The role of hepcidin in iron metabolism

Abstract

Hepcidin is the central regulator of systemic iron homeostasis. Dysregulation of hepcidin production results in a variety of iron disorders. Hepcidin deficiency is the cause of iron overload in hereditary hemochromatosis, iron-loading anemias, and hepatitis C. Hepcidin excess is associated with anemia of inflammation, chronic kidney disease and iron-refractory iron deficiency anemia. Diagnostic and therapeutic applications of this new knowledge are beginning to emerge. Dr. Ernest Beutler played a significant role in advancing our understanding of the function of hepcidin. This review is dedicated to his memory.

Fig. 1

Hepcidin structure with revised disulfide connectivities.

Fig. 2

Hepcidin-ferroportin (Fpn) interaction determines the flow of iron into plasma. Hepcidin concentration is in turn regulated by iron, erythropoietic activity and inflammation.

Fig. 3

Hepcidin binding to ferroportin causes internalization of the receptor-ligand complex, and their eventual degradation. HEK293 cells expressing ferroportin-GFP were treated with Texas-red-labeled hepcidin and imaged using fluorescent microscopy.

Fig. 4

A model of hepcidin regulation by iron Tf (a) and intracellular iron (b). a Increased iron Tf concentrations stabilize TfR2 protein, HFE is displaced from TfR1 and associates with TfR2. The HFE-TfR2 complex likely interacts with the HJV-BMP receptor (BMPR), BMP signaling is potentiated and hepcidin transcription increases. b Elevated intracellular iron increases BMP6 production. Secreted BMP6 binds to the HJV-BMPR complex, stimulates Smad signaling, and increases hepcidin transcription.