In vertebrates, hepcidin is the peptide hormone that homeostatically regulates the body's supply of elemental iron, an indispensible reactant in many biological processes. Worldwide over a billion people are affected by diseases associated with iron imbalance. These conditions can be categorized as disorders in which hepcidin responds physiologically and disorders in which hepcidin is dysregulated. In the former, lack of dietary iron appropriately suppresses hepcidin to maximize dietary iron absorption capacity. Iron-restricted anemia can develop, nevertheless, if the iron content of food is not sufficient. In the latter, inappropriate hepcidin stimulation by cytokines, during chronic inflammation for example, reduces plasma iron and anemia results despite adequate levels of dietary and body iron.
Iron absorption depends on the interaction between hepcidin and its receptor, the iron exporting channel, ferroportin. When hepcidin activity is insufficient, iron pathways saturate and excess iron intoxicates the organs in which it accumulates. When plasma iron levels need to be reduced, hepcidin is secreted by the liver into circulation where it finds ferroportin and initiates its internalization and degradation. Plasma iron flow is thus blocked from the principle ferroportin-expressing cell types including, but not limited to, enterocytes, macrophages of the spleen and liver and hepatocytes until an unknown signaling mechanism suppresses hepcidin production to allow iron to flow to sites of need.
How the liver moderates hepcidin production in response to increased body iron is still not completely understood, but Chapter 1 of this dissertation, describes the use of mouse models of hepcidin deficiency to define two signals that independently regulate hepcidin production. Chapter 2 builds on a collaboration described in Chapter 3, and details the optimization and use of hepcidin mimetics to treat iron overload caused by hepcidin deficiency. Chapter 4 is another collaboration that elucidates novel signaling pathways that suppress hepcidin and their connection to iron overload in conditions that damage cells of the liver.
