Autophagy reduces acute ethanol-induced hepatotoxicity and steatosis in mice.
OBJECTIVE
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.
Ding
Wen-Xing
WX
Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Li
Min
M
Chen
Xiaoyun
X
Ni
Hong-Min
HM
Lin
Chih-Wen
CW
Gao
Wentao
W
Lu
Binfeng
B
Stolz
Donna B
DB
Clemens
Dahn L
DL
Yin
Xiao-Ming
XM
D000208:Acute Disease; D000818:Animals; D001343:Autophagy / Q000502:physiology*; D002460:Cell Line; D004195:Disease Models, Animal; D018450:Disease Progression; D000431:Ethanol / Q000633:toxicity; D005235:Fatty Liver, Alcoholic / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017382:Reactive Oxygen Species / Q000378:metabolism
D017382:Reactive Oxygen Species; D000431:Ethanol