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ResearchIn-Press PreviewMetabolismNephrology Open Access | 10.1172/JCI179882

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

Michaela A.A. Fuchs,1 Alexander Grabner,1 Melody Shi,1 Susan L. Murray,1 Emily J. Burke,1 Nejla Latic,2 Venkataramana Thiriveedi,3 Jatin Roper,3 Shintaro Ide,1 Koki Abe,1 Hiroki Kitai,1 Tomokazu Souma,1 and Myles Wolf1

1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

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1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

Find articles by Souma, T. in: JCI | PubMed | Google Scholar |

1Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

2Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria

3Division of Gastroenterology, Department of Medicine, Duke University School of Medicine, Durham, United States of America

Find articles by Wolf, M. in: JCI | PubMed | Google Scholar |

Published December 17, 2024 - More info

J Clin Invest. https://doi.org/10.1172/JCI179882.
Copyright © 2024, Fuchs et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published December 17, 2024 - Version history
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Abstract

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. 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.

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