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ALDH2 Deficiency Promotes Ethanol‐Induced Gut Barrier Dysfunction and Fatty Liver in Mice
Author(s) -
Chaudhry Kamaljit K.,
Samak Geetha,
Shukla Pradeep K.,
Mir Hina,
Gangwar Ruchika,
Manda Bhargavi,
Isse Toyohi,
Kawamoto Toshihiro,
Salaspuro Mikko,
Kaihovaara Pertti,
Dietrich Paula,
Dragatsis Ioannis,
Nagy Laura E.,
Rao Radha Krishna
Publication year - 2015
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.12777
Subject(s) - tight junction , adherens junction , aldh2 , endocrinology , medicine , intestinal permeability , ileum , aldehyde dehydrogenase , occludin , chemistry , liver injury , biology , biochemistry , gene , cell , cadherin
Background Acetaldehyde, the toxic ethanol (EtOH) metabolite, disrupts intestinal epithelial barrier function. Aldehyde dehydrogenase ( ALDH ) detoxifies acetaldehyde into acetate. Subpopulations of Asians and Native Americans show polymorphism with loss‐of‐function mutations in ALDH 2. We evaluated the effect of ALDH 2 deficiency on EtOH‐induced disruption of intestinal epithelial tight junctions and adherens junctions, gut barrier dysfunction, and liver injury. Methods Wild‐type and ALDH2‐deficient mice were fed EtOH (1 to 6%) in Lieber–DeCarli diet for 4 weeks. Gut permeability in vivo was measured by plasma‐to‐luminal flux of FITC ‐inulin, tight junction and adherens junction integrity was analyzed by confocal microscopy, and liver injury was assessed by the analysis of plasma transaminase activity, histopathology, and liver triglyceride. Results EtOH feeding elevated colonic mucosal acetaldehyde, which was significantly greater in ALDH 2‐deficient mice. ALDH 2 −/− mice showed a drastic reduction in the EtOH diet intake. Therefore, this study was continued only in wild‐type and ALDH 2 +/− mice. EtOH feeding elevated mucosal inulin permeability in distal colon, but not in proximal colon, ileum, or jejunum of wild‐type mice. In ALDH 2 +/− mice, EtOH‐induced inulin permeability in distal colon was not only higher than that in wild‐type mice, but inulin permeability was also elevated in the proximal colon, ileum, and jejunum. Greater inulin permeability in distal colon of ALDH 2 +/− mice was associated with a more severe redistribution of tight junction and adherens junction proteins from the intercellular junctions. In ALDH 2 +/− mice, but not in wild‐type mice, EtOH feeding caused a loss of junctional distribution of tight junction and adherens junction proteins in the ileum. Histopathology, plasma transaminases, and liver triglyceride analyses showed that EtOH‐induced liver damage was significantly greater in ALDH 2 +/− mice compared to wild‐type mice. Conclusions These data demonstrate that ALDH 2 deficiency enhances EtOH‐induced disruption of intestinal epithelial tight junctions, barrier dysfunction, and liver damage.