1,25-dihydroxyvitamin D3 and its nuclear receptor repress human α1(I) collagen expression and type I collagen formation

• Published in: Liver international 2013-05, Vol.33 (5), p.677-686
• Main Authors: Potter, James J., Liu, Xiaopu, Koteish, Ayman, Mezey, Esteban
• Format: Article
• Language: English
• Subjects: 1,25‐dihydroxyvitamin D3; 25-dihydroxyvitamin D3; Analysis of Variance; Animals; Apoptosis - drug effects; Blotting, Western; Calcitriol - metabolism; Calcitriol - pharmacology; Caspase 3 - metabolism; Cell Line; Chromatin Immunoprecipitation; Collagen Type I - antagonists & inhibitors; Collagen Type I - biosynthesis; Collagen Type I - drug effects; Collagen Type I - genetics; Drosophila; Electrophoretic Mobility Shift Assay; Enzyme-Linked Immunosorbent Assay; Gene Expression Regulation - drug effects; Hepatic Stellate Cells - metabolism; Humans; Luciferases; Oligonucleotides - genetics; Plasmids - genetics; Promoter Regions, Genetic - genetics; Receptors, Calcitriol - metabolism; Sp1; stellate cells; Transforming Growth Factor beta1 - metabolism; transforming growth factor β1; vitamin D receptor; α1(I) collagen
• ISSN: 1478-3223; 1478-3231
• DOI: 10.1111/liv.12122

Background Vitamin D deficiency is common in chronic liver disease particularly in those with severe liver fibrosis. Aims To determine the effect of 1,25‐dihydroxyvitamin D3 (1,25‐(OH)2D3) on the human α1(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 α1(I) collagen promoter was determined by EMSA and ChIP assays. Results 1,25‐(OH)2D3 decreased human α1(I) collagen mRNA and protein and the secretion of type I collagen by stellate cells after exposure to TGFβ1. Furthermore, 1,25‐(OH)2D3 inhibited TGFβ1–induced activation of the α1(I) collagen promoter in transfected LX‐2 cells. The effect of 1,25‐(OH)2D3 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)2D3 inhibits type I collagen formation in human stellate cells. The effect of 1,25‐(OH)2D3 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.