Transcriptional regulation of hepcidin, a hormone that maintains iron homeostasis

Iron homeostasis is maintained through meticulous regulation of circulating hepcidin levels. Studies have demonstrated that inappropriately low hepcidin gene expression leads to unregulated iron absorption and systemic iron overload while inappropriately high hepcidin expression results in decreased iron absorption and iron deficiency anemia. Hepcidin regulates systemic iron homeostasis by binding to a cellular iron exporter, ferroportin (FPN1), and targeting it for degradation. Hepcidin gene expression is influenced by hypoxia, erythroid demand, iron and inflammation, however, the mechanisms responsible are not well defined. In an effort to illuminate the mechanism by which the body maintains iron homeostasis, we initiated a study of hepcidin transcriptional regulation. We report that stimulation of hepatocytes with BMPs upregulates hepcidin transcription. BMP regulation of hepcidin is enhanced by interaction with the BMP coreceptor hemojuvelin (HJV). This is consistent with the finding that loss of function mutations in the HJV gene result in iron overload due to low hepcidin gene expression. We begin to characterize the relationship between hemojuvelin and two other proteins that when mutated cause genetic iron overload, the classical hemochromatosis protein (HFE) and transferrin receptor-2 (TFR-2). Loss of function mutations in either of these genes results in inappropriately low hepcidin expression. We demonstrate that HJV, HFE and TFR2 interact to form a protein complex. Within the complex, TFR2 may inhibit the release of soluble HJV from the cell membrane while HFE likely amplifies BMP signals. The anemia of inflammation (AI) is an acquired condition that affects patients with a variety of disorders characterized by chronic elevation of inflammatory cytokines. We show that the inflammatory cytokine interleukin-6 (IL-6) directly regulates hepcidin transcription through induction and subsequent promoter binding of signal transducer and activator of transcription 3 (STAT3). The study of hepcidin gene expression regulation is not only important to understand normal iron homeostasis, but also to understand the pathophysiology of diseases like hemochromatosis and AI. Knowledge of the mechanisms by which hepcidin is regulated will inform medicine and pharmacology in their pursuit for effective diagnostic tools and treatments for these and other diseases of iron homeostasis.