EGF receptor plays a role in the mechanism of glutamine-mediated prevention of alcohol-induced gut barrier dysfunction and liver injury
| Autor: | Pradeep K. Shukla, Radhakrishna Rao, Avtar S. Meena, Parimal Sheth |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Alcoholic liver disease Colon Glutamine Endocrinology Diabetes and Metabolism Clinical Biochemistry Mice Transgenic Pharmacology Biochemistry Article Antioxidants Tight Junctions 03 medical and health sciences 0302 clinical medicine Epidermal growth factor medicine Animals Humans Intestinal Mucosa Molecular Biology Barrier function Liver injury Nutrition and Dietetics Ethanol Tight junction Chemistry Fatty liver medicine.disease Actin cytoskeleton Endotoxemia ErbB Receptors Gastrointestinal Tract 030104 developmental biology Actin Depolymerizing Factors Cytokines Female Caco-2 Cells Chemical and Drug Induced Liver Injury Chemokines 030217 neurology & neurosurgery |
| Zdroj: | The Journal of Nutritional Biochemistry. 64:128-143 |
| ISSN: | 0955-2863 |
| DOI: | 10.1016/j.jnutbio.2018.10.016 |
| Popis: | Recent study indicated that glutamine prevents alcoholic tissue injury in mouse gut and liver. Here we investigated the potential role of Epidermal Growth Factor Receptor (EGFR) in glutamine-mediated prevention of ethanol-induced colonic barrier dysfunction, endotoxemia and liver damage. Wild-type and EGFR*Tg transgenic (expressing dominant negative EGFR) mice were fed 1-6% ethanol in Lieber-DeCarli diet. Gut permeability was measured by vascular-to-luminal flux of FITC-inulin, and junctional integrity assessed by confocal microscopy. Liver injury was evaluated by plasma transaminases, histopathology and triglyceride analyses. Glutamine effect on acetaldehyde-induced tight junction disruption was investigated in Caco-2 cell monolayers. Doxycycline-induced expression of EGFR* blocked glutamine-mediated prevention of ethanol-induced disruption of colonic epithelial tight junction, mucosal permeability and endotoxemia. Ethanol activated cofilin and disrupted actin cytoskeleton, which was blocked by glutamine in an EGFR-dependent mechanism. Ethanol down-regulated antioxidant gene expression and up-regulated cytokine and chemokine gene expression, which were blocked by glutamine in wild-type mice in the presence or absence of doxycycline, but not in EGFR*Tg mice in the presence of doxycycline. Histopathology, plasma transaminases, triglyceride and expression of chemokine and antioxidant genes indicated ethanol-induced liver damage, which were blocked by glutamine in an EGFR-dependent mechanism. Src kinase activity and extracellular ligand binding domain of EGFR are required for glutamine-mediated protection of barrier function in Caco-2 cell monolayers. Glutamine released metalloproteinases into the medium, and metalloproteinase inhibitors blocked glutamine-mediated protection of barrier function. Results demonstrate that EGFR plays an important role in glutamine-mediated prevention of alcoholic gut permeability, endotoxemia and liver damage. |
| Databáze: | OpenAIRE |
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