This decreased availability of iron may be a host defense mechanism against invading microorganisms ( 15, 18). It is characterized by low serum iron levels (hypoferremia), low serum iron-binding capacity, and normal to elevated ferritin concentrations ( 17). AI is a common condition that affects patients with acute and chronic infections, inflammatory disorders, and neoplastic diseases ( 15, 16). This also suggested that hepcidin could be the pathogenic mediator of anemia of inflammation (AI), also called anemia of chronic disease. In agreement with a potential role for hepcidin in host defense, hepcidin mRNA was increased in the livers of LPS-treated mice and in LPS-treated hepatocytes ( 3). Structurally, hepcidin is similar to disulfide-rich antimicrobial peptides such as those produced in the fat body of insects (the equivalent of the vertebrate liver) in response to infections ( 2, 14). These observations suggest that human hepcidin is the functional equivalent of hepcidin-1 in mice. Conversely, autonomous overexpression of hepcidin mRNA expression was seen in large hepatic adenomas associated with iron-refractory anemia ( 13). Hepcidin production was also diminished in another form of juvenile hemochromatosis due to mutations in the hemojuvelin gene ( 10) and in the most common form of hemochromatosis, that caused by mutations in the HFE gene ( 11, 12). There is a single human hepcidin gene whose essential role in iron homeostasis was confirmed by identifying homozygous frameshift or nonsense mutations in affected individuals with severe juvenile hemochromatosis ( 9). Thus, hepcidin mRNA expression was increased in mice with diet-induced or genetically induced iron overload ( 3, 7) and decreased in mice with anemia caused by bleeding or hemolysis or in mice with hypoxemia due to decreased ambient oxygen ( 8). In accord with the proposed role of hepcidin as a homeostatic regulator of iron transport and erythropoiesis, hepcidin synthesis is regulated by dietary iron and iron stores, as well as by tissue oxygenation. Overexpression of the other known murine hepcidin gene, hepcidin-2, had no effect on iron metabolism in mice ( 6). Conversely, in transgenic mice overexpressing hepcidin-1 ( 4), transplacental and intestinal iron transport was blocked, and the mice died at birth from severe iron deficiency unless given parenteral iron supplementation. Thus, in mice, ablation of hepcidin expression removed the inhibition and resulted in iron overload resembling human hemochromatosis, with iron excess in most tissues except the macrophage-rich spleen ( 5). Recent studies indicate that hepcidin (in mice, hepcidin-1) inhibits intestinal iron absorption ( 4, 5), placental iron transport ( 4), and release of recycled iron from macrophages ( 5), effectively decreasing the delivery of iron to maturing erythrocytes in the bone marrow. Hepcidin, a disulfide-rich peptide produced by hepatocytes ( 1– 3), may be the long-anticipated central regulator of iron metabolism.
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