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Hepcidin, a key regulator of iron metabolism Volume 9, issue 1, Janvier - Février 2003

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Institut national de la santé et de la recherche médicale 409, faculté de médecine Xavier Bichat, 75018, Paris, France. Département de génétique, développement et pathologie moléculaire, Institut Cochin, Inserm, CNRS, et université René‐Descartes, faculté de médecine Cochin‐Port‐Royal, 24, rue du Fg S Jacques, 75014 Paris, France

Iron balance is maintained by meticulous regulation of iron absorption from the intestine and iron release by macrophages. This balance is modulated in response to body iron stores (stores regulator) and the demand for iron for erythropoiesis (erythroid regulator). The regulation of iron balance prevents deleterious extremes of iron deficiency or excess. For many years, the stores and the erythroid regulators have been thought to be soluble plasma factors, but their identities were unknown. Recently, hepcidin has been proposed to be a key component of these regulatory systems. Hepcidin is a circulating peptide hormone synthesized predominantly in the liver and secreted in the plasma in the form of 20 and 25 amino acid peptides. Its synthesis is increased by dietary iron loading. Hepcidin‐deficient mice accumulate iron in parenchymal cells, due to increased intestinal iron absorption and poor retention of iron by reticuloendothelial macrophage cells. Similarly, loss‐of‐function mutations in the human hepcidin gene have been identified in two families with juvenile haemochromatosis. Conversely, transgenic animals overexpressing hepcidin have markedly decreased iron stores, leading to severe microcytic anemia. These data all indicate a direct role for hepcidin in regulating iron homeostasis. Its action can be explained by a simple model, which postulates that hepcidin is a negative regulator of iron release from both reticuloendothelial macrophages as from the enterocytes that mediate intestinal absorption of dietary iron. Its role in human has been very recently highlighted by the discovery of hepcidin gene mutations associated with severe juvenile haemochromatosis.