Role and mechanisms of autophagy in alcohol-induced liver injury

Abstract

Alcoholic liver disease (ALD) is one of the major causes of chronic liver disease worldwide. Currently, no successful treatments are available for ALD. The pathogenesis of ALD is characterized as simple steatosis, fibrosis, cirrhosis, alcoholic hepatitis (AH), and eventually hepatocellular carcinoma (HCC). Autophagy is a highly conserved intracellular catabolic process, which aims at recycling cellular components and removing damaged organelles in response to starvation and stresses. Therefore, autophagy is considered as an important cellular adaptive and survival mechanism under various pathophysiological conditions. Recent studies from our lab and others suggest that chronic alcohol consumption may impair autophagy and contribute to the pathogenesis of ALD. In this chapter, we summarize recent progress on the role and mechanisms of autophagy in the development of ALD. Understanding the roles of autophagy in ALD may offer novel therapeutic avenues against ALD by targeting these pathways.

Keywords: Alcoholic liver disease; Lysosome; Mitophagy; Steatosis; TFEB.

Fig. 1

A proposed model for the molecular events and mechanisms underlying the protection of autophagy against alcoholic liver disease. Alcohol is mainly metabolized in the liver through a major oxidative pathway. In this pathway, alcohol is catalyzed by alcohol dehydrogenase (ADH), which converts alcohol into highly reactive metabolite, acetaldehyde. A small portion of alcohol can also be oxidized into acetaldehyde by cytochrome P450 family 2, subfamily E, polypeptide 1 (Cyp2E1) and catalase. Acetaldehyde is further metabolized by mitochondrial aldehyde dehydrogenase 2 (ALDH2) into more harmless acetate. Alcohol consumption leads to mitochondria damage due to increased reactive oxygen species, lipid accumulation and formation of protein aggregates. Autophagy can be induced as an adapted protective mechanism to remove damaged mitochondria, accumulated lipid droplets and protein aggregates. The removal of damaged mitochondria is through selective mitophagy, which is mediated by the PINK1/Parkin pathway that promotes mitochondrial ubiquitination. However, chronic alcohol drinking inhibits the activity of transcription factor EB, which is a master regulator of lysosomal biogenesis and autophagy, leading to insufficient autophagy. Pharmacological induction of autophagy (Torin 1 or rapamycin) or inhibition of autophagy (Leupeptin, CQ or 3-MA) protects or exacerbates alcohol-induced liver injury and steatosis, respectively.