Mechanisms of disease: The role of hepcidin in iron homeostasis--implications for hemochromatosis and other disorders.
The defensin-like circulatory peptide hepcidin is the iron-regulatory hormone that links innate immunity and iron metabolism. In response to inflammatory stimuli, the liver produces hepcidin: this antimicrobial peptide then limits the iron that is vital to invading pathogens, by decreasing iron release/transfer from enterocytes and macrophages and causing secondary hypoferremia. This may lead, however, to reduced iron availability for erythropoiesis and therefore to anemia (and anemia of chronic disease). When iron is scarce, the rate at which it is released into the bloodstream must be enhanced: indeed, iron starvation and hypoxia readily abrogate hepcidin expression. Conversely, if excess iron enters the circulation, hepcidin transcription is turned on and iron release from the intestine and macrophages abrogated. Circumstantial evidence indicates that the effect of circulatory iron on hepcidin requires functional HFE and hemojuvelin, two proteins of unknown function that have recently been linked to human hereditary hemochromatosis. In this disease it is likely that inadequate levels of circulating hepcidin lead to the uncontrolled release of iron from the intestine and macrophages, followed by tissue iron overload and organ damage. Given its role as the iron-regulatory hormone, the modulation of hepcidin activity using agonists or antagonists might offer new treatment opportunities in different human iron-dependent disorders.
Pietrangelo
Antonello
A
Center for Hemochromatosis and Hereditary Liver Disease, University Hospital of Modena, Italy. pietrangelo.antonello@unimore.it
Trautwein
Christian
C
D023181:Antimicrobial Cationic Peptides / Q000276:immunology / Q000502:physiology*; D006432:Hemochromatosis / Q000276:immunology / Q000378:metabolism* / Q000503:physiopathology; D064451:Hepcidins; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000276:immunology / Q000378:metabolism*; D019189:Iron Metabolism Disorders / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology
D023181:Antimicrobial Cationic Peptides; C578702:HAMP protein, human; D064451:Hepcidins; D007501:Iron