Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Hepatology (Impact Factor: 11.06). 05/2008; 47(5):1483-94. DOI: 10.1002/hep.22222
Source: PubMed


Cytochrome P450 2E1 (CYP2E1) is suggested to play a role in alcoholic liver disease, which includes alcoholic fatty liver, alcoholic hepatitis, and alcoholic cirrhosis. In this study, we investigated whether CYP2E1 plays a role in experimental alcoholic fatty liver in an oral ethanol-feeding model. After 4 weeks of ethanol feeding, macrovesicular fat accumulation and accumulation of triglyceride in liver were observed in wild-type mice but not in CYP2E1-knockout mice. In contrast, free fatty acids (FFAs) were increased in CYP2E1-knockout mice but not in wild-type mice. CYP2E1 was induced by ethanol in wild-type mice, and oxidative stress induced by ethanol was higher in wild-type mice than in CYP2E1-knockout mice. Peroxisome proliferator-activated receptor alpha (PPARalpha), a regulator of fatty acid oxidation, was up-regulated in CYP2E1-knockout mice fed ethanol but not in wild-type mice. A PPARalpha target gene, acyl CoA oxidase, was decreased by ethanol in wild-type but not in CYP2E1-knockout mice. Chlormethiazole, an inhibitor of CYP2E1, lowered macrovesicular fat accumulation, inhibited oxidative stress, and up-regulated PPARalpha protein level in wild-type mice fed ethanol. The introduction of CYP2E1 to CYP2E1-knockout mice via an adenovirus restored macrovesicular fat accumulation. These results indicate that CYP2E1 contributes to experimental alcoholic fatty liver in this model and suggest that CYP2E1-derived oxidative stress may inhibit oxidation of fatty acids by preventing up-regulation of PPARalpha by ethanol, resulting in fatty liver.

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Available from: Jian Zhuge, Dec 09, 2014
    • "The ethanol metabolite acetaldehyde directly inhibits the transcriptional activation activity and DNA-binding ability of PPARα in hepatocytes (Fig. 1U; Galli et al. 2001). Ethanol consumption can also indirectly inhibit PPARα via up-regulation of cytochrome P4502E1-derived oxidative stress and adenosine, both of which inhibit PPARα (Lu et al. 2008; Peng et al. 2009). The inhibition of PPARα by ethanol promotes the inhibition of fatty acid oxidation, resulting in lipid accumulation. "
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    ABSTRACT: Chronic ethanol consumption is a strong risk factor for the development of liver disease. Multiple mechanisms are involved in ethanol-mediated liver injury; oxidative stress being pointed has an important factor. However, it should be noted that moderate consumption of red wine has been associated with hepatoprotective effects, mainly due to the antioxidant effect of resveratrol, one of its polyphenolic compounds. In this paper, the potential molecular mechanisms through which the protective effects of resveratrol counteract the oxidative effect of ethanol and the way as this dual effect impacts liver oxidative stress are reviewed. Mechanistic evaluation of modulation of oxidative signaling pathways by ethanol and resveratrol may explain the pathogenesis of various liver diseases and ultimately to disclose possible pharmacological therapies.
    No preview · Article · May 2015 · Archives of Toxicology
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    • "Induction of CYP2E1 by ethanol or pyrazole SV129 male wild type or CYP2E1 knockout mice were initially fed a control liquid dextrose diet (Bio-Serv, Frenchtown, NJ) for 3 days to acclimate them to Lieber and DeCarli liquid diets [16] [34]. Afterward, the mice were fed either the liquid ethanol diet or the control liquid dextrose diet for 4 weeks. "
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    ABSTRACT: The cytochrome P450 mixed function oxidase enzymes are the major catalysts involved in drug metabolism. There are many forms of P450. CYP2E1 metabolizes many toxicologically important compounds including ethanol and is active in generating reactive oxygen species. Since several of the contributions in the common theme series “Role of CYP2E1 and Oxidative/Nitrosative Stress in the Hepatotoxic Actions of Alcohol” discuss CYP2E1, this methodology review describes assays on how CYP2E1 catalytic activity and its induction by ethanol and other inducers can be measured using substrate probes such as the oxidation of para-nitrophenol to para-nitrocatechol and the oxidation of ethanol to acetaldehyde. Approaches to validate that a particular reaction e.g. oxidation of a drug or toxin is catalyzed by CYP2E1 or that induction of that reaction is due to induction of CYP2E1 are important and specific examples using inhibitors of CYP2E1, anti-CYP2E1 IgG or CYP2E1 knockout and knockin mice will be discussed.
    Full-text · Article · Oct 2014
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    • "CYP2E1 could catalyze the two electron oxidation of ethanol to acetaldehyde, and can also promote the one electron oxidation to produce 1-hydroxyethyl radicals [14]. Recently, Lu et al. demonstrated that CYP2E1 was a pivotal contributor to AFL by using CYP2E1 knockdown mice [15]. In that study, 4 weeks of ethanol-containing Lieber-DeCarli liquid diet treatment induced significant microvesicular fatty liver in wild type mice, but not in the CYP2E1-deficient mice [15]. "
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    ABSTRACT: Background Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms. Methods Mice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods. Results CYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3β pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ. Conclusion These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3β pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.
    Full-text · Article · Jun 2014 · PLoS ONE
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