Suppression of iron-regulatory hepcidin by vitamin D

J Am Soc Nephrol. 2014 Mar;25(3):564-72. doi: 10.1681/ASN.2013040355. Epub 2013 Nov 7.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Adult
  • Animals
  • Antimicrobial Cationic Peptides / metabolism*
  • Cation Transport Proteins / metabolism
  • Female
  • Ferritins / metabolism
  • Healthy Volunteers
  • Hep G2 Cells
  • Hepcidins / metabolism*
  • Humans
  • Male
  • Mice
  • Middle Aged
  • Pilot Projects
  • Vitamin D / physiology*

Substances

  • Antimicrobial Cationic Peptides
  • Cation Transport Proteins
  • HAMP protein, human
  • Hamp protein, mouse
  • Hepcidins
  • metal transporting protein 1
  • Vitamin D
  • ropocamptide
  • Ferritins