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Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity.

Publication ,  Journal Article
Ni, H-M; Du, K; You, M; Ding, W-X
Published in: Am J Pathol
December 2013

Autophagy is a lysosomal degradation process that degrades long-lived cellular proteins and damaged organelles as a critical cell survival mechanism in response to stress. We recently reported that acute ethanol induces autophagy, which then reduces ethanol-induced liver injury. However, the mechanisms by which ethanol induces autophagy are not known. In the present study, ethanol treatment significantly increased both mRNA and protein levels of various essential autophagy-related genes in primary cultured mouse hepatocytes and in mouse liver. Both nuclear translocation of FoxO3a and expression of FoxO3a target genes were increased in ethanol-treated primary hepatocytes and mouse liver. Overexpression of a dominant negative form of FoxO3a inhibited ethanol-induced autophagy-related gene expression and enhanced ethanol-induced cell death in primary hepatocytes, which suggests that FoxO3a is a key factor in regulating ethanol-induced autophagy and cell survival. Resveratrol, a well-known SIRT1 agonist, further enhanced ethanol-induced expression of autophagy-related genes, likely via increased deacetylation of FoxO3a. Moreover, acute ethanol-treated Foxo3a(-/-) mice exhibited decreased autophagy-related gene expression, but enhanced steatosis and liver injury, compared with wild-type mice. FoxO3a thus plays a critical role in ethanol-induced autophagy in mouse liver. Modulating the FoxO3a autophagy pathway may offer novel therapeutic approaches for treating alcoholic liver pathogenesis.

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Published In

Am J Pathol

DOI

EISSN

1525-2191

Publication Date

December 2013

Volume

183

Issue

6

Start / End Page

1815 / 1825

Location

United States

Related Subject Headings

  • Stilbenes
  • Sirtuin 1
  • Resveratrol
  • Pathology
  • Mice, Knockout
  • Mice
  • Liver Diseases, Alcoholic
  • Liver
  • Hepatocytes
  • Gene Expression Regulation
 

Citation

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ICMJE
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Ni, H.-M., Du, K., You, M., & Ding, W.-X. (2013). Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol, 183(6), 1815–1825. https://doi.org/10.1016/j.ajpath.2013.08.011
Ni, Hong-Min, Kuo Du, Min You, and Wen-Xing Ding. “Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity.Am J Pathol 183, no. 6 (December 2013): 1815–25. https://doi.org/10.1016/j.ajpath.2013.08.011.
Ni H-M, Du K, You M, Ding W-X. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol. 2013 Dec;183(6):1815–25.
Ni, Hong-Min, et al. “Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity.Am J Pathol, vol. 183, no. 6, Dec. 2013, pp. 1815–25. Pubmed, doi:10.1016/j.ajpath.2013.08.011.
Ni H-M, Du K, You M, Ding W-X. Critical role of FoxO3a in alcohol-induced autophagy and hepatotoxicity. Am J Pathol. 2013 Dec;183(6):1815–1825.
Journal cover image

Published In

Am J Pathol

DOI

EISSN

1525-2191

Publication Date

December 2013

Volume

183

Issue

6

Start / End Page

1815 / 1825

Location

United States

Related Subject Headings

  • Stilbenes
  • Sirtuin 1
  • Resveratrol
  • Pathology
  • Mice, Knockout
  • Mice
  • Liver Diseases, Alcoholic
  • Liver
  • Hepatocytes
  • Gene Expression Regulation