Autophagy in alcohol-induced liver diseases

Abstract

Alcohol is the most abused substance worldwide and a significant source of liver injury; the mechanisms of alcohol-induced liver disease are not fully understood. Significant cellular toxicity and impairment of protein synthesis and degradation occur in alcohol-exposed liver cells, along with changes in energy balance and modified responses to pathogens. Autophagy is the process of cellular catabolism through the lysosomal-dependent machinery, which maintains a balance among protein synthesis, degradation, and recycling of self. Autophagy is part of normal homeostasis and it can be triggered by multiple factors that threaten cell integrity, including starvation, toxins, or pathogens. Multiple factors regulate autophagy; survival and preservation of cellular integrity at the expense of inadequately folded proteins and damaged high-energy generating intracellular organelles are prominent targets of autophagy in pathological conditions. Coincidentally, inadequately folded proteins accumulate and high-energy generating intracellular organelles, such as mitochondria, are damaged by alcohol abuse; these alcohol-induced pathological findings prompted investigation of the role of autophagy in the pathogenesis of alcohol-induced liver damage. Our review summarizes the current knowledge about the role and implications of autophagy in alcohol-induced liver disease.

Figure 1. Macroautophagy in mammals

This diagram was built based on the latest knowledge in the field of autophagy. Only known mammalian counterparts of yeast autophagy factors are included. The mammalian target of rapamycin (mTOR) suppresses autophagy when nutrient supply is adequate or insulin levels are elevated. Under conditions of starvation or rapamycin treatment, mTOR suppression is prevented, causing induction of autophagy (1) by formation of the ULK·FIP200· Atg13 complex, which, in the presence of the phagophore (the autophagosome precursor membrane originating from the endoplasmic reticulum (ER) and/or plasma membrane (PM)), triggers initiation of autophagosome formation (2). This involves the formation of coordinated complexes among beclin-1 and Atg14 and conjugation systems (see text) that enable lipidation of LC3I with phosphatidylethanolamine (PE) to form LC3II. Proteins and organelles are sequestered within the double membrane–bound autophagosome. The latter undergoes fusion with lysosomes (3) to form an autolysosome, which is a degradative organelle. The contents of the autolysosome are acidified and then degraded by lysosomal hydrolases (4). Figure reproduced and modified with permission after Liu, et. al. (2009).

Figure 2. The proposed mechanism of the alcohol-induced autophagy in the liver

Cellular receptors trigger the autophagy following the classic 4 stages, as described in the text. Alcohol exposure triggers autophagy. Alcohol and/or its metabolites inhibit the mTOR pathway thus releasing its inhibition of autophagy. The effect of alcohol on protein in the final stages of autophagy, namely autophagosome-lysosome fusion, and on catabolism of cargo proteins is still unclear. The existence of alcohol-induced mitophagy is unknown. The effect of alcohol on receptor-initiated autophagy and their downstream signaling pathways remain largely unexplored. Known effects are depicted with lines and arrows; unknowns are depicted with “?” sign; the up- and down-regulation is depicted by the orientation of the arrows.

Figure 3. Scheme of Type 1 and Type 2 mitophagy

In nutrient deprivation-induced (Type 1) mitophagy, activation of Beclin1/PI3K leads to formation of an GFP-LC3-labeled phagophore, which closes with onset of the MPT to form a mitophagosome. The mitophagosome so formed then fuses with lysosomes in a PI3K-dependent fashion to form an autolysosome where acidic digestion of the entrapped organelle occurs. In photodamage-induced (Type 2) mitophagy, photoirradiation through ROS generation causes MPT onset and mitochondrial depolarization. Membrane vesicles containing GFP-LC3 attach to the depolarized mitochondria and coalesce to form a mitophagosome in a PI3K-independent fashion. The mitophagosome is then processed in a fashion identical to the Type 1 pathway.