A Mechanistic Review of Cell Death in Alcohol-Induced Liver Injury

Abstract

Alcoholic liver disease (ALD) is a major health problem in the United States and worldwide without successful treatments. Chronic alcohol consumption can lead to ALD, which is characterized by steatosis, inflammation, fibrosis, cirrhosis, and even liver cancer. Recent studies suggest that alcohol induces both cell death and adaptive cell survival pathways in the liver, and the balance of cell death and cell survival ultimately decides the pathogenesis of ALD. This review summarizes the recent progress on the role and mechanisms of apoptosis, necroptosis, and autophagy in the pathogenesis of ALD. Understanding the complex regulation of apoptosis, necrosis, and autophagy may help to develop novel therapeutic strategies by targeting all 3 pathways simultaneously.

Keywords: Alcohol; Apoptosis; Autophagy; Liver Injury; Necroptosis.

Figure 1. Possible pathways leading to alcohol-induced apoptosis and necrosis

Alcohol metabolism via ADH, ALDH, Cyp2E1 and catalase increases ROS production that triggers mitochondrial damage and onset of MPT resulting in the release of mitochondrial Cyto c and Smac. Released Cyto c promotes the activation of caspase-9 and caspase-3, whereas Smac inhibits XIAP to remove its inhibition on caspases. Activated caspase-3 then leads to hepatocyte apoptosis. Alcohol consumption also increases gut permeability resulting in elevated influx of LPS into the liver. LPS activates Kupffer cells to produce TNF-α. TNF-α binds to its receptor (TNFR1), which further recruits TRADD, FADD, caspase-8 and FLIPl resulting in caspase-8 activation when RIP1 is de-ubiquitinated by CYLD. Activated caspase-8 cleaves Bid to activate the mitochondrial apoptotic pathway and trigger apoptosis. Activated caspase-8 also cleaves RIP1 and RIP3 to inactivate RIP1-RIP3-mediated necroptosis. When cIAPs are depleted and caspase-8 is inhibited, RIP1 and RIP3 interact with each other via RHIM domains to from the amyloid-like necrosome. Auto- and transphosphorylated RIP1 and RIP3 then further recruit and phosphorylate downstream MLKL to initiate necroptosis. In the absence of cIAPs, RIP1, RIP3, TRADD, caspase-8 and FLIPl form a complex called the, which induces caspase-8 activation and apoptosis and depends on RIP1 kinase activity.