Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative
Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative
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DOI：
10.1194/jlr.m400294-jlr200
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发表时间：
2005-01-01
影响因子：
6.5
通讯作者：
Makishima, M
中科院分区：
文献类型：
--
作者：
Adachi, R;Honma, Y;Makishima, M
维生素D受体（VDR）是核受体超家族的成员，介导维生素D活性形式1 α，25-二羟基维生素D-3的生物学作用。它调节钙稳态、免疫、细胞分化和其他生理过程。最近发现，VDR对胆汁酸以及其他核受体，法尼醇X受体（FXR）和胆甾烷X受体（PXR）有反应。毒性胆汁酸石胆酸（LCA）通过VDR相互作用诱导其代谢。为了阐明VDR和胆汁酸之间的结构-功能关系，我们研究了几种LCA衍生物对VDR活化的影响，并鉴定了比LCA具有更有效活性的化合物。LCA醋酸盐是这些VDR激动剂中最有效的。它直接与VDR结合，并以LCA 30倍的效力激活受体，对FXR和PXR没有或具有最小的活性。LCA醋酸盐有效地诱导肠细胞中VDR靶基因的表达。与LCA不同，LCA醋酸盐抑制人单核细胞白血病细胞的增殖并诱导其单核细胞分化。我们提出了一个对接模型LCA乙酸结合VDR。开发来源于胆汁酸的VDR激动剂将有助于阐明配体选择性VDR功能。
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.