title: Aldehyde dedydrogenase-2 plays a beneficial role in ameliorating chronic alcohol-induced hepatic steatosis and inflammation through regulation of autophagy.
abstract: OBJECTIVE
  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.
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, USA.
authors.forename: Rui
authors.initials: R
authors.lastname: Guo
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, USA.
authors.forename: Xihui
authors.initials: X
authors.lastname: Xu
authors.affiliation: Center for Cardiovascular Research and Alternative Medicine, University of Wyoming College of Health Sciences, Laramie, USA.
authors.forename: Sara A
authors.initials: SA
authors.lastname: Babcock
authors.affiliation: 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.
authors.forename: Yingmei
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
mesh_terms: D000079:Acetaldehyde / Q000378:metabolism; D000437:Alcoholism / Q000150:complications / Q000378:metabolism; D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology*; D002784:Cholesterol / Q000097:blood; D016207:Cytokines / Q000378:metabolism; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008104:Liver Cirrhosis, Alcoholic / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D008822:Mice, Transgenic; D046912:Multiprotein Complexes / Q000378:metabolism; D018384:Oxidative Stress; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D016207:Cytokines; D046912:Multiprotein Complexes; D002784:Cholesterol; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000079:Acetaldehyde; D020123:Sirolimus
keywords: ALDH2; Alcohol; Autophagy; Inflammation; Steatosis