Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice

• Published in: Biochimica et biophysica acta Vol. 1860; no. 4; pp. 765 - 774
• Main Authors: Mir, Hina, Meena, Avtar S., Chaudhry, Kamaljit K., Shukla, Pradeep K., Gangwar, Ruchika, Manda, Bhargavi, Padala, Mythili K., Shen, Le, Turner, Jerrold R., Dietrich, Paula, Dragatsis, Ioannis, Rao, RadhaKrishna
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.04.2016
• Subjects: Actin; Adherens junction; Alcohol; Animals; body weight changes; Caco-2 Cells; cadherins; Claudin; colon; Colon - metabolism; Colon - pathology; confocal microscopy; diet; digestive system diseases; endotoxemia; ethanol; Ethanol - adverse effects; Ethanol - pharmacology; Fatty liver; histopathology; human cell lines; Humans; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; inulin; Inulin - pharmacokinetics; Inulin - pharmacology; liver; Liver - metabolism; Liver - pathology; Liver Diseases - genetics; Liver Diseases - metabolism; Liver Diseases - pathology; Mice; Mice, Knockout; microfilaments; mucosa; Occludin - deficiency; Occludin - metabolism; occludins; pathogenesis; permeability; Permeability - drug effects; Tight junction; tight junctions; Tight Junctions - genetics; Tight Junctions - metabolism; Toll-like receptor 4; transmembrane proteins; triacylglycerols; Triglycerides - genetics; Triglycerides - metabolism; TER; EF; HRP; ALT; Alcohol; LPS; ECL; Adherens junction; FITC; Cldn; Ocln; ZO-1; Fatty liver; shRNA; Actin; PF; Claudin; Tight junction; WT
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2015.12.013

Disruption of epithelial tight junctions (TJ), gut barrier dysfunction and endotoxemia play crucial role in the pathogenesis of alcoholic tissue injury. Occludin, a transmembrane protein of TJ, is depleted in colon by alcohol. However, it is unknown whether occludin depletion influences alcoholic gut and liver injury. Wild type (WT) and occludin deficient (Ocln−/−) mice were fed 1–6% ethanol in Lieber–DeCarli diet. Gut permeability was measured by vascular-to-luminal flux of FITC-inulin. Junctional integrity was analyzed by confocal microscopy. Liver injury was assessed by plasma transaminase, histopathology and triglyceride analyses. The effect of occludin depletion on acetaldehyde-induced TJ disruption was confirmed in Caco-2 cell monolayers. Ethanol feeding significantly reduced body weight gain in Ocln−/− mice. Ethanol increased inulin permeability in colon of both WT and Ocln−/− mice, but the effect was 4-fold higher in Ocln−/− mice. The gross morphology of colonic mucosa was unaltered, but ethanol disrupted the actin cytoskeleton, induced redistribution of occludin, ZO-1, E-cadherin and β-catenin from the junctions and elevated TLR4, which was more severe in Ocln−/− mice. Occludin knockdown significantly enhanced acetaldehyde-induced TJ disruption and barrier dysfunction in Caco-2 cell monolayers. Ethanol significantly increased liver weight and plasma transaminase activity in Ocln−/− mice, but not in WT mice. Histological analysis indicated more severe lesions and fat deposition in the liver of ethanol-fed Ocln−/− mice. Ethanol-induced elevation of liver triglyceride was also higher in Ocln−/− mice. This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice. •Occludin deficiency enhances chronic ethanol-induced increase in mucosal permeability in mouse colon.•Ethanol-induced disruption of apical junctional complexes in colonic epithelium is more severe in occludin deficient mice.•Occludin deficiency promotes ethanol-induced liver damage.•Ethanol-induced fatty liver is more severe in occludin deficient mice.