Ferroportin Mediated Control of Iron Metabolism and Disease

Ferroportin, the only known mammalian iron export protein, releases iron from the duodenum, reticuloendothelial system and liver, the sites of iron absorption, recycling and storage respectively. By downregulating ferroportin, the liver-derived hormone hepcidin controls systemic iron availability in response to erythroid demand and inflammation. This ferroportin/hepcidin axis has long been recognized as essential for systemic iron homeostasis. However, both ferroportin and hepcidin are found in tissues not recognized for their role in systemic iron control, such as the heart, the kidney, the brain and the placenta. Co-existence within the same tissue suggests a possible function for hepcidin and ferroportin in local iron homeostasis. However, this hypothesis has not been formally explored. Using mouse models with cardiac-specific manipulation of hepcidin and ferroportin, we have uncovered a role for the cardiac hepcidin/ferroportin axis in cell-autonomous iron homeostasis within cardiomyocytes. Disruption of this cardiac pathway leads to fatal cardiac dysfunction, even against a background of normal systemic iron homeostasis. One the one hand, loss of cardiac ferroportin causes by fatal cardiac iron overload that is preventable by dietary iron restriction ¹. On the other hand, loss of cardiac hepcidin or of cardiac hepcidin responsiveness causes fatal cardiomyocyte iron deficiency that is preventable by intravenous iron administration. Comparative study of cardiac iron homeostasis and function in cardiac versus systemic models of ferroportin/hepcidin disruption provides insight into the interplay between systemic and cellular iron homeostasis. A role for the hepcidin/ferroportin axis in cell-autonomous iron control, demonstrated here in the context of the heart, has not previously been described in any other tissue. A pertinent question is whether our findings in the heart extend to other tissues that express both hepcidin and ferroportin, such as the kidney, brain and placenta. Disturbances in iron homeostasis are of clinical importance in cardiovascular disease, renal failure, neurodegeneration and developmental defects. Our findings have two clinically relevant implications: a) that disruption of the local hepcidin/ferroportin axis may in itself have a disease-modifying effect, and b) that therapeutic strategies developed to target the systemic hepcidin/ferroportin axis may have off-target effects relating to local iron control within some tissues.

Reference

1.Lakhal-Littleton S, Wolna M, Carr C, et al. Cardiac ferroportin regulates cellular iron homeostasis and is important for cardiac function. PNAS. 2015; 10;112(10):3164-3169.