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. 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.

Vitamin D levels and liver histological alterations in children with nonalcoholic fatty liver disease

“…After activation, HSCs transform from quiescent vitamin A-storing cells to myofibroblast-like cells and accumulate ECM proteins, mostly type 1 collagen. Interestingly, there is in vitro evidence that VD administration may inhibit HSC activation by different pro-fibrogenic pathways (26,32). The recent findings that phototherapy improves liver histology (33) and that VD supplementation prevents liver fibrosis (26) in animal models of NAFLD support a potential role of VD in the prevention and treatment of NASH.…”

Roles of 1,25(OH)2D3 and Vitamin D Receptor in the Pathogenesis of Rheumatoid Arthritis and Systemic Lupus Erythematosus by Regulating the Activation of CD4+ T Cells and the PKCδ/ERK Signaling Pathway

“…Therefore, 1,25(OH) 2 D 3 could inhibit the expression of CD40 [36]. Also, VDR overexpression vector could reduce the activities of the collagen promoter in transfected cells [37]. Previous study had illustrated that evaluation of fibroblast VDR has revealed three general classes of molecular defects, and one was decreased or absent 1,25(OH) 2 D 3 binding [38].…”

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“…There is ample mechanistic understanding of the antifibrotic actions of vitamin D, including the following: (1) suppression of the renin-angiotensin and nuclear factor κB systems, 8,37,38 (2) increased expression of hepatocyte growth factor, 39 (3) direct repression of collagen I expression, 40 and (4) interference with transforming growth factor-betapromoted activation of fibrogenic genes by direct dislodging by activated vitamin D receptor complexes of SMAD3 binding to its DNA-binding elements. 41,42 We postulate that the clear decrease in fibrosis elicited by 2AMD and 2MD will lead to frank improvement in renal function with extended therapy.…”