Aldehyde Dehydrogenase-2 ( ALDH 2 ) Ameliorates Chronic Alcohol Ingestion-Induced Hepatic Steatosis and Inflammation : Role of Autophagy

Background & Aims—Mitochondrial aldehyde dehydrogenase (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. This study was designed to examine the impact of global ALDH2 overexpression on alcohol-induced hepatic steatosis. Methods—Wild-type friendly virus B (FVB) and ALDH2 transgenic mice were placed on a 4% alcohol or control diet for 12 weeks. Serum levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), bilirubin and cholesterol, hepatic triglyceride, steatosis, fat metabolismrelated proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signaling were examined. The role of autophagy was evaluated in ADH1-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without autophagy inducer rapamycin and lysosomal inhibitors. Results—Chronic alcohol intake led to elevated AST, ALT, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides, hepatic fat deposition as evidenced by H&E and oil Red O staining, associated with disturbed fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, the effects of which were attenuated or ablated by ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100, 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, the effects of which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62 accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors. © 2014 European Association for the Study of the Liver. Elsevier B.V. All rights reserved. Correspondence should be addressed to: Dr. Jun Ren or Dr. Yingmei Zhang, Center for Cardiovascular Research and Alternative Medicine, University of Wyoming, Laramie, WY 82071; Tel: (307)-766-6131; Fax: (307)-766-2953; jren@uwyo.edu or zhangyingmeimegan@gmail.com. Authors' contribution: RG, XX, SAB and YZ, data collection; YZ and JR: study design, funding and manuscript writing Conflict of Interest: No Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript J Hepatol. Author manuscript; available in PMC 2016 March 01. Published in final edited form as: J Hepatol. 2015 March ; 62(3): 647–656. doi:10.1016/j.jhep.2014.10.009. N IH -P A A uhor M anscript N IH -P A A uhor M anscript N IH -P A A uhor M anscript Conclusions—In summary, our results revealed that ALDH2 plays a beneficial role in ameliorating chronic alcohol intake-induced hepatic steatosis and inflammation through regulation of autophagy.