Emerging Roles of Impaired Autophagy in Fatty Liver Disease and Hepatocellular Carcinoma

Figure 3

Schematic model represents the molecular role of acute and chronic intake of alcohol in the induction of autophagy/impaired autophagy in AFLD. Acute ethanol induces ADH- and CYP2E1-mediated ROS production that inactivates ATG4B protein and induces autophagy. Acute consumption of alcohol inhibits AKT and mTORC1 complex and increases FoxO3a- and TFEB-mediated expression of ATG5, ATG7, Beclin 1, and ULK1 proteins upregulating autophagosomal-lysosomal fusion and functional autophagy. In contrast, chronic intake/consumption of alcohol inactivates AMPK but activates the mTORC1 complex which in turn inactivates the ULK1 complex and inhibits phagophore formation. Moreover, chronic consumption of alcohol downregulates the nuclear localization of TFEB, reduces expression of Beclin-1, and ATG5 that inhibits the phagophore to autophagosome transition. Chronic alcohol also inhibits Dynamin 2, disturbs the transportation of Rab7 into the lysosomal membrane, and impairs autophagosomal-lysosomal fusion.