The Regulation of Iron Absorption and Homeostasis

Abstract

Iron is an essential element in biology, required for numerous cellular processes. Either too much or too little iron can be detrimental, and organisms have developed mechanisms for balancing iron within safe limits. In mammals there are no controlled mechanisms for the excretion of excess iron, hence body iron homeostasis is regulated at the sites of absorption, utilisation and recycling. This review will discuss the discoveries that have been made in the past 20 years into advancing our understanding of iron homeostasis and its regulation. The study of iron-associated disorders, such as the iron overload condition hereditary haemochromatosis and various forms of anaemia have been instrumental in increasing our knowledge in this area, as have cellular and animal model studies. The liver has emerged as the major site of systemic iron regulation, being the location where the iron regulatory hormone hepcidin is produced. Hepcidin is a negative regulator of iron absorption and recycling, achieving this by binding to the only known cellular iron exporter ferroportin and causing its internalisation and degradation, thereby reducing iron efflux from target cells and reducing serum iron levels. Much of the research in the iron metabolism field has focussed on the regulation of hepcidin and its interaction with ferroportin. The advances in this area have greatly increased our knowledge of iron metabolism and its regulation and have led to the development of novel diagnostics and therapeutics for iron-associated disorders.

Figure 1.

The regulation of hepcidin and iron homeostasis. Schematic showing the major molecules and pathways involved in the regulation of hepcidin (HAMP) gene expression in hepatocytes and the functions of hepcidin in regulating the surface expression of the iron export protein ferroportin (FPN) in other cell types. The major molecules and pathways responsible for the iron, inflammation and erythropoietic regulation of HAMP in hepatocytes are depicted at the top of the figure. The role of hepatocyte-derived hepcidin in regulating iron absorption in duodenal enterocytes and iron recycling in macrophages via its interaction with FPN is depicted at the bottom of the figure. Small red circles represent iron. IL-6, interleukin 6; IL-6-R, IL-6 receptor; JAK, Janus kinase; STAT3, signal transducer and activator of transcription 3; BMP6, bone morphogenetic protein 6; BMP-R, BMP receptor; HJV, hemojuvelin; MT-2, matriptase-2; HFE, haemochromatosis protein; TF, transferrin; TFR1, TF receptor 1; TFR2, TF receptor 2; GDF15, growth differentiation factor 15; TWSG1, twisted gastrulation; ERFE, erythroferrone; SMAD, mothers against decapentaplegic homologue; DMT1, divalent metal transporter 1; DcytB, duodenal cytochrome B; Heph, hephaestin; CP, caeruloplasmin; RBC, red blood cell.