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The effect of the putative iron regulatory peptide hepcidin on iron absorption was investigated in mice. Hepcidin peptide was synthesized and injected into mice for up to 3 days, and in vivo iron absorption was measured with tied-off segments of duodenum. Liver hepcidin expression was measured by reverse transcriptasepolymerase chain reaction. Hepcidin significantly reduced mucosal iron uptake and transfer to the carcass at doses of at least 10 g/mouse per day, the reduction in transfer to the carcass being proportional to the reduction in iron uptake. Synthetic hepcidin injections down-regulated endogenous liver hepcidin expression excluding the possibility that synthetic hepcidin was functioning by a secondary induction of endogenous hepcidin. The effect of hepcidin was significant at least 24 hours after injection of hepcidin. Liver iron stores and hemoglobin levels were unaffected by hepcidin injection. Similar effects of hepcidin on iron absorption were seen in irondeficient and Hfe knockout mice. Hepcidin inhibited the uptake step of duodenal iron absorption but did not affect the proportion of iron transferred to the circulation. The effect was independent of iron status of mice and did not require Hfe gene product. The data support a key role for hepcidin in the regulation of intestinal iron uptake. IntroductionRecent advances in molecular-level understanding of iron absorption regulation have implicated several genes as regulators of iron absorption, 2 of which (Hfe and hepcidin) have received particular attention. [1][2][3] Hepcidin was originally identified as an antimicrobial peptide synthesized in liver, but evidence from knockout mice suggests this peptide is a negative regulator of iron absorption. 3,4 Initial work implicated hepcidin as the long-sought "stores regulator" of iron absorption proposed by Finch. 5 However, recent work has suggested a wider role for this peptide as it also shows an expression pattern consistent with the "erythroid regulator." 6 A mutation in hepcidin has recently been implicated as a cause of juvenile hemochromatosis. 7 Transgenic mice overexpressing hepcidin were found to develop an iron-deficient phenotype, consistent with an effect on placental iron transport and intestinal iron absorption. 8 Frazer et al 9 provided data that quantitatively relates hepcidin expression to iron absorption rates and expression of duodenal transporters in an iron-deficient rat model. It can be deduced that a similar inverse correlation between hepcidin expression and iron absorption probably exists in humans, based on data provided by Nemeth et al 10 relating urinary hepcidin to serum ferritin levels. Thus far, however, no data measuring the direct effect of injecting hepcidin on iron absorption rates is available. We therefore synthesized hepcidin peptide and injected this into normal, iron-deficient, and Hfe knockout mice and measured iron absorption rates. Materials and methodsMice (129/Ola-C57BL/6 mixed background strain) with a 2-kb pgk-neor gene flanked by loxP sites replacing a...