Albertine Donker

Iron Function and Iron Handling from Fetus to Adult 55 2 HEPCIDIN PLAYS A KEY ROLE IN SYSTEMIC IRON HOMEOSTASIS The systemic and cellular iron homeostasis cooperate in the human body Cells predominantly involved in the systemic iron homeostasis are duodenal enterocytes, erythroid precursors, hepatocytes and macrophages. The duodenal enterocyte absorbs 1-2 mg per day to compensate for the small amount of iron loss that occurs through epidermal and enteral desquamation. Once inside the enterocyte, iron is stored by ferritin or released into the plasma. After oxidation by ferroxidases, iron is loaded to transferrin for transport in the plasma. Iron binding to transferrin prevents the formation of unbound iron (non-transferrin-bound iron; NTBI) that is highly toxic because it catalyzes the formation of oxidative radicals and allows the unrestricted influx of iron in parenchymal organs. 13 Ferric-transferrin binds to the transferrin receptor, expressed on all iron-containing cells, but mainly on erythroid precursors in the bone marrow and on hepatocytes. In the bone marrow, iron is used for erythropoiesis, in the liver iron is stored in hepatocytes as ferritin or hemosiderin. However, the majority of iron in the circulation is derived from the recycling of senescent erythrocytes (20-25 mg of iron per day). Because both ID and IO may have detrimental effects, a highly sophisticated regulatory system is required to maintain iron homeostasis on both the systemic and cellular level. Systemic iron homeostasis relies on the regulatory hormone hepcidin and the cellular iron exporter ferroportin. 11,14 Cellular iron homeostasis is predominantly controlled in a post-transcriptional way by iron-regulatory proteins (IRP) that bind iron- responsive elements (IRE) in regulated messenger RNA’s of cellular iron importers, exporters and storage genes. 11,14 This complex system is beyond the scope of this review; the interested reader is referred to the literature. 11,14-16 Intracellular iron is also sensed and regulated by the hypoxia-inducible factor (HIF) system. 17-19 Under low iron and oxygen (O2) conditions, HIFα induces the expression of various genes involved in iron homeostasis, encoding the transferrin receptor 1(TfR1), ferroportin, ceruloplasmin and erythropoietin (EPO). On the contrary, under iron-replete, normoxic conditions, degradation of HIFα occurs by iron- and oxygen independent hydoxylases. 17-19