scholarly journals Analysis of 1,25-Dihydroxyvitamin D3 Genomic Action Reveals Calcium-Regulating and Calcium-Independent Effects in Mouse Intestine and Human Enteroids

2020 ◽  
Vol 41 (1) ◽  
pp. e00372-20
Author(s):  
Shanshan Li ◽  
Jessica De La Cruz ◽  
Steven Hutchens ◽  
Somshuvra Mukhopadhyay ◽  
Zachary K. Criss ◽  
...  
Keyword(s):  
Vitamin D ◽  
Calcium Transport ◽  
Target Genes ◽  
Dihydroxyvitamin D3 ◽  
Transgenic Expression ◽  
Distal Intestine ◽  
Dihydroxyvitamin D ◽  
Active Calcium ◽  
Independent Effects ◽  
Proximal Intestine

ABSTRACTAlthough vitamin D is critical for the function of the intestine, most studies have focused on the duodenum. We show that transgenic expression of the vitamin D receptor (VDR) only in the distal intestine of VDR null mice (KO/TG mice) results in the normalization of serum calcium and rescue of rickets. Although it had been suggested that calcium transport in the distal intestine involves a paracellular process, we found that the 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]-activated genes in the proximal intestine associated with active calcium transport (Trpv6, S100g, and Atp2b1) are also induced by 1,25(OH)2D3 in the distal intestine of KO/TG mice. In addition, Slc30a10, encoding a manganese efflux transporter, was one of the genes most induced by 1,25(OH)2D3 in both proximal and distal intestine. Both villus and crypt were found to express Vdr and VDR target genes. RNA sequence (RNA-seq) analysis of human enteroids indicated that the effects of 1,25(OH)2D3 observed in mice are conserved in humans. Using Slc30a10−/− mice, a loss of cortical bone and a marked decrease in S100g and Trpv6 in the intestine was observed. Our findings suggest an interrelationship between vitamin D and intestinal Mn efflux and indicate the importance of distal intestinal segments to vitamin D action.

Duodenal and ileal calcium absorption in the rat and effects of vitamin D

1983 ◽  
Vol 244 (6) ◽  
pp. G695-G700 ◽  
Author(s):  
D. Pansu ◽  
C. Bellaton ◽  
C. Roche ◽  
F. Bronner
Keyword(s):  
Vitamin D ◽  
Calcium Binding ◽  
Calcium Transport ◽  
Calcium Absorption ◽  
Cytosolic Calcium ◽  
Chemical Gradient ◽  
Dihydroxyvitamin D3 ◽  
1,25 Dihydroxyvitamin D3 ◽  
Loop Procedure ◽  
Proximal Intestine

An in situ ligated loop procedure was applied to dissect transmural calcium transport in the intestine into two components, a saturable and a nonsaturable process. The existence of two such processes was confirmed in the duodenum, but ileal calcium transport was devoid of the saturable component. There was a small saturable component in the upper jejunum. The level of CaBP, the vitamin D-dependent cytosolic calcium-binding protein (Mr, approximately or equal to 9,000), corresponded to the magnitude of the saturable component. No CaBP was detected in the ileum. Vitamin D dependence of the saturable component was established by inducing it in the duodenum of vitamin D-deficient animals following intraperitoneal injection of 1,25-dihydroxyvitamin D3. In these same animals, conversely, the ileum did not respond to exogenous 1,25-dihydroxyvitamin D3. This confirms the absence in the ileum of the saturable component of transmural calcium movement and the fact that the nonsaturable component is not vitamin D dependent. Everted sac experiments also showed that duodenal sacs from vitamin D-replete or -repleted animals transported calcium against a chemical gradient, whereas ileal sacs did not. Vitamin D regulation of intestinal calcium absorption thus occurs only in the proximal intestine, even though calcium is absorbed down its chemical gradient all along the small intestine.

Temporal changes in tissue 1α,25-dihydroxyvitamin D3, vitamin D receptor target genes, and calcium and PTH levels after 1,25(OH)2D3 treatment in mice

2013 ◽  
Vol 304 (9) ◽  
pp. E977-E989 ◽  
Author(s):  
Edwin C. Y. Chow ◽  
Holly P. Quach ◽  
Reinhold Vieth ◽  
K. Sandy Pang
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Calcium Ion ◽  
Target Genes ◽  
Feedback Regulation ◽  
Plasma Calcium ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Temporal Correlations ◽  
Temporal Profiles

The vitamin D receptor (VDR) maintains a balance of plasma calcium and 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3], its natural active ligand, by directly regulating the calcium ion channel (TRPV6) and degradation enzyme (CYP24A1), and indirectly regulating the parathyroid hormone (PTH) for feedback regulation of the synthetic enzyme CYP27B1. Studies that examined the intricate relationships between plasma and tissue 1,25(OH)2D3 levels and changes in VDR target genes and plasma calcium and PTH are virtually nonexistent. In this study, we investigated temporal correlations between tissue 1,25(OH)2D3 concentrations and VDR target genes in ileum and kidney and plasma calcium and PTH concentrations in response to 1,25(OH)2D3 treatment in mice (2.5 μg/kg ip, singly or q2d × 4). After a single ip dose, plasma 1,25(OH)2D3 peaked at ∼0.5 h and then decayed biexponentially, falling below basal levels after 24 h and then returning to baseline after 8 days. Upon repetitive ip dosing, plasma, ileal, renal, and bone 1,25(OH)2D3 concentrations rose and decayed in unison. Temporal profiles showed increased expressions of ileal Cyp24a1 and renal Cyp24a1, Mdr1/P-gp, and VDR but decreased renal Cyp27b1 mRNA after a time delay in VDR activation. Increased plasma calcium and attenuated PTH levels and increased ileal and renal Trpv6 expression paralleled the changes in tissue 1,25(OH)2D3 concentrations. Gene changes in the kidney were more sustained than those in intestine, but the magnitudes of change for Cyp24a1 and Trpv6 were lower than those in intestine. The data revealed that 1,25(OH)2D3 equilibrates with tissues rapidly, and VDR target genes respond quickly to exogenously administered 1,25(OH)2D3.

Calcium transport in small intestine during pregnancy and lactation

1980 ◽  
Vol 239 (1) ◽  
pp. E64-E68 ◽  
Author(s):  
B. P. Halloran ◽  
H. F. DeLuca
Keyword(s):  
Vitamin D ◽  
Reproductive Cycle ◽  
Calcium Transport ◽  
Plasma Concentrations ◽  
Dihydroxyvitamin D ◽  
Control Value ◽  
1,25 Dihydroxyvitamin D ◽  
Everted Gut Sac ◽  
Pregnancy And Lactation ◽  
Active Calcium

The factors involved in calcium homeostasis during the mammalian reproductive cycle and specifically in the control of active calcium transport in the intestine have not been thoroughly investigated. For this reason calcium transport in the intestine was measured in vitamin D-replete and vitamin D-deficient rats during pregnancy and lactation using the everted gut sac technique. In addition the changes in the plasma concentrations of calcium and 1,25-dihydroxyvitamin D were measured and correlated with transport. During the later stages of pregnancy and during lactation, the concentration of calcium in the plasma is reduced 10-30%. In turn, in the vitamin D-replete rat, the concentration of 1,25-dihydroxyvitamin D in the plasma increases from a control value of 26 pg/ml to 158 pg/ml at day 14 of lactation. Calcium transport in the intestine increases late in pregnancy, peaks during lactation, and then falls to control values by 3 wk postweaning in both vitamin D-replete and D-deficient animals. These findings strengthen the established relationship between 1,25-dihydroxyvitamin D and active calcium transport in the intestine as well as suggest that some factor(s) independent of vitamin D is stimulating intestinal calcium transport during the reproductive cycle.

Vitamin D

2005 ◽  
Vol 289 (1) ◽  
pp. F8-F28 ◽  
Author(s):  
Adriana S. Dusso ◽  
Alex J. Brown ◽  
Eduardo Slatopolsky
Keyword(s):  
Vitamin D ◽  
Target Genes ◽  
Endocrine System ◽  
Target Cells ◽  
Vitamin D Metabolism ◽  
Diverse Range ◽  
Hydroxyvitamin D ◽  
Dihydroxyvitamin D ◽  
Single Receptor ◽  
Recent Developments

The vitamin D endocrine system plays an essential role in calcium homeostasis and bone metabolism, but research during the past two decades has revealed a diverse range of biological actions that include induction of cell differentiation, inhibition of cell growth, immunomodulation, and control of other hormonal systems. Vitamin D itself is a prohormone that is metabolically converted to the active metabolite, 1,25-dihydroxyvitamin D [1,25(OH)2D]. This vitamin D hormone activates its cellular receptor (vitamin D receptor or VDR), which alters the transcription rates of target genes responsible for the biological responses. This review focuses on several recent developments that extend our understanding of the complexities of vitamin D metabolism and actions: the final step in the activation of vitamin D, conversion of 25-hydroxyvitamin D to 1,25(OH)2D in renal proximal tubules, is now known to involve facilitated uptake and intracellular delivery of the precursor to 1α-hydroxylase. Emerging evidence using mice lacking the VDR and/or 1α-hydroxylase indicates both 1,25(OH)2D3-dependent and -independent actions of the VDR as well as VDR-dependent and -independent actions of 1,25(OH)2D3. Thus the vitamin D system may involve more than a single receptor and ligand. The presence of 1α-hydroxylase in many target cells indicates autocrine/paracrine functions for 1,25(OH)2D3in the control of cell proliferation and differentiation. This local production of 1,25(OH)2D3is dependent on circulating precursor levels, providing a potential explanation for the association of vitamin D deficiency with various cancers and autoimmune diseases.

scholarly journals 1,25-Dihydroxyvitamin D3 and Development of Tuberculosis in Cattle

2003 ◽  
Vol 10 (6) ◽  
pp. 1129-1135 ◽  
Author(s):  
S. G. Rhodes ◽  
L. A. Terry ◽  
J. Hope ◽  
R. G. Hewinson ◽  
H. M. Vordermeier
Keyword(s):  
Vitamin D ◽  
T Cell ◽  
Mononuclear Cells ◽  
T Cell Proliferation ◽  
Accessory Cell ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Cell Responses ◽  
1,25 Dihydroxyvitamin D ◽  
Accessory Cells

ABSTRACT This report describes the presence and activity of 1,25-dihydroxyvitamin D3 (1,25-D3) in experimental bovine tuberculosis. Animals that went on to develop tuberculous lesions exhibited a rapid transient increase in serum 1,25-D3 within the first 2 weeks following infection with Mycobacterium bovis. 1,25-D3-positive mononuclear cells were later identified in all tuberculous granulomas by immunohistochemical staining of postmortem lymph node tissue. These results suggest a role for 1,25-D3 both at the onset of infection and in the development of the granuloma in these infected animals. Using a monoclonal antibody to the vitamin D receptor (VDR) as a VDR agonist, we confirmed that activation of the vitamin D pathway profoundly depresses antigen-specific, but not mitogenic, bovine peripheral blood T-cell responses (proliferation and gamma interferon production). Investigation of the mechanism of this suppression showed that the VDR antibody modified the expression of CD80 by accessory cells, such that a significant positive correlation between T-cell proliferation and accessory cell CD80 emerged.

scholarly journals Genome-wide effects of chromatin on vitamin D signaling

2020 ◽  
Vol 64 (4) ◽  
pp. R45-R56 ◽  
Author(s):  
Andrea Hanel ◽  
Henna-Riikka Malmberg ◽  
Carsten Carlberg
Keyword(s):  
Vitamin D ◽  
Binding Sites ◽  
Target Genes ◽  
Chromatin Accessibility ◽  
Transcription Start Sites ◽  
Dihydroxyvitamin D ◽  
Genome Wide ◽  
Spatio Temporal ◽  
Vitamin D Signaling ◽  
The Impact

Molecular endocrinology of vitamin D is based on the activation of the transcription factor vitamin D receptor (VDR) by the vitamin D metabolite 1α,25-dihydroxyvitamin D3. This nuclear vitamin D-sensing process causes epigenome-wide effects, such as changes in chromatin accessibility as well as in the contact of VDR and its supporting pioneer factors with thousands of genomic binding sites, referred to as vitamin D response elements. VDR binding enhancer regions loop to transcription start sites of hundreds of vitamin D target genes resulting in changes of their expression. Thus, vitamin D signaling is based on epigenome- and transcriptome-wide shifts in VDR-expressing tissues. Monocytes are the most responsive cell type of the immune system and serve as a paradigm for uncovering the chromatin model of vitamin D signaling. In this review, an alternative approach for selecting vitamin D target genes is presented, which are most relevant for understanding the impact of vitamin D endocrinology on innate immunity. Different scenarios of the regulation of primary upregulated vitamin D target genes are presented, in which vitamin D-driven super-enhancers comprise a cluster of persistent (constant) and/or inducible (transient) VDR-binding sites. In conclusion, the spatio-temporal VDR binding in the context of chromatin is most critical for the regulation of vitamin D target genes.

Effects of 1,25-dihydroxyvitamin D3 on colonic calcium transport in vitamin D-deficient and normal rats

1984 ◽  
Vol 246 (3) ◽  
pp. G268-G273
Author(s):  
M. J. Favus ◽  
C. B. Langman
Keyword(s):  
Vitamin D ◽  
Calcium Transport ◽  
Calcium Absorption ◽  
Biological Response ◽  
Vehicle Control ◽  
Normal Diet ◽  
Dihydroxyvitamin D3 ◽  
Vitamin D Intake ◽  
1,25 Dihydroxyvitamin D3

To determine whether prior vitamin D intake influences the intestinal calcium absorptive action of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], we measured in vitro the two unidirectional transepithelial fluxes of calcium across descending colon segments from rats fed either a vitamin D-deficient or normal diet and injected with either 10, 25, or 75 ng of 1,25(OH)2D3 or vehicle alone. Vitamin D deficiency abolished net calcium absorption [J net, -2 +/- 2 vs. 12 +/- 2 (SE) nmol X cm-2 X h-1, P less than 0.001], and 10 ng of 1,25(OH)2D3 raised J net to levels found in normal rats. Larger doses (25 and 75 ng) increased J net above levels in normal rats given the same dose. In normal rats only 75 ng of 1,25(OH)2D3 increased calcium J net above vehicle control values (12 +/- 2 vs. 38 +/- 4 nmol X cm-2 X h-1, P less than 0.001). Circulating 1,25(OH)2D3 measured by radioreceptor assay was well correlated with calcium transport. For each dose of 1,25(OH)2D3 higher serum 1,25(OH)2D3 levels were reached in vitamin D-deficient rats. Only the 75-ng dose increased circulating 1,25(OH)2D3 and colonic calcium transport in normal rats. Intravenous [3H]-1,25(OH)2D3 disappeared more rapidly from the circulation of normal rats, suggesting that accelerated metabolic degradative processes for 1,25(OH)2D3 may be present in normal but not in vitamin D-deficient rats and may account for the lack of a biological response to 1,25(OH)2D3 in normal animals.

Insulin modulates the stimulation of renal 1,25-dihydroxyvitamin D3 production by parathyroid hormone

1985 ◽  
Vol 109 (2) ◽  
pp. 243-248 ◽  
Author(s):  
Nirandon Wongsurawat ◽  
H. James Armbrecht
Keyword(s):  
Vitamin D ◽  
Parathyroid Hormone ◽  
Diabetic Rats ◽  
Biologically Active ◽  
Renal Handling ◽  
Dihydroxyvitamin D3 ◽  
Dihydroxyvitamin D ◽  
Maximal Stimulation ◽  
Insulin Replacement ◽  
Stimulation Of

Abstract. Previous studies have shown that there is an impairment in renal production of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the major biologically active metabolite of vitamin D3, in diabetes. This impairment is not due to a deficiency in the parathyroid hormone (PTH), a major stimulator of renal 1,25(OH)2D3 production. Therefore, we have investigated the capacity of PTH to stimulate 1,25(OH)2D3 production in insulin deficiency and with insulin replacement. Experiments were performed in rats fed a 0.6% calcium, vitamin D sufficient diet for 2 weeks. Thyroparathyroidectomy was performed on all rats. Rats to be rendered diabetic were injected with streptozotocin immediately after surgery. In non-diabetic rats, PTH administration significantly increased renal 1,25(OH)2D3 production (11 ± 2 vs 46 ± 5 pg/min/g; P < 0.05). In diabetic rats, however, PTH caused only a modest increase in 1,25(OH)2D3 production (11 ± 1 vs 19 ± 4 pg/min/g; P < 0.05). With insulin replacement, PTH stimulation of 1,25(OH)2D3 production was markedly increased over that seen in diabetic rats (48 ± 12 vs 19 ± 4 pg/min/g; P < 0.05). PTH was equally effective in raising serum calcium, depressing serum phosphorus and tubular reabsorption of phosphate in non-diabetic as well as in diabetic rats. These results demonstrate that insulin is necessary for the maximal stimulation of renal 1,25(OH)2D3 production by PTH. However, insulin is not necessary for PTH action in terms of renal handling of phosphate and inducing hypercalcaemia. These results suggest multiple pathways for the action of PTH, only some of which are insulin requiring.

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