title: Cytochrome P4502E1, oxidative stress, JNK, and autophagy in acute alcohol-induced fatty liver.
abstract: Binge alcohol drinking induces hepatic steatosis. Recent studies showed that chronic ethanol-induced fatty liver was, at least in part, CYP2E1 dependent. The mechanism of acute alcohol-induced steatosis and whether CYP2E1 plays any role are still unclear. Increasing oxidative stress by alcohol can activate the JNK MAP kinase signaling pathway, suggesting that JNK might be a target for prevention of alcohol-induced steatosis. We used CYP2E1 knockout (KO) mice, a JNK inhibitor, and JNK1 or JNK2 knockout mice to test the role of CYP2E1, JNK, and the individual role of JNK1 and JNK2 in acute alcohol-induced steatosis. In wild-type (WT) mice, acute alcohol activates CYP2E1 and increases oxidative stress, which reciprocally increases activation of the JNK signaling pathway. Acute alcohol-induced fatty liver and oxidative stress were blunted in CYP2E1 KO mice and by the JNK inhibitor in WT mice. The antioxidant N-acetylcysteine decreased the acute alcohol-induced oxidative stress, the activation of JNK, and the steatosis but not the activation of CYP2E1. Acute alcohol decreased autophagy and increased expression of SREBP, effects blocked by the JNK inhibitor. Acute alcohol-induced fatty liver was the same in JNK1 and JNK2 KO mice as in WT mice; thus either JNK1 or JNK2 per se is sufficient for induction of steatosis by acute alcohol. The results show that acute alcohol elevation of CYP2E1, oxidative stress, and activation of JNK interact to lower autophagy and increase lipogenic SREBP resulting in fatty liver.
authors: Department of Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, Box 1603, One Gustave L. Levy Place, New York, NY 10029, USA. liliyanglili@yahoo.com
authors: Lili
authors: L
authors: Yang
authors: Defeng
authors: D
authors: Wu
authors: Xiaodong
authors: X
authors: Wang
authors: Arthur I
authors: AI
authors: Cederbaum
mesh_terms: D000818:Animals; D001343:Autophagy; D019392:Cytochrome P-450 CYP2E1 / Q000172:deficiency / Q000378:metabolism*; D000431:Ethanol / Q000008:administration & dosage; D005235:Fatty Liver, Alcoholic / Q000378:metabolism*; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000378:metabolism*; D048056:Mitogen-Activated Protein Kinase 9 / Q000172:deficiency / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D000431:Ethanol; D019392:Cytochrome P-450 CYP2E1; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8