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.

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.

The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D (1,25D), produced primarily in the kidney, acts in numerous end-organs via the nuclear vitamin D receptor (VDR) to trigger molecular events that orchestrate bone mineral homeostasis, immune responsiveness, and aspects of behavior. Tyrosine hydroxylase (TH) encodes a neuronally expressed enzyme that catalyzes the initial, rate-limiting step in the production of several catecholamine neurotransmitters and hormones, including dopamine, norepinephrine, and epinephrine. Herein we report that TH mRNA is significantly induced (2.5-fold) and NURR1 mRNA is induced 9.3-fold by 10 nM 1,25D in differentiated human SH-SY5Y neuroblastoma cells. Similar results were observed in human U87 glioblastoma cells (TH, 2.6-fold; NURR1, 3.6-fold). Comparative analysis of TH gene promoter-proximal sequences from human, mouse, and rat identifies candidate NURR1-responsive elements (NBREs) at the following positions: −35, −855, −1470, and −2343 bp in the human gene; −34 and −961 bp in the mouse gene; and −34, −350, and −873 bp in the rat gene, consistent with NURR1 acting as a recurring regulatory factor at TH promoters across mammalian species. Furthermore, by interrogating VDR ChIP-seq/cistrome datasets, we identified candidate vitamin D-responsive elements (VDREs) at the human NURR1 locus that provide a plausible genomic framework for direct regulation of NURR1 by 1,25D/VDR. We propose that 1,25D-liganded VDR acts as a primary inducer of NURR1, which in turn secondarily activates expression of the TH gene, thereby defining a transcriptional route through which 1,25D/VDR signaling may influence TH-linked dopaminergic gene programs. Retinoid X receptor (RXR) may facilitate both NURR1-dependent and -independent potentiation of TH transcription because the rexinoid, bexarotene, significantly enhances TH mRNA in human U87 cells, either alone (2.0-fold) or in combination with 1,25D (4.1-fold). In addition, bexarotene and its novel analogs, A41 and A55, induce NURR1 mRNA expression in U87 cells by 2.8-, 3.1-, and 4.8-fold, respectively, with A55 outperforming the parent compound at matched concentration. Because Parkinson’s disease is characterized by the selective degeneration of dopaminergic neurons and impaired NURR1-dependent transcriptional programs, our findings identify a 1,25D/VDR–NURR1–RXR transcriptional axis as a previously underappreciated regulatory framework for studying TH gene expression and dopaminergic gene regulation in Parkinson’s disease-relevant neural contexts.