Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease.

D of iron homeostasis, resulting in iron deficiency or overload, are very common worldwide (1). Normal iron homeostasis depends on a close link between dietary iron absorption and body iron needs (2). The paper by Nicolas et al. in this issue of PNAS (3) presents the exciting possibility that a central player in the communication of body iron stores to the intestinal absorptive cells may have been identified. This unlikely player, originally identified as a circulating antimicrobial peptide, is the hepatic protein hepcidin. Nicolas et al. found absence of hepcidin expression in mice exhibiting iron overload consequent to targeted disruption of the gene encoding the transcription factor Upstream Stimulatory Factor 2 (USF2). A brief review of normal iron metabolism is useful in understanding the proposed role for hepcidin. Dietary free iron, on reduction from the ferric (Fe31) to the ferrous (Fe21) state on the luminal surface of the proximal small intestine (4), is transported into the enterocytes by the apical transporter DMT1 (also known as DCT1, Nramp2) (5). Dietary heme iron is taken up by an as-yetunidentified transporter and released from the heme molecule within the enterocyte. The iron may be stored within the enterocyte as ferritin (and lost with the senescent enterocyte) or transferred across the basolateral membrane to the plasma by the transport protein Ireg1 (6) [other names are ferroportin1 (7) and MTP1 (8)]. This latter process requires oxidation of Fe21 to Fe31 by hephaestin (9). Once iron has entered the circulation, there are no significant physiologic mechanisms for iron loss other than menstruation. Absorbed iron is bound to circulating transferrin and passes initially through the portal system of the liver, which is the major site of iron storage. Hepatocytes take up transferrin-bound iron via the classical transferrin receptor (TfR1) but likely in greater amounts by the recently identified homologous protein, TfR2 (10, 11). The major site of iron utilization is the bone marrow, where iron is taken up via TfRs on erythrocyte precursors for use in heme synthesis. Heme iron is recycled on ingestion of senescent erythrocytes by reticuloendothelial (RE) macrophages. Macrophages also express surface TfRs and take up iron from the circulation directly. Macrophage iron is either retained (stored as ferritin) or released into the plasma, where it is oxidized by ceruloplasmin and transported via transferrin for reutilization. The liver and the RE system thus represent the major sites of mobilizable iron stores. Tight linkage of dietary iron absorption with body stores occurs in the proximal small intestine. Here duodenal crypt cells, the precursor cells for the absorptive enterocytes, sense the iron needs of the body and are ‘‘programmed’’ as they mature into absorptive enterocytes (12) to express appropriate levels of the previously described iron transport proteins (13). The crypt cells obtain information about body iron needs from two postulated regulators (2), the ‘‘stores regulator,’’ which responds to body iron stores, and the ‘‘erythropoietic regulator,’’ which responds to the body’s requirement for erythropoiesis. The capacity of the stores regulator to change iron absorption is low relative to the erythropoietic regulator. Nonetheless, it plays an essential role in meeting increased iron needs and in preventing excess (14). The importance of the stores regulator is highlighted by findings in hereditary hemochromatosis (HH). Patients with HH absorb excessive dietary iron relative to body stores, suggesting that the set-point for the stores regulator is altered. The excess iron accumulates over time, leading to tissue damage and organ failure (15). HFE, the gene defective in HH, encodes a major histocompatibility complex class I integral membrane protein found in a physical complex with b2-microglobulin (b2M) (16). This association with b2M is necessary for transport of HFE to the cell surface (17). In the duodenum, the HFEyb2M complex is confined to the crypt cells, where it is physically associated with TfR1 (18). These observations strongly suggest that HFE modulates the uptake (or release) of plasma-derived iron in these cells. Surprisingly, the duodenal mucosa in HH manifests features more characteristic of iron depletion than overload (6, 13, 19), suggesting that functional loss of HFE in the crypt cells leads to decreased iron uptake (or retention) of plasma iron, which programs the daughter enterocytes for increased dietary iron absorption. A situation reciprocal in many regards to HH occurs in another common disorder of iron homeostasis, the anemia of infection or chronic disease. In HH, circulating iron levels are high, RE stores are low, and intestinal iron absorption is excessive. By contrast, in anemia of chronic disease, circulating iron levels are low, RE stores are high, and intestinal iron absorption is decreased (20, 21). Both disorders affect communication between the sites of iron storage (hepatocytes and the RE system) and uptake (duodenum). However, the means by which these sites communicate has been a mystery. A clue to solving this mystery may lie in the unexpected phenotype of USF2 knockout mice. Why unexpected? The investigators generated these mice to understand the role of USF2 in the glucose responsiveness