title: Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Hina
authors.initials: H
authors.lastname: Mir
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Avtar S
authors.initials: AS
authors.lastname: Meena
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Kamaljit K
authors.initials: KK
authors.lastname: Chaudhry
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Pradeep K
authors.initials: PK
authors.lastname: Shukla
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Ruchika
authors.initials: R
authors.lastname: Gangwar
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Bhargavi
authors.initials: B
authors.lastname: Manda
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Mythili K
authors.initials: MK
authors.lastname: Padala
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL, United States.
authors.forename: Le
authors.initials: L
authors.lastname: Shen
authors.affiliation: Department of Pathology, University of Chicago, Chicago, IL, United States.
authors.forename: Jerrold R
authors.initials: JR
authors.lastname: Turner
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Paula
authors.initials: P
authors.lastname: Dietrich
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Dragatsis
authors.affiliation: Department of Physiology, University of Tennessee, Memphis, TN, United States. Electronic address: rrao2@uthsc.edu.
authors.forename: RadhaKrishna
authors.initials: R
authors.lastname: Rao
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D003106:Colon / Q000378:metabolism* / Q000473:pathology; D000431:Ethanol / Q000009:adverse effects* / Q000494:pharmacology; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D007444:Inulin / Q000493:pharmacokinetics / Q000494:pharmacology; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D062793:Occludin / Q000172:deficiency* / Q000378:metabolism; D010539:Permeability / Q000187:drug effects; D019108:Tight Junctions / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000235:genetics / Q000378:metabolism
chemical_list: C568985:OCLN protein, human; D062793:Occludin; C568986:Ocln protein, mouse; D014280:Triglycerides; D000431:Ethanol; D007444:Inulin
keywords: Actin; Adherens junction; Alcohol; Claudin; Fatty liver; Tight junction