The Liver as a Conductor of Systemic Iron Regulation: the Central Role of Hepcidin and BMP Signaling

Abstract SCI-22

Iron is a necessary trace element found in nearly all living organisms and is critical to many cellular processes, including electron transport in the mitochondrial membrane, DNA synthesis, and hemoglobin synthesis. Iron deficiency leads to anemia, and excess iron can promote free radical formation and result in cellular injury (1). Thus, iron balance is tightly regulated to provide sufficient amounts of iron for critical cellular processes, while avoiding the detrimental effects of excess iron. Iron homeostasis is disrupted in many hematologic diseases, including hemochromatosis, the anemia of chronic disease, and β-thalassemia, affecting hundreds of millions of people worldwide. Hepcidin is a peptide hormone secreted by the liver that plays a central role in iron homeostasis. Hepcidin binding to ferroportin, the only known mammalian cellular iron exporter, leads to internalization and degradation of ferroportin in lysosomes, which decreases iron absorption from the diet and iron release from macrophages that recycle iron from senescent erythrocytes. As a central regulator of body iron metabolism, hepcidin is modulated by the same factors that alter iron homeostasis, including changes in body iron stores, inflammation, rate of erythropoiesis, anemia, and hypoxia. Hepcidin levels are increased in response to oral and parenteral iron loading and decreased under iron deficient conditions (2). Inflammation stimulates hepcidin expression by increasing IL-6 levels, which activates the JAK/STAT signaling cascade and binding of the transcriptional activator STAT3 to the hepcidin promoter (3, 4). In contrast, anemia and hypoxia are associated with decreased hepcidin levels (5). Studies of patients with autosomal recessive hemochromatosis, an iron overload disorder, have revealed that several hepatocyte proteins are required for appropriate hepcidin regulation, including those coded by HFE (6), TFR2 (7), and HJV (also called HFE2 and RGMc) (8). Mutations in either the hepcidin gene (HAMP) or HJV cause a more severe form of hemochromatosis that presents in the first or second decade of life. In juvenile hemochromatosis, patients who carry HJV mutations, urinary hepcidin is undetectable, suggesting that HJV is a key regulator of hepcidin (8). Disruption of Hjv in the mouse results in decreased hepcidin expression and increased iron deposition in the liver, pancreas, and heart but decreased iron levels in tissue macrophages (9, 10). HJV (RGMc) encodes hemojuvelin, a member of the repulsive guidance molecule family, which resides on the cell membrane as a glycosylphosphatidylinositol (GPI)-linked protein. It functions as a BMP6 coreceptor to activate hepcidin expression through a BMP/SMAD signaling pathway (11, 12, 13). Accordingly, disease-associated mutations in HJV result in decreased BMP/SMAD signaling and decreased hepcidin expression (11, 14). Hemojuvelin, acting through the BMP signaling pathway, thus plays an essential role in the regulation of hepcidin expression. BMP signaling also appears to be central in order for iron and inflammation to regulate hepcidin expression.