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Anthony W. Norman - One of the best experts on this subject based on the ideXlab platform.
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a molecular Description of liganD binDing to the two overlapping binDing pockets of the Nuclear Vitamin D receptor vDr structure function implications
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Mathew T Mizwicki, Helen L Henry, Sepideh Yaghmaei, Danusa Menegaz, Anthony W. NormanAbstract:Molecular moDeling results inDicate that the VDR contains two overlapping liganD binDing pockets (LBP). Differential liganD stability anD fractional occupancy of the two LBP has been physiochemically linkeD to the regulation of VDR-DepenDent genomic anD non-genomic cellular responses. The purpose of this report is to Develop an unbiaseD molecular moDeling protocol that serves as a gooD starting point in simulating the Dynamic interaction between 1alpha,25(OH)2-Vitamin D3 (1,25D3) anD the VDR LBP. To accomplish this goal, the flexible Docking protocol DevelopeD alloweD for flexibility in the VDR liganD anD the VDR atoms that form the surfaces of the VDR LBP. This approach blinDly replicateD the 1,25D3 conformation anD siDe-chain Dynamics observeD in the VDR X-ray structure. The results are also consistent with the previously publisheD tenants of the Vitamin D sterol (VDS)-VDR conformational ensemble moDel. Furthermore, we useD flexible Docking in combination with whole-cell patch-clamp electrophysiology anD steroiD competition assays to Demonstrate that (a) new non-Vitamin D VDR liganDs show a Different pocket selectivity when compareD to 1,25D3 that is qualitatively consistent with their ability to stimulate chloriDe channels anD (b) a new route of liganD binDing proviDes a novel hypothesis Describing the structural nuances that unDerlie hypercalceamia.
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on the mechanism unDerlying 23s 25 DehyDro 1α oh Vitamin D3 26 23 lactone antagonism of hvDrwt gene activation anD its switch to a superagonist
Journal of Biological Chemistry, 2009Co-Authors: Mathew T Mizwicki, Craig M Bula, Paween Mahinthichaichan, Helen L Henry, Seiichi Ishizuka, Anthony W. NormanAbstract:(23S)-25-DehyDro-1alpha(OH)-Vitamin D(3)-26,23-lactone (MK) is an antagonist of the 1alpha,25(OH)(2)-Vitamin D(3) (1,25D)/human Nuclear Vitamin D receptor (hVDR) transcription initiation complex, where the activation helix (i.e. helix-12) is closeD. To stuDy the moDe of antagonism of MK an hVDR mutant library was DesigneD to alter the free molecular volume in the region of the hVDR liganD binDing pocket occupieD by the liganD siDe-chain atoms (i.e. proximal to helix-12). The 1,25D-hVDR structure-function stuDies Demonstrate that 1) van Der Waals contacts between helix-12 resiDues Leu-414 anD Val-418 anD 1,25D enhance the stability of the closeD helix-12 conformer anD 2) removal of the siDe-chain H-bonDs to His-305(F) anD/or His-397(F) have no effect on 1,25D transactivation, even though they reDuce the binDing affinity of 1,25D. The MK structure-function results Demonstrate that the His-305, Leu-404, Leu-414, anD Val-418 mutations, which increase the free volume of the hVDR liganD binDing pocket, significantly enhance MK antagonist potency. Surprisingly, the H305F anD H305F/H397F mutations turn MK into a VDR superagonist (EC(50) approximately 0.05 nm) but Do not concomitantly alter MK binDing affinity. Molecular moDeling stuDies Demonstrate that MK antagonism stems from its siDe chain energetically preferring a pose in the VDR liganD binDing pocket where its terminal C26-methylene atom is far removeD from helix-12. MK superagonism results from an energetically favoreD increase in interaction between Leu-404/Val-418 anD C26, resulting in an increase in the stability anD population of the closeD, helix-12 conformer. Finally, the results/moDel generateD, coupleD with application of a VDR ensemble allosterics moDel, proviDe an unDerstanDing for the species specificity of MK.
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iDentification of an alternative liganD binDing pocket in the Nuclear Vitamin D receptor anD its functional importance in 1α 25 oh 2 Vitamin D3 signaling
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Mathew T Mizwicki, June E. Bishop, Don Keidel, Craig M Bula, Laura P Zanello, Jeanmarie Wurtz, Dino Moras, Anthony W. NormanAbstract:Structural anD molecular stuDies have shown that the Vitamin D receptor (VDR) meDiates 1α,25(OH)2-Vitamin D3 gene transactivation. Recent eviDence inDicates that both VDR anD the estrogen receptor are localizeD to plasma membrane caveolae anD are requireD for initiation of nongenomic (NG) responses. Computer Docking of the NG-specific 1α,25(OH)2-lumisterol to the VDR resulteD in iDentification of an alternative liganD-binDing pocket that partially overlaps the genomic pocket DescribeD in the experimentally DetermineD x-ray structure. Data obtaineD from Docking five Different Vitamin D sterols in the genomic anD alternative pockets were useD to generate a receptor conformational ensemble moDel, proviDing an explanation for how VDR anD possibly the estrogen receptor can have genomic anD NG functionality. The VDR moDel is compatible with the following: (i) NG chloriDe channel agonism anD antagonism; (ii) variable liganD-stabilizeD trypsin Digest banDing patterns; anD (iii) Differential transcriptional activity, employing Different VDR point mutants anD 1α,25(OH)2-Vitamin D3 analogs.
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rapiD moDulation of osteoblast ion channel responses by 1α 25 oh 2 Vitamin D3 requires the presence of a functional Vitamin D Nuclear receptor
Proceedings of the National Academy of Sciences of the United States of America, 2004Co-Authors: Laura P Zanello, Anthony W. NormanAbstract:1alpha,25(OH)(2)-Vitamin D(3) (1,25D) moDulates osteoblast gene expression of bone matrix proteins via a Nuclear Vitamin D receptor (VDR) anD also moDifies the electrical state of the plasma membrane through rapiD nongenomic mechanisms still not fully unDerstooD. The physiological significance of 1,25D membrane-initiateD effects remains unclear. To eluciDate whether the VDR is requireD for 1,25D-promoteD electrical responses, we stuDieD 1,25D moDulation of ion channel activities in calvarial osteoblasts isolateD from VDR knockout (KO) anD WT mice. At Depolarizing potentials, Cl(-) currents were significantly potentiateD (13.5 +/- 1.6-folD increase, n = 12) by 5 nM 1,25D in VDR WT but not in KO (0.96 +/- 0.3 folD increase, n = 11) osteoblasts. L-type Ca(2+) currents significantly shift their peak activation by -9.3 +/- 0.7 mV (n = 10) in the presence of 5 nM 1,25D in VDR WT but not in KO cells, thus facilitating Ca(2+) influx. Furthermore, we founD that 1,25D significantly increaseD whole-cell capacitance in VDR WT (DeltaCap = 2.3 +/- 0.4 pF, n = 8) but not in KO osteoblasts (DeltaCap = 0.3 +/- 0.1 pF, n = 8); this corresponDs to a rapiD (1-2 min) fusion in WT of 71 +/- 33 versus in KO only 9 +/- 6 inDiviDual secretory granules. We concluDe that, in calvarial osteoblasts, 1,25D moDulates ion channel activities only in cells with a functional VDR anD that this effect is coupleD to exocytosis. This is a Demonstration of the requirement of a functional classic steroiD receptor for the rapiD hormonal moDulation of electric currents linkeD to secretory activities in a target cell.
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1alpha 25 DihyDroxyVitamin D3 inhibits uncoupling protein 2 expression in human aDipocytes
The FASEB Journal, 2002Co-Authors: Hang Shi, William H Okamura, Anindita Sen, Anthony W. Norman, Michael B ZemelAbstract:We recently DemonstrateD that suppressing 1alpha,25-(OH)2-D3 by increasing Dietary calcium Decreases aDipocyte intracellular Ca2+ ([Ca2+]i), stimulates lipolysis, anD inhibits lipogenesis. High calcium Diets also increase core temperature anD white aDipose tissue uncoupling protein 2 (UCP2) expression in aP2-agouti transgenic mice. AccorDingly, we have evaluateD the role of 1alpha,25-(OH)2-D3 in regulating human aDipocyte UCP2 expression. Treatment of human aDipocytes for 48 h with 1 nM 1alpha,25-(OH)2-D3 inhibiteD UCP2 mRNA anD protein levels by 50% (P<0.002) anD completely blockeD isoproterenol- or fatty aciD-stimulateD two- to threefolD increases in UCP2 expression. However, a specific agonist for the membrane Vitamin D receptor (mVDR), 1alpha,25-DihyDroxylumisterol3, was unable to inhibit basal, isoproterenol-stimulateD, or fatty aciD-stimulateD UCP2 expression, whereas a specific mVDR antagonist,1beta,25-DihyDroxyVitamin D3, was unable to prevent the 1alpha,25-(OH)2-D3 inhibition of UCP2 expression. In contrast, Nuclear Vitamin D receptor (nVDR) knockout via antisense oligoDeoxynucleotiDe (ODN) preventeD the inhibitory effect of 1alpha,25-(OH)2-D3 on aDipocyte UCP2 expression anD protein levels. These Data inDicate that 1a,25-(OH)2-D3 exerts an inhibitory effect on aDipocyte UCP2 expression via the nVDR. Thus, suppression of 1alpha,25-(OH)2-D3 anD consequent up-regulation of UCP2 may contribute to our previous observation of increaseD thermogenesis in mice feD with high calcium Diets.
Peter W. Jurutka - One of the best experts on this subject based on the ideXlab platform.
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Vitamin D receptor meDiates a myriaD of biological actions DepenDent on its 1 25 DihyDroxyVitamin D liganD Distinct regulatory themes revealeD by inDuction of klotho anD fibroblast growth factor 23
JBMR plus, 2021Co-Authors: Mark R. Haussler, Peter W. Jurutka, Carol A. Haussler, Sarah Livingston, Zhela L SabirAbstract:The hormonal Vitamin D metabolite, 1,25-DihyDroxyVitamin D [1,25(OH)2D], proDuceD in kiDney, acts in numerous enD organs via the Nuclear Vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a liganD-controlleD transcription factor that obligatorily heteroDimerizes with retinoiD X receptor (RXR) to target Vitamin D responsive elements (VDREs) in the vicinity of Vitamin D-regulateD genes. Circulating 1,25(OH)2D concentrations are governeD by PTH, an inDucer of renal D-hormone biosynthesis catalyzeD by CYP27B1 that functions as the key player in a calcemic enDocrine circuit, anD by fibroblast growth factor-23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic enDocrine loop. 1,25(OH)2D/VDR-RXR acts in kiDney to inDuce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, anD TRPV5 anD CaBP28k to enhance calcium reabsorption. 1,25(OH)2D-liganDeD VDR-RXR functions in osteoblasts/osteocytes by augmenting RANK-liganD expression to paracrine signal osteoclastic bone resorption, while simultaneously inDucing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, anD TNAP, anD conversely repressing RUNX2 anD PHEX expression, effecting localizeD control of mineralization to sculpt the skeleton. Herein, we Document the history of 1,25(OH)2D/VDR anD summarize recent aDvances in characterizing their physiology, biochemistry, anD mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR-meDiateD primary inDuction of Klotho mRNA by 1,25(OH)2D in kiDney via a mechanism initiateD by the Docking of liganDeD VDR-RXR on a VDRE at -35 kb in the mouse Klotho gene. In contrast, the seconDary inDuction of FGF23 by 1,25(OH)2D in bone is proposeD to involve rapiD nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the inDuction of MZF1, a transcription factor that, in cooperation with c-ets1-P, binDs to an enhancer element centereD at -263 bp in the promoter-proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D-inDuceD osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus publisheD by Wiley PerioDicals LLC on behalf of American Society for Bone anD Mineral Research.
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pomegranate Derivative urolithin a enhances Vitamin D receptor signaling to amplify serotonin relateD gene inDuction by 1 25 DihyDroxyVitamin D
Biochemistry and biophysics reports, 2020Co-Authors: Sarah Livingston, Carol A. Haussler, Mark R. Haussler, Sanchita Mallick, Daniel A Lucas, Marya S Sabir, Zhela L Sabir, Hespera Purdin, Sree Nidamanuri, Peter W. JurutkaAbstract:Abstract MeDiateD by the Nuclear Vitamin D receptor (VDR), the hormonally active Vitamin D metabolite, 1,25-DihyDroxyVitamin D3 (1,25D), is known to regulate expression of genes impacting calcium anD phosphorus metabolism, the immune system, anD behavior. Urolithin A, a nutrient metabolite DeriveD from pomegranate, possibly acting through AMP kinase (AMPK) signaling, supports respiratory muscle health in roDents anD longevity in C. elegans by inDucing oxiDative Damage-reversing genes anD mitophagy. We show herein that urolithin A enhances transcriptional actions of 1,25D Driven by co-transfecteD Vitamin D responsive elements (VDREs), anD Dissection of this genomic effect in cell culture reveals: 1) urolithin A concentration-DepenDency, 2) occurrence with isolateD natural VDREs, 3) Nuclear receptor selectivity for VDR over ER, LXR anD RXR, anD 4) significant 3- to 13-folD urolithin A-augmentation of 1,25D-DepenDent mRNA encoDing the wiDely expresseD 1,25D-Detoxification enzyme, CYP24A1, a benchmark Vitamin D target gene. Relevant to potential behavioral effects of Vitamin D, urolithin A elicits enhancement of 1,25D-DepenDent mRNA encoDing tryptophan hyDroxylase-2 (TPH2), the serotonergic neuron-expresseD initial enzyme in tryptophan metabolism to serotonin. Employing quantitative real time-PCR, we Demonstrate that TPH2 mRNA is inDuceD 1.9-folD by 10 nM 1,25D treatment in culture of DifferentiateD rat serotonergic raphe (RN46A-B14) cells, an effect magnifieD 2.5-folD via supplementation with 10 μM urolithin A. This potentiation of 1,25D-inDuceD TPH2 mRNA by urolithin A is followeD by a 3.1- to 3.7-folD increase in serotonin concentration in culture meDium from the pertinent neuronal cell line, RN46A-B14. These results are consistent with the concept that two natural nutrient metabolites, urolithin A from pomegranate anD 1,25D from sunlight/Vitamin D, likely acting via AMPK anD VDR, respectively, cooperate mechanistically to effect VDRE-meDiateD regulation of gene expression in neuroenDocrine cells. Finally, geDunin, a neuroprotective natural proDuct from InDian neem tree that impacts the brain DeriveD neurotropic factor pathway, similarly potentiates 1,25D/VDR-action.
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1 25 DihyDroxyVitamin D 3 regulation of fibroblast growth factor 23 expression in bone cells eviDence for primary anD seconDary mechanisms moDulateD by leptin anD interleukin 6
Calcified Tissue International, 2013Co-Authors: Rimpi K Saini, Peter W. Jurutka, Mark R. Haussler, Jui Cheng Hsieh, Ichiro Kaneko, Ryan Forster, Antony Hsieh, Kerr G WhitfieldAbstract:Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption anD to prevent hyperVitaminosis D by feeDback repressing 1,25-DihyDroxyVitamin D3 (1,25(OH)2D3) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is inDuceD by the Nuclear Vitamin D receptor (VDR) bounD to 1,25(OH)2D3, but cycloheximiDe sensitivity of this inDuction suggests that it may occur largely via seconDary mechanisms requiring cooperating transcription factors. We therefore sought to iDentify 1,25(OH)2D3-regulateD transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was founD to potentiate 1,25(OH)2D3 upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunteD this upregulation. Genomic analyses revealeD conserveD binDing sites for STATs (signal transDuction meDiators of leptin anD IL-6 action) along with transcription factor ETS1 in human anD other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, anD VDR mRNAs were inDuceD in a Dose-DepenDent manner by 1,25(OH)2D3 in UMR-106 cells. Bioinformatic analysis iDentifieD nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of meDiating Direct transcriptional activation of a heterologous reporter gene when bounD by a 1,25(OH)2D3-liganDeD VDR complex. A moDel is proposeD wherein 1,25(OH)2D3 upregulates FGF23 proDuction Directly via multiple VDREs anD inDirectly via inDuction of STAT3, ETS1, anD VDR transcription factors that are then activateD via cell surface anD intracellular signaling to cooperate in the inDuction of FGF23 through DNA looping anD generation of euchromatin architecture.
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Nuclear Vitamin D receptor natural liganDs molecular structure function anD transcriptional control of vital genes
Vitamin D (Third Edition)#R##N#Vitamin D, 2011Co-Authors: Mark R. Haussler, Carol A. Haussler, Kerr G Whitfield, Jui Cheng Hsieh, Peter W. JurutkaAbstract:Publisher Summary Small Angle X-ray Scattering anD Fluorescence Resonance Energy Transfer techniques have DetermineD the structure of the hypocalcemic Vitamin-D-resistant rickets (hVDR) DNA-binDing Domain (DBD) anD liganD-binDing Domain (LBD) together in the full-length receptor, heteroDimerizeD with full-length RXR α, DockeD on a VDRE, anD occupieD with 1,25(OH)2D3 plus a single coactivator, allowing one to begin to unDerstanD the interactions between the DBD anD the liganD-binDing/heteroDimerization Domains of both VDR anD its RXR heteropartner. A seconD major realm of accomplishment has been the iDentification of numerous aDDitional VDR-regulateD genes, incluDing those meDiating calcium anD particularly phosphate homeostasis, bone metabolism, Detoxification, cell proliferation, Differentiation, migration anD Death, immunity anD antimicrobial action, as well as carbohyDrate, lipiD, anD amino aciD metabolism. Equally exciting has been the Discovery of aDDitional natural VDR liganDs, especially in the more-recently iDentifieD anD stuDieD VDR target tissues such as the hair follicle/skin anD immune systems. The availability of this information will facilitate molecular investigations of transcriptional control by VDR in target-cell specific environments in the presence of novel liganDs anD the context of a myriaD of promoters/genes. Such experiments are likely to extenD the unDerstanDing of the variety of conformations anD coregulator associations that the VDR-RXR heteroDimer is capable of achieving while performing its multituDe of extraosseous effects to lower the risk of the chronic Diseases of aging.
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functionally relevant polymorphisms in the human Nuclear Vitamin D receptor gene
Molecular and Cellular Endocrinology, 2001Co-Authors: Kerr G Whitfield, Peter W. Jurutka, Carol A. Haussler, L S Remus, Heike Zitzer, Anish K Oza, Hope Dang, Michael A Galligan, Michelle L Thatcher, Carlos Encinas DominguezAbstract:The functional significance of two unlinkeD human Vitamin D receptor (hVDR) gene polymorphisms was evaluateD in twenty human fibroblast cell lines. Genotypes at both a Fok I restriction site (F/f) in exon II anD a singlet (A) repeat in exon IX (L/S) were DetermineD, anD relative transcription activities of enDogenous hVDR proteins were measureD using a transfecteD, 1,25-DihyDroxyVitamin D(3)-responsive reporter gene. ObserveD activities rangeD from 2--100-folD inDuction by hormone, with higher activity being DisplayeD by the F anD the L biallelic forms. Only when genotypes at both sites were consiDereD simultaneously DiD statistically significant Differences emerge. Moreover, the correlation between hVDR activity anD genotype segregateD further into clearly DefineD high anD low activity groups with similar genotypic Distributions. These results not only Demonstrate functional relevance for both the F/f anD L/S common polymorphisms in hVDR, but also proviDe novel eviDence for a thirD genetic variable impacting receptor potency.
Mark R. Haussler - One of the best experts on this subject based on the ideXlab platform.
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Vitamin D receptor meDiates a myriaD of biological actions DepenDent on its 1 25 DihyDroxyVitamin D liganD Distinct regulatory themes revealeD by inDuction of klotho anD fibroblast growth factor 23
JBMR plus, 2021Co-Authors: Mark R. Haussler, Peter W. Jurutka, Carol A. Haussler, Sarah Livingston, Zhela L SabirAbstract:The hormonal Vitamin D metabolite, 1,25-DihyDroxyVitamin D [1,25(OH)2D], proDuceD in kiDney, acts in numerous enD organs via the Nuclear Vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a liganD-controlleD transcription factor that obligatorily heteroDimerizes with retinoiD X receptor (RXR) to target Vitamin D responsive elements (VDREs) in the vicinity of Vitamin D-regulateD genes. Circulating 1,25(OH)2D concentrations are governeD by PTH, an inDucer of renal D-hormone biosynthesis catalyzeD by CYP27B1 that functions as the key player in a calcemic enDocrine circuit, anD by fibroblast growth factor-23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic enDocrine loop. 1,25(OH)2D/VDR-RXR acts in kiDney to inDuce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, anD TRPV5 anD CaBP28k to enhance calcium reabsorption. 1,25(OH)2D-liganDeD VDR-RXR functions in osteoblasts/osteocytes by augmenting RANK-liganD expression to paracrine signal osteoclastic bone resorption, while simultaneously inDucing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, anD TNAP, anD conversely repressing RUNX2 anD PHEX expression, effecting localizeD control of mineralization to sculpt the skeleton. Herein, we Document the history of 1,25(OH)2D/VDR anD summarize recent aDvances in characterizing their physiology, biochemistry, anD mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR-meDiateD primary inDuction of Klotho mRNA by 1,25(OH)2D in kiDney via a mechanism initiateD by the Docking of liganDeD VDR-RXR on a VDRE at -35 kb in the mouse Klotho gene. In contrast, the seconDary inDuction of FGF23 by 1,25(OH)2D in bone is proposeD to involve rapiD nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the inDuction of MZF1, a transcription factor that, in cooperation with c-ets1-P, binDs to an enhancer element centereD at -263 bp in the promoter-proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D-inDuceD osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus publisheD by Wiley PerioDicals LLC on behalf of American Society for Bone anD Mineral Research.
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pomegranate Derivative urolithin a enhances Vitamin D receptor signaling to amplify serotonin relateD gene inDuction by 1 25 DihyDroxyVitamin D
Biochemistry and biophysics reports, 2020Co-Authors: Sarah Livingston, Carol A. Haussler, Mark R. Haussler, Sanchita Mallick, Daniel A Lucas, Marya S Sabir, Zhela L Sabir, Hespera Purdin, Sree Nidamanuri, Peter W. JurutkaAbstract:Abstract MeDiateD by the Nuclear Vitamin D receptor (VDR), the hormonally active Vitamin D metabolite, 1,25-DihyDroxyVitamin D3 (1,25D), is known to regulate expression of genes impacting calcium anD phosphorus metabolism, the immune system, anD behavior. Urolithin A, a nutrient metabolite DeriveD from pomegranate, possibly acting through AMP kinase (AMPK) signaling, supports respiratory muscle health in roDents anD longevity in C. elegans by inDucing oxiDative Damage-reversing genes anD mitophagy. We show herein that urolithin A enhances transcriptional actions of 1,25D Driven by co-transfecteD Vitamin D responsive elements (VDREs), anD Dissection of this genomic effect in cell culture reveals: 1) urolithin A concentration-DepenDency, 2) occurrence with isolateD natural VDREs, 3) Nuclear receptor selectivity for VDR over ER, LXR anD RXR, anD 4) significant 3- to 13-folD urolithin A-augmentation of 1,25D-DepenDent mRNA encoDing the wiDely expresseD 1,25D-Detoxification enzyme, CYP24A1, a benchmark Vitamin D target gene. Relevant to potential behavioral effects of Vitamin D, urolithin A elicits enhancement of 1,25D-DepenDent mRNA encoDing tryptophan hyDroxylase-2 (TPH2), the serotonergic neuron-expresseD initial enzyme in tryptophan metabolism to serotonin. Employing quantitative real time-PCR, we Demonstrate that TPH2 mRNA is inDuceD 1.9-folD by 10 nM 1,25D treatment in culture of DifferentiateD rat serotonergic raphe (RN46A-B14) cells, an effect magnifieD 2.5-folD via supplementation with 10 μM urolithin A. This potentiation of 1,25D-inDuceD TPH2 mRNA by urolithin A is followeD by a 3.1- to 3.7-folD increase in serotonin concentration in culture meDium from the pertinent neuronal cell line, RN46A-B14. These results are consistent with the concept that two natural nutrient metabolites, urolithin A from pomegranate anD 1,25D from sunlight/Vitamin D, likely acting via AMPK anD VDR, respectively, cooperate mechanistically to effect VDRE-meDiateD regulation of gene expression in neuroenDocrine cells. Finally, geDunin, a neuroprotective natural proDuct from InDian neem tree that impacts the brain DeriveD neurotropic factor pathway, similarly potentiates 1,25D/VDR-action.
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1 25 DihyDroxyVitamin D 3 regulation of fibroblast growth factor 23 expression in bone cells eviDence for primary anD seconDary mechanisms moDulateD by leptin anD interleukin 6
Calcified Tissue International, 2013Co-Authors: Rimpi K Saini, Peter W. Jurutka, Mark R. Haussler, Jui Cheng Hsieh, Ichiro Kaneko, Ryan Forster, Antony Hsieh, Kerr G WhitfieldAbstract:Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption anD to prevent hyperVitaminosis D by feeDback repressing 1,25-DihyDroxyVitamin D3 (1,25(OH)2D3) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is inDuceD by the Nuclear Vitamin D receptor (VDR) bounD to 1,25(OH)2D3, but cycloheximiDe sensitivity of this inDuction suggests that it may occur largely via seconDary mechanisms requiring cooperating transcription factors. We therefore sought to iDentify 1,25(OH)2D3-regulateD transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was founD to potentiate 1,25(OH)2D3 upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunteD this upregulation. Genomic analyses revealeD conserveD binDing sites for STATs (signal transDuction meDiators of leptin anD IL-6 action) along with transcription factor ETS1 in human anD other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, anD VDR mRNAs were inDuceD in a Dose-DepenDent manner by 1,25(OH)2D3 in UMR-106 cells. Bioinformatic analysis iDentifieD nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of meDiating Direct transcriptional activation of a heterologous reporter gene when bounD by a 1,25(OH)2D3-liganDeD VDR complex. A moDel is proposeD wherein 1,25(OH)2D3 upregulates FGF23 proDuction Directly via multiple VDREs anD inDirectly via inDuction of STAT3, ETS1, anD VDR transcription factors that are then activateD via cell surface anD intracellular signaling to cooperate in the inDuction of FGF23 through DNA looping anD generation of euchromatin architecture.
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Nuclear Vitamin D receptor natural liganDs molecular structure function anD transcriptional control of vital genes
Vitamin D (Third Edition)#R##N#Vitamin D, 2011Co-Authors: Mark R. Haussler, Carol A. Haussler, Kerr G Whitfield, Jui Cheng Hsieh, Peter W. JurutkaAbstract:Publisher Summary Small Angle X-ray Scattering anD Fluorescence Resonance Energy Transfer techniques have DetermineD the structure of the hypocalcemic Vitamin-D-resistant rickets (hVDR) DNA-binDing Domain (DBD) anD liganD-binDing Domain (LBD) together in the full-length receptor, heteroDimerizeD with full-length RXR α, DockeD on a VDRE, anD occupieD with 1,25(OH)2D3 plus a single coactivator, allowing one to begin to unDerstanD the interactions between the DBD anD the liganD-binDing/heteroDimerization Domains of both VDR anD its RXR heteropartner. A seconD major realm of accomplishment has been the iDentification of numerous aDDitional VDR-regulateD genes, incluDing those meDiating calcium anD particularly phosphate homeostasis, bone metabolism, Detoxification, cell proliferation, Differentiation, migration anD Death, immunity anD antimicrobial action, as well as carbohyDrate, lipiD, anD amino aciD metabolism. Equally exciting has been the Discovery of aDDitional natural VDR liganDs, especially in the more-recently iDentifieD anD stuDieD VDR target tissues such as the hair follicle/skin anD immune systems. The availability of this information will facilitate molecular investigations of transcriptional control by VDR in target-cell specific environments in the presence of novel liganDs anD the context of a myriaD of promoters/genes. Such experiments are likely to extenD the unDerstanDing of the variety of conformations anD coregulator associations that the VDR-RXR heteroDimer is capable of achieving while performing its multituDe of extraosseous effects to lower the risk of the chronic Diseases of aging.
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the Nuclear Vitamin D receptor controls the expression of genes encoDing factors which feeD the fountain of youth to meDiate healthful aging
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Mark R. Haussler, Paul Thompson, Carol A. Haussler, Kerr G Whitfield, Jui Cheng Hsieh, Thomas K Barthel, Leonid Bartik, Jan B Egan, Jana L Kubicek, Christine L LowmillerAbstract:The Nuclear Vitamin D receptor (VDR) binDs 1,25-DihyDroxyVitamin D3 (1,25D), its high affinity renal enDocrine liganD, to signal intestinal calcium anD phosphate absorption plus bone remoDeling, generating a mineralizeD skeleton free of rickets/osteomalacia with a reDuceD risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL anD OPG, while achieving feeDback control of mineral ions to prevent age-relateD ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, anD klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hyDroxyVitamin D3, the metabolite reflecting Vitamin D status, is converteD to 1,25D locally by extrarenal CYP27B1, anD binDs VDR to promote immunoregulation, antimicrobial Defense, xenobiotic Detoxification, anti-inflammatory/anticancer actions anD carDiovascular benefits. VDR also affects Wnt signaling through Direct interaction with β-catenin, liganD-DepenDently blunting β-catenin meDiateD transcription in colon cancer cells to attenuate growth, while potentiating β-catenin signaling via VDR liganD-inDepenDent mechanisms in osteoblasts anD keratinocytes to function osteogenically anD as a pro-hair cycling receptor, respectively. Finally, VDR also Drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, anD PTHrP. Hair proviDes a shielD against UV-inDuceD skin Damage anD cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.
Carol A. Haussler - One of the best experts on this subject based on the ideXlab platform.
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Vitamin D receptor meDiates a myriaD of biological actions DepenDent on its 1 25 DihyDroxyVitamin D liganD Distinct regulatory themes revealeD by inDuction of klotho anD fibroblast growth factor 23
JBMR plus, 2021Co-Authors: Mark R. Haussler, Peter W. Jurutka, Carol A. Haussler, Sarah Livingston, Zhela L SabirAbstract:The hormonal Vitamin D metabolite, 1,25-DihyDroxyVitamin D [1,25(OH)2D], proDuceD in kiDney, acts in numerous enD organs via the Nuclear Vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis. VDR is a liganD-controlleD transcription factor that obligatorily heteroDimerizes with retinoiD X receptor (RXR) to target Vitamin D responsive elements (VDREs) in the vicinity of Vitamin D-regulateD genes. Circulating 1,25(OH)2D concentrations are governeD by PTH, an inDucer of renal D-hormone biosynthesis catalyzeD by CYP27B1 that functions as the key player in a calcemic enDocrine circuit, anD by fibroblast growth factor-23 (FGF23), a repressor of the CYP27B1 renal enzyme, creating a hypophosphatemic enDocrine loop. 1,25(OH)2D/VDR-RXR acts in kiDney to inDuce Klotho (a phosphaturic coreceptor for FGF23) to correct hyperphosphatemia, NPT2a/c to correct hypophosphatemia, anD TRPV5 anD CaBP28k to enhance calcium reabsorption. 1,25(OH)2D-liganDeD VDR-RXR functions in osteoblasts/osteocytes by augmenting RANK-liganD expression to paracrine signal osteoclastic bone resorption, while simultaneously inDucing FGF23, SPP1, BGLP, LRP5, ANK1, ENPP1, anD TNAP, anD conversely repressing RUNX2 anD PHEX expression, effecting localizeD control of mineralization to sculpt the skeleton. Herein, we Document the history of 1,25(OH)2D/VDR anD summarize recent aDvances in characterizing their physiology, biochemistry, anD mechanism of action by highlighting two examples of 1,25(OH)2D/VDR molecular function. The first is VDR-meDiateD primary inDuction of Klotho mRNA by 1,25(OH)2D in kiDney via a mechanism initiateD by the Docking of liganDeD VDR-RXR on a VDRE at -35 kb in the mouse Klotho gene. In contrast, the seconDary inDuction of FGF23 by 1,25(OH)2D in bone is proposeD to involve rapiD nongenomic action of 1,25(OH)2D/VDR to acutely activate PI3K, in turn signaling the inDuction of MZF1, a transcription factor that, in cooperation with c-ets1-P, binDs to an enhancer element centereD at -263 bp in the promoter-proximal region of the mouse fgf23 gene. Chronically, 1,25(OH)2D-inDuceD osteopontin apparently potentiates MZF1. © 2020 The Authors. JBMR Plus publisheD by Wiley PerioDicals LLC on behalf of American Society for Bone anD Mineral Research.
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pomegranate Derivative urolithin a enhances Vitamin D receptor signaling to amplify serotonin relateD gene inDuction by 1 25 DihyDroxyVitamin D
Biochemistry and biophysics reports, 2020Co-Authors: Sarah Livingston, Carol A. Haussler, Mark R. Haussler, Sanchita Mallick, Daniel A Lucas, Marya S Sabir, Zhela L Sabir, Hespera Purdin, Sree Nidamanuri, Peter W. JurutkaAbstract:Abstract MeDiateD by the Nuclear Vitamin D receptor (VDR), the hormonally active Vitamin D metabolite, 1,25-DihyDroxyVitamin D3 (1,25D), is known to regulate expression of genes impacting calcium anD phosphorus metabolism, the immune system, anD behavior. Urolithin A, a nutrient metabolite DeriveD from pomegranate, possibly acting through AMP kinase (AMPK) signaling, supports respiratory muscle health in roDents anD longevity in C. elegans by inDucing oxiDative Damage-reversing genes anD mitophagy. We show herein that urolithin A enhances transcriptional actions of 1,25D Driven by co-transfecteD Vitamin D responsive elements (VDREs), anD Dissection of this genomic effect in cell culture reveals: 1) urolithin A concentration-DepenDency, 2) occurrence with isolateD natural VDREs, 3) Nuclear receptor selectivity for VDR over ER, LXR anD RXR, anD 4) significant 3- to 13-folD urolithin A-augmentation of 1,25D-DepenDent mRNA encoDing the wiDely expresseD 1,25D-Detoxification enzyme, CYP24A1, a benchmark Vitamin D target gene. Relevant to potential behavioral effects of Vitamin D, urolithin A elicits enhancement of 1,25D-DepenDent mRNA encoDing tryptophan hyDroxylase-2 (TPH2), the serotonergic neuron-expresseD initial enzyme in tryptophan metabolism to serotonin. Employing quantitative real time-PCR, we Demonstrate that TPH2 mRNA is inDuceD 1.9-folD by 10 nM 1,25D treatment in culture of DifferentiateD rat serotonergic raphe (RN46A-B14) cells, an effect magnifieD 2.5-folD via supplementation with 10 μM urolithin A. This potentiation of 1,25D-inDuceD TPH2 mRNA by urolithin A is followeD by a 3.1- to 3.7-folD increase in serotonin concentration in culture meDium from the pertinent neuronal cell line, RN46A-B14. These results are consistent with the concept that two natural nutrient metabolites, urolithin A from pomegranate anD 1,25D from sunlight/Vitamin D, likely acting via AMPK anD VDR, respectively, cooperate mechanistically to effect VDRE-meDiateD regulation of gene expression in neuroenDocrine cells. Finally, geDunin, a neuroprotective natural proDuct from InDian neem tree that impacts the brain DeriveD neurotropic factor pathway, similarly potentiates 1,25D/VDR-action.
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Nuclear Vitamin D receptor natural liganDs molecular structure function anD transcriptional control of vital genes
Vitamin D (Third Edition)#R##N#Vitamin D, 2011Co-Authors: Mark R. Haussler, Carol A. Haussler, Kerr G Whitfield, Jui Cheng Hsieh, Peter W. JurutkaAbstract:Publisher Summary Small Angle X-ray Scattering anD Fluorescence Resonance Energy Transfer techniques have DetermineD the structure of the hypocalcemic Vitamin-D-resistant rickets (hVDR) DNA-binDing Domain (DBD) anD liganD-binDing Domain (LBD) together in the full-length receptor, heteroDimerizeD with full-length RXR α, DockeD on a VDRE, anD occupieD with 1,25(OH)2D3 plus a single coactivator, allowing one to begin to unDerstanD the interactions between the DBD anD the liganD-binDing/heteroDimerization Domains of both VDR anD its RXR heteropartner. A seconD major realm of accomplishment has been the iDentification of numerous aDDitional VDR-regulateD genes, incluDing those meDiating calcium anD particularly phosphate homeostasis, bone metabolism, Detoxification, cell proliferation, Differentiation, migration anD Death, immunity anD antimicrobial action, as well as carbohyDrate, lipiD, anD amino aciD metabolism. Equally exciting has been the Discovery of aDDitional natural VDR liganDs, especially in the more-recently iDentifieD anD stuDieD VDR target tissues such as the hair follicle/skin anD immune systems. The availability of this information will facilitate molecular investigations of transcriptional control by VDR in target-cell specific environments in the presence of novel liganDs anD the context of a myriaD of promoters/genes. Such experiments are likely to extenD the unDerstanDing of the variety of conformations anD coregulator associations that the VDR-RXR heteroDimer is capable of achieving while performing its multituDe of extraosseous effects to lower the risk of the chronic Diseases of aging.
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the Nuclear Vitamin D receptor controls the expression of genes encoDing factors which feeD the fountain of youth to meDiate healthful aging
The Journal of Steroid Biochemistry and Molecular Biology, 2010Co-Authors: Mark R. Haussler, Paul Thompson, Carol A. Haussler, Kerr G Whitfield, Jui Cheng Hsieh, Thomas K Barthel, Leonid Bartik, Jan B Egan, Jana L Kubicek, Christine L LowmillerAbstract:The Nuclear Vitamin D receptor (VDR) binDs 1,25-DihyDroxyVitamin D3 (1,25D), its high affinity renal enDocrine liganD, to signal intestinal calcium anD phosphate absorption plus bone remoDeling, generating a mineralizeD skeleton free of rickets/osteomalacia with a reDuceD risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL anD OPG, while achieving feeDback control of mineral ions to prevent age-relateD ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, anD klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hyDroxyVitamin D3, the metabolite reflecting Vitamin D status, is converteD to 1,25D locally by extrarenal CYP27B1, anD binDs VDR to promote immunoregulation, antimicrobial Defense, xenobiotic Detoxification, anti-inflammatory/anticancer actions anD carDiovascular benefits. VDR also affects Wnt signaling through Direct interaction with β-catenin, liganD-DepenDently blunting β-catenin meDiateD transcription in colon cancer cells to attenuate growth, while potentiating β-catenin signaling via VDR liganD-inDepenDent mechanisms in osteoblasts anD keratinocytes to function osteogenically anD as a pro-hair cycling receptor, respectively. Finally, VDR also Drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, anD PTHrP. Hair proviDes a shielD against UV-inDuceD skin Damage anD cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.
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functionally relevant polymorphisms in the human Nuclear Vitamin D receptor gene
Molecular and Cellular Endocrinology, 2001Co-Authors: Kerr G Whitfield, Peter W. Jurutka, Carol A. Haussler, L S Remus, Heike Zitzer, Anish K Oza, Hope Dang, Michael A Galligan, Michelle L Thatcher, Carlos Encinas DominguezAbstract:The functional significance of two unlinkeD human Vitamin D receptor (hVDR) gene polymorphisms was evaluateD in twenty human fibroblast cell lines. Genotypes at both a Fok I restriction site (F/f) in exon II anD a singlet (A) repeat in exon IX (L/S) were DetermineD, anD relative transcription activities of enDogenous hVDR proteins were measureD using a transfecteD, 1,25-DihyDroxyVitamin D(3)-responsive reporter gene. ObserveD activities rangeD from 2--100-folD inDuction by hormone, with higher activity being DisplayeD by the F anD the L biallelic forms. Only when genotypes at both sites were consiDereD simultaneously DiD statistically significant Differences emerge. Moreover, the correlation between hVDR activity anD genotype segregateD further into clearly DefineD high anD low activity groups with similar genotypic Distributions. These results not only Demonstrate functional relevance for both the F/f anD L/S common polymorphisms in hVDR, but also proviDe novel eviDence for a thirD genetic variable impacting receptor potency.
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the impact of Vitamin D in breast cancer genomics pathways metabolism
Frontiers in Physiology, 2014Co-Authors: Carmen J Narvaez, Donald G Matthews, Erika Laporta, Katrina Simmons, Sarah Beaudin, Joellen WelshAbstract:Nuclear receptors exert profounD effects on mammary glanD physiology anD have complex roles in the etiology of breast cancer. In aDDition to receptors for classic steroiD hormones such as estrogen anD progesterone, the Nuclear Vitamin D receptor (VDR) interacts with its liganD 1α,25(OH)2D3 to moDulate the normal mammary epithelial cell genome anD subsequent phenotype. Observational stuDies suggest that Vitamin D Deficiency is common in breast cancer patients anD that low Vitamin D status enhances the risk for Disease Development or progression. Genomic profiling has characterizeD many 1α,25(OH)2D3 responsive targets in normal mammary cells anD in breast cancers, proviDing insight into the molecular actions of 1α,25(OH)2D3 anD the VDR in regulation of cell cycle, apoptosis anD Differentiation. New areas of emphasis incluDe regulation of tumor metabolism anD innate immune responses. However, the role of VDR in inDiviDual cell types (ie epithelial, aDipose, fibroblast, enDotelial, immune) of normal anD tumor tissues remains to be clarifieD. Furthermore, the mechanisms by which VDR integrates signaling between Diverse cell types anD controls soluble signals anD paracrine pathways in the tissue/tumor microenvironment remain to be DefineD. MoDel systems of carcinogenesis have proviDeD eviDence that both VDR expression anD 1α,25(OH)2D3 actions change with transformation but clinical Data regarDing Vitamin D responsiveness of establisheD tumors is limiteD anD inconclusive. Because breast cancer is heterogeneous, analysis of VDR actions in specific molecular subtypes of the Disease may help to clarify the conflicting Data. The expanDeD use of genomic, proteomic anD metabolomic approaches on a Diverse array of in vitro anD in vivo moDel systems is clearly warranteD to comprehensively unDerstanD the nework of Vitamin D regulateD pathways in the context of breast cancer.
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breast cancer cell regulation by high Dose Vitamin D compounDs in the absence of Nuclear Vitamin D receptor
The Journal of Steroid Biochemistry and Molecular Biology, 2004Co-Authors: Meggan Valrance, Joellen WelshAbstract:1alpha,25-DihyDroxyVitamin D(3) (1,25D(3)) inhibits growth anD inDuces apoptosis in breast cancer cells in vivo anD in vitro. To examine the role of the Vitamin D receptor (VDR) in meDiating the actions of 1,25D(3) at nanomolar anD micromolar concentrations, mammary epithelial tumor cell lines generateD in wilD type (WT) anD VDR knockout (VDRKO) mice were utilizeD. WT cells express VDR anD are growth inhibiteD by 1,25D(3) anD synthetic analogs EB1089 anD CB1093 at 1nM concentrations, while VDRKO cells Do not express VDR anD are insensitive to Vitamin D compounDs at concentrations up to 100nM. In the current stuDies, we have confirmeD anD extenDeD these previous observations. At nanomolar concentrations of 1,25D(3) anD all analogs testeD, incluDing EB1089, CB1093, MC1288, anD KH1230, WT cells are growth inhibiteD anD exhibit apoptotic morphology, while VDRKO cells show no growth inhibition or apoptosis. At concentrations of 1-10microM, however, 1,25D(3) anD synthetic analogs inDuce growth inhibition anD apoptotic morphology in both WT anD VDRKO cell lines. These Data inDicate that nanomolar concentrations of 1,25D(3) anD analogs meDiate growth regulatory effects via mechanisms requiring the Nuclear VDR, but that micromolar concentrations of Vitamin D compounDs can exert non VDR-meDiateD effects.
