Modulation of Autophagy Affects the Hepatic Pathology in Alcoholic and Non‐alcoholic Liver Diseases

Abstract

Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We explored whether modulation of autophagy could affect the progression of alcoholic and non‐alcoholic liver diseases. C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4‐week oral feeding regime (chronic), or given high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before the sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. Carbamazepine, as well as rapamycin, could activate, and enhance ethanol‐induced, macroautophagy in hepatocytes in vitro and in vivo. In both acute and chronic ethanol condition, macroautophagy could be activated. The levels of hepatic steatosis and liver injury could be further enhanced by chloroquine, but reduced by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity could be also demonstrated in high fat diet‐induced non‐alcoholic fatty liver condition. These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury.