Abstract
1alpha,25-Dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], 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 D(3) 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 1alpha,25-dihydroxyvitamin D(3) 24-hydroxylase (CYP24A1), whereas 1,25(OH)(2)D(3) 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.
Highlights
1a,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and exhibits noncalcemic actions on immunity and cell differentiation
We previously reported that modification of lithocholic acid (LCA) at the 3ahydroxyl group increases VDR transactivation, with LCA acetate being the most potent compound tested [13]
The retinoid X receptor (RXR) ligand 9-cis retinoic acid induced the transactivation of RXRa (NR1B1), RXRb (NR1B2), and RXRg (NR1B3) very effectively, LCA, LCA acetate, and LCA propionate did not activate RXRs
Summary
1a,25-Dihydroxyvitamin D3 [1,25(OH)2D3], a vitamin D receptor (VDR) ligand, regulates calcium homeostasis and exhibits noncalcemic actions on immunity and cell differentiation. We found that an additional derivative, LCA propionate, is a more selective VDR activator than LCA acetate. 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.—Ishizawa, M., M. VDR activation by 1,25(OH)2D3 induces the cathelicidin antimicrobial peptide (CAMP) and kills Mycobacterium tuberculosis in monocytes [6] They have been used successfully in the treatment of bone and skin disorders, adverse effects, especially hypercalcemia, limit the clinical application of vitamin D and its synthetic analogs in the management of diseases other than bone and mineral disorders [5]. This article is available online at http://www.jlr.org
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