Figure 1.

The hepcidin pathway and the regulation of body iron homeostasis. Hepcidin is the master regulator of body iron homeostasis. It is synthesized predominantly by hepatocytes and, after secretion, binds to the iron export protein ferroportin (FPN) and removes it from the surface of target cells. This in turn decreases iron export from these cells. Macrophages and intestinal enterocytes are prime targets, but most cells express FPN on their surface. The HAMP gene, which encodes hepcidin, is regulated by a complex series of upstream signalling pathways. The bone morphogenetic protein (BMP)/SMAD pathway is the core regulatory pathway that responds to body iron requirements. Mutations in various proteins that modulate signalling through this pathway lead to hemochromatosis by reducing hepcidin expression. These include hemojuvelin (HJV) which acts as a BMP co-receptor, and homeostatic iron regulator (HFE) and transferrin receptor 2 (TFR2), which modulate signalling through the BMP/SMAD pathway via mechanisms that are not yet fully understood. Increased body iron levels normally stimulate hepcidin expression via the BMP/SMAD pathway, while proinflammatory cytokines increase hepcidin by signalling through the JAK/STAT pathway. The suppression of hepcidin by enhanced erythropoiesis is, at least in part, mediated by erythroferrone.