title: Suppression of iron-regulatory hepcidin by vitamin D.
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.
authors.affiliation: Department of Orthopaedic Surgery, UCLA Orthopaedic Hospital, and.
authors.forename: Justine
authors.initials: J
authors.lastname: Bacchetta
authors.forename: Joshua J
authors.initials: JJ
authors.lastname: Zaritsky
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Sea
authors.forename: Rene F
authors.initials: RF
authors.lastname: Chun
authors.forename: Thomas S
authors.initials: TS
authors.lastname: Lisse
authors.forename: Kathryn
authors.initials: K
authors.lastname: Zavala
authors.forename: Anjali
authors.initials: A
authors.lastname: Nayak
authors.forename: Katherine
authors.initials: K
authors.lastname: Wesseling-Perry
authors.forename: Mark
authors.initials: M
authors.lastname: Westerman
authors.forename: Bruce W
authors.initials: BW
authors.lastname: Hollis
authors.forename: Isidro B
authors.initials: IB
authors.lastname: Salusky
authors.forename: Martin
authors.initials: M
authors.lastname: Hewison
mesh_terms: D016475:3T3 Cells; D000328:Adult; D000818:Animals; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism*; D027682:Cation Transport Proteins / Q000378:metabolism; D005260:Female; D005293:Ferritins / Q000378:metabolism; D064368:Healthy Volunteers; D056945:Hep G2 Cells; D064451:Hepcidins / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010865:Pilot Projects; D014807:Vitamin D / Q000502:physiology*; D054804:Cathelicidins; D000098742:Ferroportin
chemical_list: D023181:Antimicrobial Cationic Peptides; D027682:Cation Transport Proteins; C578702:HAMP protein, human; C579599:Hamp protein, mouse; D064451:Hepcidins; D000098742:Ferroportin; D014807:Vitamin D; D005293:Ferritins; D054804:Cathelicidins