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Suppression of Iron-Regulatory Hepcidin by Vitamin D

Justine Bacchetta, Joshua J. Zaritsky, Jessica L. Sea, Rene F. Chun, Thomas S. Lisse, Kathryn Zavala, Anjali Nayak, Katherine Wesseling-Perry, Mark Westerman, Bruce W. Hollis, Isidro B. Salusky and Martin Hewison
JASN March 2014, 25 (3) 564-572; DOI: https://doi.org/10.1681/ASN.2013040355
Justine Bacchetta
*Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and
†Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California;
‡Centre de Référence des Maladies Rénales Rares, Institut de Génomique Fonctionnelle à l’Ecole Normale Supérieure de Lyon et Université de Lyon, Lyon, France;
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Joshua J. Zaritsky
†Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California;
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Jessica L. Sea
*Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and
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Rene F. Chun
*Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and
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Thomas S. Lisse
*Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and
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Kathryn Zavala
*Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and
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Anjali Nayak
†Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California;
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Katherine Wesseling-Perry
†Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California;
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Mark Westerman
§Intrinsic Life Sciences, La Jolla, California; and
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Bruce W. Hollis
‖Departments of Pediatrics, Biochemistry, and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina
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Isidro B. Salusky
†Department of Pediatrics, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California;
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Martin Hewison
*Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and
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Abstract

The antibacterial protein hepcidin regulates the absorption, tissue distribution, and extracellular concentration of iron by suppressing ferroportin-mediated export of cellular iron. In CKD, elevated hepcidin and vitamin D deficiency are associated with anemia. Therefore, we explored a possible role for vitamin D in iron homeostasis. Treatment of cultured hepatocytes or monocytes with prohormone 25-hydroxyvitamin D or active 1,25-dihydroxyvitamin D decreased expression of hepcidin mRNA by 0.5-fold, contrasting the stimulatory effect of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D on related antibacterial proteins such as cathelicidin. Promoter-reporter and chromatin immunoprecipitation analyses indicated that direct transcriptional suppression of hepcidin gene (HAMP) expression mediated by 1,25-dihydroxyvitamin D binding to the vitamin D receptor caused the decrease in hepcidin mRNA levels. Suppression of HAMP expression was associated with a concomitant increase in expression of the cellular target for hepcidin, ferroportin protein, and decreased expression of the intracellular iron marker ferritin. In a pilot study with healthy volunteers, supplementation with a single oral dose of vitamin D (100,000 IU vitamin D2) increased serum levels of 25D-hydroxyvitamin D from 27±2 ng/ml before supplementation to 44±3 ng/ml after supplementation (P<0.001). This response was associated with a 34% decrease in circulating levels of hepcidin within 24 hours of vitamin D supplementation (P<0.05). These data show that vitamin D is a potent regulator of the hepcidin-ferroportin axis in humans and highlight a potential new strategy for the management of anemia in patients with low vitamin D and/or CKD.

  • Copyright © 2014 by the American Society of Nephrology
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Journal of the American Society of Nephrology: 25 (3)
Journal of the American Society of Nephrology
Vol. 25, Issue 3
March 2014
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Suppression of Iron-Regulatory Hepcidin by Vitamin D
Justine Bacchetta, Joshua J. Zaritsky, Jessica L. Sea, Rene F. Chun, Thomas S. Lisse, Kathryn Zavala, Anjali Nayak, Katherine Wesseling-Perry, Mark Westerman, Bruce W. Hollis, Isidro B. Salusky, Martin Hewison
JASN Mar 2014, 25 (3) 564-572; DOI: 10.1681/ASN.2013040355

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Suppression of Iron-Regulatory Hepcidin by Vitamin D
Justine Bacchetta, Joshua J. Zaritsky, Jessica L. Sea, Rene F. Chun, Thomas S. Lisse, Kathryn Zavala, Anjali Nayak, Katherine Wesseling-Perry, Mark Westerman, Bruce W. Hollis, Isidro B. Salusky, Martin Hewison
JASN Mar 2014, 25 (3) 564-572; DOI: 10.1681/ASN.2013040355
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