Augmenter of Liver Regeneration Protects against Ethanol-Induced Acute Liver Injury by Promoting Autophagy

Abstract

Alcoholic liver disease is associated with high morbidity and mortality, and treatment options are limited to date. Augmenter of liver regeneration (ALR) may protect against hepatic injury from chemical poisons, including ethanol. Autophagy appears to positively influence survival in cases of liver dysfunction, although the mechanisms are poorly understood. Herein, we investigated effects of ALR-induced autophagy invitro and invivo in an ethanol-induced model of acute liver injury. Decreased serum levels of alanine aminotransferase and aspartate aminotransferase and reduced histologic lesions revealed that mice overexpressing ALR experienced less liver damage than wild-type. ALR-knockdown mice experienced more severe liver damage than wild-type. ALR-transfected HepG2 cells showed increased survival rates, improved maintenance of mitochondrial membrane potential, and increased ATP levels after ethanol treatment. The observed protection was associated with up-regulation of autophagy-markers, including light chain 3II, beclin-1, and autophagy-related gene 5, and down-regulation of p62 by ALR. Autophagy was inhibited in ALR-knockdown mice and HepG2 cells, and autophagy inhibitor bafilomycin A1 attenuated the protective effects of ALR. Results showed phosphorylated mammalian target of rapamycin (mTOR) was down-regulated when ALR was overexpressed and up-regulated when ALR was knocked down. These data show that ALR is protective against ethanol-induced acute liver injury by promoting autophagy, probably via repressing the mTOR pathway. These results have potential implications for the clinical treatment of alcoholic liver disease patients.