Abstract
The vitamin D receptor (VDR) is a nuclear receptor that mediates the biological action of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], and regulates calcium and bone metabolism. Lithocholic acid (LCA), which is a secondary bile acid produced by intestinal bacteria, acts as an additional physiological VDR ligand. Despite recent progress, however, the physiological function of the LCA−VDR axis remains unclear. In this study, in order to elucidate the differences in VDR action induced by 1,25(OH)2D3 and LCA, we compared their effect on the VDR target gene induction in the intestine of mice. While the oral administration of 1,25(OH)2D3 induced the Cyp24a1 expression effectively in the duodenum and jejunum, the LCA increased target gene expression in the ileum as effectively as 1,25(OH)2D3. 1,25(OH)2D3, but not LCA, increased the expression of the calcium transporter gene Trpv6 in the upper intestine, and increased the plasma calcium levels. Although LCA could induce an ileal Cyp24a1 expression as well as 1,25(OH)2D3, the oral LCA administration was not effective in the VDR target gene induction in the kidney. No effect of LCA on the ileal Cyp24a1 expression was observed in the VDR-null mice. Thus, the results indicate that LCA is a selective VDR ligand acting in the lower intestine, particularly the ileum. LCA may be a signaling molecule, which links intestinal bacteria and host VDR function.
Highlights
The vitamin D receptor (VDR) mediates the physiological functions of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], including calcium and bone metabolism, immunity, and cardiovascular function [1,2]. 1,25(OH)2D3 and its synthetic derivatives exhibit many pharmacological effects, including the regulation of cellular proliferation and differentiation and lipid metabolism, through VDR activation [3]
The retinoid X receptor (RXR)−VDR heterodimer binds preferentially to a specific DNA element that consists of a two-hexanucleotide (AGGTCA or a related sequence) direct repeat motif separated by three nucleotides, known as a direct repeat 3 element, in target genes, such as cytochrome P450 (CYP) 24A1, and the transient receptor potential vanilloid (TRPV) type 6
The VDR activation by these bile acids and 1,25(OH)2D3 induces the expression of CYP3A enzymes, which metabolize drugs and secondary bile acids in the xenobiotic metabolism pathway [5,6]
Summary
The vitamin D receptor (VDR) mediates the physiological functions of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], including calcium and bone metabolism, immunity, and cardiovascular function [1,2]. 1,25(OH)2D3 and its synthetic derivatives exhibit many pharmacological effects, including the regulation of cellular proliferation and differentiation and lipid metabolism, through VDR activation [3]. The vitamin D receptor (VDR) mediates the physiological functions of the active form of vitamin D, 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], including calcium and bone metabolism, immunity, and cardiovascular function [1,2]. VDR undergoes a ligand-dependent conformational change that results in a dynamic interaction with the heterodimer partner retinoid X receptor (RXR) and an exchange of cofactor complexes [4]. VDR is activated by bile acids, such as lithocholic acid (LCA) and its metabolite, 3-ketocholanic acid. The VDR activation by these bile acids and 1,25(OH)2D3 induces the expression of CYP3A enzymes, which metabolize drugs and secondary bile acids in the xenobiotic metabolism pathway [5,6]. The VDR activation by LCA may induce vitamin D insufficiency or deficiency by enhancing vitamin D catabolism
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