Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice

Wenxing Ding, Min Li, Xiaoyun Chen, Hongmin Ni, Chihwen Lin, Wentao Gao, Binfeng Lu, Donna B. Stolz, Dahn L. Clemens, Xiao-Ming Yin

Research output: Contribution to journalArticle

274 Citations (Scopus)

Abstract

Background & Aims: Alcohol abuse is a major cause of liver injury. The pathologic features of alcoholic liver disease develop over prolonged periods, yet the cellular defense mechanisms against the detrimental effects of alcohol are not well understood. We investigated whether macroautophagy, an evolutionarily conserved cellular mechanism that is commonly activated in response to stress, could protect liver cells from ethanol toxicity. Methods: Mice were acutely given ethanol by gavage. The effects of ethanol on primary hepatocytes and hepatic cell lines were also studied in vitro. Results: Ethanol-induced macroautophagy in the livers of mice and cultured cells required ethanol metabolism, generation of reactive oxygen species, and inhibition of mammalian target of rapamycin signaling. Suppression of macroautophagy with pharmacologic agents or small interfering RNAs significantly increased hepatocyte apoptosis and liver injury; macroautophagy therefore protected cells from the toxic effects of ethanol. Macroautophagy induced by ethanol seemed to be selective for damaged mitochondria and accumulated lipid droplets, but not long-lived proteins, which could account for its protective effects. Increasing macroautophagy pharmacologically reduced hepatotoxicity and steatosis associated with acute ethanol exposure. Conclusions: Macroautophagy protects against ethanol-induced toxicity in livers of mice. Reagents that modify macroautophagy might be developed as therapeutics for patients with alcoholic liver disease.

Original languageEnglish (US)
Pages (from-to)1740-1752
Number of pages13
JournalGastroenterology
Volume139
Issue number5
DOIs
StatePublished - Nov 2010
Externally publishedYes

Fingerprint

Autophagy
Ethanol
Liver
Hepatocytes
Alcoholic Liver Diseases
Poisons
Wounds and Injuries
Defense Mechanisms
Sirolimus
Small Interfering RNA
Alcoholism
Cultured Cells
Reactive Oxygen Species
Mitochondria
Alcohols
Apoptosis
Cell Line

Keywords

  • Autophagy Flux
  • Bodipy Staining
  • GFP-LC3
  • Long-Lived Protein Degradation

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. / Ding, Wenxing; Li, Min; Chen, Xiaoyun; Ni, Hongmin; Lin, Chihwen; Gao, Wentao; Lu, Binfeng; Stolz, Donna B.; Clemens, Dahn L.; Yin, Xiao-Ming.

In: Gastroenterology, Vol. 139, No. 5, 11.2010, p. 1740-1752.

Research output: Contribution to journalArticle

Ding, W, Li, M, Chen, X, Ni, H, Lin, C, Gao, W, Lu, B, Stolz, DB, Clemens, DL & Yin, X-M 2010, 'Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice', Gastroenterology, vol. 139, no. 5, pp. 1740-1752. https://doi.org/10.1053/j.gastro.2010.07.041
Ding, Wenxing ; Li, Min ; Chen, Xiaoyun ; Ni, Hongmin ; Lin, Chihwen ; Gao, Wentao ; Lu, Binfeng ; Stolz, Donna B. ; Clemens, Dahn L. ; Yin, Xiao-Ming. / Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice. In: Gastroenterology. 2010 ; Vol. 139, No. 5. pp. 1740-1752.
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