Disorders of iron homeostasis are among the most common nutritional problems worldwide. Because there are no physiologic mechanisms to modulate iron excretion in humans, homeostasis depends entirely upon tightly linking dietary iron absorption with iron utilization and storage. The circulating liver peptide hepcidin appears to be a central regulator of this process. However, the means by which hepatocytes sense plasma iron and modulate hepcidin expression remain unknown. Like the classic Tf receptor (TfR1), the recently identified second Tf receptor (TfR2) mediates cellular uptake of holoTf. We propose that the role of TfR2 in the hepatoeyte is to serve as a hepatocellular sensor of circulating holoTf, and modulator of expression of the iron-regulatory peptide hepcidin. This hypothesis is supported by observations in our mouse model with a non-functional TfR2 (TfR2 YaaSX homozygous mice) It is the broad goal of this proposal to define and characterize the role of TfR2 in iron homeostasis. We have four specific aims: 1) Identify and characterize the participation of TfR2 in the hepatocellular uptake of holoTf. 2) Define the role of TfR2 in modulating the hepatocellular expression of hepcidin. 3) Distinguish the hepatocellular role of TfR2 by the cell-specific and regulatable restoration of wild-type TfR2 in TfR2 v245x mouse hepatocytes. 4) Determine the molecular basis for the functional defect caused by the TfR2 M172K mutation. These studies will identify and characterize the role of TfR2 as a hepatocellular iron sensor, and its participation in the modulation of hepcidin expression. This knowledge will increase our understanding of iron homeostasis, and may suggest new approaches to the management of diseases of iron overload and maldistribution.
