期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1867, 期 4, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.bbadis.2020.166067
关键词
Cholangiocyte; Cholestasis; Ductular reaction; Liver fibrosis; Protein disulfide-isomerase A3
资金
- Microbiome Foundation
- PSC Partners Seeking a Cure
- ANR (Agence Nationale de la Recherche) [15-CE14-0007-01]
- Fondation pour la Recherche Medicale (FRM)
- Spanish Association for the Study of the Liver (AEEH)
- Alfonso Martin Escudero Foundation (FAME)
- CIBEREHD, Spanish National Biomedical Research Institute on Liver and Gastrointestinal Diseases, Instituto de Salud Carlos III
- LABEX Plas@par project
- ANR, as part of the programme Investissements d'avenir [ANR-11-IDEX-0004-02]
- INSERM Contrat d'Interface Hospitalier
The study showed that VDR signaling has an anti-inflammatory role in cholangiocytes and cholangiopathy, while PDIA3-mediated effects of vitamin D and its analogs also have anti-inflammatory effects in these settings.
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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