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

Research output: Contribution to journalArticlepeer-review

185 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)564-572
Number of pages9
JournalJournal of the American Society of Nephrology
Volume25
Issue number3
DOIs
StatePublished - Mar 2014
Externally publishedYes

ASJC Scopus subject areas

  • Nephrology

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