Autophagy is Important for the Mitigation of Ethanol‐Induced Hepatotoxicity and Steatosis

Abstract

Alcohol abuse is a major cause of liver injury. Whereas the pathology of alcoholic liver disease develops over a prolonged period the cellular defense mechanisms against the detrimental effects of alcohol are not well understood. We investigated whether macroautophagy, an evolutionarily conserved mechanism commonly activated in response to stress, could be a protective mechanism against ethanol toxicity. Using both an animal binge model and cell cultures, we found that ethanol treatment strongly activated macroautophagy. This induction relied on the metabolism of ethanol, ROS generation and inhibition of mTOR signaling. Suppression of macroautophagy with pharmacological agents or specific siRNAs led to a significant increase in hepatocyte apoptosis and liver injury, indicating that autophagy was a key defense mechanism in the mitigation of the toxic effects of alcohol. Further analysis demonstrated that macroautophagy protected hepatocytes by removing damaged mitochondria and accumulated lipid droplets. Thus enhancement of macroautophagy greatly reduced the hepatotoxicity and steatosis associated with acute ethanol exposure. This study established the physiological significance of macroautophagy in ethanol‐induced pathogenesis in the liver and the potential therapeutic values of modulating macroautophagy in alcoholic liver disease.