Apoptosis of enterocytes and nitration of junctional complex proteins promote alcohol-induced gut leakiness and liver injury

被引:80
作者
Cho, Young-Eun [1 ]
Yu, Li-Rong [2 ]
Abdelmegeed, Mohamed A. [1 ]
Yoo, Seong-Ho [3 ]
Song, Byoung-Joon [1 ]
机构
[1] NIAAA, Sect Mol Pharmacol & Toxicol, Lab Membrane Biochem, Bethesda, MD 20892 USA
[2] US FDA, Biomarkers & Alternat Models Branch, Div Syst Biol, Natl Ctr Toxicol Res, Jefferson, AR 72079 USA
[3] Seoul Natl Univ, Dept Forens Med, Coll Med, Seoul, South Korea
关键词
Cytochrome P450-2E1 (CYP2E1); Ethanol; Gut leakiness; Nitroxidative stress; Apoptosis; Protein nitration; Ubiquitin-dependent proteolysis; Tight and adherens junction proteins; INTESTINAL BARRIER DYSFUNCTION; CACO-2 CELL MONOLAYER; PARACELLULAR PERMEABILITY; MICROBIAL TRANSLOCATION; HIV-INFECTION; FATTY LIVER; DISEASE; MICE; DISRUPTION; CYP2E1;
D O I
10.1016/j.jhep.2018.02.005
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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 (b-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. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver.
引用
收藏
页码:142 / 153
页数:12
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