title: Vitamin D nuclear receptor deficiency promotes cholestatic liver injury by disruption of biliary epithelial cell junctions in mice.
abstract: Alterations in apical junctional complexes (AJCs) have been reported in genetic or acquired biliary diseases. The vitamin D nuclear receptor (VDR), predominantly expressed in biliary epithelial cells in the liver, has been shown to regulate AJCs. The aim of our study was thus to investigate the role of VDR in the maintenance of bile duct integrity in mice challenged with biliary-type liver injury. Vdr(-/-) mice subjected to bile duct ligation (BDL) displayed increased liver damage compared to wildtype BDL mice. Adaptation to cholestasis, ascertained by expression of genes involved in bile acid metabolism and tissue repair, was limited in Vdr(-/-) BDL mice. Furthermore, evaluation of Vdr(-/-) BDL mouse liver tissue sections indicated altered E-cadherin staining associated with increased bile duct rupture. Total liver protein analysis revealed that a truncated form of E-cadherin was present in higher amounts in Vdr(-/-) mice subjected to BDL compared to wildtype BDL mice. Truncated E-cadherin was also associated with loss of cell adhesion in biliary epithelial cells silenced for VDR. In these cells, E-cadherin cleavage occurred together with calpain 1 activation and was prevented by the silencing of calpain 1. Furthermore, VDR deficiency led to the activation of the epidermal growth factor receptor (EGFR) pathway, while EGFR activation by EGF induced both calpain 1 activation and E-cadherin cleavage in these cells. Finally, truncation of E-cadherin was blunted when EGFR signaling was inhibited in VDR-silenced cells.
  
  
  CONCLUSIONS
  Biliary-type liver injury is exacerbated in Vdr(-/-) mice by limited adaptive response and increased bile duct rupture. These results indicate that loss of VDR restricts the adaptation to cholestasis and diminishes bile duct integrity in the setting of biliary-type liver injury.
authors.affiliation: INSERM UMR_S 938, CdR Saint-Antoine, F-75012, Paris, France; UPMC Univ Paris 06, F-75012, Paris, France.
authors.forename: Delphine
authors.initials: D
authors.lastname: Firrincieli
authors.forename: Silvia
authors.initials: S
authors.lastname: Zúñiga
authors.forename: Colette
authors.initials: C
authors.lastname: Rey
authors.forename: Dominique
authors.initials: D
authors.lastname: Wendum
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lasnier
authors.forename: Dominique
authors.initials: D
authors.lastname: Rainteau
authors.forename: Thomas
authors.initials: T
authors.lastname: Braescu
authors.forename: Thomas
authors.initials: T
authors.lastname: Falguières
authors.forename: Mathieu
authors.initials: M
authors.lastname: Boissan
authors.forename: Axelle
authors.initials: A
authors.lastname: Cadoret
authors.forename: Chantal
authors.initials: C
authors.lastname: Housset
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chignard
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001652:Bile Ducts / Q000503:physiopathology; D001659:Biliary Tract / Q000473:pathology*; D015820:Cadherins / Q000032:analysis / Q000502:physiology; D002154:Calpain / Q000502:physiology; D002779:Cholestasis / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000473:pathology*; D066246:ErbB Receptors / Q000502:physiology; D007365:Intercellular Junctions / Q000473:pathology*; D008026:Ligation; D008099:Liver / Q000473:pathology / Q000503:physiopathology*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000502:physiology
chemical_list: D015820:Cadherins; D018167:Receptors, Calcitriol; D066246:ErbB Receptors; D002154:Calpain; C112682:Capn1 protein, mouse