Regulation of vitamin D metabolizing enzymes in murine renal and extrarenal tissues by dietary phosphate, FGF23, and 1,25(OH)2D3
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BACKGROUND: The 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) together with parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23) regulates calcium (Ca2+) and phosphate (Pi) homeostasis, 1,25(OH)2D3 synthesis is mediated by hydroxylases of the cytochrome P450 (Cyp) family. Vitamin D is first modified in the liver by the 25-hydroxylases CYP2R1 and CYP27A1 and further activated in the kidney by the 1α-hydroxylase CYP27B1, while the renal 24-hydroxylase CYP24A1 catalyzes the first step of its inactivation. While the kidney is the main organ responsible for circulating levels of active 1,25(OH)2D3, other organs also express some of these enzymes. Their regulation, however, has been studied less. METHODS AND RESULTS: Here we investigated the effect of several Pi-regulating factors including dietary Pi, PTH and FGF23 on the expression of the vitamin D hydroxylases and the vitamin D receptor VDR in renal and extrarenal tissues of mice. We found that with the exception of Cyp24a1, all the other analyzed mRNAs show a wide tissue distribution. High dietary Pi mainly upregulated the hepatic expression of Cyp27a1 and Cyp2r1 without changing plasma 1,25(OH)2D3. FGF23 failed to regulate the expression of any of the studied hydroxylases at the used dosage and treatment length. As expected, renal mRNA expression of Cyp27b1 was reduced and Cyp24a1 was increased in response to 1,25(OH)2D3 treatment. However, the 25-hydroxylases were rather unaffected by 1,25(OH)2D3 treatment. CONCLUSIONS: The analyzed vitamin D hydroxylases are regulated in a tissue and treatment-specific manner.
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Lower calcitriol levels likely reflect suppression of the calcitriol-synthesizing enzyme CYP27B1 and stimulation of the catabolic CYP24A1 enzyme by iFGF23, as observed in animal studies.
“lower calcitriol levels likely reflecting the suppression of calcitriol synthesizing enzyme CYP27B1 and stimulation of the catabolic CYP24A1 enzyme by iFGF23 as observed in animal studies [31, 33, 51].”
From Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels (2025) · cites this paper as [31]
The Introduction says FGF23 downregulates renal CYP27B1, induces CYP24A1, and suppresses calcitriol production. In Results & discussion (page not provided), the authors report that earlier mouse experiments found these enzyme changes and lower calcitriol shortly after FGF23 treatment, but that the effects were transient; their own FGF23-treated mice showed no significant change in either enzyme’s expression or in calcitriol. The claim omits that timing qualification and does not reflect this study’s experimental result. (LLM, conf=0.88)
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Research works printed but not linked: 2
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Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels
Gerber, J. S., Arroyo, E. M. P., Pastor, J., Correia, M., Rudloff, S., Moe, O. W., Egli-Spichtig, D., Mohebbi, N., & Wagner, C. A. (2025) · Pflügers Archiv - European Journal of Physiology · doi:10.1007/s00424-024-03046-4 · Cited by 15 · see citing works
Self-citation
- Authors
- Kägi, L., Bettoni, C., Pastor-Arroyo, E. M., Schnitzbauer, U., Hernando, N., & Wagner, C. A.
- Affiliations
- University of Zurich (CH)
- Corresponding author
- Wagner, Carsten A.
- Venue
- PLOS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2018-05-17
- Volume
- 13
- Issue
- 5
- Pages
- e0195427
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC5957386
- OpenAlex
- W2803128906
- Cited by
- 46
- References
- 51
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 6 · 2023: 4 · 2022: 3 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 4
- FWCI
- 4.71
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS ONE (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Zurich Open Repository and Archive (University of Zurich) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich) (submittedVersion, cc-by)
- Zurich Open Repository and Archive (University of Zurich)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (31003A_176125)
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Alkaline Phosphatase Research Studies
- Keywords
- vitamin D metabolism, vitamin D hydroxylases, CYP27B1, CYP24A1, CYP2R1, CYP27A1, 1,25-dihydroxyvitamin D3, fibroblast growth factor 23, dietary phosphorus, parathyroid hormone, vitamin D receptor, renal vitamin D metabolism, calcium and phosphate homeostasis, gene expression regulation
- MeSH terms
- Fibroblast Growth Factor-23, Animals, Calcitriol, Cytochrome P-450 Enzyme System, Diet, Fibroblast Growth Factors, Homeostasis, Humans, Kidney, Male, Parathyroid Hormone, Phosphates, Vitamin D, Gene Expression Regulation, Enzymologic, Mice
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