Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice

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dc.contributor.authorFirrincieli, Delphine
dc.contributor.authorZuniga, Silvia
dc.contributor.authorRey, Colette
dc.contributor.authorWendum, Dominique
dc.contributor.authorLasnier, Elisabeth
dc.contributor.authorRainteau, Dominique
dc.contributor.authorBraescu, Thomas
dc.contributor.authorFalguieres, Thomas
dc.contributor.authorBoissan, Mathieu
dc.contributor.authorCadoret, Axelle
dc.contributor.authorHousset, Chantal
dc.contributor.authorChignard, Nicolas
dc.date.accessioned2024-01-10T13:44:11Z
dc.date.available2024-01-10T13:44:11Z
dc.date.issued2013
dc.description.abstractAlterations 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. Conclusion: 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. (Hepatology 2013;58:1401-1412)
dc.description.funderFrench Association for the Study of the Liver (AFEF)
dc.description.funder"Association pour la lutte contre les maladies inflammatoires du foie et des voies biliaires" (ALBI)
dc.description.funder"Fond CSP Vaincre la Cholangite Sclerosante Primitive"
dc.description.funderEuropean Union
dc.description.funderfellowship BECAS CHILE from Conicyt
dc.description.funderINSERM
dc.description.funderFondation pour la Recherche Medicale (FRM)
dc.fechaingreso.objetodigital05-04-2024
dc.format.extent12 páginas
dc.fuente.origenWOS
dc.identifier.doi10.1002/hep.26453
dc.identifier.issn0270-9139
dc.identifier.pubmedidMEDLINE:23696511
dc.identifier.urihttps://doi.org/10.1002/hep.26453
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/78860
dc.identifier.wosidWOS:000325150100026
dc.information.autorucMedicina;Zuniga S;S/I;135611
dc.issue.numero4
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final1412
dc.pagina.inicio1401
dc.publisherWILEY-BLACKWELL
dc.revistaHEPATOLOGY
dc.rightsacceso abierto
dc.subjectPRIMARY SCLEROSING CHOLANGITIS
dc.subjectGROWTH-FACTOR RECEPTOR
dc.subjectTIGHT JUNCTIONS
dc.subjectE-CADHERIN
dc.subjectTRANSPORTER EXPRESSION
dc.subjectBILE-ACIDS
dc.subjectCALPAIN
dc.subjectASSOCIATION
dc.subjectCIRRHOSIS
dc.subjectFIBROSIS
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleVitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
dc.typeartículo
dc.volumen58
sipa.codpersvinculados135611
sipa.indexWOS
sipa.indexScopus
sipa.trazabilidadCarga SIPA;09-01-2024
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