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

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.