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

TitlePharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice
Authors
KeywordsAlcohol
Alda-1
Aldehyde dehydrogenase 2
Apoptosis
Steatosis
Issue Date2015
Citation
Journal of Hepatology, 2015, v. 62, n. 6, p. 1375-1381 How to Cite?
AbstractBackground & 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.
Persistent Identifierhttp://hdl.handle.net/10722/342489
ISSN
2023 Impact Factor: 26.8
2023 SCImago Journal Rankings: 9.857

 

DC FieldValueLanguage
dc.contributor.authorZhong, Wei-
dc.contributor.authorZhang, Wenliang-
dc.contributor.authorLi, Qiong-
dc.contributor.authorXie, Guoxiang-
dc.contributor.authorSun, Qian-
dc.contributor.authorSun, Xiuhua-
dc.contributor.authorTan, Xiaobing-
dc.contributor.authorSun, Xinguo-
dc.contributor.authorJia, Wei-
dc.contributor.authorZhou, Zhanxiang-
dc.date.accessioned2024-04-17T07:04:10Z-
dc.date.available2024-04-17T07:04:10Z-
dc.date.issued2015-
dc.identifier.citationJournal of Hepatology, 2015, v. 62, n. 6, p. 1375-1381-
dc.identifier.issn0168-8278-
dc.identifier.urihttp://hdl.handle.net/10722/342489-
dc.description.abstractBackground & 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.-
dc.languageeng-
dc.relation.ispartofJournal of Hepatology-
dc.subjectAlcohol-
dc.subjectAlda-1-
dc.subjectAldehyde dehydrogenase 2-
dc.subjectApoptosis-
dc.subjectSteatosis-
dc.titlePharmacological activation of aldehyde dehydrogenase 2 by Alda-1 reverses alcohol-induced hepatic steatosis and cell death in mice-
dc.typeArticle-
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1016/j.jhep.2014.12.022-
dc.identifier.pmid25543082-
dc.identifier.scopuseid_2-s2.0-84929605783-
dc.identifier.volume62-
dc.identifier.issue6-
dc.identifier.spage1375-
dc.identifier.epage1381-
dc.identifier.eissn1600-0641-

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