Regulation of the Iron Homeostatic Hormone Hepcidin

Iron is required for many biological processes but is also toxic in excess; thus, body iron balance is maintained through sophisticated regulatory mechanisms. The lack of a regulated iron excretory mechanism means that body iron balance is controlled at the level of absorption from the diet. Iron absorption is regulated by the hepatic peptide hormone hepcidin. Hepcidin also controls iron release from cells that recycle or store iron, thus regulating plasma iron concentrations. Hepcidin exerts its effects through its receptor, the cellular iron exporter ferroportin. Important regulators of hepcidin, and therefore of systemic iron homeostasis, include plasma iron concentrations, body iron stores, infection and inflammation, and erythropoiesis. Disturbances in the regulation of hepcidin contribute to the pathogenesis of many iron disorders: hepcidin deficiency causes iron overload in hereditary hemochromatosis and nontransfused β-thalassemia, whereas overproduction of hepcidin is associated with iron-restricted anemias seen in patients with chronic kidney disease, chronic inflammatory diseases, some cancers, and inherited iron-refractory iron deficiency anemia. This review summarizes our current understanding of the molecular mechanisms and signaling pathways involved in the control of hepcidin synthesis in the liver, a principal determinant of plasma hepcidin concentrations.