Pharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol- induced hepatic steatosis and cell death in mice

JOURNAL OF HEPATOLOGY

卷:62

Article

Zhong, Wei¹  Zhang, Wenliang¹  Li, Qiong¹  Xie, Guoxiang³  Sun, Qian^1,2  Sun, Xiuhua¹  Tan, Xiaobing¹  Sun, Xinguo¹  Jia, Wei³  Zhou, Zhanxiang^1,2 

[1] Univ North Carolina Greensboro, Ctr Translat Biomed Res, Kannapolis, NC 28081 USA

[2] Univ N Carolina, Dept Nutr, Greensboro, NC 27412 USA

[3] Univ Hawaii, Ctr Canc, Honolulu, HI 96813 USA

关键词: Aldehyde dehydrogenase 2;    Alda-1;    Alcohol;    Steatosis;    Apoptosis;   

DOI  :  10.1016/j.jhep.2015.02.011

来源: Elsevier

【 摘 要 】

Background & Aims: 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

Free