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Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice.
Hepatology. 2008 May; 47(5):1483-94.Hep

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 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.

Authors+Show Affiliations

Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18393316

Citation

Lu, Yongke, et al. "Cytochrome P450 2E1 Contributes to Ethanol-induced Fatty Liver in Mice." Hepatology (Baltimore, Md.), vol. 47, no. 5, 2008, pp. 1483-94.
Lu Y, Zhuge J, Wang X, et al. Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. Hepatology. 2008;47(5):1483-94.
Lu, Y., Zhuge, J., Wang, X., Bai, J., & Cederbaum, A. I. (2008). Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. Hepatology (Baltimore, Md.), 47(5), 1483-94. https://doi.org/10.1002/hep.22222
Lu Y, et al. Cytochrome P450 2E1 Contributes to Ethanol-induced Fatty Liver in Mice. Hepatology. 2008;47(5):1483-94. PubMed PMID: 18393316.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cytochrome P450 2E1 contributes to ethanol-induced fatty liver in mice. AU - Lu,Yongke, AU - Zhuge,Jian, AU - Wang,Xiaodong, AU - Bai,Jingxiang, AU - Cederbaum,Arthur I, PY - 2008/4/9/pubmed PY - 2008/8/2/medline PY - 2008/4/9/entrez SP - 1483 EP - 94 JF - Hepatology (Baltimore, Md.) JO - Hepatology VL - 47 IS - 5 N2 - 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. SN - 1527-3350 UR - https://www.unboundmedicine.com/medline/citation/18393316/Cytochrome_P450_2E1_contributes_to_ethanol_induced_fatty_liver_in_mice_ L2 - https://doi.org/10.1002/hep.22222 DB - PRIME DP - Unbound Medicine ER -