Hepcidin excess induces the sequestration of iron and exacerbates tumor-associated anemia

Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA.
Blood (Impact Factor: 10.45). 03/2005; 105(4):1797-802. DOI: 10.1182/blood-2004-08-3375
Source: PubMed


The iron-regulatory hormone hepcidin has been proposed as the mediator of anemia of inflammation (AI). We examined the acute and chronic effects of hepcidin in the mouse. Injections of human hepcidin (50 microg/mouse), but not of its diluent, induced hypoferremia within 4 hours. To examine the chronic effects of hepcidin, we implanted either tumor xenografts engineered to overexpress human hepcidin or control tumor xenografts into nonobese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Despite abundant dietary iron, mice with hepcidin-producing tumors developed more severe anemia, lower serum iron, and increased hepatic iron compared with mice with control tumors. Hepcidin contributes to AI by shunting iron away from erythropoiesis and sequestering it in the liver, predominantly in hepatocytes.

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    • "Secreted hepcidin binds to the transmembrane iron transporter ferroportin in macrophages of the RES as well as in hepatocytes and enterocytes , down-regulating its expression by post-translational mechanisms [6]. In addition to decreased transport of iron from enterocytes to the circulation, the downregulated ferroportin reduces iron efflux from macrophages [7] [8], thus making less iron available for erythropoiesis , the ultimate consequence of which is IRE and anemia [9]. Most of our current knowledge of IRE and its treatment with iron supplementation stems from the nephrology setting [10]. "
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    • "Secreted hepcidin binds to the transmembrane iron-transporting protein ferroportin in macrophages of the reticuloendothelial system (RES) as well as in hepatocytes and in enterocytes and downregulates its expression by posttranslational mechanisms [15]. In addition to decreased transport of iron from enterocytes to the circulation, the downregulated ferroportin expression reduces iron efflux from macrophages [16] [17], thus making less iron available for erythropoiesis, the ultimate consequence of which is FID and anemia [18]. FID has also been observed in CKD patients treated with ESAs [19]. "
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    • "IRIDA and mouse models overexpressing hepcidin demonstrate that elevated hepcidin is sufficient to cause hypoferremia and anemia [4]. Moderate overproduction of hepcidin in transgenic mice or in mice bearing hepcidin-producing tumors caused an iron-restricted anemia [4, 53]. Transgenic mice also had blunted erythropoietic response to EPO, another characteristic of AI. "
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    ABSTRACT: The hepatic peptide hormone hepcidin regulates dietary iron absorption, plasma iron concentrations, and tissue iron distribution. Hepcidin acts by causing the degradation of its receptor, the cellular iron exporter ferroportin. The loss of ferroportin decreases iron flow into plasma from absorptive enterocytes, from macrophages that recycle the iron of senescent erythrocytes, and from hepatocytes that store iron, thereby lowering plasma iron concentrations. Malfunctions of the hepcidin-ferroportin axis contribute to the pathogenesis of different anemias. Deficient production of hepcidin causes systemic iron overload in iron-loading anemias such as beta-thalassemia; whereas hepcidin excess contributes to the development of anemia in inflammatory disorders and chronic kidney disease, and may cause erythropoietin resistance. The diagnosis of different forms of anemia will be facilitated by improved hepcidin assays, and the treatment will be enhanced by the development of hepcidin agonists and antagonists.
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