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A more recent version of this article appeared on January 1, 2005

Papers In Press, published online ahead of print October 16, 2004
J. Lipid Res., doi:10.1194/jlr.M400294-JLR200
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Submitted on August 2, 2004
Revised on September 30, 2004
Accepted on October 1, 2004

Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative

Ryutaro Adachi, Yoshio Honma, Hiroyuki Masuno, Katsuyoshi Kawana, Iichiro Shimomura, Sachiko Yamada, and Makoto Makishima

Department of Biochemistry, Nihon University, Itabashi-ku, Tokyo 173-8610

Corresponding Author: maxima{at}med.nihon-u.ac.jp

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 D3 [1,25(OH)2D3]. 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 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.


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