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. Key words: Alcohol metabolism; Acetaldehyde; Reactive oxygen species; Alcoholic liver disease; Protein adducts; Hepatic stellate cells; Liver fibrosis; CYP2E1Core tip: The goal of this article is to review the mechanisms of alcohol-mediated toxicity in parenchymal and non-parenchymal cells of the liver. Specifically, we highlight the effect of oxidative ethanol metabolites such as acetaldehyde and reactive oxygen species in the development of fat accumulation, fibrosis and deranged immune response.Ceni E, Mello T, Galli A. Pathogenesis of alcoholic liver disease: Role of oxidative metabolism.

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H epatic fibrosis is a major histological finding associated with the progression of chronic liver disease to cirrhosis; it is characterized by increased deposition of components of the extracellular matrix (ECM), in particular fibrillar collagens type I and type III. 1 Hepatic stellate cells (HSC) are currently considered to be one of the major sources of ECM proteins in the liver; expansion of their pool is a key step in the fibrogenic process. 2 Following hepatic injury, HSC develop a myofibroblast-like phenotype, characterized by a reduced content of vitamin A, increased proliferation and migration, enhanced expression of matrix protein, and production of matrix metalloproteinases (MMPs). 3 Evidence from experimental and clinical studies indicates that production of reactive oxygen species (ROS) and lipid peroxidation of cell membranes are often associated with the development of hepatic fibrogenesis and

Hepatic fibrosis is the main histological feature that accomExperimental evidence indicates that the lipid peroxipanies the progression of alcoholic liver injury to cirrhosis dation of biological membranes is often associated with in chronic alcohol abusers. 1,2 Acetaldehyde, a potential prothe development of liver fibrosis. We have studied the oxidant factor linked to ethanol metabolism, has been proeffect of neutrophil-derived reactive oxygen species posed as a mediator of fibrogenesis in alcoholic liver disease. (ROS) on collagen synthesis by human hepatic stellateIn fact, an immunohistochemical association between acetalcells (HSC), the major source of collagen in the liver, in dehyde-protein adducts and extracellular matrix deposition a coculture system. Lipid peroxidation in the cocultures in alcohol-induced liver injury has been reported. of extracellular matrix components in the liver. 6,13-16 When ROS resulted in the early induction of lipid peroxidation isolated and cultured on plastic, they undergo spontaneous and was associated with a marked increase (threefold) transformation into myofibroblast-like cells, thereby mimickof procollagen I mRNA expression and synthesis. The ing in vitro 17 conditions that prevail in vivo after chronic addition of antioxidants, such as vitamin E or superoxalcohol consumption. [18][19][20] However, different mechanisms, ide dismutase (SOD), impaired this stimulation. The other than acetaldehyde-induced fibrogenesis, may be ininhibition of neutrophil NO formation by N G -monovolved in alcoholic hepatic fibrosis. Evidence coming from methyl-L-arginine made the ROS-induced stimulation of either experimental or clinical studies indicates that lipid procollagen I more evident. The addition of xanthine/ peroxidation of biological membranes is often associated with xanthine oxidase X/XO, a superoxide anion donor, to the development of liver fibrosis. [21][22][23][24][25] We have recently shown HSC cultures strongly increased procollagen I synthesis.that the induction of lipid peroxidation phenomena or that This stimulation was hampered by the addition of both treatment with 4-hydroxynonenal (a highly reactive alde-SOD and sodium nitroprusside (an NO donor). The conhydic end-product of lipid peroxidation) stimulates procollatribution of HSC to the production of NO in our coculgen type I synthesis in human HSC by acting at the level ture system was negligible, because inducible NO synof gene expression. 26 Moreover, malondialdehyde has been thase (iNOS) mRNA was almost undetectable in these shown to stimulate collagen production by rat HSC upon acticells, and also because the amount of NO produced by vation in primary culture. 27 HSC stimulated with tumor necrosis factor a (TNF-a)Although alcoholic liver fibrosis may develop in the absence and lipopolysaccharide (LPS) was 500 times less than of evident inflammation, 1,2 the occurrence of alcoholic hepatithat synthesized by neutrophils. In conclusion, these retis may contribute to the increased extracellular matrix deposults ind...