title: 1,25-dihydroxyvitamin D3 and its nuclear receptor repress human α1 (I) collagen expression and type I collagen formation.
abstract: BACKGROUND
  Vitamin D deficiency is common in chronic liver disease particularly in those with severe liver fibrosis.
  
  
  OBJECTIVE
  To determine the effect of 1,25-dihydroxyvitamin D3 (1,25-(OH)2 D3 ) on the human α(1) (I) collagen promoter and collagen formation by human stellate LX-2 cells and the mechanism of the effect of the vitamin D receptor (VDR) on the promoter.
  
  
  METHODS
  Type I collagen was assessed by measurements of collagen mRNA and collagen protein and by transfection experiments. Binding of VDR to the α(1) (I) collagen promoter was determined by EMSA and ChIP assays.
  
  
  RESULTS
  1,25-(OH)2 D3 decreased human α(1) (I) collagen mRNA and protein and the secretion of type I collagen by stellate cells after exposure to TGFβ1. Furthermore, 1,25-(OH)2 D3 inhibited TGFβ1-induced activation of the α(1) (I) collagen promoter in transfected LX-2 cells. The effect of 1,25-(OH)2 D3 is mediated by the VDR, which binds at a proximal Sp1 site and also at a newly identified distal site on the collagen promoter. A VDR expression vector reduced the activities of the collagen promoter in transfected LX-2 cells.
  
  
  CONCLUSIONS
  1,25-(OH)2 D3 inhibits type I collagen formation in human stellate cells. The effect of 1,25-(OH)2 D3 is mediated by its receptor which binds at a proximal Sp1.1 site and at a newly identified distal site on the collagen promoter. Correction of vitamin D deficiency in patients with chronic liver disease is a potential therapy to inhibit progression of fibrosis.
authors: Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: James J
authors: JJ
authors: Potter
authors: Xiaopu
authors: X
authors: Liu
authors: Ayman
authors: A
authors: Koteish
authors: Esteban
authors: E
authors: Mezey
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002117:Calcitriol / Q000378:metabolism / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D024042:Collagen Type I / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000187:drug effects* / Q000235:genetics; D004330:Drosophila; D024202:Electrophoretic Mobility Shift Assay; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects*; D055166:Hepatic Stellate Cells / Q000378:metabolism*; D006801:Humans; D008156:Luciferases; D009841:Oligonucleotides / Q000235:genetics; D010957:Plasmids / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D018167:Receptors, Calcitriol / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D024042:Collagen Type I; D009841:Oligonucleotides; D018167:Receptors, Calcitriol; D053773:Transforming Growth Factor beta1; D008156:Luciferases; D053148:Caspase 3; D002117:Calcitriol