title: Vitamin D modulates biliary fibrosis in ABCB4-deficient mice.
abstract: OBJECTIVE
  Impaired vitamin D receptor signaling represents an aggravating factor during liver injury, and recent studies suggest that vitamin D might exert a protective role in chronic hepatobiliary diseases. We hypothesized that vitamin D supplementation would ameliorate liver fibrosis in ATP-binding cassette transporter B4 knockout (Abcb4 (-/-)) mice as a preclinical model of sclerosing cholangitis.
  
  
  METHODS
  Abcb4 (-/-) and wild-type mice were fed a regular chow diet (600 IU vitamin D/kg food) or diets with lower (100 IU/kg) and higher (2,400 IU/kg) vitamin D concentrations for 12 weeks. Serum 25-hydroxyvitamin D concentrations were measured by chemiluminescence immunoassays. Liver injury and biliary fibrosis were assessed by liver enzyme activities, histopathology and hepatic collagen contents. Hepatic mRNA expression of markers for fibrosis, vitamin D and bile acid metabolism were analyzed by quantitative PCR.
  
  
  RESULTS
  Different vitamin D concentrations were observed depending on genotype and diet group, with Abcb4 (-/-) mice on the control diet showing lower vitamin D concentrations compared to wild-type mice. Abcb4 (-/-) animals on the low vitamin D diet demonstrated the most advanced liver fibrosis and highest hepatic collagen contents. Feeding Abcb4 (-/-) mice a high vitamin D diet enriched serum vitamin D levels, lowered liver enzyme activities, altered expression levels of profibrogenic genes and ameliorated, in part, liver injury.
  
  
  CONCLUSIONS
  This is the first report to demonstrate that fibrogenesis in the established Abcb4 (-/-) model is influenced by vitamin D supplementation. Since vitamin D modulates sclerosing cholangitis in vivo, we speculate that sufficient vitamin D intake might improve liver damage and induce antifibrotic effects in chronic cholestasis in humans.
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hochrath
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany.
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Stokes
authors.affiliation: Institute of Clinical Chemistry and Laboratory Medicine, Saarland University Medical Center, Homburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Geisel
authors.affiliation: Insititute of Pathology, Medical University Graz, Graz, Austria.
authors.forename: Marion J
authors.initials: MJ
authors.lastname: Pollheimer
authors.affiliation: Insititute of Pathology, Medical University Graz, Graz, Austria ; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Fickert
authors.affiliation: Division of Molecular Hepatology-Alcohol Associated Diseases, Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany.
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.affiliation: Department of Medicine II, Saarland University Medical Center, Kirrberger Str. 100, 66421 Homburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Lammert
keywords: ABC transporters; Cholecalciferol; Chronic cholangitis; Fibrogenesis; Liver injury