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.