Rui Guo1, Xihui Xu1, Sara A Babcock1, Yingmei Zhang2, Jun Ren3. 1. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, USA. 2. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, USA; Department of Cardiology, Xijing Hospital, Fourth Military Medical University, Xi'an, China; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: yingmeimeganzhang@gmail.com. 3. Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, USA; Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China. Electronic address: jren@uwyo.edu.
Abstract
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 Friend 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 metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signalling were examined. The role of autophagy was evaluated in alcohol dehydrogenase 1 (ADH1)-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without the autophagy inducer rapamycin and lysosomal inhibitors. RESULTS: Chronic alcohol intake led to elevated AST-, ALT-levels, bilirubin, AST/ALT ratio, cholesterol, hepatic triglycerides and hepatic fat deposition as evidenced by H&E and Oil Red O staining. Hepatic fat deposition was associated with disturbed levels of fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, effects which were attenuated or ablated by the ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100 and 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, effects 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. 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.
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 Friend virus B (FVB) and ALDH2transgenic 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 metabolism-related proteins, pro-inflammatory cytokines, glutathione (GSH), oxidized glutathione (GSSG), autophagy and autophagy signalling were examined. The role of autophagy was evaluated in alcohol dehydrogenase 1 (ADH1)-transfected human hepatocellular liver carcinoma cells (VA-13) treated with or without the autophagy inducer rapamycin and lysosomal inhibitors. RESULTS: Chronic alcohol intake led to elevated AST-, ALT-levels, bilirubin, AST/ALTratio, cholesterol, hepatic triglycerides and hepatic fat deposition as evidenced by H&E and Oil Red O staining. Hepatic fat deposition was associated with disturbed levels of fat metabolism-related proteins (fatty acid synthase, SCD1), upregulated interleukin-6, TNF-α, cyclooxygenase, oxidative stress, and loss of autophagy, effects which were attenuated or ablated by the ALDH2 transgene. Moreover, ethanol (100 mM) and acetaldehyde (100 and 500 μM) increased levels of IL-6 and IFN-γ, and suppressed autophagy in VA-13 cells, effects which were markedly alleviated by rapamycin. In addition, lysosomal inhibitors mimicked ethanol-induced p62accumulation with little additive effect with ethanol. Ethanol significantly suppressed LC3 conversion in the presence of lysosomal inhibitors. 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.
Authors: Blanca Eugenia Farfán Labonne; Mario Gutiérrez; Luis Enrique Gómez-Quiroz; Mina Konigsberg Fainstein; Leticia Bucio; Verónica Souza; Oscar Flores; Victor Ortíz; Elizabeth Hernández; David Kershenobich; María Concepción Gutiérrez-Ruíz Journal: Cell Biol Toxicol Date: 2009-01-11 Impact factor: 6.691
Authors: Joanne M Ajmo; Xiaomei Liang; Christopher Q Rogers; Brandi Pennock; Min You Journal: Am J Physiol Gastrointest Liver Physiol Date: 2008-08-28 Impact factor: 4.052
Authors: Anna L Lang; Austin M Krueger; Regina D Schnegelberger; Brenna R Kaelin; Maxwell J Rakutt; Liya Chen; Gavin E Arteel; Juliane I Beier Journal: Toxicol Appl Pharmacol Date: 2019-09-06 Impact factor: 4.219