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

Abstract

Autophagy is a conserved catabolic process that eliminates dysfunctional cytosolic biomolecules through vacuole-mediated sequestration and lysosomal degradation. Although the molecular mechanisms that regulate autophagy are not fully understood, recent work indicates that dysfunctional/impaired autophagic functions are associated with the development and progression of nonalcoholic fatty liver disease (NAFLD), alcoholic fatty liver disease (AFLD), and hepatocellular carcinoma (HCC). Autophagy prevents NAFLD and AFLD progression through enhanced lipid catabolism and decreasing hepatic steatosis, which is characterized by the accumulation of triglycerides and increased inflammation. However, as both diseases progress, autophagy can become impaired leading to exacerbation of both pathological conditions and progression into HCC. Due to the significance of impaired autophagy in these diseases, there is increased interest in studying pathways and targets involved in maintaining efficient autophagic functions as potential therapeutic targets. In this review, we summarize how impaired autophagy affects liver function and contributes to NAFLD, AFLD, and HCC progression. We will also explore how recent discoveries could provide novel therapeutic opportunities to effectively treat these diseases.

Conflict of interest statement

The authors declare that they have no competing interests.

Copyright © 2021 Suryakant Niture et al.

Figures

Figure 1

Schematic model represents the overview of the autophagy process. Molecular regulation of the autophagic process in normal and starvation conditions is presented. In the presence of sufficient nutrients, activation of mTOR inhibits the ULK1 complex, whereas, under conditions of nutrient starvation, AMPK inhibits mTOR and activates the ULK1 and PI3KC3 complex leading to initiation of phagophore biosynthesis. During autophagosome maturation, cargo recruitment takes place through the recruitment of ATGs and LC3, and mature autophagosome formation occurs. Ultimately, the autophagosome fuses with a lysosome, facilitated by Rab7 and LAMP proteins. The fully functional autolysosome then degrades the autolysosomal cargo and releases the degradation products into the cytosol for recycling.

Figure 2

Schematic model represents the molecular mechanisms and dysregulation of autophagy components in a high-fat diet (HFD)/obesity-induced impaired autophagic function in NAFLD. HFD-/obesity-mediated activation of SIRT3 inactivates AMPK, mTORC1, and ULK1 complex leading to inhibition of phagophore formation. A high fatty acid diet upregulates Rubicon expression, increasing its interaction with Beclin 1 and decreasing autophagosome-lysosome fusion. HFD/obesity decreases the expression and activities of cathepsin family enzymes and downregulates autolysosomal proteolysis. HFD/obesity induces changes in the membrane lipid composition of the lysosome, affects autophagosomal-lysosomal acidification, and inhibits fusion of the autophagosome with the lysosome.

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.

Figure 4

Schematic model represents the role of functional and impaired autophagy in the modulation of NAFLD, AFLD, and HCC. Functional autophagy can reverse hepatic steatosis, NASH, or hepatitis by the degradation of lipid droplets in the initial stages of NAFLD and acute AFLD. When a functional autophagic process is unable to process the overloaded-lipid content in the liver, particularly in chronic NAFLD and AFLD, defective autophagy exists. Due to defective/impaired autophagic function (increasing expression of p62, LC3, Rab7, and Glypican-3), NASH progresses to fibrosis/cirrhosis and subsequently to HCC.