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

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...

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Autores principales: Firrincieli, Delphine, Zúñiga, Silvia, Rey, Colette, Wendum, Dominique, Lasnier, Elisabeth, Rainteau, Dominique, Braescu, Thomas, Falguières, Thomas, Boissan, Mathieu, Cadoret, Axelle, Housset, Chantal, Chignard, Nicolas
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BlackWell Publishing Ltd 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286017/
https://www.ncbi.nlm.nih.gov/pubmed/23696511
http://dx.doi.org/10.1002/hep.26453
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author Firrincieli, Delphine
Zúñiga, Silvia
Rey, Colette
Wendum, Dominique
Lasnier, Elisabeth
Rainteau, Dominique
Braescu, Thomas
Falguières, Thomas
Boissan, Mathieu
Cadoret, Axelle
Housset, Chantal
Chignard, Nicolas
author_facet Firrincieli, Delphine
Zúñiga, Silvia
Rey, Colette
Wendum, Dominique
Lasnier, Elisabeth
Rainteau, Dominique
Braescu, Thomas
Falguières, Thomas
Boissan, Mathieu
Cadoret, Axelle
Housset, Chantal
Chignard, Nicolas
author_sort Firrincieli, Delphine
collection PubMed
description 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. 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)
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spelling pubmed-42860172015-01-14 Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice Firrincieli, Delphine Zúñiga, Silvia Rey, Colette Wendum, Dominique Lasnier, Elisabeth Rainteau, Dominique Braescu, Thomas Falguières, Thomas Boissan, Mathieu Cadoret, Axelle Housset, Chantal Chignard, Nicolas Hepatology Autoimmune, Cholestatic and Biliary Disease 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. 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) BlackWell Publishing Ltd 2013-10 2013-09-06 /pmc/articles/PMC4286017/ /pubmed/23696511 http://dx.doi.org/10.1002/hep.26453 Text en Copyright © 2013 The Authors. HEPATOLOGY published by Wiley on behalf of the American Association for the Study of Liver Diseases. http://creativecommons.org/licenses/by-nc/3.0/ This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Autoimmune, Cholestatic and Biliary Disease
Firrincieli, Delphine
Zúñiga, Silvia
Rey, Colette
Wendum, Dominique
Lasnier, Elisabeth
Rainteau, Dominique
Braescu, Thomas
Falguières, Thomas
Boissan, Mathieu
Cadoret, Axelle
Housset, Chantal
Chignard, Nicolas
Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
title Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
title_full Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
title_fullStr Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
title_full_unstemmed Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
title_short Vitamin D Nuclear Receptor Deficiency Promotes Cholestatic Liver Injury by Disruption of Biliary Epithelial Cell Junctions in Mice
title_sort vitamin d nuclear receptor deficiency promotes cholestatic liver injury by disruption of biliary epithelial cell junctions in mice
topic Autoimmune, Cholestatic and Biliary Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4286017/
https://www.ncbi.nlm.nih.gov/pubmed/23696511
http://dx.doi.org/10.1002/hep.26453
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