Hepcidin is the principal iron regulatory hormone and its overproduction contributes to anemia of inflammation (AI). In vitro, hepcidin binds to and induces the degradation of the exclusive iron exporter ferroportin. We explored the effects and distribution of synthetic hepcidin in the mouse. A single intraperitoneal injection of hepcidin caused a rapid fall of serum iron in a dose-dependent manner, with a 50-g dose resulting in iron levels 80% lower than in control mice. The full effect was seen within only 1 hour, consistent with a blockade of iron export from tissue stores and from macrophages involved in iron recycling. Serum iron remained suppressed for more than 48 hours after injection. Using radiolabeled hepcidin, we demonstrated that the serum concentration of hepcidin at the 50-

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In extracellular fluid, iron is in the ferric (oxidized form) but the intracellular form is ferrous iron (reduced). The outflow of iron from cells is dependent on oxidase activity that converts ferrous to ferric iron. Iron-absorbing enterocytes possess a unique iron oxidase, hephaestin. It is presumed that the circulating hephaestin paralog ceruloplasmin fulfils this role in hepatocytes and macrophages. The DiSnA mouse lacks ceruloplasmin. We hypothesized that iron homeostasis in this mouse would be unusually dependent on dietary iron because the mouse would not be able to mobilize iron from tissue stores in hepatocytes and macrophages. We fed 4-week-old DiSnA and wildtype (WT) mice a high iron (1%) diet for 4 weeks to load tissue stores. We then switched them to an iron-deficient diet and analyzed them weekly to measure iron and hemoglobin concentrations. Even on the high iron diet, DiSnA mice had lower serum iron concentrations than WT control (32.9±17.9 vs. 53.5±17.6 μM, p=0.05) but after two weeks on the iron deficient diet, the DiSnA mice had almost undetectable serum iron (4.2±1.8 μM) whereas the WT controls had only declined slightly (43.2±9.6 μM, p<0.001). Iron saturation followed a similar trend. Neither WT nor DiSnA mice were anemic at baseline (Hgb = 13.9±0.3 and 13.9±1.1 g/dL, respectively; p=0.994) but by the end of two weeks, the DiSnA mice had developed anemia whereas the WT mice had not (Hgb = 10.4±0.5 vs. 12.6±0.5 g/dL; p<0.001). The difference in hemoglobin concentrations persisted to the 6-week timepoint (Hgb = 8.4±0.5 vs. 12.6±1.4; p<0.001). After 6-weeks on a low iron diet, iron was still present in livers and spleens of both groups. Ceruloplasmin is essential for the mobilization of iron stores to protect against iron deficiency anemia in response to periods of dietary iron deficiency.