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Vitamin D counteracts fibrogenic TGF-β signalling in human hepatic stellate cells both receptor-dependently and independently
  1. Anja Beilfuss1,
  2. Jan-Peter Sowa1,
  3. Svenja Sydor1,
  4. Mechthild Beste1,
  5. Lars P Bechmann1,
  6. Martin Schlattjan1,
  7. Wing-Kin Syn2,
  8. Inga Wedemeyer3,
  9. Zoltan Mathé4,
  10. Christoph Jochum1,
  11. Guido Gerken1,
  12. Robert K Gieseler1,5,
  13. Ali Canbay1
  1. 1Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany
  2. 2The Institute of Hepatology, Regeneration and Repair Group, London, UK
  3. 3Institute for Pathology, University Hospital Cologne, Cologne, Germany
  4. 4Department of General, Visceral and Transplantation Surgery, University Hospital, University Duisburg-Essen, Essen, Germany
  5. 5Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany
  1. Correspondence to Professor Ali Canbay, Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Hufelandstr. 55, Essen 45147, Germany; ali.canbay{at}uni-due.de

Abstract

Objective Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity and constitutes part of the metabolic syndrome, which have been associated with low serum vitamin D (VD). Due to known crosstalk between VD and transforming growth factor (TGF)-β signalling, VD has been proposed as an antifibrotic treatment.

Design We evaluated the association between VD, the vitamin D receptor (VDR) and liver fibrosis in primary human hepatic stellate cells (phHSC) and 106 morbidly obese patients with NAFLD.

Results Treating phHSC with VD ameliorated TGF-β-induced fibrogenesis via both VDR-dependent and VDR-independent mechanisms. Reduction of fibrogenic response was abolished in cells homozygous for GG at the A1012G single nucleotide polymorphisms within the VDR gene. Compared with healthy livers, NAFLD livers expressed higher levels of VDR mRNA and VDR fragments. VDR mRNA was lower in patients homozygous for GG at A1012G and expression of pro-fibrogenic genes was higher in patients carrying the G allele.

Conclusions VD may be an antifibrotic treatment option early in the onset of fibrosis in specific genotypes for VDR. Known polymorphisms of the VDR may influence the response to VD treatment.

  • CELL SIGNALLING
  • GENETIC POLYMORPHISMS
  • HEPATIC FIBROSIS
  • HEPATIC STELLATE CELL
  • NONALCOHOLIC STEATOHEPATITIS

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