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. Promoterreporter 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 D 2 ) increased serum levels of 25D-hydroxyvitamin D from 2762 ng/ml before supplementation to 4463 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.

Gestational Iron Deficiency Anemia Is Not Simply a Consequence of Iron Deficiency: An Observational Study for Cofounders.

“…and SFC levels could be attributed to a modulatory effect for VD on hepcidin/Fpn pathway inducing more iron release, thus increasing SFC, to be available for more synthesis of hemoglobin, so increasing Hb conc. These findings and assumption supported that previously reported by Bacchetta et al (10) who documented that VD is a potent regulator of the hepcidin-Fpn axis in humans and Azizi-Soleiman et al (32) who found VDD is associated with higher hepcidin level in the body. Smith & Tangpricha (33) attributed the regulatory effect of VD on hepcidin/Fpn axis to a direct suppression of hepcidin mRNA transcription.…”

“…Interestingly, the current study detected a negative association between levels of 25OH-VD and hepcidin. On basis of hepcidin regulatory action on iron homeostasis through its effects on ferroportin (Fpn)-mediated export of cellular iron through binding to Fpn and inducing its internalization (10) , thus the reported positive association between 25OH-VD levels and both Hb conc. and SFC levels could be attributed to a modulatory effect for VD on hepcidin/Fpn pathway inducing more iron release, thus increasing SFC, to be available for more synthesis of hemoglobin, so increasing Hb conc.…”

“…Inappropriate hepcidin production contributes to the pathogenesis of common iron disorders as its deficiency causes iron overload, while elevated hepcidin levels especially during inflammatory conditions causes iron restriction (9) . Hepcidin regulates iron intestinal absorption, tissue distribution, macrophage iron release and extracellular concentration through its effects on ferroportin (Fpn)-mediated export of cellular iron (10) .…”

Immunological role of vitamin D at the maternal–fetal interface

“…It is also important to recognise that intracrine activation of vitamin D promotes antibacterial responses beyond simple induction of cathelicidin and other antibacterial proteins such as b-defensins (Liu et al 2009). These include the induction of autophagy (Shin et al 2011) and possible effects on intracellular iron concentrations via the iron export modulator hepcidin (Bacchetta et al 2014). Crucially, these mechanisms are focused on an intracellular function for vitamin D, and enhanced antibacterial responses to vitamin D are optimal for intracellular pathogens such as M. tuberculosis.…”

Anaemia of Chronic Kidney Disease: What We Know Now

“…Initially, this was attributed to the anti-inflammatory and pro-erythropoietic effects of vitamin D (46). Data now suggest that vitamin D may actually modulate iron homeostasis via hepcidin, with a study showing that 1,25-dihydroxycholecalciferol directly inhibits hepcidin expression by binding to a vitamin D response element in the gene coding for hepcidin (47).…”