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Vitamin D Receptor in gut can be activated by lithocholic acid produced by gut bacteria

Japan Nov 2017

Clin Calcium. 2017;27(11):1533-1541. doi: CliCa171115331541.
[Update on recent progress in vitamin D research. Vitamin D receptor and the nuclear receptor superfamily.]
[Article in Japanese]
Makishima M1.

The vitamin D receptor(VDR)is a ligand-dependent transcription factor of the nuclear receptor superfamily. VDR belongs to the NR1I subfamily along with other nuclear receptors involved in xenobiotic metabolism, such as pregnane X receptor. The oxysterol receptors liver X receptors α/β and the bile acid receptor farnesoid X receptor belong to the NR1H subfamily, which are closely related to the NR1I subfamily. NR1I and NR1H nuclear receptors form heterodimers with retinoid X receptor. The active form of vitamin D, 1α,25-dihydroxyvitamin D3[1,25(OH)2D3], acts as a physiological VDR ligand, and regulates various physiological processes, including calcium and bone metabolism, cellular growth and differentiation, immunity, and cardiovascular function. The secondary bile acid lithocholic acid, which is produced by intestinal bacteria, is another natural VDR ligand. lithocholic acid stimulates xenobiotic metabolism and regulates immune and inflammatory responses via VDR, and its calcemic action is limited and observed only in vitamin D-deficient animals. Thus, lithocholic acid may be a function-selective VDR ligand. VDR is a promising drug in the treatment of bone and mineral disorders, cancer, autoimmune disease, inflammation, and cardiovascular disease. However, the adverse effect hypercalcemia limits wider clinical application of 1,25(OH)2D3 and its derivatives. Elucidation of the mechanism of VDR function by lithocholic acid should expand the possibility of VDR-targeted approaches.

PMID: 29074825 DOI: CliCa171115331541


Japan 2005

J Lipid Res. 2005 Jan;46(1):46-57. Epub 2004 Oct 16.
Selective activation of vitamin D receptor by lithocholic acid acetate, a bile acid derivative.
Adachi R1, Honma Y, Masuno H, Kawana K, Shimomura I, Yamada S, Makishima M.

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.

PMID: 15489543 DOI: 10.1194/jlr.M400294-JLR200
[Indexed for MEDLINE] Free full text online


US 2010

Mol Endocrinol. 2010 Jun;24(6):1151-64. doi: 10.1210/me.2009-0482. Epub 2010 Apr 6.
A novel bile acid-activated vitamin D receptor signaling in human hepatocytes.
Han S1, Li T, Ellis E, Strom S, Chiang JY.

Vitamin D receptor (VDR) is activated by natural ligands, 1alpha, 25-dihydroxy-vitamin D(3) [1alpha,25(OH)(2)-D(3)] and lithocholic acid (LCA). Our previous study shows that VDR is expressed in human hepatocytes, and VDR ligands inhibit bile acid synthesis and transcription of the gene encoding cholesterol 7alpha-hydroxylase (CYP7A1). Primary human hepatocytes were used to study LCA and 1alpha,25(OH)(2)-D(3) activation of VDR signaling. Confocal immunofluorescent microscopy imaging and immunoblot analysis showed that LCA and 1alpha, 25(OH)(2)-D(3) induced intracellular translocation of VDR from the cytosol to the nucleus and also plasma membrane where VDR colocalized with caveolin-1. VDR ligands induced tyrosine phosphorylation of c-Src and VDR and their interaction. Inhibition of c-Src abrogated VDR ligand-dependent inhibition of CYP7A1 mRNA expression. Kinase assays showed that VDR ligands specifically activated the c-Raf/MEK1/2/extracellular signal-regulated kinase (ERK) 1/2 pathway, which stimulates serine phosphorylation of VDR and hepatocyte nuclear factor-4alpha, and their interaction. Mammalian two-hybrid assays showed a VDR ligand-dependent interaction of nuclear receptor corepressor-1 and silencing mediator of retinoid and thyroid with VDR/retinoid X receptor-alpha (RXRalpha). Chromatin immunoprecipitation assays revealed that an ERK1/2 inhibitor reversed VDR ligand-induced recruitment of VDR, RXRalpha, and corepressors to human CYP7A1 promoter. In conclusion, VDR ligands activate membrane VDR signaling to activate the MEK1/2/ERK1/2 pathway, which stimulates nuclear VDR/RXRalpha recruitment of corepressors to inhibit CYP7A1 gene transcription in human hepatocytes. This membrane VDR-signaling pathway may be activated by bile acids to inhibit bile acid synthesis as a rapid response to protect hepatocytes from cholestatic liver injury.

PMID: 20371703 PMCID: PMC2875805 DOI: 10.1210/me.2009-0482
[Indexed for MEDLINE] Free PMC Article


Japan 2008

Role of Vitamin D Receptor in the lithocholic acid-Mediated CYP3A Induction in Vitro and in Vivo

Tsutomu Matsubara, Kouichi Yoshinari, Kazunobu Aoyama, Mika Sugawara, Yuji Sekiya, Kiyoshi Nagata and Yasushi Yamazoe
Drug Metabolism and Disposition October 2008, 36 (10) 2058-2063; DOI: https://doi.org/10.1124/dmd.108.021501

Lipophilic bile acids are suggested to be involved in the endogenous expression of CYP3A4 in human and experimental animals as ligands of nuclear receptors. To verify the nuclear receptor specificity, the bile acid-mediated induction of CYP3A4 has been studied in vitro and in vivo in the present study. lithocholic acid (LCA) strongly enhanced the activities of the CYP3A4 reporter gene, which contained multiple nuclear receptor binding elements, in both HepG2 and LS174T cells. The introduction of small interfering RNA for human vitamin D receptor (VDR), but not for human pregnane X receptor, reduced the LCA-induced activation of the reporter gene in these cells, suggesting the major role of VDR in the LCA induction of CYP3A4. Consistently, oral administration of LCA (100 mg/kg/day for 3 days) increased Cyp3a protein levels in the intestine but not in the liver, where a negligible level of VDR mRNA is detected. The selective role of VDR was tested in mice with the adenoviral overexpression of the receptor. Oral administration of LCA had no clear influence on the CYP3A4 reporter activity in the liver of control mice. In mice with the adenovirally expressed VDR, LCA treatment (100 or 400 mg/kg/day for 3 days) resulted in the enhanced reporter activities and increased levels of Cyp3a proteins in the liver. These results indicate the selective involvement of VDR, but not pregnane X receptor, in the LCA-mediated induction of both human and mouse CYP3As in vivo.

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