Apoptosis of enterocytes and nitration of junctional complex proteins promote alcohol-induced gut leakiness and liver injury
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Background & aims Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury, although the molecular mechanisms are still elusive. This study was aimed at investigating the roles of apoptosis of enterocytes and nitration followed by degradation of intestinal tight junction (TJ) and adherens junction (AJ) proteins in binge alcohol-induced gut leakiness.Methods The levels of intestinal (ileum) junctional complex proteins, oxidative stress markers and apoptosis-related proteins in rodents, T84 colonic cells and autopsied human ileums were determined by immunoblot, immunoprecipitation, immunofluorescence, and mass-spectral analyses.Results Binge alcohol exposure caused apoptosis of gut enterocytes with elevated serum endotoxin and liver injury. The levels of intestinal CYP2E1, iNOS, nitrated proteins and apoptosis-related marker proteins were significantly elevated in binge alcohol-exposed rodents. Differential, quantitative mass-spectral analyses of the TJ-enriched fractions of intestinal epithelial layers revealed that several TJ, AJ and desmosome proteins were decreased in binge alcohol-exposed rats compared to controls. Consistently, the levels of TJ proteins (claudin-1, claudin-4, occludin and zonula occludens-1), AJ proteins (β-catenin and E-cadherin) and desmosome plakoglobin were very low in binge alcohol-exposed rats, wild-type mice, and autopsied human ileums but not in Cyp2e1-null mice. Additionally, pretreatment with specific inhibitors of CYP2E1 and iNOS prevented disorganization and/or degradation of TJ proteins in alcohol-exposed T84 colonic cells. Furthermore, immunoprecipitation followed by immunoblot confirmed that intestinal TJ and AJ proteins were nitrated and degraded via ubiquitin-dependent proteolysis, resulting in their decreased levels.Conclusions These results demonstrated for the first time the critical roles of CYP2E1, apoptosis of enterocytes, and nitration followed by ubiquitin-dependent proteolytic degradation of the junctional complex proteins, in promoting binge alcohol-induced gut leakiness and endotoxemia, contributing to inflammatory liver disease.Lay summary Binge alcohol exposure causes gut leakiness, contributing to increased endotoxemia and inflammatory liver injury. Our results demonstrated for the first time the critical roles of apoptosis of enterocytes and nitration followed by ubiquitin-dependent proteolytic degradation of the junctional complex proteins in promoting this gut leakiness and endotoxemia. These results provide insight into the molecular mechanisms of alcohol-induced inflammatory liver disease.
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Excessive alcohol intake is known to cause leaky gut with increased intestinal cell permeability and endotoxemia, possibly via increased CYP2E1 and oxidative stress.
“Excessive alcohol intake is known to cause leaky gut with increased intestinal cell permeability and endotoxemia, possibly via increased CYP2E1 and oxidative stress245–248.”
From Advanced glycation end products (AGEs) and other adducts in aging-related diseases and alcohol-mediated tissue injury (2021) · cites this paper as [248]
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- Authors
- Cho, Y.-E., Yu, L.-R., Abdelmegeed, M. A., Yoo, S.-H., & Song, B.-J.
- Affiliations
- National Institutes of Health (US)
- National Center for Toxicological Research (US)
- Seoul National University (KR)
- Corresponding author
- Song, Byoung-Joon
- Venue
- Journal of Hepatology
- Publisher
- Elsevier BV
- Published
- 2018-07
- Volume
- 69
- Issue
- 1
- Pages
- 142-153
- ISSN
- 0168-8278 (ISSN-L)
- PMC
- PMC6008177
- OpenAlex
- W2789510455
- Cited by
- 99
- References
- 38
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 18 · 2023: 11 · 2022: 11 · 2021: 13 · 2020: 8 · 2019: 9 · 2018: 3
- FWCI
- 6.27
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Hepatology (acceptedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (Z99‐AA999999)
- National Institute on Alcohol Abuse and Alcoholism (ZIAAA000036)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Alcohol Consumption and Health Effects
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Keywords
- binge drinking, leaky gut, intestinal permeability, enterocyte apoptosis, nitration, tight junction proteins, adherens junction proteins, CYP2E1, inducible nitric oxide synthase, endotoxemia, liver injury, oxidative stress, ubiquitin-mediated proteolysis, claudins, E-cadherin, plakoglobin, inflammatory liver disease, alcohol-induced liver injury
- MeSH terms
- Cytochrome P450 Family 2, Adult, Aged, Ethanol, Animals, Cells, Cultured, Endotoxins, Female, Humans, Ileum, Liver, Liver Diseases, Alcoholic, Male, Middle Aged, Rats, Inbred F344, Immunoblotting, Apoptosis, Oxidative Stress, Enterocytes, Hepatocytes, Immunoprecipitation, Rats
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