UCLA

Iron is vital for bodily function but is potentially toxic and accordingly, tightly controlled in the body. Systemic iron homeostasis is regulated by the liver-produced hormone hepcidin which controls cellular iron efflux through ferroportin, the only known iron exporter. Ferroportin delivers iron into the plasma from duodenal enterocytes which absorb dietary iron, from macrophages in the spleen and the liver which recycle iron from senescent erythrocytes, and from hepatocytes in the liver which store iron and deliver it to plasma when systemic iron requirements increase. Ferroportin is the hepcidin receptor: hepcidin binds to ferroportin, leading to its endocytosis and degradation, thus preventing the entry of iron into plasma.

Regulation of hepcidin production is crucial for iron homeostasis. Iron, inflammation, and erythropoiesis are three factors which regulate hepcidin transcription. Iron and inflammation increase hepcidin expression whereas erythropoiesis suppresses it. Dysregulation of hepcidin leads to iron disorders. Hepcidin deficiency causes unrestrained iron absorption resulting in iron overloading disorders, such as hereditary hemochromatosis and β-thalassemia. However, hepcidin excess leads to iron restriction causing anemia, such as iron-refractory iron deficiency anemia.

Neither the mechanism of hepcidin action nor the regulation of hepcidin is completely understood, and these are the two areas on which I focused my research. Chapter 1 elucidates the structural basis of hepcidin-Fpn interaction whereas Chapters 2 and 3 examine potential signaling pathways which regulate hepcidin transcription. More specifically, Chapter 1A examines the structural basis of genetic resistance to hepcidin and details an alternative hepcidin mechanism of action. Chapter 1B provides preclinical support for a potential therapy to treat a genetic iron overload disease caused by resistance to hepcidin. Chapter 2 examines the signaling pathway used by erythroferrone, a protein hormone involved in hepcidin regulation by erythropoiesis, and Chapter 3 examines a candidate hepcidin regulator, Nrf2, a transcription factor induced by oxidative stress.

In summary, this body of work examines the structural basis of hepcidin action, the mechanism of its regulation by iron and erythropoiesis, and a potential therapeutic application to a genetic iron overload disorder.