Cited by 521Alcohol Consumption and Health EffectsLiver physiology and pathologyLiver Disease Diagnosis and Treatment

Pathogenesis of alcoholic liver disease: Role of oxidative metabolism

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Ceni, Elisabetta, Mello, Tommaso, Galli, Andrea·2014·World Journal of Gastroenterology

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.

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Crossref · 10.3748/wjg.v20.i47.17756

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245 of 245 references verified0 citation errors · 0 not checkable

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  • Acetaldehyde activates HSCs in ALD by inducing oxidative stress.

    “An accumulating body of evidence indicates that acetaldehyde activates HSCs in ALD by inducing oxidative stress [60].”
  • MAA adducts are found in HSCs, liver sinusoidal endothelial cells, and Kupffer cells in ALD models; they stimulate transformation of HSCs into activated myofibroblasts, resulting in elevated production of profibrotic factors such as PDGF, and can induce proinflammatory cytokines such as TNF-α, IL-12, IL-18, and MIF.

    “In addition to individual AA and MDA adducts, MAA adducts (AA-MDA-protein hybrid adducts) are found in HSCs, liver sinusoidal endothelial cells, and Kupffer cells in ALD models.”

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Authors
Ceni, E., Mello, T., & Galli, A.
Affiliations
University of Florence (IT)
Venue
World Journal of Gastroenterology
Published
2014-12-21
Volume
20
Issue
47
Pages
17756-17772
ISSN
1007-9327 (ISSN-L)
OpenAlex
W1456504179
Cited by
521
References
245
Citations by year
2026: 42 · 2025: 39 · 2024: 58 · 2023: 75 · 2022: 56 · 2021: 59 · 2020: 47 · 2019: 38 · 2018: 40 · 2017: 21 · 2016: 25 · 2015: 21
FWCI
3.15
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • World Journal of Gastroenterology (publishedVersion, cc-by-nc)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Florence Research (University of Florence) (submittedVersion)
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
Keywords
alcoholic liver disease, acetaldehyde, reactive oxygen species, alcoholic fatty liver, alcoholic hepatitis, liver fibrosis, hepatocellular carcinoma, hepatic stellate cells, collagen synthesis, AMPK, autophagy, lipid peroxidation, lipopolysaccharide translocation, intestinal barrier, Kupffer cells, natural killer cells, innate immunity, adaptive immunity, DNA adducts, DNA methylation
MeSH terms
Acetaldehyde, Ethanol, Animals, Humans, Immunity, Innate, Liver, Liver Diseases, Alcoholic, Oxidation-Reduction, Prognosis, Risk Factors, Signal Transduction, Reactive Oxygen Species, Oxidative Stress, Disease Progression, Adaptive Immunity

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