Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice

Title (eng)
Intestinal Cyp24a1 regulates vitamin D locally independent of systemic regulation by renal Cyp24a1 in mice
Author
Michaela A.A. Fuchs
Author
Susan L. Murray
Author
Emily J. Burke
Author
Nejla Latic
Author
Venkataramana Thiriveedi
Author
Jatin Roper
Author
Shintaro Ide
Author
Koki Abe
Author
Hiroki Kitai
Author
Tomokazu Souma
Author
Myles Wolf
Author
Alexander Grabner
Author
Melody Shi
Abstract (eng)
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 is 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. Here, we describe the responses of mice with inducible global deletion, kidney-specific, and intestine-specific deletion of Cyp24a1 to dietary calcium challenge and chronic kidney disease (CKD). Global and kidney-specific Cyp24a1 deletion caused similar syndromes of systemic vitamin D intoxication: elevated circulating 1,25D, 25D, and fibroblast growth factor 23 (FGF23), activation of vitamin D target genes in the kidney and intestine, hypercalcemia, and suppressed parathyroid hormone (PTH). In contrast, mice with intestine-specific Cyp24a1 deletion demonstrated activation of vitamin D target genes exclusively in the intestine, despite no changes in systemic vitamin D levels. In response to a high calcium diet, PTH was suppressed, despite normal serum calcium. In mice with CKD, intestinal Cyp24a1 deletion decreased PTH and FGF23 without precipitating hypercalcemia. These results implicate kidney CYP24A1 in systemic vitamin D regulation while independent local effects of intestinal CYP24A1 could be targeted to treat secondary hyperparathyroidism in CKD.
Keywords (eng)
MetabolismNephrology
Type (eng)
journal article
Language
[eng]
Persistent identifier
https://phaidra.vetmeduni.ac.at/o:4736
DOI
10.1172/JCI179882
Is in series
Title (eng)
Journal of Clinical Investigation
Volume
135
Issue
4
ISSN
1558-8238
Issued
2025
Number of pages
15
Publication
American Society for Clinical Investigation
Version type (eng)
version of record (published version)
Date issued
2025
Access rights (eng)
open access
License
CC BY 4.0 International
Rights statement (eng)
© 2024 Fuchs et al.