scholarly journals Lithocholic Acid Amides as Potent Vitamin D Receptor Agonists

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 130
Author(s):  
Ayana Yoshihara ◽  
Haru Kawasaki ◽  
Hiroyuki Masuno ◽  
Koki Takada ◽  
Nobutaka Numoto ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Lithocholic Acid ◽  
Active Form ◽  
Binding Pocket ◽  
Carboxyl Group ◽  
Amino Acid Residues ◽  
Dihydroxyvitamin D3 ◽  
Biological Phenomena ◽  
Amide Derivatives

1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3, 1] is an active form of vitamin D3 and regulates various biological phenomena, including calcium and phosphate homeostasis, bone metabolism, and immune response via binding to and activation of vitamin D receptor (VDR). Lithocholic acid (LCA, 2) was identified as a second endogenous agonist of VDR, though its potency is very low. However, the lithocholic acid derivative 3 (Dcha-20) is a more potent agonist than 1α,25(OH)2D3, (1), and its carboxyl group has similar interactions to the 1,3-dihydroxyl groups of 1 with amino acid residues in the VDR ligand-binding pocket. Here, we designed and synthesized amide derivatives of 3 in order to clarify the role of the carboxyl group. The synthesized amide derivatives showed HL-60 cell differentiation-inducing activity with potency that depended upon the substituent on the amide nitrogen atom. Among them, the N-cyanoamide 6 is more active than either 1 or 3.

scholarly journals Is the Vitamin D Receptor Found in Muscle?

Endocrinology ◽  
2010 ◽  
Vol 152 (2) ◽  
pp. 354-363 ◽  
Author(s):  
Yongji Wang ◽  
Hector F. DeLuca
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Bone Mineralization ◽  
Active Form ◽  
Dihydroxyvitamin D3 ◽  
Neuromuscular Activity ◽  
Immunohistochemical Assay ◽  
Underlying Mechanisms ◽  
Positive Results ◽  
Phosphorus Levels

Abstract The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is critical for the regulation of serum calcium and phosphorus levels that in turn support bone mineralization and neuromuscular activity. It is well known that vitamin D deficiency causes rachitic/osteomalacic myopathy and cardiac disorder and the provision of vitamin D can reverse the symptoms. However, the underlying mechanisms remain unclear. The question of whether the vitamin D receptor is found in muscle has been debated but not settled. We recently studied all available antibodies against the vitamin D receptor and found that most antibodies used detect proteins other than the vitamin D receptor, and therefore, the utility of these antibodies may generate the false-positive results. Using antibodies that do not detect proteins in tissues from vitamin D receptor null mice, we have developed a specific and sensitive immunohistochemical assay. The results from this investigation show that the vitamin D receptor is undetectable in skeletal, cardiac, and smooth muscle, suggesting that the function of vitamin D on muscle is either of an indirect nature or does not involve the known receptor.

scholarly journals Calmodulin-Dependent Kinase IV Stimulates Vitamin D Receptor-Mediated Transcription

2005 ◽  
Vol 19 (9) ◽  
pp. 2309-2319 ◽  
Author(s):  
Tara I. Ellison ◽  
Diane R. Dowd ◽  
Paul N. MacDonald
Keyword(s):  
Gene Expression ◽  
Vitamin D ◽  
Reporter Gene ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Metabolic Labeling ◽  
Dihydroxyvitamin D3 ◽  
Steroid Receptor Coactivator ◽  
Functional Consequences ◽  
Dependent Interaction

Abstract 1,25-Dihydroxyvitamin D3 [1,25-(OH)2D3] promotes intestinal absorption of calcium primarily by binding to the vitamin D receptor (VDR) and regulating gene expression. 1,25-(OH)2D3 also exerts rapid actions at the cell membrane that include increasing intracellular calcium levels and activating protein kinase cascades. To explore potential cross talk between calcium signaling elicited by the nongenomic actions of 1,25-(OH)2D3 and the genomic pathway mediated by VDR, we examined the effects of activated Ca2+/calmodulin-dependent kinases (CaMKs) on 1,25-(OH)2D3/VDR-mediated transcription. Expression of a constitutively active form of CaMKIV dramatically stimulated 1,25-(OH)2D3-activated reporter gene expression in COS-7, HeLa, and ROS17/2.8 cell lines. Metabolic labeling studies indicated that CaMKIV increased VDR phosphorylation levels. In addition, CaMKIV increased the independent transcription activity of the VDR coactivator SRC (steroid receptor coactivator) 1, and promoted ligand-dependent interaction between VDR and SRC coactivator proteins in mammalian two-hybrid studies. The functional consequences of this multifaceted mechanism of CaMKIV action were revealed by reporter gene studies, which showed that CaMKIV and select SRC coactivators synergistically enhanced VDR-mediated transcription. These studies support a model in which CaMKIV signaling stimulates VDR-mediated transcription by increasing phosphorylation levels of VDR and enhancing autonomous SRC activity, resulting in higher 1,25-(OH)2D3-dependent interaction between VDR and SRC coactivators.

scholarly journals Vitamin D receptor and STAT3 cooperate to establish TET2-mediated tolerogenesis

2020 ◽  
Author(s):  
Francesc Català-Moll ◽  
Tianlu Li ◽  
Laura Ciudad ◽  
Javier Rodríguez-Ubreva ◽  
Esteban Ballestar
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Transcriptional Activation ◽  
Binding Sites ◽  
Active Form ◽  
Dna Demethylation ◽  
Phenotypic Stability ◽  
Dihydroxyvitamin D3 ◽  
Phosphorylated Form ◽  
Stat3 Phosphorylation

SUMMARYThe active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), induces stable tolerogenesis in dendritic cells (DCs). This process involves the vitamin D receptor (VDR), which translocates to the nucleus, binds its cognate genomic sites, and promotes epigenetic and transcriptional remodeling. In this study, we investigated the interplay between the VDR and other transcription factors to induce DNA methylation changes that might provide phenotypic stability to the tolerogenic phenotype of DCs. Our study reveals the occurrence of vitamin D-specific DNA demethylation and transcriptional activation at VDR binding sites associated with the acquisition of tolerogenesis. Tolerogenic properties in DCs are acquired together with activation of the IL6-JAK-STAT3 pathway. In fact, VDR directly binds the IL6 gene, and JAK2-mediated STAT3 phosphorylation is specific to vitamin D stimulation. VDR and the phosphorylated form of STAT3 interact with each other and with methylcytosine dioxygenase TET2 following vitamin D treatment. Most importantly, pharmacological inhibition of STAT3 phosphorylation reverts the vitamin-induced tolerogenic properties of DCs. Our results reveal an interplay between VDR and STAT3 leading to the DNA demethylation-dependent induction of tolerogenesis by vitamin D.

scholarly journals Is the Vitamin D Receptor Found in Muscle?

2011 ◽  
Vol 32 (1) ◽  
pp. 152-152 ◽  
Author(s):  
Yongji Wang ◽  
Hector F. DeLuca
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Bone Mineralization ◽  
Active Form ◽  
Dihydroxyvitamin D3 ◽  
Neuromuscular Activity ◽  
Immunohistochemical Assay ◽  
Underlying Mechanisms ◽  
Positive Results ◽  
Phosphorus Levels

Abstract The active form of vitamin D, 1α,25-dihydroxyvitamin D3, is critical for the regulation of serum calcium and phosphorus levels that in turn support bone mineralization and neuromuscular activity. It is well known that vitamin D deficiency causes rachitic/osteomalacic myopathy and cardiac disorder and the provision of vitamin D can reverse the symptoms. However, the underlying mechanisms remain unclear. The question of whether the vitamin D receptor is found in muscle has been debated but not settled. We recently studied all available antibodies against the vitamin D receptor and found that most antibodies used detect proteins other than the vitamin D receptor, and therefore, the utility of these antibodies may generate the false-positive results. Using antibodies that do not detect proteins in tissues from vitamin D receptor null mice, we have developed a specific and sensitive immunohistochemical assay. The results from this investigation show that the vitamin D receptor is undetectable in skeletal, cardiac, and smooth muscle, suggesting that the function of vitamin D on muscle is either of an indirect nature or does not involve the known receptor.

Lithocholic Acid-Based Design of Noncalcemic Vitamin D Receptor Agonists

2021 ◽  
pp. 104878
Author(s):  
Sunil Gaikwad ◽  
Carmen M. González ◽  
Daniel Vilariño ◽  
Gonzalo Lasanta ◽  
Carmen Villaverde ◽  
...  
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Lithocholic Acid ◽  
Receptor Agonists

scholarly journals Vitamin D-Mediated Hypercalcemia: Mechanisms, Diagnosis, and Treatment

2016 ◽  
Vol 37 (5) ◽  
pp. 521-547 ◽  
Author(s):  
Peter J. Tebben ◽  
Ravinder J. Singh ◽  
Rajiv Kumar
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Active Form ◽  
Elevated Serum ◽  
Diagnosis And Treatment ◽  
Vitamin D Metabolites ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Stone Formers ◽  
25 Hydroxyvitamin D

AbstractHypercalcemia occurs in up to 4% of the population in association with malignancy, primary hyperparathyroidism, ingestion of excessive calcium and/or vitamin D, ectopic production of 1,25-dihydroxyvitamin D [1,25(OH)2D], and impaired degradation of 1,25(OH)2D. The ingestion of excessive amounts of vitamin D3 (or vitamin D2) results in hypercalcemia and hypercalciuria due to the formation of supraphysiological amounts of 25-hydroxyvitamin D [25(OH)D] that bind to the vitamin D receptor, albeit with lower affinity than the active form of the vitamin, 1,25(OH)2D, and the formation of 5,6-trans 25(OH)D, which binds to the vitamin D receptor more tightly than 25(OH)D. In patients with granulomatous disease such as sarcoidosis or tuberculosis and tumors such as lymphomas, hypercalcemia occurs as a result of the activity of ectopic 25(OH)D-1-hydroxylase (CYP27B1) expressed in macrophages or tumor cells and the formation of excessive amounts of 1,25(OH)2D. Recent work has identified a novel cause of non-PTH-mediated hypercalcemia that occurs when the degradation of 1,25(OH)2D is impaired as a result of mutations of the 1,25(OH)2D-24-hydroxylase cytochrome P450 (CYP24A1). Patients with biallelic and, in some instances, monoallelic mutations of the CYP24A1 gene have elevated serum calcium concentrations associated with elevated serum 1,25(OH)2D, suppressed PTH concentrations, hypercalciuria, nephrocalcinosis, nephrolithiasis, and on occasion, reduced bone density. Of interest, first-time calcium renal stone formers have elevated 1,25(OH)2D and evidence of impaired 24-hydroxylase-mediated 1,25(OH)2D degradation. We will describe the biochemical processes associated with the synthesis and degradation of various vitamin D metabolites, the clinical features of the vitamin D-mediated hypercalcemia, their biochemical diagnosis, and treatment.

Structural Insights into the Molecular Mechanism of Vitamin D Receptor Activation by Lithocholic Acid Involving a New Mode of Ligand Recognition

2014 ◽  
Vol 57 (11) ◽  
pp. 4710-4719 ◽  
Author(s):  
Anna Y. Belorusova ◽  
Jérôme Eberhardt ◽  
Noëlle Potier ◽  
Roland H. Stote ◽  
Annick Dejaegere ◽  
...  
Keyword(s):  
Vitamin D ◽  
Molecular Mechanism ◽  
Vitamin D Receptor ◽  
Lithocholic Acid ◽  
Receptor Activation ◽  
Ligand Recognition ◽  
Structural Insights

scholarly journals The Role of Vitamin D and Vitamin D Receptor in Immunity toLeishmania majorInfection

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
James P. Whitcomb ◽  
Mary DeAgostino ◽  
Mark Ballentine ◽  
Jun Fu ◽  
Martin Tenniswood ◽  
...  
Keyword(s):  
Vitamin D ◽  
Immune Responses ◽  
Vitamin D Receptor ◽  
Leishmania Major ◽  
Active Form ◽  
Wild Type ◽  
Vitamin D Signaling ◽  
Deficient Mice ◽  
Th 1

Vitamin D signaling modulates a variety of immune responses. Here, we assessed the role of vitamin D in immunity to experimental leishmaniasis infection in vitamin D receptor-deficient mice (VDRKO). We observed that VDRKO mice on a genetically resistant background have decreasedLeishmania major-induced lesion development compared to wild-type (WT) mice; additionally, parasite loads in infected dermis were significantly lower at the height of infection. Enzymatic depletion of the active form of vitamin D mimics the ablation of VDR resulting in an increased resistance toL. major. Conversely, VDRKO or vitamin D-deficient mice on the susceptible Th2-biased background had no change in susceptibility. These studies indicate vitamin D deficiency, either through the ablation of VDR or elimination of its ligand, 1,25D3, leads to an increase resistance toL. majorinfection but only in a host that is predisposed for Th-1 immune responses.

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