The mechanism by which the intestine responds to alterations in body iron requirements is poorly understood, but recent evidence has strongly implicated the liver-derived peptide hepcidin in this process. Using a variety of experimental systems, we are investigating how intestinal iron transport responds to variations in body iron demand, such as those associated with changes in body iron stores and the rate of erythropoiesis, and how these changes correlate with variations in hepcidin expression.
We are also studying physiological and pathological situations in which iron absorption is altered, such as during pregnancy, in the neonate, in haemochromatosis, end-stage liver disease and thalassaemia, and during the acute phase response. Emphasis is being placed on analysing the expression of recently identified proteins of iron metabolism. These include hephaestin, the haemochromatosis gene product HFE, hepcidin, the iron transporters DMT1 and ferroportin 1, the ferric reductase Dcytb, hemojuvelin (mutated in most cases of juvenile haemochromatosis) and TfR2.
The role of HFE in controlling iron absorption remains particularly enigmatic, but we have recently shown that hepcidin expression is inappropriately low in haemochromatosis patients and HFE knockout mice. These studies represent a major advance in our understanding of the pathogenesis of this disease. They suggest that HFE is an upstream regulator of hepcidin and imply that the major site of HFE action is in the liver and not in the small intestine as previously believed. Elucidating the signal transduction pathways linking HFE to hepcidin is an area of active investingation by our lab. Studies by our group and others have also shown that HFE is able to interact with a transferrin receptor/transferrin complex, indicating a link between HFE and cellular iron uptake. We have recently proposed that the degree of saturation of plasma transferrin with iron could be an important signal in influencing hepcidin expression through the HFE pathway. Our HFE studies are continuing in collaboration with the laboratories of Dr Nathan Subramaniam and Dr Grant Ramm at QIMR.