate and the elevation of serum transaminase levels. The results tend to link central-central bridging fibrosis with increased lipid peroxidation and aldehyde-protein adduct formation caused by ethanol.
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PMID:Effect of ethanol on cytochrome P450 2E1 (CYP2E1), lipid peroxidation, and serum protein adduct formation in relation to liver pathology pathogenesis. 845 37

Juvenile visceral steatosis (jvs) mice, isolated from the C3H-H-2 degrees strain, exibit a systemic carnitine deficiency (SCD) phenotype and develop fatty liver, hyperammonemia and hypoglycemia. This phenotype is caused by a missense mutation (Leu352Arg) of a sodium-dependent carnitine/organic cation transporter, Octn2 (Slc22a5). The jvs mouse could be a useful model for pharmacokinetics and drug metabolism studies concerning Octn2 substrate drugs. In the present study, the effects of the SCD phenotype on the cytochrome P450 (P450 or CYP) dependent activities of four endobiotic and seven xenobiotic oxidations catalyzed by liver and kidney microsomes from jvs mice were investigated. The jvs-type mutation was genotyped by PCR-RFLP. The contents of total P450 and NADPH-P450 reductase were similar in the the liver microsomes from male or female mice of the wild-type and those heterozygous or homozygous for the jvs-type mutation. The 6beta-hydroxylation activities of testosterone and progesterone (marker for Cyp3a) based on the protein contents were 1.2- to 2.0-fold higher in liver microsomes from jvs/jvs-type mice compared to jvs/wt- or wt/wt-type mice. Coumarin 7-hydroxylation activities (marker for Cyp2a) were decreased to 0.7-fold in the male jvs/jvs-type mice. The activities of lauric acid 12-hydroxylation (a marker for Cyp4a) and aniline p-hydroxylation (a marker for Cyp2e1) in liver microsomes were increased 1.4- to 1.9-fold in female jvs/jvs-type mice. Genotoxic activation of 2-aminofluorene (a marker for Cyp4b1) by male and female mouse kidney microsomes were not affected by the SCD phenotype. These results demonstrated that the SCD phenotype affected the P450-dependent catalytic activities in liver microsomes. The jvs mouse could provide valuable information in drug interaction and drug metabolism studies of OCTN2 substrate drugs and new compounds in development.
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PMID:Activities of cytochrome p450 enzymes in liver and kidney microsomes from systemic carnitine deficiency mice with a gene mutation of carnitine/organic cation transporter. 1561 52

The traditional concept of adipose tissue as a passive reservoir for energy storage is no longer valid because it has been demonstrated that adipose tissue is a complex, essential, and highly active metabolic and endocrine organ that not only responds to afferent signals from traditional hormone systems and the central nervous system (CNS), but also expresses and secretes factors with important endocrine functions. These factors include leptin and other cytokines. Adipose tissue is also a major site for metabolism of sex steroids and glucocorticoids. The important endocrine function of adipose tissue is emphasized by adverse metabolic consequences of both adipose tissue excess and deficiency. Adipose tissue excess, particularly in visceral compartment, is associated with insulin resistance, hyperglycemia, dyslipidemia, hypertension, and prothrombotic and proinflammatory states. Liver is one of the principal targets of lipid-associated damage by mechanisms that involve apoptosis activation by source of tumoral necrosis factor-alpha and caspase activation and liberation of oxygen-reactive species by oxidative stress and enzymatic chains such as P450, CYP2E1, and CYP3A4, resulting in a continuum involving non alcohol-related fatty liver, non-alcoholic steatohepatitis with or without fibrosis, and liver cirrhosis. This work presents an overview of endocrine functions of adipose tissue and its influence on mechanisms of liver damage.
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PMID:[Obesity and steatohepatitis. Histologic aspects]. 1564 70

NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-alpha by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid translocase (Cd36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (Cpt1a) and acyl-CoA synthetase long chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis and an altered fatty acid profile observed in liver-Cpr-null mice.
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PMID:Hepatic gene expression changes in mouse models with liver-specific deletion or global suppression of the NADPH-cytochrome P450 reductase gene. Mechanistic implications for the regulation of microsomal cytochrome P450 and the fatty liver phenotype. 1600 52

Inulin enzymatically synthesized from sucrose is a dietary component that completely escapes glucide digestion. Supplementing inulin to a high-fat and high-sucrose diet (HF) ameliorated hypertriglycemia and hepatic steatosis in 8-week-fed rats by suppressing elevated levels of serum triacylglycerols, fatty acids, and glucose, and the accumulation of hepatic triacylglycerols and fatty acids. Inulin intake prevented phenobarbital (PB)- and dexamethasone-induced liver injuries in the HF group. No significant alteration in the baseline expression of CYP2B, CYP2C11, CYP3A, and NADPH-cytochrome P450 (P450) reductase mRNAs and proteins was found. In contrast, baseline and PB-treated expressions of CYP2E1 mRNA were reduced in HF-fed rats. The induction of P450s in response to PB was affected by the nutritional status of the rats; mRNA levels of CYP2B1 and CYP3A1 after PB treatment, as assessed by quantitative real-time polymerase chain reaction analysis were reduced in the inulin-supplemented HF (HF+I) group, compared with those in the HF group. Western blot analysis detected the corresponding changes of CYP2B and CYP3A proteins. These alterations were correlated with changes in hepatic thiobarbituric acid-reactive substances. Furthermore, no significant difference in the expression of nuclear receptors constitutive androstane receptor, pregnane X receptor, and retinoid X receptor alpha and coactivator peroxisome proliferator-activated receptor-gamma coactivator 1alpha proteins was found in the hepatic nucleus between the HF and HF+I groups, but the expression of hepatocyte nuclear factor alpha (HNF4alpha) protein was significantly reduced in the HF+I group. Taken together, these results indicate that inulin intake ameliorates PB-induced liver injury, associated with a decline in lipid accumulation and PB-induced expression of CYP2B and CYP3A, which may be related by a reduction in the nuclear expression of HNF4alpha.
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PMID:Dietary inulin alleviates hepatic steatosis and xenobiotics-induced liver injury in rats fed a high-fat and high-sucrose diet: association with the suppression of hepatic cytochrome P450 and hepatocyte nuclear factor 4alpha expression. 1681 62

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

Previous studies demonstrated that chronic dermal exposure to the pesticide adjuvant (surfactant), Toximul (Tox), has significant detrimental effects on hepatic lipid metabolism. This study demonstrated that young mice dermally exposed to Tox for 12 days have significant increases in expression of peroxisomal acyl-CoA oxidase (mRNA and protein), bifunctional enzyme (mRNA) and thiolase (mRNA), as well as the P450 oxidizing enzymes Cyp4A10 and Cyp4A14 (mRNA and protein). Tox produced a similar pattern of increases in wild type adult female mice but did not induce these responses in PPARalpha-null mice. These data support the hypothesis that Tox, a heterogeneous blend of nonionic and anionic surfactants, modulates hepatic metabolism at least in part through activation of PPARalpha. Notably, all three groups of Tox-treated mice had increased relative liver weights due to significant accumulation of lipid. This could be endogenous in nature and/or a component(s) of Tox or a metabolite thereof. The ability of Tox and other hydrocarbon pollutants to induce fatty liver despite being PPARalpha agonists indicates a novel consequence of exposure to this class of chemicals, and may provide a new understanding of fatty liver in populations with industrial exposure.
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PMID:The pesticide adjuvant, Toximul, alters hepatic metabolism through effects on downstream targets of PPARalpha. 1764 67

Blockade of brain melanin-concentrating hormone 1 receptor (MCH1R) significantly ameliorates fatty liver as well as obesity. However, the mode of action of this effect is unknown. This study examined the effect of a MCH1R antagonist in murine steatohepatitis models with and without obesity and clarified whether these pharmacological effects were attributed to anti-obesity effects. Steatohepatitis with concomitant obese phenotypes was developed after 52-week exposure to a high-fat diet, and steatohepatitis with reduced body weight was developed by exposure to a methionine- and choline-deficient diet for 10 days. Chronic intracerebroventricular infusion of a peptidic MCH1R antagonist reduced hepatic triglyceride contents and ameliorated steatohepatitis on histological observations in both mice models. Improvement of steatohepatitis was concomitant with amelioration of obese phenotypes such as hyperinsulinemia and hyperleptinemia in the case of the obese model, whereas body weight reduction was not associated with amelioration of steatohepatitis by the antagonist in the lean model. Reduction of hepatic gene expressions encoding cytochromes P450 4A was identified by treatment with the antagonist in both the obese and lean models. These results suggest that brain blockade of MCH1R could alleviate steatohepatitis independently from anti-obesity effects. In conclusion, MCH1R antagonist could have a new therapeutic potential for the treatment of human nonalcoholic steatohepatitis.
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PMID:Antagonism of central melanin-concentrating hormone 1 receptor alleviates steatohepatitis in mice. 1852 32

The liver is responsible for key metabolic functions, including control of normal homoeostasis in response to diet and xenobiotic metabolism/detoxification. We have shown previously that inactivation of the hepatic cytochrome P450 system through conditional deletion of POR (P450 oxidoreductase) induces hepatic steatosis, liver growth and P450 expression. We have exploited a new conditional model of POR deletion to investigate the mechanism underlying these changes. We demonstrate that P450 induction, liver growth and hepatic triacylglycerol (triglyceride) homoeostasis are intimately linked and provide evidence that the observed phenotypes result from hepatic accumulation of unsaturated fatty acids, which mediate these phenotypes by activation of the nuclear receptor CAR (constitutive androstane receptor) and, to a lesser degree, PXR (pregnane X receptor). To our knowledge this is the first direct evidence that P450s play a major role in controlling unsaturated fatty acid homoeostasis via CAR. The regulation of P450s involved in xenobiotic metabolism by this mechanism has potentially significant implications for individual responses to drugs and environmental chemicals.
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PMID:Unsaturated fatty acid regulation of cytochrome P450 expression via a CAR-dependent pathway. 1877 45

Members of the cytochrome P450 (P450) enzyme families CYP1, CYP2, and CYP3 are responsible for the metabolism of approximately 75% of all clinically relevant drugs. With the increased prevalence of nonalcoholic fatty liver disease (NAFLD), it is likely that patients with this disease represent an emerging population at significant risk for alterations in these important drug-metabolizing enzymes. The purpose of this study was to determine whether three progressive stages of human NALFD alter hepatic P450 expression and activity. Microsomes isolated from human liver samples diagnosed as normal, n = 20; steatosis, n = 11; nonalcoholic steatohepatitis (NASH) (fatty liver), n = 10; and NASH (no longer fatty), n = 11 were analyzed for P450 mRNA, protein, and enzyme activity. Microsomal CYP1A2, CYP2D6, and CYP2E1 mRNA levels were decreased with NAFLD progression, whereas CYP2A6, CYP2B6, and CYP2C9 mRNA expression increased. Microsomal protein expression of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 tended to decrease with NAFLD progression. Likewise, functional activity assays revealed decreasing trends in CYP1A2 (p = 0.001) and CYP2C19 (p = 0.05) enzymatic activity with increasing NAFLD severity. In contrast, activity of CYP2A6 (p = 0.001) and CYP2C9 (diclofenac, p = 0.0001; tolbutamide, p = 0.004) was significantly increased with NAFLD progression. Increased expression of proinflammatory cytokines tumor necrosis factor alpha and interleukin 1beta was observed and may be responsible for observed decreases in respective P450 activity. Furthermore, elevated CYP2C9 activity during NAFLD progression correlated with elevated hypoxia-induced factor 1alpha expression in the later stages of NAFLD. These results suggest that significant and novel changes occur in hepatic P450 activity during progressive stages of NAFLD.
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PMID:Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease. 1965 58


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