The Role of BMP6 in the Regulation of Hepcidin By Iron

Abstract

Normally, hepcidin synthesis is increased in response to iron loading to limit further absorption of dietary iron and its release from stores. Mutations in HFE, TfR2 or HJV cause hepcidin insufficiency which results in the inability to downregulate the absorption of dietary iron, and eventually leads to iron overload. In order to understand the role each of these proteins plays in hepcidin regulation by iron, we analyzed hepcidin responsiveness to short and long‐term iron challenge in HFE, TfR2 and HJV mutant mouse models. While HFE mutants partially increased hepcidin expression after acute iron challenge, both TfR2 and HJV mutants showed no response. After chronic iron challenge, both HFE and TfR2 mutants increased hepcidin expression to near WT levels, but the hepcidin expression in HJV mutants remained severely impaired. We also analyzed BMP6 expression and show that BMP6 upregulation by iron is independent of HFE, TfR2 and HJV. Because of the different roles HFE, TfR2 and HJV play in the hepcidin response to short and long term iron challenges, we propose that there are two independent signals by which iron regulates hepcidin expression. The first is most likely mediated by iron‐transferrin and acts through HFE, TfR2 and HJV, while the long term signal may depend on intracellular iron concentration and requires HJV.