title: Reversal of liver fibrosis in aryl hydrocarbon receptor null mice by dietary vitamin A depletion.
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 factor beta (TGF beta) 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 TGF beta 1, TGF beta 2, and TGF beta 3 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 TGF beta receptors, TGF beta RI and TGF beta 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 gamma (PPAR gamma) 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 PPAR gamma 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.
authors.affiliation: Laboratory of Cellular Carcinogenesis and Tumor Promotion, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Fausto
authors.initials: F
authors.lastname: Andreola
authors.forename: Diego F
authors.initials: DF
authors.lastname: Calvisi
authors.forename: Guillermo
authors.initials: G
authors.lastname: Elizondo
authors.forename: Sonia B
authors.initials: SB
authors.lastname: Jakowlew
authors.forename: Jennifer
authors.initials: J
authors.lastname: Mariano
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Luigi M
authors.initials: LM
authors.lastname: De Luca
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D000818:Animals; D003094:Collagen / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000178:diet therapy* / Q000378:metabolism* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D010641:Phenotype; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics*; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D011503:Transglutaminases / Q000378:metabolism; D014801:Vitamin A / Q000494:pharmacology*; D014802:Vitamin A Deficiency / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D004268:DNA-Binding Proteins; D018336:Receptors, Aryl Hydrocarbon; D018160:Receptors, Cytoplasmic and Nuclear; D018125:Receptors, Transforming Growth Factor beta; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; C508961:Tgfb1 protein, mouse; C509045:Tgfb3 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D053782:Transforming Growth Factor beta3; D014801:Vitamin A; D003094:Collagen; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D011503:Transglutaminases; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D019204:GTP-Binding Proteins