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VDR Ligands (vdr + ligand)

Distribution by Scientific Domains

Medical Sciences	75%

Selected Abstracts

Expression and regulation of the bile acid transporter, OST, -OST, in rat and human intestine and liver

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 5 2009
Ansar A. Khan
Abstract The regulation of the OST, and OST, expression was studied in the rat jejunum, ileum, colon and liver and in human ileum and liver by ligands for the farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR) and glucocorticoid receptor (GR) using precision cut tissue slices. The gradient of protein and mRNA expression in segments of the intestine for rOST, and rOST, paralleled that of rASBT. OST, and OST, mRNA expression, quantified by qRT-PCR, in rat jejunum, ileum, colon and liver, and in human ileum and liver was positively regulated by FXR and GR ligands. In contrast, the VDR ligand, 1,25(OH)2D3 decreased the expression of rOST, -rOST, in rat intestine, but had no effect on human ileum, and rat and human liver slices. Lithocholic acid (LCA) decreased the expression of rOST, and rOST, in rat ileum but induced OST, -OST, expression in rat liver slices, and human ileum and liver slices. The PXR ligand, pregnenolone-16, carbonitrile (PCN) had no effect. This study suggest that, apart from FXR ligands, the OST, and OST, genes are also regulated by VDR and GR ligands and not by PXR ligands. This study show that VDR ligands exerted different effects on OST, -OST, in the rat and human intestine and liver compared with other nuclear receptors, FXR, PXR, and GR, pointing to species- and organ-specific differences in the regulation of OST, -OST, genes. Copyright © 2009 John Wiley & Sons, Ltd. [source]

Vitamin D Receptor: Key Roles in Bone Mineral Pathophysiology, Molecular Mechanism of Action, and Novel Nutritional Ligands,

JOURNAL OF BONE AND MINERAL RESEARCH, Issue S2 2007
Peter W Jurutka
Abstract The vitamin D hormone, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], binds with high affinity to the nuclear vitamin D receptor (VDR), which recruits its retinoid X receptor (RXR) heterodimeric partner to recognize vitamin D responsive elements (VDREs) in target genes. 1,25(OH)2D3 is known primarily as a regulator of calcium, but it also controls phosphate (re)absorption at the intestine and kidney. Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone produced in osteoblasts that, like PTH, lowers serum phosphate by inhibiting renal reabsorption through Npt2a/Npt2c. Real-time PCR and reporter gene transfection assays were used to probe VDR-mediated transcriptional control by 1,25(OH)2D3. Reporter gene and mammalian two-hybrid transfections, plus competitive receptor binding assays, were used to discover novel VDR ligands. 1,25(OH)2D3 induces FGF23 78-fold in osteoblasts, and because FGF23 in turn represses 1,25(OH)2D3 synthesis, a reciprocal relationship is established, with FGF23 indirectly curtailing 1,25(OH)2D3 -mediated intestinal absorption and counterbalancing renal reabsorption of phosphate, thereby reversing hyperphosphatemia and preventing ectopic calcification. Therefore, a 1,25(OH)2D3,FGF23 axis regulating phosphate is comparable in importance to the 1,25(OH)2D3,PTH axis that regulates calcium. 1,25(OH)2D3 also elicits regulation of LRP5, Runx2, PHEX, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic. Regulation of mouse RANKL by 1,25(OH)2D3 supports a cloverleaf model, whereby VDR-RXR heterodimers bound to multiple VDREs are juxtapositioned through chromatin looping to form a supercomplex, potentially allowing simultaneous interactions with multiple co-modulators and chromatin remodeling enzymes. VDR also selectively binds certain ,3/,6 polyunsaturated fatty acids (PUFAs) with low affinity, leading to transcriptionally active VDR-RXR complexes. Moreover, the turmeric-derived polyphenol, curcumin, activates transcription of a VDRE reporter construct in human colon cancer cells. Activation of VDR by PUFAs and curcumin may elicit unique, 1,25(OH)2D3 -independent signaling pathways to orchestrate the bioeffects of these lipids in intestine, bone, skin/hair follicle, and other VDR-containing tissues. [source]

Dissociation of growth arrest and CYP24 induction by VDR ligands in mammary tumor cells

JOURNAL OF CELLULAR BIOCHEMISTRY, Issue 6 2007
Meggan E. Valrance
Abstract Murine mammary tumor cells with differential vitamin D receptor (VDR) expression were used to study the mechanisms of growth inhibition by vitamin D steroids. In VDR-expressing WT145 cells, 1,25D and its synthetic analog EB1089 induce growth arrest and transcriptionally upregulate the well-characterized VDR target gene CYP24. 1,25D also induces apoptosis in WT145 cells through activation of initiator and executioner caspases and the calcium-dependent protease calpain. We also demonstrate that WT145 cells express CYP27B1, the enzyme that converts 25-hydroxyvitamin D3 (25D) to 1,25D, and that 25D inhibits growth of these cells but does not trigger apoptosis or induce CYP24 expression. Comparative studies were conducted in KO240 cells, which were derived from VDR knockout mice and found to retain expression of CYP27B1. KO240 cells were not growth inhibited nor rendered apoptotic by any of the tested vitamin D compounds. These data conclusively demonstrate that VDR mediates the anti-proliferative and pro-apoptotic effects of vitamin D metabolites and analogs, but that the potency of a vitamin D compound to induce the VDR target gene CYP24 does not accurately predict its potency in mediating growth regulation. J. Cell. Biochem. 101: 1505,1519, 2007. © 2007 Wiley-Liss, Inc. [source]