Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs
Synthetic hepcidin causes rapid dose-dependent hypoferremia and is concentrated in ferroportin-containing organs
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DOI：
10.1182/blood-2005-04-1766
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发表时间：
2005-09-15
期刊：
影响因子：
20.3
通讯作者：
Ganz, T
中科院分区：
文献类型：
--
作者：
Rivera, S;Nemeth, E;Ganz, T
铁调素是主要的铁调节激素，其过量产生导致炎症性贫血（AI）。在体外，铁调素结合并诱导排他性铁输出蛋白ferroportin的降解。我们探索了合成的铁调素在小鼠体内的作用和分布。单次腹膜内注射铁调素引起血清铁以剂量依赖性方式迅速下降，50 μ g剂量导致铁水平比对照小鼠低80%。仅在1小时内就看到了全部效果，这与组织储存和参与铁再循环的巨噬细胞的铁输出的阻断一致。血清铁在注射后保持抑制超过48小时。使用放射性标记的铁调素，我们证明在50 μ g剂量下铁调素的血清浓度为1.4 μ M，与体外测量的铁调素的50%抑制浓度（IC 50）一致。放射性标记的铁调素在富含铁转运蛋白的器官、肝脏、脾脏和近端十二指肠中积累。我们的研究强调了铁调素-膜铁转运蛋白相互作用在铁稳态中的核心作用。单剂量铁调素的快速和持续作用使其成为预防遗传性血色病铁蓄积的有吸引力的药物。
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-mu 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 mu g dose was 1.4 mu M, 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.