Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs

UCLA Department of Medicine, 10833 Le Conte Ave, CHS 37-131, Los Angeles, CA 90095, USA.
Blood (Impact Factor: 10.45). 10/2005; 106(6):2196-9. DOI: 10.1182/blood-2005-04-1766
Source: PubMed


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-microg 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-microg dose was 1.4 microM, consistent with the inhibitory concentration of 50% (IC50) of hepcidin measured in vitro. Radiolabeled hepcidin accumulated in the ferroportin-rich organs, liver, spleen, and proximal duodenum. Our study highlights the central role of the hepcidin-ferroportin interaction in iron homeostasis. The rapid and sustained action of a single dose of hepcidin makes it an appealing agent for the prevention of iron accumulation in hereditary hemochromatosis.

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    • "A second method is chemical synthesis of hepcidin, which requires various refolding procedures. In addition, synthetized hepcidin molecules have different sizes that may interfere with hepcidin function (Rivera et al. 2005). "
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    • "Hepcidin is a master regulator of iron homoeostasis in humans and other mammals [46]. It inhibits the absorption of iron in the small intestine and the release of recycled iron from macrophages, effectively decreasing the delivery of iron to maturing erythrocytes in the bone marrow [47]. In this regard, IL-6 is known to induce hepcidin production in liver cells [48]. "
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    • "Short- and long-term hepcidin injections, or hepatic over-expression of hepcidin transgene in Hfe-deficient mice resulted in successful reconstitution of hepcidin expression to the levels present in wild type mice. Furthermore, high plasma iron levels present in Hfe-/- mice were significantly reduced by hepcidin treatments, without affecting hepatic iron load which remained inappropriately high in regard to hepcidin levels (Nicolas et al., 2003; Laftah et al., 2004; Rivera et al., 2005; Viatte et al., 2006; Moran-Jimenez et al., 2010). Neither has exogenous Bmp6 administration to Hfe-/- mice succeeded to reduce hepatic iron burden, although hepcidin expression was restored to the levels present in wild type mice, followed by a significant drop in serum iron levels and redistribution of iron in the spleen and duodenum in Hfe-/- mice (Corradini et al., 2010). "
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