Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia

Ishizawa, Michiyasu; Matsunawa, Manabu; Adachi, Ryutaro; Uno, Shigeyuki; Ikeda, Kazumasa; Masuno, Hiroyuki; Shimizu, Masato; Iwasaki, Katsurô; Yamada, Sachiko; Makishima, Makoto

doi:10.1194/jlr.m700293-jlr200

Cited by 97 publications

(110 citation statements)

References 34 publications

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“…1␣(OH)D 3 is rapidly converted to 1,25(OH) 2 D 3 after injection and is more effective than 1,25(OH) 2 D 3 in prolonging survival time in a mouse model of leukemia (11). As reported previously (13,27), 1␣(OH)D 3 induced mRNA expression of VDR target genes, Cyp24a1, calbindin D9k, Trpv5, and Trpv6, in the kidney of ICR mice (Fig. 3A).…”

Section: Effects Of Hypergravity On Gene Expression In Icr Micesupporting

confidence: 56%

“…Vitamin D-induced expression of intestinal calbindin D9k and Trpv6 was not enhanced by hypergravity. Although the Cyp24a1 gene may be more sensitive to vitamin D signaling than other target genes, our previous study shows that 1,25(OH) 2 D 3 induces TRPV6 more potently than CYP24A1 in colon cancer cells (13). These findings suggest that hypergravity modulates vitamin D signal- Fig.…”

Section: Discussionmentioning

confidence: 74%

“…Real-time PCR was performed on the ABI PRISM 7000 Sequence Detection System (Applied Biosystems, Foster City, CA) using Power SYBR Green PCR Master Mix (Applied Biosystems). Some primer sequences have been reported previously (13,27), and others are listed in Table 1. The mRNA values were normalized to the expression level of glyceraldehyde-3-phosphate dehydrogenase mRNA.…”

Section: Methodsmentioning

confidence: 99%

“…For examination of the effects of vitamin D, mice were injected intraperitoneally with 12.5 nmol/kg 1␣(OH)D 3 (alfacalcidol), which was kindly provided by Dr. Yoji Tachibana (Nisshin Flour Milling, Tokyo, Japan), 16 h before death. 1␣(OH)D 3 was diluted in PBS before injection (13). VDR-null (Vdr Ϫ/Ϫ ) mice and control wild-type (Vdr ϩ/ϩ ) mice were generated from C57BL/6J Vdr ϩ/Ϫ mouse breeding (31).…”

Section: Methodsmentioning

confidence: 99%

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Hypergravity modulates vitamin D receptor target gene mRNA expression in mice

Ishizawa

Iwasaki²,

Kato³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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The possibility of pathological calcium metabolism is a critical health concern introduced by long-term space travel. Because vitamin D plays an important role in calcium homeostasis, we evaluated the effects of hypergravity on the expression of genes involved in vitamin D and calcium metabolism in ICR mice. When exposed to 2G hypergravity for 2 days, the mRNA expression of renal 25-hydroxyvitamin D 24-hydroxylase (Cyp24a1) was increased and that of 25-hydroxyvitamin D 1␣-hydroxylase (Cyp27b1) was decreased. Although hypergravity decreased food intake and increased the expression of starvation-induced genes, the changes in Cyp24a1 and Cyp27b1 expression were not due to starvation, suggesting that hypergravity affects these genes directly. Hypergravity decreased plasma 1␣,25-dihydroxyvitamin D3 levels in ICR mice, suggesting a consequence of decreased Cyp27b1 and increased Cyp24a1 expression. Although 1␣-hydroxyvitamin D3 [1␣(OH)D3] treatment induced the expression of vitamin D receptor (VDR) target genes in the kidney of 2G-exposed ICR mice to similar levels as controls, 1␣(OH)D3 increased the intestinal expression of Cyp24a1 in ICR mice. Hypergravity-dependent changes of Cyp24a1 and Cyp27b1 expression were diminished in mice exposed to hypergravity for 14 days, which may represent an adaptation to hypergravity stress. Hypergravity exposure also increased Cyp24a1 expression in the kidney of C57BL/6J mice. We examined the effects of hypergravity on VDRnull mice and found that renal Cyp27b1 expression in VDR-null mice was decreased by hypergravity while renal Cyp24a1 expression was not detected in VDR-null mice. Thus hypergravity modifies the expression of genes involved in vitamin D metabolism. 12), and vitamin D 2 is less effective than vitamin D 3 in maintaining serum 25(OH)D levels (1). Vitamin D deficiency, mainly caused by inadequate sun exposure, results in rickets and osteomalacia, and is also associated with increased risk of cancer, autoimmune disease, infection, and cardiovascular disease (10). 1,25(OH) 2 D 3 exhibits physiological and pharmacological effects by binding to the vitamin D receptor (VDR; NR1I1), a transcription factor of the nuclear receptor superfamily, which is highly expressed in the target organs of calcium homeostasis, such as the intestine, bone, kidney, and parathyroid glands (6, 21). VDR regulates the expression of many target genes, including 25-hydroxyvitamin D 24-hydroxylase (CYP24A1), calbindin D9k, and transient receptor potential vanilloid type 6 (TRPV6).Bone mineral loss is one of the critical health concerns raised by the prospect of long-term space travel (19,29). Space flight induces uncoupled bone remodeling, including increased bone resorption and urinary calcium excretion and decreased calcium absorption. Vitamin D deficiency due to the absence of ultraviolet light and decreased dietary intake of vitamin D during space flight has been considered to be one reason for dysregulated bone and calcium metabolism (30). Supplemental vitamin D and calcium intake increase blood...

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Section: Effects Of Hypergravity On Gene Expression In Icr Micesupporting

confidence: 56%

Section: Discussionmentioning

confidence: 74%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Hypergravity modulates vitamin D receptor target gene mRNA expression in mice

Ishizawa

Iwasaki²,

Kato³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

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“…Cells were harvested after 24 h and total RNAs were prepared by the acid guanidine thiocyanate-phenol/chloroform method. 17) cDNA were synthesized using an ImProm- Figure 2A. 7,9) Protein expression of all VDR mutants was detected in HEK293 cells with immunoblotting using anti-VDR and anti-FLAG antibodies (Fig.…”

Section: 7)mentioning

confidence: 99%

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Chuma

Endo-Umeda

Shimba

et al. 2012

Biological & Pharmaceutical Bulletin

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1) VDR acts as an allosteric transcription factor that undergoes a ligand-dependent conformational change in the cofactor binding site and activation function 2 (AF2) domain, structural rearrangements that result in dynamic interaction with the heterodimer partner retinoid X receptor (RXR; NR2B) and exchange of cofactor complexes.2,3) While corepressors bind to the VDR-RXR heterodimer in the absence of ligand, the ligand binding reduces the affinity of corepressors and increases the affinity for coactivators, a structural transition that induces transcription of specific genes. The VDR-RXR heterodimer binds preferentially to a DNA response element that consists of a two hexanucleotide (AGGTCA or a related sequence) direct repeat motif separated by three nucleotides (DR3).4) The DR3 VDRbinding element has been identified in the regulatory regions of many target genes, including cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), cathelicidin antimicrobial peptide (CAMP), and osteopontin.2,4) An everted repeat of the hexanucleotide motif separated by six nucleotides (ER6) is another VDR-binding element that regulates expression of the human CYP3A4 gene.2) Dynamic and coordinated interactions of VDR with RXR and cofactor complexes are required for the efficient regulation of transcription.3,5) Lithocholic acid (LCA), a secondary bile acid, acts as an additional physiological VDR ligand and interacts with the VDR ligand-binding pocket in a mode distinct from 1,25(OH) 2 D 3 , and alternate contacts are seen particularly with helices 3 and 4/5, components of the AF2 surface. [6][7][8] A statistical coupling analysis has demonstrated that RXR heterodimer allosteric communication is required for effective activation of VDR by LCA but not by 1,25(OH) 2 D 3 . 9) Indeed, LCA induces the interaction of VDR with RXR, steroid receptor coactivator 1 (SRC-1), and silencing mediator of retinoic acid and thyroid hormone receptor (SMRT) in a manner distinct from 1,25(OH) 2 D 3 in cells.3)Although the role of VDR in mediating the biological effects of 1,25(OH) 2 D 3 has been investigated for decades, an understanding of the biology of VDR regulation by LCA is only now emerging.Hairless (HR) is a nuclear protein that functions as a corepressor of nuclear receptors, including thyroid hormone receptor, retinoic acid receptor-related orphan receptors and VDR.10-12) HR interacts with VDR via multiple protein-protein interfaces in the absence of ligand and represses VDR transactivation by 1,25(OH) 2 D 3 and LCA.12,13) Interestingly, LCA but not 1,25(OH) 2 D 3 enhances the interaction, 12) suggesting that LCA induces a conformation of the VDR-RXR heterodimer with enhanced affinity for HR binding. In both mice and humans, mutation of HR results in hair-loss phenotypes similar to VDR mutation, suggesting a functional interaction of HR and VDR in vivo. 14) In contrast to the in vitro interaction, 1,25(OH) 2 D 3 treatment decreases HR binding to VDR in keratinocytes. 15) Although the in vivo role of HR in VDR function remains ...

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Frontline Science: Concanavalin A-induced acute hepatitis is attenuated in vitamin D receptor knockout mice with decreased immune cell function

Umeda

Endo-Umeda

Nakashima

et al. 2019

Journal of Leukocyte Biology

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The vitamin D receptor (VDR) is a nuclear receptor for the active form of vitamin D, 1 ,25dihydroxyvitamin D 3 , and regulates various physiologic processes, such as bone and calcium metabolism, cellular proliferation and differentiation, and immunity. VDR is highly expressed in the intestine, kidney, bone, and macrophages, but is expressed at a low level in the liver. The liver is a major metabolic organ and also acts as an immune gateway for dietary nutrients and xenobiotics. In this study, we investigated the function of VDR in hepatic immune cells, such as Kupffer cells/macrophages, utilizing VDR knockout (KO) mice. We showed that VDR is functionally expressed in hepatic mononuclear cells, specifically resident Kupffer cells. We examined the role of VDR in acute hepatitis induced by concanavalin A (Con-A) and found that Con-A-induced hepatitis is attenuated in VDR-KO mice compared to wild-type (WT) mice. Con-A-induced hepatitis is known to be mediated by NKT cell activation, cytokine production, and reactive oxygen species (ROS) production in Kupffer cells/macrophages. However, the proportions of Kupffer cells/macrophages and the NKT cell activation were similar in the liver of WT and VDR-KO mice and inflammatory cytokine gene expression was increased in VDR-KO mice. On the other hand, plasma and hepatic ROS levels were decreased in the liver of VDR-KO mice compared to WT mice.The phagocytic activity of resident Kupffer cells and hepatic neutrophils were also decreased in VDR-KO mice. Therefore, VDR is necessary for Con-A-induced acute hepatitis and plays an important role in hepatic immune cell functions.

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Lithocholic acid derivatives act as selective vitamin D receptor modulators without inducing hypercalcemia

Cited by 97 publications

References 34 publications

Hypergravity modulates vitamin D receptor target gene mRNA expression in mice

Hypergravity modulates vitamin D receptor target gene mRNA expression in mice

Hairless Modulates Ligand-Dependent Activation of the Vitamin D Receptor-Retinoid X Receptor Heterodimer

Frontline Science: Concanavalin A-induced acute hepatitis is attenuated in vitamin D receptor knockout mice with decreased immune cell function

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