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Alcohol Clin Exp Res. 2015 Aug;39(8):1465-75. doi: 10.1111/acer.12777. Epub 2015 Jul 14.

ALDH2 Deficiency Promotes Ethanol-Induced Gut Barrier Dysfunction and Fatty Liver in Mice.

Author information

1
Department of Physiology , University of Tennessee, Memphis, Tennessee.
2
University of Occupational and Environmental Health , Kitakyushu, Japan.
3
Res Unit Acetaldehyde and Cancer, University of Helsinki, Helsinki, Finland.
4
Cleveland Clinic Foundation , Cleveland, Ohio.

Abstract

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 ALDH2. We evaluated the effect of ALDH2 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 ALDH2-deficient mice. ALDH2(-/-) mice showed a drastic reduction in the EtOH diet intake. Therefore, this study was continued only in wild-type and ALDH2(+/-) mice. EtOH feeding elevated mucosal inulin permeability in distal colon, but not in proximal colon, ileum, or jejunum of wild-type mice. In ALDH2(+/-) 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 ALDH2(+/-) mice was associated with a more severe redistribution of tight junction and adherens junction proteins from the intercellular junctions. In ALDH2(+/-) 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 ALDH2(+/-) mice compared to wild-type mice.

CONCLUSIONS:

These data demonstrate that ALDH2 deficiency enhances EtOH-induced disruption of intestinal epithelial tight junctions, barrier dysfunction, and liver damage.

KEYWORDS:

Acetaldehyde; Adherens Junction; Alcohol; Gut Permeability; Tight Junction

PMID:
26173414
PMCID:
PMC4515212
DOI:
10.1111/acer.12777
[Indexed for MEDLINE]
Free PMC Article

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