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

Hina Mir, Avtar Meena, Kamaljit K. Chaudhry, Pradeep Kumar Shukla, Ruchika Gangwar, Bhargavi Manda, Mythili K. Padala, Le Shen, Jerrold R. Turner, Paula Dietrich, Ioannis Dragatsis, Radhakrishna Rao

Research output: Contribution to journalArticle

24 Citations (Scopus)

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. Conclusion This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.

Original languageEnglish (US)
Pages (from-to)765-774
Number of pages10
JournalBiochimica et Biophysica Acta - General Subjects
Volume1860
Issue number4
DOIs
StatePublished - Apr 1 2016

Fingerprint

Occludin
Liver
Liver Diseases
Ethanol
Tight Junctions
Caco-2 Cells
Acetaldehyde
Transaminases
Monolayers
Permeability
Wounds and Injuries
Colon
Triglycerides
Tight Junction Proteins
Plasmas
Catenins
Endotoxemia
Inulin
Confocal microscopy
Cadherins

All Science Journal Classification (ASJC) codes

  • Biophysics
  • Biochemistry
  • Molecular Biology

Cite this

Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice. / Mir, Hina; Meena, Avtar; Chaudhry, Kamaljit K.; Shukla, Pradeep Kumar; Gangwar, Ruchika; Manda, Bhargavi; Padala, Mythili K.; Shen, Le; Turner, Jerrold R.; Dietrich, Paula; Dragatsis, Ioannis; Rao, Radhakrishna.

In: Biochimica et Biophysica Acta - General Subjects, Vol. 1860, No. 4, 01.04.2016, p. 765-774.

Research output: Contribution to journalArticle

@article{93fdeb71335941c786df9256a7490439,
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. Conclusion This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.",
author = "Hina Mir and Avtar Meena and Chaudhry, {Kamaljit K.} and Shukla, {Pradeep Kumar} and Ruchika Gangwar and Bhargavi Manda and Padala, {Mythili K.} and Le Shen and Turner, {Jerrold R.} and Paula Dietrich and Ioannis Dragatsis and Radhakrishna Rao",
year = "2016",
month = "4",
day = "1",
doi = "10.1016/j.bbagen.2015.12.013",
language = "English (US)",
volume = "1860",
pages = "765--774",
journal = "Biochimica et Biophysica Acta - General Subjects",
issn = "0304-4165",
publisher = "Elsevier",
number = "4",

}

TY - JOUR

T1 - Occludin deficiency promotes ethanol-induced disruption of colonic epithelial junctions, gut barrier dysfunction and liver damage in mice

AU - Mir, Hina

AU - Meena, Avtar

AU - Chaudhry, Kamaljit K.

AU - Shukla, Pradeep Kumar

AU - Gangwar, Ruchika

AU - Manda, Bhargavi

AU - Padala, Mythili K.

AU - Shen, Le

AU - Turner, Jerrold R.

AU - Dietrich, Paula

AU - Dragatsis, Ioannis

AU - Rao, Radhakrishna

PY - 2016/4/1

Y1 - 2016/4/1

N2 - 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. Conclusion This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.

AB - 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. Conclusion This study indicates that occludin deficiency increases susceptibility to ethanol-induced colonic mucosal barrier dysfunction and liver damage in mice.

UR - http://www.scopus.com/inward/record.url?scp=84956906927&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84956906927&partnerID=8YFLogxK

U2 - 10.1016/j.bbagen.2015.12.013

DO - 10.1016/j.bbagen.2015.12.013

M3 - Article

C2 - 26721332

AN - SCOPUS:84956906927

VL - 1860

SP - 765

EP - 774

JO - Biochimica et Biophysica Acta - General Subjects

JF - Biochimica et Biophysica Acta - General Subjects

SN - 0304-4165

IS - 4

ER -