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Reversal of liver fibrosis in aryl hydrocarbon receptor null mice by dietary vitamin A depletion
Author(s) -
Andreola Fausto,
Calvisi Diego F.,
Elizondo Guillermo,
Jakowlew Sonia B.,
Mariano Jennifer,
Gonzalez Frank J.,
De Luca Luigi M.
Publication year - 2004
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.20004
Subject(s) - aryl hydrocarbon receptor , retinoid , endocrinology , medicine , vitamin , biology , fibrosis , hepatic stellate cell , receptor , hepatic fibrosis , chemistry , retinoic acid , transcription factor , biochemistry , gene
Abstract Aryl hydrocarbon receptor (AHR)‐ null mice display a liver fibrosis phenotype that is associated with a concomitant increase in liver retinoid concentration, tissue transglutaminase type II (TGaseII) activity, transforming growth factorβ (TGFβ) overexpression, and accumulation of collagen. To test the hypothesis that this phenotype might be triggered by the observed increase in liver retinoid content, we induced the condition of retinoid depletion by feeding AHR‐ null mice a vitamin A‐ deficient diet with the purpose to reverse the phenotype. Liver retinoid content decreased sharply within the first few weeks on the retinoid‐deficient diet. Analysis of TGFβ1, TGFβ2, and TGFβ3 expression revealed a reduction to control levels in the AHR ‐/‐ mice accompanied by parallel changes in TGaseII protein levels. In addition, we observed an increase in the TGFβ receptors, TGFβ RI and TGFβ RII, as well as in Smad4, and their reduction to wild‐type mouse liver levels in AHR ‐/‐ mice fed the retinoid‐deficient diet. Reduction of peroxisomal proliferator‐activated receptor γ (PPARγ) messenger RNA (mRNA) and protein levels in AHR ‐/‐ mice was consistent with the presence of hepatic stellate cell (HSC) activation and liver fibrosis. Vitamin A deficiency normalized PPARγ expression in AHR ‐/‐ mice. In conclusion, livers from AHR ‐/‐ mice fed the vitamin A‐deficient diet showed a decrease in collagen deposition, consistent with the absence of liver fibrosis. (H EPATOLOGY 2004;39:157–166.)