Autophagy Reduces Acute Ethanol-Induced Hepatotoxicity and Steatosis in Mice

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 studied in vitro.

Results:

Ethanol-induced macroautophagy in the livers of mice and cultured cells required ethanol metabolism, generated reactive oxygen species, and inhibited mTOR signaling. Suppression of macroautophagy with pharmacological 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 cells with 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.

Keywords: GFP-LC3, bodipy staining, autophagy flux, long-lived protein degradation

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