What regulates the iron regulator?

Abstract

Early in my career, we were pretty ignorant about iron (we did not pump it yet), although we did know a few things. We were aware that the daily intake of iron is (should be) about 10 mg and that 1–2 mg of this iron was absorbed. Iron traveled in the blood bound to a carrier protein called “transferrin” and was stored in various places, such as the reticulo-endothelial system (RES) and bone marrow. As a matter of fact, the court-of-last-appeals for iron deficiency was the staining of bone marrow for iron with “Prussian blue”. We were aware that 200 billion erythrocytes were produced daily and that this production would take about 20 mg elemental iron, more than was absorbed. Thus, active recycling had to take place. Total body iron stores were known to be about 5 g and that half this amount resided in the erythrocytes. We were aware of hereditary hemochromatosis (HH), a favorite examination issue by oral examiners who generally had never ever seen a case either. And we knew about the poor Bantus and their ironcontaining cooking-pots. That was about it, although the iron storage mechanism and the way to measure it, namely ferritin, were introduced about 10 years later. The rest was a mystery, including the other common anemia, termed the “anemia of chronic disease”, that not even our smartest professors understood. Fortunately, all that ignorance is behind us, or at any rate, much of it is. Hepcidin (also known as HFE2) is a hepatic iron regulatory hormone that maintains systemic iron homeostasis. Hepcidin is made by the liver and secreted into the blood stream, where it binds to the iron exporter ferroportin that is located on macrophages, hepatocytes, and intestinal enterocytes. Hepcidin causes ferroportin to be internalized and proteolyzed (chewed up). As a result, hepcidin reduces gastrointestinal iron absorption and macrophage-mediated iron recycling. If hepcidin is so critical to iron-metabolic regulation, then the regulation of hepcidin is critical for our understanding how this very basic portion of human physiology works. In this issue, Casanovas et al. shed light on this question [1]. As is now commonly the case, the understanding of a rare Mendelian disease, HH, led the way. We now know that HH can be caused by mutations in a membrane protein encoded by a gene that is similar to those coding MHC class I-type proteins. The protein product associates with beta2-microglobulin (beta2M) and is called “HFE” although I am uncertain why. HFE is thought to regulate iron absorption by influencing the interaction of the transferrin receptor with transferrin. The HH phenotype is also produced by mutations in transferrin receptor 2 (TfR2), hemojuvelin (HJV), or hepcidin itself. Mutations in any of these proteins results in increased duodenal iron absorption, increased macrophage iron release, increased serum iron levels, and liver iron overload. HJV is a member of the “repulsive guidance molecule” (RGM) family, which also includes the bone-morphogenetic protein (BMP) coreceptors RGMA and DRAGON (RGMB). Babitt et al. [2] reported that HJV is a BMP coreceptor and that HJV mutants associated with the HH phenotype have impaired BMP signaling ability. They showed that BMP upregulates hepatocyte hepcidin expression, a process enhanced by HJV, and that is blunted in hepcidin genedeleted hepatocytes. Their data suggested a mechanism by which hepcidin mutations cause hemochromatosis, namely HJV dysfunction decreases BMP signaling, thereby lowering hepcidin expression. Babbitt et al. [3] next showed that BMP-2 administration increases hepcidin expression and J Mol Med (2009) 87:447–449 DOI 10.1007/s00109-009-0453-4