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Article: Genomically anchored vitamin D receptor mediates an abundance of bioprotective actions elicited by its 1,25-dihydroxyvitamin D hormonal ligand.

Haussler, Mark R / Haussler, Carol A / Jurutka, Peter W

2023 Volume 123, Page(s) 313–383

Abstract: The nuclear vitamin D receptor (VDR) mediates the actions of its physiologic 1,25-dihydroxyvitamin ... ...

Abstract	The nuclear vitamin D receptor (VDR) mediates the actions of its physiologic 1,25-dihydroxyvitamin D
MeSH term(s)	Humans ; Calcium ; Ligands ; Parathyroid Hormone ; Receptors, Calcitriol/genetics
Chemical Substances	1,25-dihydroxyvitamin D (66772-14-3) ; Calcium (SY7Q814VUP) ; Ligands ; Parathyroid Hormone ; Receptors, Calcitriol ; VDR protein, human
Language	English
Publishing date	2023-06-08
Publishing country	United States
Document type	Journal Article
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2022.12.008
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Article ; Online: Vitamin D Receptor Mediates a Myriad of Biological Actions Dependent on Its 1,25-Dihydroxyvitamin D Ligand: Distinct Regulatory Themes Revealed by Induction of Klotho and Fibroblast Growth Factor-23.

Haussler, Mark R / Livingston, Sarah / Sabir, Zhela L / Haussler, Carol A / Jurutka, Peter W

JBMR plus

2020 Volume 5, Issue 1, Page(s) e10432

Abstract: The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH) ...

Abstract	The hormonal vitamin D metabolite, 1,25-dihydroxyvitamin D [1,25(OH)
Language	English
Publishing date	2020-12-03
Publishing country	England
Document type	Journal Article
ISSN	2473-4039
ISSN (online)	2473-4039
DOI	10.1002/jbm4.10432
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Article: Optimal vitamin D spurs serotonin: 1,25-dihydroxyvitamin D represses serotonin reuptake transport (

Sabir, Marya S / Haussler, Mark R / Mallick, Sanchita / Kaneko, Ichiro / Lucas, Daniel A / Haussler, Carol A / Whitfield, G Kerr / Jurutka, Peter W

Genes & nutrition

2018 Volume 13, Page(s) 19

Abstract: Background: Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5-HT; serotonin) and 1,25-dihydroxyvitamin D: Results: Employing quantitative real-time PCR, we demonstrate that : Conclusions: These results are consistent with the ... ...

Abstract	Background: Diminished brain levels of two neurohormones, 5-hydroxytryptamine (5-HT; serotonin) and 1,25-dihydroxyvitamin D Results: Employing quantitative real-time PCR, we demonstrate that Conclusions: These results are consistent with the concept that vitamin D maintains extracellular fluid serotonin concentrations in the brain, thereby offering an explanation for how vitamin D could influence the trajectory and development of neuropsychiatric disorders. Given the profile of gene regulation in cultured RN46A-B14 serotonergic neurons, we conclude that 1,25D acts not only to induce serotonin synthesis, but also functions at an indirect, molecular-genomic stage to mimic SSRIs and MAO inhibitors, likely elevating serotonin in the CNS. These data suggest that optimal vitamin D status may contribute to improving behavioral pathophysiologies resulting from dysregulation of serotonergic neurotransmission.
Language	English
Publishing date	2018-07-11
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2416599-2
ISSN	1865-3499 ; 1555-8932
ISSN (online)	1865-3499
ISSN	1555-8932
DOI	10.1186/s12263-018-0605-7
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Article: Bioactive Dietary VDR Ligands Regulate Genes Encoding Biomarkers of Skin Repair That Are Associated with Risk for Psoriasis

Karrys, Amitis / Rady, Islam / Chamcheu, Roxane-Cherille N / Sabir, Marya S / Mallick, Sanchita / Chamcheu, Jean Christopher / Jurutka, Peter W / Haussler, Mark R / Whitfield, G. Kerr

Nutrients. 2018 Feb. 04, v. 10, no. 2

2018

Abstract: Treatment with 1,25-dihydroxyvitamin D ... 3 ... (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (LCE)3 genes involved in skin repair. In psoriasis patients, the majority of whom harbor genomic ... ...

Abstract	Treatment with 1,25-dihydroxyvitamin D<inf>3</inf> (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (LCE)3 genes involved in skin repair. In psoriasis patients, the majority of whom harbor genomic deletion of LCE3B and LCE3C (LCE3C_LCE3B-del), we propose that certain dietary analogues of 1,25D activate the expression of residual LCE3A/LCE3D/LCE3E genes to compensate for the loss of LCE3B/LCE3C in the deletant genotype. Herein, human keratinocytes (HEKn) homozygous for LCE3C_LCE3B-del were treated with docosahexaenoic acid (DHA) and curcumin, two low-affinity, nutrient ligands for the vitamin D receptor (VDR). DHA and curcumin induce the expression of LCE3A/LCE3D/LCE3E mRNAs at concentrations corresponding to their affinity for VDR. Moreover, immunohistochemical quantitation revealed that the treatment of keratinocytes with DHA or curcumin stimulates LCE3 protein expression, while simultaneously opposing the tumor necrosis factor-alpha (TNFα)-signaled phosphorylation of mitogen activated protein (MAP) kinases, p38 and Jun amino-terminal kinase (JNK), thereby overcoming inflammation biomarkers elicited by TNFα challenge. Finally, DHA and curcumin modulate two transcription factors relevant to psoriatic inflammation, the activator protein-1 factor Jun B and the nuclear receptor NR4A2/NURR1, that is implicated as a mediator of VDR ligand-triggered gene control. These findings provide insights into the mechanism(s) whereby dietary VDR ligands alter inflammatory and barrier functions relevant to skin repair, and may provide a molecular basis for improved treatments for mild/moderate psoriasis.
Keywords	biomarkers ; calcitriol receptors ; curcumin ; docosahexaenoic acid ; genes ; homozygosity ; immunohistochemistry ; inflammation ; keratinocytes ; ligands ; messenger RNA ; mitogen-activated protein kinase ; mitogens ; patients ; phosphorylation ; protein synthesis ; psoriasis ; risk factors ; sequence deletion ; transcription factors ; tumor necrosis factor-alpha
Language	English
Dates of publication	2018-0204
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2518386-2
ISSN	2072-6643
ISSN	2072-6643
DOI	10.3390/nu10020174
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Pomegranate derivative urolithin A enhances vitamin D receptor signaling to amplify serotonin-related gene induction by 1,25-dihydroxyvitamin D.

Livingston, Sarah / Mallick, Sanchita / Lucas, Daniel A / Sabir, Marya S / Sabir, Zhela L / Purdin, Hespera / Nidamanuri, Sree / Haussler, Carol A / Haussler, Mark R / Jurutka, Peter W

Biochemistry and biophysics reports

2020 Volume 24, Page(s) 100825

Abstract: Mediated by the nuclear vitamin D receptor (VDR), the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin ... ...

Abstract	Mediated by the nuclear vitamin D receptor (VDR), the hormonally active vitamin D metabolite, 1,25-dihydroxyvitamin D
Language	English
Publishing date	2020-10-13
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	2831046-9
ISSN	2405-5808 ; 2405-5808
ISSN (online)	2405-5808
ISSN	2405-5808
DOI	10.1016/j.bbrep.2020.100825
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Article ; Online: Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: genomic and non-genomic mechanisms.

Haussler, Mark R / Jurutka, Peter W / Mizwicki, Mathew / Norman, Anthony W

Best practice & research. Clinical endocrinology & metabolism

2011 Volume 25, Issue 4, Page(s) 543–559

Abstract: The conformationally flexible secosteroid, 1α,25(OH)₂vitamin D₃ (1α,25(OH)₂D₃) initiates biological responses via binding to the vitamin D receptor (VDR). The VDR contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative ...

Abstract	The conformationally flexible secosteroid, 1α,25(OH)₂vitamin D₃ (1α,25(OH)₂D₃) initiates biological responses via binding to the vitamin D receptor (VDR). The VDR contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative pocket (VDR-AP), that respectively bind a bowl-like ligand configuration (gene transcription) or a planar-like ligand shape (rapid responses). When occupied by 1α,25(OH)₂D₃, the VDR-GP interacts with the retinoid X receptor to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1α,25(OH)₂D₃. By recruiting complexes of either coactivators or corepressors, activated VDR modulates the transcription of genes encoding proteins that promulgate the traditional genomic functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. 1α,25(OH)₂D₃/VDR control of gene expression and rapid responses also delays chronic diseases of aging such as osteoporosis, cancer, type-1 and -2 diabetes, arteriosclerosis, vascular disease, and infection.
MeSH term(s)	Animals ; Calcitriol/metabolism ; Caveolae/metabolism ; Gene Expression Regulation ; Gene Regulatory Networks ; Humans ; Ligands ; Molecular Conformation ; Receptors, Calcitriol/chemistry ; Receptors, Calcitriol/genetics ; Receptors, Calcitriol/metabolism ; Signal Transduction
Chemical Substances	Ligands ; Receptors, Calcitriol ; Calcitriol (FXC9231JVH)
Language	English
Publishing date	2011-08
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2052339-7
ISSN	1878-1594 ; 1532-1908 ; 1521-690X
ISSN (online)	1878-1594 ; 1532-1908
ISSN	1521-690X
DOI	10.1016/j.beem.2011.05.010
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Article ; Online: Association between Circulating Vitamin D Metabolites and Fecal Bile Acid Concentrations.

Jacobs, Elizabeth T / Haussler, Mark R / Alberts, David S / Kohler, Lindsay N / Lance, Peter / Martínez, María Elena / Roe, Denise J / Jurutka, Peter W

Cancer prevention research (Philadelphia, Pa.)

2016 Volume 9, Issue 7, Page(s) 589–597

Abstract: Although hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in ... ...

Abstract	Although hydrophobic bile acids have been demonstrated to exhibit cytotoxic and carcinogenic effects in the colorectum, ursodeoxycholic acid (UDCA) has been investigated as a potential chemopreventive agent. Vitamin D has been shown to play a role in both bile acid metabolism and in the development of colorectal neoplasia. Using a cross-sectional design, we sought to determine whether baseline circulating concentrations of the vitamin D metabolites 25(OH)D and 1,25(OH)2D were associated with baseline fecal bile acid concentrations in a trial of UDCA for the prevention of colorectal adenoma recurrence. We also prospectively evaluated whether vitamin D metabolite concentrations modified the effect of UDCA on adenoma recurrence. After adjustment for age, sex, BMI, physical activity, and calcium intake, adequate concentrations of 25(OH)D (≥30 ng/mL) were statistically significantly associated with reduced odds for high levels of total [OR, 0.61; 95% confidence interval (CI), 0.38-0.97], and primary (OR, 0.61; 95% CI, 0.38-0.96) bile acids, as well as individually with chenodeoxycholic acid (OR, 0.39; 95% CI, 0.24-0.63) and cholic acid (OR, 0.56; 95% CI, 0.36-0.90). No significant associations were observed for 1,25(OH)2D and high versus low fecal bile acid concentrations. In addition, neither 25(OH)D nor 1,25(OH)2D modified the effect of UDCA on colorectal adenoma recurrence. In conclusion, this is the first study to demonstrate an inverse relationship between circulating levels of 25(OH)D and primary fecal bile acid concentrations. These results support prior data demonstrating that vitamin D plays a key role in bile acid metabolism, and suggest a potential mechanism of action for 25(OH)D in colorectal cancer prevention. Cancer Prev Res; 9(7); 589-97. ©2016 AACR.
MeSH term(s)	Adenoma/drug therapy ; Adenoma/metabolism ; Adult ; Aged ; Bile Acids and Salts/analysis ; Cholagogues and Choleretics/therapeutic use ; Colorectal Neoplasms/drug therapy ; Colorectal Neoplasms/metabolism ; Cross-Sectional Studies ; Feces/chemistry ; Female ; Humans ; Male ; Middle Aged ; Neoplasm Recurrence, Local/prevention & control ; Ursodeoxycholic Acid/therapeutic use ; Vitamin D/blood
Chemical Substances	Bile Acids and Salts ; Cholagogues and Choleretics ; Vitamin D (1406-16-2) ; Ursodeoxycholic Acid (724L30Y2QR)
Language	English
Publishing date	2016-07
Publishing country	United States
Document type	Clinical Trial, Phase III ; Journal Article ; Randomized Controlled Trial
ZDB-ID	2434717-6
ISSN	1940-6215 ; 1940-6207
ISSN (online)	1940-6215
ISSN	1940-6207
DOI	10.1158/1940-6207.CAPR-16-0033
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Article: 1,25-Dihydroxyvitamin D and Klotho: A Tale of Two Renal Hormones Coming of Age.

Haussler, Mark R / Whitfield, G Kerr / Haussler, Carol A / Sabir, Marya S / Khan, Zainab / Sandoval, Ruby / Jurutka, Peter W

Vitamins and hormones

2016 Volume 100, Page(s) 165–230

Abstract: 1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate ... ...

Abstract	1,25-Dihydroxyvitamin D3 (1,25D) is the renal metabolite of vitamin D that signals through binding to the nuclear vitamin D receptor (VDR). The ligand-receptor complex transcriptionally regulates genes encoding factors stimulating calcium and phosphate absorption plus bone remodeling, maintaining a skeleton with reduced risk of age-related osteoporotic fractures. 1,25D/VDR signaling exerts feedback control of Ca/PO4 via regulation of FGF23, klotho, and CYP24A1 to prevent age-related, ectopic calcification, fibrosis, and associated pathologies. Vitamin D also elicits xenobiotic detoxification, oxidative stress reduction, neuroprotective functions, antimicrobial defense, immunoregulation, anti-inflammatory/anticancer actions, and cardiovascular benefits. Many of the healthspan advantages conferred by 1,25D are promulgated by its induction of klotho, a renal hormone that is an anti-aging enzyme/coreceptor that protects against skin atrophy, osteopenia, hyperphosphatemia, endothelial dysfunction, cognitive defects, neurodegenerative disorders, and impaired hearing. In addition to the high-affinity 1,25D hormone, low-affinity nutritional VDR ligands including curcumin, polyunsaturated fatty acids, and anthocyanidins initiate VDR signaling, whereas the longevity principles resveratrol and SIRT1 potentiate VDR signaling. 1,25D exerts actions against neural excitotoxicity and induces serotonin mood elevation to support cognitive function and prosocial behavior. Together, 1,25D and klotho maintain the molecular signaling systems that promote growth (p21), development (Wnt), antioxidation (Nrf2/FOXO), and homeostasis (FGF23) in tissues crucial for normal physiology, while simultaneously guarding against malignancy and degeneration. Therefore, liganded-VDR modulates the expression of a "fountain of youth" array of genes, with the klotho target emerging as a major player in the facilitation of health span by delaying the chronic diseases of aging.
MeSH term(s)	Animals ; Gene Expression Regulation/physiology ; Glucuronidase/genetics ; Glucuronidase/metabolism ; Humans ; Signal Transduction/physiology ; Vitamin D/analogs & derivatives ; Vitamin D/chemistry ; Vitamin D/pharmacology
Chemical Substances	Vitamin D (1406-16-2) ; 1,25-dihydroxyvitamin D (66772-14-3) ; Glucuronidase (EC 3.2.1.31) ; klotho protein (EC 3.2.1.31)
Language	English
Publishing date	2016
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	201161-x
ISSN	2162-2620 ; 0083-6729
ISSN (online)	2162-2620
ISSN	0083-6729
DOI	10.1016/bs.vh.2015.11.005
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Article ; Online: Bioactive Dietary VDR Ligands Regulate Genes Encoding Biomarkers of Skin Repair That Are Associated with Risk for Psoriasis.

Karrys, Amitis / Rady, Islam / Chamcheu, Roxane-Cherille N / Sabir, Marya S / Mallick, Sanchita / Chamcheu, Jean Christopher / Jurutka, Peter W / Haussler, Mark R / Whitfield, G Kerr

Nutrients

2018 Volume 10, Issue 2

Abstract: Treatment with 1,25-dihydroxyvitamin D₃ (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope ( ...

Abstract	Treatment with 1,25-dihydroxyvitamin D₃ (1,25D) improves psoriasis symptoms, possibly by inducing the expression of late cornified envelope (
MeSH term(s)	Animals ; Cell Line, Tumor ; Cells, Cultured ; Curcumin/pharmacology ; Diet ; Docosahexaenoic Acids/pharmacology ; Gene Expression Regulation/drug effects ; Genetic Markers ; Genetic Predisposition to Disease ; Humans ; Keratinocytes/drug effects ; Keratinocytes/metabolism ; Ligands ; Psoriasis/genetics ; Psoriasis/prevention & control ; Rats ; Receptors, Calcitriol/agonists ; Receptors, Calcitriol/genetics ; Receptors, Calcitriol/metabolism ; Skin/metabolism
Chemical Substances	Genetic Markers ; Ligands ; Receptors, Calcitriol ; Docosahexaenoic Acids (25167-62-8) ; Curcumin (IT942ZTH98)
Language	English
Publishing date	2018-02-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2518386-2
ISSN	2072-6643 ; 2072-6643
ISSN (online)	2072-6643
ISSN	2072-6643
DOI	10.3390/nu10020174
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Article: Vitamin D receptor (VDR)-mediated actions of 1α,25(OH)₂vitamin D₃: Genomic and non-genomic mechanisms

Haussler, Mark R / Jurutka, Peter W / Mizwicki, Mathew / Norman, Anthony W

Best Practice & Research Clinical Endocrinology & Metabolism. 2011 Aug., v. 25, no. 4

2011

Abstract	The conformationally flexible secosteroid, 1α,25(OH)₂vitamin D₃ (1α,25(OH)₂D₃) initiates biological responses via binding to the vitamin D receptor (VDR). The VDR contains two overlapping ligand binding sites, a genomic pocket (VDR-GP) and an alternative pocket (VDR-AP), that respectively bind a bowl-like ligand configuration (gene transcription) or a planar-like ligand shape (rapid responses). When occupied by 1α,25(OH)₂D₃, the VDR-GP interacts with the retinoid X receptor to form a heterodimer that binds to vitamin D responsive elements in the region of genes directly controlled by 1α,25(OH)₂D₃. By recruiting complexes of either coactivators or corepressors, activated VDR modulates the transcription of genes encoding proteins that promulgate the traditional genomic functions of vitamin D, including signaling intestinal calcium and phosphate absorption to effect skeletal and calcium homeostasis. 1α,25(OH)₂D₃/VDR control of gene expression and rapid responses also delays chronic diseases of aging such as osteoporosis, cancer, type-1 and -2 diabetes, arteriosclerosis, vascular disease, and infection.
Keywords	absorption ; binding sites ; calcium ; calcium phosphates ; chronic diseases ; diabetes ; gene expression ; genes ; homeostasis ; osteoporosis ; proteins ; transcription (genetics) ; vitamin D
Language	English
Dates of publication	2011-08
Size	p. 543-559.
Publishing place	Elsevier Ltd
Document type	Article
ZDB-ID	1493559-4
ISSN	1521-690X
ISSN	1521-690X
DOI	10.1016/j.beem.2011.05.010
Database	NAL-Catalogue (AGRICOLA)

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