Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice.
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.
Lu
Yongke
Y
Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.
Zhuge
Jian
J
Wang
Xiaodong
X
Bai
Jingxiang
J
Cederbaum
Arthur I
AI
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity*; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000201:enzymology* / Q000473:pathology; D005260:Female; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000378:metabolism; D017392:Thiobarbituric Acid Reactive Substances / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D005230:Fatty Acids, Nonesterified; D047493:PPAR alpha; D017392:Thiobarbituric Acid Reactive Substances; D014280:Triglycerides; D014409:Tumor Necrosis Factor-alpha; D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D000410:Alanine Transaminase