Regulation of systemic iron homeostasis. Hepcidin, which is encoded by the hepcidin anti-microbial peptide (HAMP) gene, is produced by the liver in response to iron status and requirements. It down-regulates ferroportin (FPN) on macrophages and duodenal enterocytes to control the amount of iron entering the circulation from recycled red blood cells (RBCs) and the diet, respectively. Dietary ferric iron is reduced by the action of duodenal cytochrome B (DCytB), imported by divalent metal transporter-1 (DMT-1) expressed on the apical enterocyte membrane, and then exported at the basolateral membrane by FPN. Ferrous iron is converted into the ferric form by hephaestin (Heph) or ceruloplasmin (Cp) and transported in the circulation bound to transferrin (holo-transferrin). Similar transport mechanisms operate in the macrophage to recycle iron from RBCs.