Pathogenesis of alcoholic liver disease: role of oxidative metabolism

Abstract

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.

Keywords: Acetaldehyde; Alcohol metabolism; Alcoholic liver disease; CYP2E1; Hepatic stellate cells; Liver fibrosis; Protein adducts; Reactive oxygen species.

Figure 1

Alcohol metabolism. Alcohol dehydrogenase (ADH) is the main cytosolic enzyme that converts alcohol to acetaldehyde. The inducible microsomal enzyme also forms acetaldehyde. The toxic metabolite acetaldehyde is then further oxidized to acetate by the mitochondrial aldehyde dehydrogenase (ALDH).

Figure 2

Molecular mechanisms of alcoholic fatty liver. Alcohol consumption via multiple pathways increases the expression of SREB-1 and downregulates PPAR-α, promoting fatty acid synthesis and impairing β-oxidation, thus resulting in fatty acid accumulation. Long-term ethanol consumption promotes fatty acid accumulation through decreased autophagy, while short-term ethanol exposure promotes autophagy and degradation of lipid droplets. HIF: Hypoxia inducible factor; ROS: Reactive oxygen species.

Figure 3

Molecular mechanisms of alcoholic fibrosis. Acetaldehyde causes increased synthesis of collagen and extracellular matrix (ECM) components through the activation of the transforming growth factor (TGF)-β/SMAD3 signaling pathway. The microsomal metabolism of ethanol leads to protein adduct formation that upregulates collagen synthesis. MDA: Malondialdehyde; OPN: Osteopontin; LPS: Lipopolysaccharide; TNF-α: Tumor necrosis factor-α; MMP: Metalloproteinase; HNE: Hydroxynonenal; AP-1: Activator protein-1; SP-1: Specificity protein-1.

Figure 4

Alcohol and innate immune response. Both alcohol and acetaldehyde increase the intestinal permeability and lipopolysaccharide (LPS) level in the portal circulation. LPS binds to TLR4 and induces the proinflammatory phenotype of Kupffer cells. Acetaldehyde and LPS also stimulate parenchymal and nonparenchymal cells to produce proinflammatory cytokines and chemokines. The innate immune system also releases anti-inflammatory and hepatoprotective cytokines that activate STAT3 signaling in liver cells. ROS: Reactive oxygen species; LPS: Lipopolysaccharide; TLR4: Toll-like receptor 4; TNF-α: Tumor necrosis factor-α; IFN-γ: Interferon-γ; IL: Interleukin; NF-κB: Nuclear factor-κB.