Role of ethanol in the regulation of hepatic stellate cell Function
Open accessAbstract
Hepatic cirrhosis resulting from alcohol abuse is one of the principal causes of liver-related morbidity and mortality.In the liver, excess ethanol leads to three pathologically distinct disorders, namely fatty liver (alcohol-associated hepatic steatosis), alcoholic hepatitis and cirrhosis.Alcohol-associated hepatic steatosis is the most common form of liver injury and is reversible with abstinence [3][4][5] .More serious forms of alcoholic liver disease (ALD) include alcoholic hepatitis characterized by persistent inflammation of the liver, and cirrhosis, characterized by progressive hepatic fibrosis.The pathogenesis of ALD is poorly understood, in part because no simple animal model exists that reproduces the full spectrum of the human disease, including the development of cirrhosis [1,4] .In addition, there is considerable variation among individuals in their susceptibility to ALD, so that among people drinking similar amounts, only a proportion develops cirrhosis [1,[3][4][5] .Almost all ingested ethanol is metabolized in the liver.Two major enzyme systems, namely the oxidative and nonoxidative pathways, mediate the initial phase of ethanol metabolism [1,5] (Figure 1).The oxidative pathway comprises the alcohol dehydrogenases (ADH) and members of the cytochrome P450 system (predominantly CYP2E1) [5][6][7] .This pathway generates acetaldehyde.Acetaldehyde is subsequently metabolized to acetate via the mitochondrial enzyme acetaldehyde dehydrogenase (ALDH).Although acetaldehyde is oxidized to acetate by ALDH, the kinetics of this reaction is sufficiently slow to allow for the accumulation of acetaldehyde in humans or animals consuming alcohol [1,2,5] .The non-oxidative pathway of ethanol metabolism involves the esterification of ethanol with fatty acids to form fatty acid ethyl esters (FAEE), a reaction catalyzed by FAEE synthases [1,5] .Ethanol and its metabolites including acetaldehyde c a u s e l ive r d a m a g e t h r o u g h s e ve r a l i n t e r r e l a t e d pathways [1,2,8,9] .The oxidation of ethanol is associated with a change in hepatocyte redox homeostasis which can lead to a number of metabolic disorders including lactic acidosis, hyperlipidaemia and hyperuricaemia.Chronic ethanol consumption does not influence ADH activity, but has a profound stimulatory effect on microsomal enzymes, particularly CYP2E1 [1,2] .This is in part responsible for the development in alcoholic liver diseases, a rise in oxygen consumption, the excessive production of free radicals and an increase in the metabolism of ethanol, vitamin A and testosterone.Ethanol and acetaldehyde have deleterious effects both direct and indirect, for example by generating reactive oxygen species (ROS) and causing damage to
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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.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [221]
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- Authors
- Wang, J.-H.
- Venue
- World Journal of Gastroenterology
- Publisher
- Baishideng Publishing Group Inc.
- Published
- 2006
- Volume
- 12
- Issue
- 43
- Pages
- 6926
- ISSN
- 1007-9327 (ISSN-L)
- PMC
- PMC4087334
- OpenAlex
- W95767044
- Cited by
- 53
- References
- 73
- Citations by year
- 2025: 2 · 2023: 5 · 2022: 2 · 2021: 6 · 2020: 4 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 3 · 2014: 3 · 2013: 2
- FWCI
- 0.27
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- World Journal of Gastroenterology (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Hepatology › Liver Disease and Transplantation
- Keywords
- ethanol, hepatic stellate cells, alcoholic liver disease, alcoholic cirrhosis, liver fibrosis, alcohol metabolism, acetaldehyde, CYP2E1, alcohol dehydrogenase, fatty acid ethyl esters, oxidative stress, Nrf2, NADPH oxidase, NOX4, NADPH oxidase 5, reactive oxygen species
- MeSH terms
- Ethanol, Animals, Central Nervous System Depressants, Collagen, Humans, Liver Cirrhosis, Liver Diseases, Alcoholic, Retinoids, Hepatocytes, Transforming Growth Factor beta1
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