Abstract
The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological actions of the active form of vitamin D, 1alpha,25-dihydroxyvitamin D(3). It regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. Recently, VDR was found to respond to bile acids as well as other nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR). The toxic bile acid lithocholic acid (LCA) induces its metabolism through VDR interaction. To elucidate the structure-function relationship between VDR and bile acids, we examined the effect of several LCA derivatives on VDR activation and identified compounds with more potent activity than LCA. LCA acetate is the most potent of these VDR agonists. It binds directly to VDR and activates the receptor with 30 times the potency of LCA and has no or minimal activity on FXR and PXR. LCA acetate effectively induced the expression of VDR target genes in intestinal cells. Unlike LCA, LCA acetate inhibited the proliferation of human monoblastic leukemia cells and induced their monocytic differentiation. We propose a docking model for LCA acetate binding to VDR. The development of VDR agonists derived from bile acids should be useful to elucidate ligand-selective VDR functions.
Highlights
The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological actions of the active form of vitamin D, 1␣,25-dihydroxyvitamin D3
We examined the effects of lithocholic acid (LCA) acetate on the growth and differentiation of human monoblastic leukemia THP-1 cells. 1,25(OH)2D3 inhibited the proliferation of THP-1 cells and enhanced nitroblue tetrazolium (NBT)-reducing activity, a differentiation marker of myeloid leukemia cells, as reported previously [26]
We found that the modification of the 3␣hydroxyl group of LCA increases the transactivation activity and selectivity on VDR
Summary
The vitamin D receptor (VDR), a member of the nuclear receptor superfamily, mediates the biological actions of the active form of vitamin D, 1␣,25-dihydroxyvitamin D3. It regulates calcium homeostasis, immunity, cellular differentiation, and other physiological processes. Structure-function relationship studies of the interaction of vitamin D analogs with VDR reveal different binding modes in the ligand-binding pocket of VDR [6] These differences in ligand-receptor interaction may contribute to the differential recruitment of coactivators to VDR and selective biological actions [7]. Nuclear receptors are ligand-inducible transcription factors that are involved in many biological processes, including cell growth and differentiation, embryonic development, and metabolic homeostasis [8].
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