Chapter 24 - Cytochrome P4502E1, Oxidative Stress, JNK, and Autophagy in Acute Alcohol-Induced Fatty Liver

Abstract

Binge alcohol drinking induces hepatic steatosis. Recent studies have shown that chronic ethanol-induced fatty liver is, at least in part, CYP2E1 dependent. The mechanism of acute alcohol-induced steatosis and the role of CYP2E1 are still unclear. Increasing oxidative stress by alcohol can activate the JNK MAP kinase signaling pathway, and 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 roles of CYP2E1, JNK, and the individual roles of JNK1 and JNK2 in acute alcohol-induced steatosis. In wild-type (WT) mice, acute alcohol activates CYP2E1, produces fatty liver, and increases oxidative stress, which reciprocally increases activation of the JNK signaling pathway. Acute alcohol-induced fatty liver and oxidative stress was blunted in CYP2E1 KO mice. The fatty liver and elevated oxidative stress was prevented by the JNK inhibitor. The antioxidant N-acetylcysteine decreased the acute alcohol-induced oxidative stress, 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 either JNK1 or JNK2 KO mice as in WT mice; thus either JNK1 alone or JNK2 alone per se is sufficient in induction of steatosis by acute alcohol. The conclusion is that acute alcohol elevation of CYP2E1, oxidative stress, and activation of JNK interact to lower autophagy and increase lipogenic SREBP, resulting in fatty liver.