Abstract
The iron regulatory hormone hepcidin limits iron fluxes to the bloodstream by promoting degradation of the iron exporter ferroportin in target cells. Hepcidin insufficiency causes hyperabsorption of dietary iron, hyperferremia and tissue iron overload, which are hallmarks of hereditary hemochromatosis. Similar responses are also observed in iron-loading anemias due to ineffective erythropoiesis (such as thalassemias, dyserythropoietic anemias and myelodysplastic syndromes) and in chronic liver diseases. On the other hand, excessive hepcidin expression inhibits dietary iron absorption and leads to hypoferremia and iron retention within tissue macrophages. This reduces iron availability for erythroblasts and contributes to the development of anemias with iron-restricted erythropoiesis (such as anemia of chronic disease and iron-refractory iron-deficiency anemia). Pharmacological targeting of the hepcidin/ferroportin axis may offer considerable therapeutic benefits by correcting iron traffic. This review summarizes the principles underlying the development of hepcidin-based therapies for the treatment of iron-related disorders, and discusses the emerging strategies for manipulating hepcidin pathways.
Highlights
Iron is an essential constituent of hemoglobin, myoglobin and several other proteins, and potentially toxic due to its redox reactivity that promotes oxidative stress (Papanikolaou and Pantopoulos, 2005)
Hereditary hemochromatosis adult forms caused by mutations in HFE or TFR2 juvenile forms caused by mutations in HJV or HAMP
Anemia of Castleman disease (inflammatory induction of hepcidin triggered by tumor-derived IL-6 dyserythropoietic anemias and myelodysplastic syndromes, and contributes to iron overload (Ginzburg and Rivella, 2011; Camaschella and Nai, 2016)
Summary
Iron is an essential constituent of hemoglobin, myoglobin and several other proteins, and potentially toxic due to its redox reactivity that promotes oxidative stress (Papanikolaou and Pantopoulos, 2005). Balanced iron homeostasis is required to satisfy metabolic needs and minimize the risk of toxic side effects. Erythroblasts require a daily supply of ∼20–30 mg and non-erythroid cells another ∼5 mg of iron, which is provided by plasma transferrin (Figure 1). The transferrin iron pool does not exceed ∼3 mg at steady state and turns over >10 times/day. It is mostly replenished with iron recycled from senescent RBCs by tissue macrophages. Hepcidin is synthesized in hepatocytes and secreted to the bloodstream for binding to the iron exporter ferroportin (FPN) in target cells, primarily macrophages and enterocytes, and to some extent hepatocytes (Figure 1). The binding of hepcidin promotes internalization and lysosomal degradation of ferroportin
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
