Figure 1. Models for control of hepcidin expression by iron.

Efficient hepcidin expression in hepatocytes requires an intact BMP signaling pathway, HJV, neogenin, TfR2, HFE, and BMP6. (A) Under high iron conditions, increased loading of Tf with iron stabilizes TfR2, disrupts the HFE-TfR1 interaction, and induces BMP6 secretion from the nonparenchymal cells of the liver, which facilitates the formation of a complex consisting of the BMP receptor/BMP6/HJV/neogenin/TfR2/HFE to induce hepcidin expression. (B) Low iron conditions increase MT2, which induces the cleavage of hepatic HJV. Decreased Tf saturation in the circulation destabilizes TfR2 protein and facilitates the HFE-TfR1 interaction. Low iron levels in the liver reduce BMP6 secretion from the nonparenchymal cells, consequently blunting BMP signaling and lowering hepcidin expression. (C) Inflammation induces the expression of IL-6 and activin B in the liver, which activates the transcription of hepcidin via the STAT3/JAK2 pathway and the BMP signaling pathway, respectively.