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Papers In Press, published online ahead of print January 1, 2005
J. Lipid Res., doi:10.1194/jlr.M400294-JLR200

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Journal of Lipid Research, Vol. 46, 46-57, January 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

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

Ryutaro Adachi^1,*, Yoshio Honma^2,, Hiroyuki Masuno, Katsuyoshi Kawana^*,**, Iichiro Shimomura^*,, Sachiko Yamada and Makoto Makishima^3,*,**,

^* Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka 565-0871, Japan
Department of Chemotherapy, Saitama Cancer Center Research Institute, Ina-machi, Saitama 362-0806, Japan
Institute of Biomaterials and Bioengineering and School of Biomedical Science, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
^** Department of Biochemistry, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan

³ To whom correspondence should be addressed. e-mail: 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, 1,25-dihydroxyvitamin D₃. 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.

Abbreviations: BSEP, bile salt export pump; CAR, constitutive androstane receptor; ER, estrogen receptor; FXR, farnesoid X receptor; IBABP, ileal bile acid binding protein; 3-keto-LCA, 3-keto-cholanic acid; LCA, lithocholic acid; LXR, liver X receptor; NBT, nitroblue tetrazolium; N-CoR, nuclear receptor corepressor; 1,25(OH)2D3, 1,25-dihydroxyvitamin D₃; PPAR, peroxisome proliferator-activated receptor; PXR, pregnane X receptor; RAR, retinoic acid receptor; RXR, retinoid X receptor; SRC-1, steroid receptor coativator-1; TR, thyroid hormone receptor; VDR, vitamin D receptor

Supplementary key words nuclear receptor • structure-function relationship • colon cancer • intestine • leukemia

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