Vitamin D metabolism centers on kidney regulation of Cyp27b1 by mineralotropic hormones, including induction by parathyroid hormone (PTH), suppression by fibroblast growth factor 23 (FGF23) and 1,25-dihydroxyvitamin D (1,25(OH)D), and reciprocal regulations for Cyp24a1. This coordinated genomic regulation results in production of endocrine 1,25(OH)D, which, together with PTH and FGF23, controls mineral homeostasis. However, how these events are coordinated is unclear. Here, using in vivo chromatin immunoprecipitation sequencing in mouse kidney, we demonstrate that PTH activation rapidly induces increased recruitment of phosphorylated (p-133) CREB (pCREB) and its coactivators, CBP (CREB-binding protein) and CRTC2 (CREB-regulated transcription coactivator 2), to previously defined kidney-specific M1 and M21 enhancers near the Cyp27b1 gene. At distal enhancers of the Cyp24a1 gene, PTH suppression dismisses CBP with only minor changes in pCREB and CRTC2 occupancy, all of which correlate with decreased genomic activity and reduced transcripts. Treatment of mice with salt-inducible kinase inhibitors (YKL-05-099 and SK-124) yields rapid genomic recruitment of CRTC2 to Cyp27b1, limited interaction of CBP, and a transcriptional response for both Cyp27b1 and Cyp24a1 that mirrors the actions of PTH. Surprisingly, we find that 1,25(OH)D suppression increases the occupancy of CRTC2 in the M1 enhancer, a novel observation for CRTC2 and 1,25(OH)D action. Suppressive actions of 1,25(OH)D and FGF23 at the Cyp27b1 gene are associated with reduced CBP recruitment at these CREB-module enhancers that disrupts full PTH induction. Our findings show that CRTC2 contributes to transcription of both Cyp27b1 and Cyp24a1, demonstrate salt-inducible kinase inhibition as a key modulator of vitamin D metabolism, and provide molecular insight into the coordinated mechanistic actions of PTH, FGF23, and 1,25(OH)D in the kidney that regulate mineral homeostasis.
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http://dx.doi.org/10.1016/j.jbc.2022.102559 | DOI Listing |
Int J Mol Sci
December 2024
Dermatology Clinic, Department of Clinical Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, 00185 Rome, Italy.
Atopic dermatitis (AD) is a chronic inflammatory skin disorder influenced by proteins involved in skin barrier maintenance and vitamin D metabolism. Using an intra-patient design, this study compared protein expression in intra-lesional (IL) and peri-lesional (PL) skin biopsies from AD patients and examined associations between protein levels, vitamin D status, and clinical features. Forty-four biopsies from twenty-two AD patients were analyzed using antibody microarrays targeting twelve proteins.
View Article and Find Full Text PDFAnimals (Basel)
December 2024
Department of Poultry Science, Mississippi State University, MS 39762, USA.
Effects of and dietary sources of calcidiol (25(OH)D), combined with Marek's disease vaccine (MDV), on the expression of genes involved with the antioxidant activity, muscle deposition, and immunity in the pectoralis major (P. major) muscle and spleen of 40 d of age (doa) broilers were investigated. The treatments were as follows: (1) non-injected; (2) the injection of 50 μL of commercial MDV, (3) MDV + 1.
View Article and Find Full Text PDFJ Clin Invest
December 2024
Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America.
Vitamin D regulates mineral homeostasis. The most biologically active form of vitamin D, 1,25-dihydroxyvitamin D (1,25D), is synthesized by CYP27B1 from 25-dihydroxyvitamin D (25D) and inactivated by CYP24A1. Human monogenic diseases and genome-wide association studies support a critical role for CYP24A1 in regulation of mineral homeostasis, but little is known about its tissue-specific effects.
View Article and Find Full Text PDFJ Clin Med
November 2024
Department of Medical Sciences, University of Turin, 10126 Turin, Italy.
: Vitamin D (VD) has immunoregulatory properties, generating interest in its potential to influence therapeutic outcomes in inflammatory bowel disease (IBD), other than affecting the expression of genes encoding enzymes and transporters involved in drug metabolism and transport. This study investigated VD-related single nucleotide polymorphisms (SNPs) as predictors of clinical responses in patients with Crohn's disease (CD) and ulcerative colitis (UC) treated with vedolizumab (VDZ) or ustekinumab (UST) after 3 (T3) and 12 months (T12), as well as the achievement of fecal calprotectin (FC) levels < 250 mg/kg, a marker of mucosal healing. : In this prospective study, 103 patients (67 CD, 36 UC) were enrolled, 40 receiving VDZ and 63 receiving UST.
View Article and Find Full Text PDFFood Funct
November 2024
Department of Forensic Pathology, School of Forensic Medicine, China Medical University, Shenyang, 110122, China.
Vitamin D plays important roles in various physiological processes such as cardiovascular health, calcium balance regulation, bone health, immune system support, neurological function regulation, muscle function maintenance, and anti-inflammatory effects. Therefore, maintaining its adequate levels is essential for overall health. Genetic polymorphisms in vitamin D metabolic pathways have become a key factor affecting the susceptibility and progression of cardiovascular disease (CVD).
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