Iron transport across the absorptive enterocyte.

Iron is presented to the enterocyte in the lumen of the gut, either as inorganic ferric iron or as heme iron.

Ferric iron is reduced to ferrous iron by a membrane-bound reductase with high homology to cytochrome b561.^35,36 Ferrous iron is then transported across the apical membrane of the enterocyte by a divalent metal transport channel (DMT1).^37,38 Heme is passively transferred across the absorptive surface of the enterocyte, and heme iron is liberated by heme oxygenase (HEME OX). Iron is transported across the basolateral membrane of the enterocyte by a transmembrane ferrous iron transporter (FERROPORTIN)^39-41 that acts in concert with a membrane-bound multicopper ferroxidase designated hephaestin (Hp).⁴² A minor pathway of transport across the basolateral membrane of the enterocyte utilizes ferroportin and the plasma multicopper ferroxidase ceruloplasmin. Both hephaestin and ceruloplasmin oxidize ferrous iron to ferric iron. Ferric iron is then bound to transferrin of delivery to cells expressing transferrin receptors. The amount of iron transported from the lumen of the gut to the plasma is “programmed” when the enterocyte resides in the crypt regions of intestinal villi in the duodenum and proximal jejunum. Programming is regulated by the diferric transferrin-transferrin receptor (TfR)-HFE complex on the basolateral membrane of the crypt cell. Programmed crypt cells then migrate to the villus tip where iron absorption occurs. The mechanism by which programming occurs remains unknown. Mutations affecting DMT1 and hephaestin cause impaired iron absorption in rodents,¹⁰ but a recently discovered mutation (presumably a gain-of-function mutation) in the ferroportin gene leads to iron overload in humans.⁴³