Mécanismes moléculaires de l’homéostasie du fer Molecular mechanisms of iron homeostasis

Résumé

En raison de sa capacité à réagir avec l’oxygène et à changer d’état d’oxydoréduction, le fer est indispensable à toute forme de vie sur terre. La découverte récente de nombreuses enzymes à activité ferroxydase (héphaestine, céruloplasmine) ou ferriréductase (Dcytb), ainsi que de transporteurs de cations divalents (Nramp2/DMT1, ferroportine) impliqués dans le transport du fer a mis en évidence l’existence d’un réseau protéique complexe et finement réglé permettant de mobiliser le fer à partir des aliments, de le transporter à travers les membranes cellulaires et de le véhiculer dans les fluides biologiques. L’homéostasie du fer repose sur un contrôle strict de son absorption intestinale, au niveau du duodénum, et de son recyclage après dégradation des globules rouges sénescents par les macrophages. L’hepcidine, un peptide synthétisé par le foie et contrôlé par le fer, ainsi que la protéine HFE, dont les mutations sont responsables de la forme prédominante d’hémochromatose héréditaire, sont impliquées dans ces régulations. Ces découvertes ouvrent de nouvelles perspectives thérapeutiques, notamment en ce qui concerne la possibilité de traiter les surcharges en fer par l’hepcidine.

Summary

Iron metabolism in mammals requires a complex and tightly regulated molecular network. The classical view of iron metabolism has been challenged over the past ten years by the discovery of several new proteins, mostly Fe (II) iron transporters, enzymes with ferro-oxydase (hephaestin or ceruloplasmin) or ferri-reductase (Dcytb) activity or regulatory proteins like HFE and hepcidin. Furthermore, a new transferrin receptor has been identified, mostly expressed in the liver, and the ability of the megalin-cubilin complex to internalise the urinary Fe (III)-transferrin complex in renal tubular cells has been highlighted. Intestinal iron absorption by mature duodenal enterocytes requires Fe (III) iron reduction by Dcytb and Fe (II) iron transport through apical membranes by the iron transporter Nramp2/DMT1. This is followed by iron transfer to the baso-lateral side, export by ferroportin and oxidation into Fe (III) by hephaestin prior to binding to plasma transferrin. Macrophages play also an important role in iron delivery to plasma transferrin through phagocytosis of senescent red blood cell, heme catabolism and recycling of iron. Iron egress from macrophages is probably also mediated by ferroportin and patients with heterozygous ferroportin mutations develop progressive iron overload in liver macrophages. Iron homeostasis at the level of the organism is based on a tight control of intestinal iron absorption and efficient recycling of iron by macrophages. Signalling between iron stores in the liver and both duodenal enterocytes and macrophages is mediated by hepcidin, a circulating peptide synthesized by the liver and secreted into the plasma. Hepcidin expression is stimulated in response to iron overload or inflammation, and down regulated by anemia and hypoxia. Hepcidin deficiency leads to iron overload and hepcidin overexpression to anemia. Hepcidin synthesis in response to iron overload seems to be controlled by the HFE molecule. Patients with hereditary hemochromatosis due to HFE mutation have impaired hepcidin synthesis and forced expression of an hepcidin transgene in HFE deficient mice prevents iron overload. These results open new therapeutic perspectives, especially with the possibility to use hepcidin or antagonists for the treatment of iron overload disorders.