Autophagy in the liver: cell's cannibalism and beyond

Abstract

Chronic liver disease and its progression to liver failure are induced by various etiologies including viral infection, alcoholic and nonalcoholic hepatosteatosis. It is anticipated that the prevalence of fatty liver disease will continue to rise due to the growing incidence of obesity and metabolic disorder. Evidence is accumulating to indicate that the onset of fatty liver disease is causatively linked to mitochondrial dysfunction and abnormal lipid accumulation. Current treatment options for this disease are limited. Autophagy is an integral catabolic pathway that maintains cellular homeostasis both selectively and nonselectively. As mitophagy and lipophagy selectively remove dysfunctional mitochondria and excess lipids, respectively, stimulation of autophagy could have therapeutic potential to ameliorate liver function in steatotic patients. This review highlights our up-to-date knowledge on mechanistic roles of autophagy in the pathogenesis of fatty liver disease and its vulnerability to surgical stress, with an emphasis on mitophagy and lipophagy.

Keywords: Autophagy; Lipophagy; Liver; Mitophagy.

Fig. 1. Diagram of autophagy process

Nutrient deprivation or rapamycin treatment initiates autophagy. Upon initiation, the preinitiation complex comprising of ULK1, ATG13, and FIP200, works in concert with the PI3K-III complex to induce membrane nucleation of a phagophore. LC3-I becomes lipidated and activated to LC3-II afterwards by a cascade of autophagy proteins, including ATG4B, ATG5, ATG7, ATG10, ATG12, and ATG16L1. This activated form of LC3 guides the phagophore to recruit intracellular cargo. During the maturation stage, LC3-II is inserted into both cytosolic and luminal plane of the growing phagophore. While LC3-II on the luminal side interacts with adaptor proteins for autophagic cargo, the cytosolic side LC3-II interacts later with the endosomal/lysosomal compartment. During the degradation phase, PLEKHM1 localizes to both the endosome and lysosome in a HOPS- and RAB7-dependent manner. The PLEKHM1-RAB7-HOPS complex aids in the fusion between two compartments. This complex may also localize to the autophagosome. Finally, the late autophagosome fuses with the lysosome to generate the autolysosome, wherein lysosome-associate membrane protein (LAMP) promotes vesicular fusion events along microtubules. Finally, luminal contents in the autolysosome are degraded by lysosomal enzymes.

Fig. 2. Mitophagy pathway

There exist at least three distinct forms of mitophagy. (A) Type 1 mitophagy is initiated by nutrient starvation and it clears polarized mitochondria in a PI3K-III-dependent way. PI3K-III inhibitors such as wortmannin or 3-methyl-adenine (3-MA) block this mitophagic pathway. (B) In contrast, type 2 mitophagy eliminates depolarized mitochondria in a PINK1/Parkin, BNIP3, and/or FUNDC1-dependent fashion. During hypoxia, HIF1-α promotes BNIP3 expression and its translocation into the mitochondrial outer membrane. BNIP3 stimulates mitophagy through its interaction with Bcl-2. The onset of type 2 mitophagy is also modulated by phosphorylation status of FUNDC1. Type 2 mitophagy occurs independently of PI3K-III. (C) Mild oxidative stress induces type 3 mitophagy by generating a multivesicular body with mitochondria-derived vesicles. PINK1 and Parkin might be involved in this process.

Fig. 3. Lipophagy pathway

Following starvation or overnutrition, AUP1 at the LD becomes ubiquitinated by UBEG2, which recruits a phagophore. In addition, the interaction of RAB7 with HOPS is likely an important step in the onset of lipophagy.