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Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy.
Free Radic Biol Med. 2012 Sep 15; 53(6):1346-57.FR

Abstract

The goal of the current study was to evaluate whether CYP2E1 plays a role in binge-ethanol induced steatosis and if autophagy impacts CYP2E1-mediated hepatotoxicity, oxidative stress and fatty liver formation produced by ethanol. Wild type (WT), CYP2E1 knockin (KI) and CYP2E1 knockout (KO) mice were gavaged with 3g/kg body wt ethanol twice a day for four days. This treatment caused fatty liver, elevation of CYP2E1 and oxidative stress in WT and KI mice but not KO mice. Autophagy was impaired in ethanol-treated KI mice compared to KO mice as reflected by a decline in the LC3-II/LC3-I ratio and lower total LC-3 and Beclin-1 levels coupled to increases in P62, pAKT/AKT and mTOR. Inhibition of macroautophagy by administration of 3-methyladenine enhanced the binge ethanol hepatotoxicity, steatosis and oxidant stress in CYP2E1 KI, but not CYP2E1 KO mice. Stimulation of autophagy by rapamycin blunted the elevated steatosis produced by binge ethanol. Treatment of HepG2 E47 cells which express CYP2E1 with 100mM ethanol for 8 days increased fat accumulation and oxidant stress but decreased autophagy. Ethanol had no effect on these reactions in HepG2 C34 cells which do not express CYP2E1. Inhibition of autophagy elevated ethanol toxicity, lipid accumulation and oxidant stress in the E47, but not C34 cells. The antioxidant N-acetylcysteine, and CYP2E1 inhibitor chlormethiazole blunted these effects of ethanol. These results indicate that CYP2E1 plays an important role in binge ethanol-induced fatty liver. We propose that CYP2E1-derived reactive oxygen species inhibit autophagy, which subsequently causes accumulation of lipid droplets. Inhibition of autophagy promotes binge ethanol induced hepatotoxicity, steatosis and oxidant stress via CYP2E1.

Authors+Show Affiliations

Department of Pharmacology & Systems Therapeutics, Mount Sinai School of Medicine, New York, NY 10029, USA. defeng.wu@mssm.eduNo 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

22819980

Citation

Wu, Defeng, et al. "Alcohol Steatosis and Cytotoxicity: the Role of Cytochrome P4502E1 and Autophagy." Free Radical Biology & Medicine, vol. 53, no. 6, 2012, pp. 1346-57.
Wu D, Wang X, Zhou R, et al. Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy. Free Radic Biol Med. 2012;53(6):1346-57.
Wu, D., Wang, X., Zhou, R., Yang, L., & Cederbaum, A. I. (2012). Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy. Free Radical Biology & Medicine, 53(6), 1346-57. https://doi.org/10.1016/j.freeradbiomed.2012.07.005
Wu D, et al. Alcohol Steatosis and Cytotoxicity: the Role of Cytochrome P4502E1 and Autophagy. Free Radic Biol Med. 2012 Sep 15;53(6):1346-57. PubMed PMID: 22819980.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Alcohol steatosis and cytotoxicity: the role of cytochrome P4502E1 and autophagy. AU - Wu,Defeng, AU - Wang,Xiaodong, AU - Zhou,Richard, AU - Yang,Lili, AU - Cederbaum,Arthur I, Y1 - 2012/07/20/ PY - 2012/02/21/received PY - 2012/07/06/revised PY - 2012/07/06/accepted PY - 2012/7/24/entrez PY - 2012/7/24/pubmed PY - 2013/1/17/medline SP - 1346 EP - 57 JF - Free radical biology & medicine JO - Free Radic Biol Med VL - 53 IS - 6 N2 - The goal of the current study was to evaluate whether CYP2E1 plays a role in binge-ethanol induced steatosis and if autophagy impacts CYP2E1-mediated hepatotoxicity, oxidative stress and fatty liver formation produced by ethanol. Wild type (WT), CYP2E1 knockin (KI) and CYP2E1 knockout (KO) mice were gavaged with 3g/kg body wt ethanol twice a day for four days. This treatment caused fatty liver, elevation of CYP2E1 and oxidative stress in WT and KI mice but not KO mice. Autophagy was impaired in ethanol-treated KI mice compared to KO mice as reflected by a decline in the LC3-II/LC3-I ratio and lower total LC-3 and Beclin-1 levels coupled to increases in P62, pAKT/AKT and mTOR. Inhibition of macroautophagy by administration of 3-methyladenine enhanced the binge ethanol hepatotoxicity, steatosis and oxidant stress in CYP2E1 KI, but not CYP2E1 KO mice. Stimulation of autophagy by rapamycin blunted the elevated steatosis produced by binge ethanol. Treatment of HepG2 E47 cells which express CYP2E1 with 100mM ethanol for 8 days increased fat accumulation and oxidant stress but decreased autophagy. Ethanol had no effect on these reactions in HepG2 C34 cells which do not express CYP2E1. Inhibition of autophagy elevated ethanol toxicity, lipid accumulation and oxidant stress in the E47, but not C34 cells. The antioxidant N-acetylcysteine, and CYP2E1 inhibitor chlormethiazole blunted these effects of ethanol. These results indicate that CYP2E1 plays an important role in binge ethanol-induced fatty liver. We propose that CYP2E1-derived reactive oxygen species inhibit autophagy, which subsequently causes accumulation of lipid droplets. Inhibition of autophagy promotes binge ethanol induced hepatotoxicity, steatosis and oxidant stress via CYP2E1. SN - 1873-4596 UR - https://www.unboundmedicine.com/medline/citation/22819980/Alcohol_steatosis_and_cytotoxicity:_the_role_of_cytochrome_P4502E1_and_autophagy_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0891-5849(12)00400-5 DB - PRIME DP - Unbound Medicine ER -