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Journal of Lipid Research, Vol. 49, 763-772, April 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia

Michiyasu Ishizawa^*,, Manabu Matsunawa^*,, Ryutaro Adachi^**, Shigeyuki Uno^*, Kazumasa Ikeda, Hiroyuki Masuno, Masato Shimizu, Ken-ichi Iwasaki^***, Sachiko Yamada^* and Makoto Makishima^1,*

^* Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
Open Research Center for Genome and Infectious Disease Control, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
^*** Division of Hygiene, Department of Social Medicine, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan
Department of Applied Biological Science, Nihon University College of Bioresource Sciences, Fujisawa, Kanagawa 252-8510, Japan
^** Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan
School of Biomedical Science, Tokyo Medical and Dental University, Chiyoda-ku, Tokyo 101-0062, Japan

Published, JLR Papers in Press, January 7, 2008.

¹ To whom correspondence should be addressed. e-mail: maxima{at}med.nihon-u.ac.jp

1,25-Dihydroxyvitamin D₃ [1,25(OH)₂D₃], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and also exhibits noncalcemic actions on immunity and cell differentiation. In addition to disorders of bone and calcium metabolism, VDR ligands are potential therapeutic agents in the treatment of immune disorders, microbial infections, and malignancies. Hypercalcemia, the major adverse effect of vitamin D₃ derivatives, limits their clinical application. The secondary bile acid lithocholic acid (LCA) is an additional physiological ligand for VDR, and its synthetic derivative, LCA acetate, is a potent VDR agonist. In this study, we found that an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. LCA acetate and LCA propionate induced the expression of the calcium channel transient receptor potential vanilloid type 6 (TRPV6) as effectively as that of 1,25-dihydroxyvitamin D₃ 24-hydroxylase (CYP24A1), whereas 1,25(OH)₂D₃ was more effective on TRPV6 than on CYP24A1 in intestinal cells. In vivo experiments showed that LCA acetate and LCA propionate effectively induced tissue VDR activation without causing hypercalcemia. These bile acid derivatives have the ability to function as selective VDR modulators.

Supplementary key words nuclear receptor • intestine • leukemia • calcium

Abbreviations: AF2, activation function 2; CAMP, cathelicidin antimicrobial peptide; CYP24A1, 1,25-dihydroxyvitamin D₃ 24-hydroxylase; FXR, farnesoid X receptor; GPBAR1, G protein-coupled bile acid receptor 1; LCA, lithocholic acid; NBT, nitroblue tetrazolium; 1(OH)D₃, 1-hydroxyvitamin D₃; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; PXR, pregnane X receptor; RXR, retinoid X receptor; TRPV6, transient receptor potential vanilloid type 6; VDR, vitamin D receptor