BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 卷:1867 |
Cholangiopathy aggravation is caused by VDR ablation and alleviated by VDR-independent vitamin D signaling in ABCB4 knockout mice | |
Article | |
Gonzalez-Sanchez, Ester1,2,3,4  El Mourabit, Haquima1  Jager, Marion1  Clavel, Marie1,2  Moog, Sophie1,2  Vaquero, Javier1,3,4,5  Ledent, Tatiana1  Cadoret, Axelle1  Gautheron, Jeremie1  Fouassier, Laura1  Wendum, Dominique1,6  Chignard, Nicolas2  Housset, Chantal1,7  | |
[1] Sorbonne Univ, INSERM, Ctr Rech St Antoine CRSA, Paris, France | |
[2] Inovarion, Paris, France | |
[3] Inst Salud Carlos III, Natl Biomed Res Inst Liver & Gastrointestinal Dis, CIBEREHD, Oncol Program, Ciberehd, Spain | |
[4] Bellvitge Biomed Res Inst IDIBELL, Oncobell Program, TGF B & Canc Grp, Barcelona, Spain | |
[5] Sorbonne Univ, Ctr Natl Rech Sci CNRS, Ecole Polytech, LPP Lab Phys Plasmas,UMR 7648, F-75005 Paris, France | |
[6] Sorbonne Univ, Hop St Antoine, Assistance Publ Hop Paris AP HP, Paris, France | |
[7] St Antoine Hosp, AP HP, Reference Ctr Inflammatory Biliary Dis & Autoimmu, MIVB H, Paris, France | |
关键词: Cholangiocyte; Cholestasis; Ductular reaction; Liver fibrosis; Protein disulfide-isomerase A3; | |
DOI : 10.1016/j.bbadis.2020.166067 | |
来源: Elsevier | |
【 摘 要 】
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 TNFa 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 chol-angiopathy. They also provide evidence for PDIA3-mediated anti-inflammatory effects of vitamin D and vitamin D analog in these settings.
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