title: Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice.
abstract: OBJECTIVE
  Effective therapies for alcoholic liver disease are currently unavailable. The present study tested the efficacy of Alda-1, a specific aldehyde dehydrogenase 2 (ALDH2) activator, in treating alcoholic liver disease.
  
  
  METHODS
  Male C57BL/6J mice were exposed to alcohol for a time-course study on aldehyde metabolism. The specificity and efficacy of Alda-1 on activating hepatic ALDH2 and aldehyde clearance were determined by acute treatments. Then, mice were fed alcohol for 8 weeks with Alda-1 administration for the last 10 days to test the therapeutic potential of Alda-1. Lastly, H4IIEC3 cells were treated with ethanol, acetaldehyde, or 4-hydroxynonenal to define the link between aldehydes and hepatotoxicity.
  
  
  RESULTS
  Alcohol feeding for 8 weeks induced hepatic ALDH2 dysfunction and aldehyde accumulation. One dose of Alda-1 administration elevated hepatic ALDH activity, which was blocked by the specific ALDH2 inhibitor, daidzin. Alda-1 accelerated acetaldehyde clearance after acute alcohol intoxication. Alda-1 treatment in the 8-week alcohol feeding model reversed liver damage along with reduction of hepatic aldehydes. Alda-1 re-activated transcription factors, upregulated fatty acid oxidation enzymes, and reversed steatosis. Alcohol-induced endoplasmic reticulum stress and apoptotic cell death were also attenuated by Alda-1. Acetaldehyde or 4-hydroxynonenal treatment to H4IIEC3 cells inactivated transcription factors and induced endoplasmic reticulum stress and apoptosis, while ethanol per se showed limited effects.
  
  
  CONCLUSIONS
  Pharmacological activation of ALDH2 by Alda-1 reversed alcoholic steatosis and apoptosis through accelerating aldehyde clearance. This study indicates that ALDH2 is a promising molecular target and Alda-1 has therapeutic potential for treating alcoholic liver disease.
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhong
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
authors.forename: Wenliang
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Li
authors.affiliation: University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Guoxiang
authors.initials: G
authors.lastname: Xie
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27412, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
authors.forename: Xiuhua
authors.initials: X
authors.lastname: Sun
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
authors.forename: Xiaobing
authors.initials: X
authors.lastname: Tan
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA.
authors.forename: Xinguo
authors.initials: X
authors.lastname: Sun
authors.affiliation: University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Jia
authors.affiliation: Center for Translational Biomedical Research, University of North Carolina at Greensboro, North Carolina Research Campus, Kannapolis, NC 28081, USA; Department of Nutrition, University of North Carolina at Greensboro, Greensboro, NC 27412, USA. Electronic address: z_zhou@uncg.edu.
authors.forename: Zhanxiang
authors.initials: Z
authors.lastname: Zhou
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000071396:Aldehyde Dehydrogenase, Mitochondrial; D000447:Aldehydes / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology*; D052117:Benzodioxoles / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D004195:Disease Models, Animal; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats
chemical_list: D000447:Aldehydes; D001549:Benzamides; D052117:Benzodioxoles; C531525:N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide; C515029:ALDH2 protein, mouse; D000444:Aldehyde Dehydrogenase; D000071396:Aldehyde Dehydrogenase, Mitochondrial
keywords: Alcohol; Alda-1; Aldehyde dehydrogenase 2; Apoptosis; Steatosis