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

Document Type

Article

Publication Date

5-2008

Abstract

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 α (PPARα), a regulator of fatty acid oxidation, was up‐regulated in CYP2E1‐knockout mice fed ethanol but not in wild‐type mice. A PPARα 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 PPARα 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 PPARα by ethanol, resulting in fatty liver.

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Copyright © 2008 by the American Association for the Study of Liver Diseases.

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