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Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative.
J Lipid Res. 2005 Jan; 46(1):46-57.JL

Abstract

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.

Authors+Show Affiliations

Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15489543

Citation

Adachi, Ryutaro, et al. "Selective Activation of Vitamin D Receptor By Lithocholic Acid Acetate, a Bile Acid Derivative." Journal of Lipid Research, vol. 46, no. 1, 2005, pp. 46-57.
Adachi R, Honma Y, Masuno H, et al. Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. J Lipid Res. 2005;46(1):46-57.
Adachi, R., Honma, Y., Masuno, H., Kawana, K., Shimomura, I., Yamada, S., & Makishima, M. (2005). Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. Journal of Lipid Research, 46(1), 46-57.
Adachi R, et al. Selective Activation of Vitamin D Receptor By Lithocholic Acid Acetate, a Bile Acid Derivative. J Lipid Res. 2005;46(1):46-57. PubMed PMID: 15489543.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative. AU - Adachi,Ryutaro, AU - Honma,Yoshio, AU - Masuno,Hiroyuki, AU - Kawana,Katsuyoshi, AU - Shimomura,Iichiro, AU - Yamada,Sachiko, AU - Makishima,Makoto, Y1 - 2004/10/16/ PY - 2004/10/19/pubmed PY - 2005/7/29/medline PY - 2004/10/19/entrez SP - 46 EP - 57 JF - Journal of lipid research JO - J. Lipid Res. VL - 46 IS - 1 N2 - 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. SN - 0022-2275 UR - https://www.unboundmedicine.com/medline/citation/15489543/Selective_activation_of_vitamin_D_receptor_by_lithocholic_acid_acetate_a_bile_acid_derivative_ L2 - http://www.jlr.org/cgi/pmidlookup?view=long&pmid=15489543 DB - PRIME DP - Unbound Medicine ER -