The human vitamin D receptor (VDR) is a key nuclear receptor that binds nutritionally derived ligands and exerts bioeffects that contribute to bone mineral homeostasis, detoxification of exogenous ...and endogenous compounds, cancer prevention, and mammalian hair cycling. Liganded VDR modulates gene expression via heterodimerization with the retinoid X receptor and recruitment of coactivators or corepressors. VDR interacts with the corepressor hairless (Hr) to control hair cycling, an action independent of the endocrine VDR ligand, 1,25-dihydroxyvitamin D3. We report novel dietary ligands for VDR including curcumin, γ-tocotrienol, and essential fatty acid derivatives that likely play a role in the bioactions of VDR.
The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D
3 (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 D
3, 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.
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 ω3/ω6 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.
The nuclear vitamin D receptor (VDR) mediates the actions of 1,25-dihydroxyvitamin D
3 (1,25D) to regulate gene transcription. Recently, the secondary bile acid, lithocholate (LCA), was recognized as ...a novel VDR ligand. Using reporter gene and mammalian two-hybrid systems, immunoblotting, competitive ligand displacement and quantitative real-time PCR, we identified curcumin (CM), a turmeric-derived bioactive polyphenol, as a likely additional novel ligand for VDR. CM (10
−5 M) activated transcription of a luciferase plasmid containing the distal vitamin D responsive element (VDRE) from the human CYP3A4 gene at levels comparable to 1,25D (10
−8 M) in transfected human colon cancer cells (Caco-2). While CM also activated transcription via a retinoid X receptor (RXR) responsive element, activation of the glucocorticoid receptor (GR) by CM was negligible. Competition binding assays with radiolabeled 1,25D confirmed that CM binds directly to VDR. In mammalian two-hybrid assays employing transfected Caco-2 cells, CM (10
−5 M) increased the ability of VDR to recruit its heterodimeric partner, RXR, and steroid receptor coactivator-1 (SRC-1). Real-time PCR studies revealed that CM-bound VDR can activate VDR target genes CYP3A4, CYP24, p21 and TRPV6 in Caco-2 cells. Numerous studies have shown chemoprotection by CM against intestinal cancers via a variety of mechanisms. Small intestine and colon are important VDR-expressing tissues where 1,25D has known anticancer properties that may, in part, be elicited by activation of CYP-mediated xenobiotic detoxification and/or up-regulation of the tumor suppressor p21. Our results suggest the novel hypothesis that nutritionally-derived CM facilitates chemoprevention via direct binding to, and activation of, VDR.
Objectives To perform a multi-institutional study to characterize CT-detected complications after PNL. Computed tomography (CT) is commonly performed after percutaneous nephrolithotomy (PNL). One ...benefit of this imaging modality is the detection of procedure-related complications. Presently, the incidence of such complications is not well-defined. Patients and Methods PNL procedures performed at 5 stone referral centers between July 2007 and June 2008 were reviewed. All patients undergoing CT within 24 hours after surgery were selected for further analysis. All CT studies were reviewed by a staff radiologist. Results One-hundred ninety-seven patients satisfied the study inclusion criteria. A body mass index >30 was present in 27.5% of patients. Treated stone burden was staghorn in 70 (35.5%), >2 cm in 72 (36.5%), and <2 cm in 55 (28%). Six treated renal units (3%) were ectopic; 45.4% of calculi were predominantly lower pole. Thoracic complications encountered were atelectasis in 88 (44.7%), pleural effusion in 17 (8.6%), pneumothorax in 3 (1.5%), hemothorax in 2 (1%), and hydrothorax in 1 (0.5%). Renal complications were perinephric hematoma in 15 (7.6%), collecting system perforation in 4 (2%), subcapsular hematoma in 3 (1.5%), urinoma in 2 (1%), and pseudoaneurysm in 1 (0.5%). There was 1 trans-splenic nephrostomy without splenic hematoma. No injuries to hollow viscera were detected. Two patients (1%) were found to have ascites. Conclusions Major post-PNL complications detected by CT are uncommon, and when encountered, they are generally amenable to conservative management.
The activity of -catenin, commonly dysregulated in human colon cancers, is inhibited by the vitamin D receptor (VDR), and this mechanism is postulated to explain the putative anti-cancer activity of ...vitamin D metabolites in the colon. We investigated the effect of a common FokI restriction site polymorphism (F/f) in the human VDR gene as well as the effect of anti-tumorigenic 1,25-dihydroxyvitamin D3 (1,25D) and pro-tumorigenic lithocholic acid (LCA) VDR ligands on -catenin transcriptional activity. Furthermore, the influence of a major regulatory protein of -catenin, the APC tumor suppressor gene, on VDR-dependent inhibition of -catenin activity was examined. We report herein that -catenin-mediated transcription is most effectively suppressed by the VDR FokI variant F/M4 when 1,25D is limiting. Using Caco-2 colorectal cancer (CRC) cells, it was observed that VDR ligands, 1,25D and LCA, both suppress -catenin transcriptional activity, though 1,25D exhibited significantly greater inhibition. Moreover, 1,25D, but not LCA, suppressed endogenous expression of the -catenin target gene DKK-4 independent of VDR DNA-binding activity. These results support -catenin sequestration away from endogenous gene targets by 1,25D-VDR. This activity is most efficiently mediated by the FokI gene variant F/M4, a VDR allele previously associated with protection against CRC. Interestingly, we found the inhibition of -catenin activity by 1,25D-VDR was significantly enhanced by wild-type APC. These results reveal a previously unrecognized role for 1,25D-VDR in APC/-catenin cross talk. Collectively, these findings strengthen evidence favoring a direct effect on the Wnt-signaling molecule -catenin as one anti-cancer target of 1,25D-VDR action in the colorectum.
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