Hepcidin-ferroportin axis in health and disease

Abstract

Hepcidin is central to regulation of iron metabolism. Its effect on a cellular level involves binding ferroportin, the main iron export protein, resulting in its internalization and degradation and leading to iron sequestration within ferroportin-expressing cells. Aberrantly increased hepcidin leads to systemic iron deficiency and/or iron restricted erythropoiesis. Furthermore, insufficiently elevated hepcidin occurs in multiple diseases associated with iron overload. Abnormal iron metabolism as a consequence of hepcidin dysregulation is an underlying factor resulting in pathophysiology of multiple diseases and several agents aimed at manipulating this pathway have been designed, with some already in clinical trials. In this chapter, we present an overview of and rationale for exploring the development of hepcidin agonists and antagonists in various clinical scenarios.

Keywords: Anemia of inflammation; Erythroferrone; Hepcidin antagonists; Hepcidin mimetics; Hepcidin:ferroportin axis; Hereditary hemochromatosis; Iron metabolism; Polycythemia vera; β-thalassemia.

Fig. 1

Central role of hepcidin in regulation of iron metabolism. Hepcidin regulates iron absorption, iron recycling and iron released from stores. Hepcidin expression is enhanced by iron regulatory pathway (blue arrow) and inflammatory cytokines (violet arrow) and suppressed by erythropoiesis (red arrow). ERFE, erythroferrone.

Fig. 2

Regulation of hepcidin expression. Hepcidin expression involves iron sensing by hepatocytes. BMP6 and possibly BMP2 bind at BMP receptor, initiating a signaling cascade of SMAD1/5/8 phosphorylation which, couples with SMAD4 and translocates into the nucleus to initiate hepcidin transcription. As part of the inflammatory cascade, IL6 binds IL6 receptor, initiating a JAK/STAT signaling cascade of STAT3 phosphorylation which translocates into the nucleus and, in a SMAD-dependent manner, initiate hepcidin expression. BMP, bone morphogenic protein; BMPR, BMP receptor; Fe, iron; HFE, high iron Fe; HJV, hemojuvulin; IL6, interleukin 6; IL6R, IL6 receptor; JAK, janus kinase; sHJV, soluble HJV; SMAD, single mother against decapentaplegic; STAT, signaling transducer and activator of transcription; Tf, transferrin; TFs, transcription factors.

Fig. 3

Regulating iron absorption by hepcidin-dependent and -independent mechanisms. At the duodenal enterocyte, where iron is absorbed, hepcidin functions as a negative regulator at the basolateral surface, where ferroportin exports iron from duodenal enterocytes into the circulation. Hypoxia functions as a positive regulator at the apical surface where DMTI imports iron into duodenal enterocytes. Together, the presence of hypoxia in the gastrointestinal tract with suppression of hepcidin would provide the most potent stimulus for iron absorption. DMTI, divalent metal transporter 1; Fpn, ferroportin.

Fig. 4

Hepcidin functions via effects on ferroportin mediated iron efflux. Hepcidin binds to and results in the internalization and degradation of ferroportin, leading to a block in iron efflux from ferroportin expressing cells (duodenal enterocytes, hepatocytes, macrophages, and placenta). In low hepcidin states, iron taken up by these cells is exported via ferroportin. Conversely, in high hepcidin states, the loss of membrane ferroportin results in iron sequestration, typically within cytosolic ferritin. Fe, iron; Fpn, ferroportin.

Fig. 5

Model of hepcidin’s effect on iron availability for erythropoiesis. Decreased hepcidin, as in systemic iron deficiency, leads to more ferroportin and consequently more iron efflux into circulation where it is available for uptake by erythroblasts via Fe-Tf binding to TfRl. Alternatively, hepcidin elevation, as in anemia of chronic disease, leads to hepcidin:Fpn binding, preventing iron egress, resulting in iron sequestration within macrophages (e.g., splenic macrophages, involved in iron recycling from senescent red blood cells), and leads to iron restricted erythropoiesis. Fe, iron; Fe-Tf, Fe loaded transferrin; Fpn, ferroportin; TfRl, transferrin receptor 1.

Fig. 6

Competitive hepcidin regulation. Hepcidin expression is enhanced by inflammation and suppressed by erythropoiesis such that the combination of both conditions would theoretically lead to equal opposite directional effects on hepcidin regulation in PV, a disease of concurrent expanded erythropoiesis and inflammation.