Iron is an essential element required for growth and survival. This metal serves as a cofactor for many heme and nonheme iron proteins. However, excess free iron is toxic for the cell. Because mammals lack a regulated pathway for iron excretion, iron balance is maintained by the tight regulation of iron absorption from the intestine. The intestinal iron absorption is modulated in response to the level of body iron stores and by the amount of iron needed for erythropoiesis. This regulation is thought to operate through two regulators, namely, the store regulator and the erythroid regulator (for review, see ref. 1
). When the amount of iron in the body stores decreases, the store regulator increases iron uptake until the reserves are replete. When iron stores are increased, it reduces intestinal iron absorption, thus preventing iron overload. Although the store regulator is capable of changing iron absorption to a relatively modest extent, its function is critical for normal iron homeostasis. The store regulator probably acts at the level of duodenal crypt cells, which become programmed in response to body store information, to influence the absorptive capacity of the daughter enterocytes.
As for the erythroid regulator, it is believed to transmit to the enterocyte the erythroid demand of the organism, iron absorption being upregulated as marrow iron requirement for erythropoiesis increases. This regulator operates over a broader range than the store regulator and probably increases intestinal iron absorption independently of the store regulator. However, an increase in erythropoiesis alone is not enough to increase iron absorption. Rather, it is the imbalance between the rate of erythropoiesis of the marrow and its iron supply that is thought to induce iron absorption. Anemia-associated hypoxia could be one of the mechanisms by which the erythroid cue is transmitted to the duodenum. Indeed, hypoxia by itself is known to increase intestinal iron absorption (2
Both the store regulator and the erythroid regulator are believed to be soluble components of the plasma able to communicate between the sites of iron utilization and mobilization and the intestinal cells. So far, the signaling pathway and molecular components involved in the regulation of iron absorption through these two regulators have remained elusive. Recently, we proposed the circulating peptide hepcidin as a new candidate of the long-postulated store regulator. Hepcidin is a disulfide-bonded peptide exhibiting antimicrobial activity (3
). It has been purified from human blood ultrafiltrate and from urine. It is synthesized predominantly in the liver as an 84–amino acid precursor that is subsequently processed and secreted as a 25–amino acid peptide form (3
). Several lines of evidence strongly suggest that this peptide plays a major role in the control of iron homeostasis. In mice experimentally induced iron loading in the liver was found to be associated with increased hepcidin gene expression (5
). We demonstrated that a complete lack of hepcidin in mice leads to progressive iron accumulation resembling the iron overload of human hemochromatosis, with excess iron in hepatocytes and iron sparing of the reticuloendothelial cells (6
). Finally, we demonstrated recently that transgenic animals overexpressing hepcidin in the liver have decreased body iron levels and presented at birth a severe microcytic hypochromic anemia (7
). Taken together, these results highlighted the role of hepcidin as an iron regulator whose induction results in a decrease in both dietary iron absorption and transplacental iron transport.
In this article we further address the physiological role of hepcidin in vivo. We first ask whether hepcidin could play a role as an erythroid regulator, contributing to the modulation of iron absorption by the intestine and iron release by the macrophages in the situation of anemia with normal or increased iron stores. To this end, we investigated the pathophysiological response of hepcidin in situations associated with increased iron absorption, such as bleeding, phenylhydrazine-induced anemia, and hypoxia. Secondly, we ask whether hepcidin plays a role during the inflammatory states that are associated with decreased intestinal iron absorption and increased sequestration of iron in reticuloendothelial cells. This question was assessed by studying inflammation induced by turpentine in wild-type mice as well as in hepcidin-deficient mice.