Iron Homeostasis: Hepcidin Regulation

Abstract The liver hormone hepcidin is the key regulator of systemic iron homeostasis in mammals. Hepcidin controls the release of iron into plasma by binding and degrading the sole cellular iron exporter ferroportin on the surface of enterocytes, macrophages, and hepatocytes. The transcription of hepcidin is enhanced in conditions of increased body iron through the bone morphogenic protein–sons of mothers against decapentaplegic (BMP6–SMAD) signaling pathway that uses hemojuvelin (HJV) as a coreceptor. Mutational inactivation of HJV, BMP6, and other components of the pathway leads to iron overload in both humans and mice, similar to what occurs in hepcidin inactivation. Because hepcidin is an antimicrobial peptide, its transcription is also increased in inflammation, especially in response to IL‐6, through JAK2‐STAT3 activation. Inhibition of the BMP–SMAD signaling reduces the hepcidin response to inflammatory cytokines, indicating a crosstalk between the two regulatory pathways. In conditions of increased iron requirement, such as iron deficiency, hypoxia, or stimulated erythropoiesis, hepcidin expression is inhibited by multiple, yet incompletely understood, mechanisms. The main hepcidin inhibitor is TMPRSS6 encoding a serine protease, which negatively affects the BMP–SMAD signaling. Mutational inactivation of this protease leads to inappropriately high hepcidin synthesis, defective intestinal iron absorption, and iron‐deficient iron‐refractory anemia in both mice and humans. Other molecules may contribute to hepcidin inhibition, including a soluble form of HJV, hypoxia, or mediators released by maturing erythroid cells, but their molecular mechanisms are uncertain. Although the picture of all potential hepcidin regulators is still incompletely defined, the identification of hepcidin and of its regulatory pathways has revolutionized our understating of iron metabolism and clarified the pathophysiology of iron‐related disorders. In addition, the discovery of the role of the hepcidin–ferroportin axis in the control of systemic iron homeostasis has stimulated a great interest in developing targeted drugs to control several human disorders characterized by iron deregulation. Novel promising therapeutic strategies are under development and some newly synthesized components have already been shown to be effective in animal models.