Cholangiopathy aggravation is caused by VDR ablation and alleviated by VDR-independent vitamin D signaling in ABCB4 knockout mice
| Autor: | Marie Clavel, Haquima El Mourabit, Marion Jager, Sophie Moog, Ester Gonzalez-Sanchez, Jérémie Gautheron, Tatiana Ledent, Chantal Housset, Laura Fouassier, Dominique Wendum, Axelle Cadoret, Javier Vaquero, Nicolas Chignard |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Vitamin Male ATP Binding Cassette Transporter Subfamily B Calcitriol receptor Cholangiocyte Proinflammatory cytokine 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Vitamin D and neurology Medicine Animals Vitamin D Molecular Biology Mice Knockout Cholestasis business.industry Vitamins Fibrosis Mice Inbred C57BL 030104 developmental biology chemistry Knockout mouse Cancer research Molecular Medicine Receptors Calcitriol 030211 gastroenterology & hepatology Tumor necrosis factor alpha Signal transduction business Gene Deletion Signal Transduction |
| Zdroj: | Biochimica et biophysica acta. Molecular basis of disease. 1867(4) |
| ISSN: | 1879-260X |
| Popis: | Background & aims Cholangiopathies are chronic liver diseases in which damaged cholangiocytes trigger a proinflammatory and profibrotic reaction. The nuclear vitamin D receptor (VDR) is highly expressed in cholangiocytes and exerts immune-regulatory functions in these cells. In the present study, we examined the protective function of VDR and other vitamin D signaling pathways in chronic cholangiopathy and cholangiocytes. Methods Vdr was invalidated in Abcb4 knockout mice, a widely used animal model of chronic cholangiopathy. The impact of vitamin D signaling on cholangiopathy features was examined in vivo and in cholangiocytes (primary and cell lines). Results Cholangiopathy features (i.e, cholestasis, ductular reaction and fibrosis) were aggravated in Vdr;Abcb4 double knockout mice compared to the Abcb4 simple knockout, and associated with an overexpression of proinflammatory factors. The proinflammatory phenotype of cholangiocytes was also exacerbated following VDR silencing in vitro. The expression of proinflammatory factors and the severity of cholangiopathy were reduced in the double knockout mice treated with the vitamin D analog calcipotriol or with vitamin D. In vitro, the inflammatory response to TNFα was significantly reduced by calcipotriol in biliary cells silenced for VDR, and this effect was abolished by co-silencing the plasma membrane receptor of vitamin D, protein disulfide-isomerase A3 (PDIA3). Conclusions Our results demonstrate an anti-inflammatory role of VDR signaling in cholangiocytes and cholangiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings. |
| Databáze: | OpenAIRE |
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