title: Vitamin D counteracts fibrogenic TGF-β signalling in human hepatic stellate cells both receptor-dependently and independently.
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.
  
  
  METHODS
  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.
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Beilfuss
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Jan-Peter
authors.initials: JP
authors.lastname: Sowa
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Svenja
authors.initials: S
authors.lastname: Sydor
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Beste
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Lars P
authors.initials: LP
authors.lastname: Bechmann
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Schlattjan
authors.affiliation: The Institute of Hepatology, Regeneration and Repair Group, London, UK.
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Syn
authors.affiliation: Institute for Pathology, University Hospital Cologne, Cologne, Germany.
authors.forename: Inga
authors.initials: I
authors.lastname: Wedemeyer
authors.affiliation: Department of General, Visceral and Transplantation Surgery, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Mathé
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Jochum
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Gerken
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany Rodos BioTarget GmbH, Medical Park Hannover, Hannover, Germany.
authors.forename: Robert K
authors.initials: RK
authors.lastname: Gieseler
authors.affiliation: Department of Gastroenterology and Hepatology, University Hospital, University Duisburg-Essen, Essen, Germany.
authors.forename: Ali
authors.initials: A
authors.lastname: Canbay
mesh_terms: D000328:Adult; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D055785:Gene Knockdown Techniques / Q000379:methods; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009767:Obesity, Morbid / Q000150:complications / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology / Q000502:physiology; D014807:Vitamin D / Q000097:blood / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D014807:Vitamin D
keywords: CELL SIGNALLING; GENETIC POLYMORPHISMS; HEPATIC FIBROSIS; HEPATIC STELLATE CELL; NONALCOHOLIC STEATOHEPATITIS