The discovery by Nicolas et al in 2001 (1) that the liver-derived peptide hepcidin plays a central role in the regulation of body iron homeostasis was a major advance in the field, and the flurry of articles that followed has further defined the mechanism by which hepcidin regulates body iron levels. Hepcidin is synthesized in the liver as an 84-amino acid prepropeptide, which is subsequently processed into a 60- to 64-residue prohepcidin peptide and then finally into the mature and biologically active 25-amino acid hepcidin (hepcidin 25), which is secreted into the serum (2). The target for serum hepcidin is the iron exporter ferroportin 1, which is found on the plasma membrane of most body cells and notably at high concentrations on duodenal enterocytes, macrophages, and hepatocytes. The binding of hepcidin to ferroportin 1 induces the internalization and degradation of the iron exporter, thus decreasing cellular iron release. Thus, increased hepcidin production reduces serum iron concentrations because of decreased iron absorption and reduced iron release from macrophages and iron storage sites.
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