Physiology and molecular biology of dietary iron absorption

Dietary iron may be taken up either as heme or nonheme forms. Absorption of dietary iron is affected by the contents of the lumen. Recent progress in the understanding of the uptake of nonheme iron indicates that uptake into the mucosa involves a ferric reductase (Dcytb) and a divalent cation transporter Nramp2/DMT1. Transfer involves a probable ferrous transporter Ireg1 (or ferroportin or MTP1) in combination with a ferroxidase hephaestin as well as ceruloplasmin. The uptake step for iron via DMT1 appears to be driven by an inwardly directed proton gradient and membrane potential. The driving force for transfer of iron across the basolateral membrane is less clear and may be some kind of facilitated diffusion or involve oxidation of ferrous iron to ferric. With the exception of hephaestin, all the proteins are regulated by iron stores and other physiological regulators of iron absorption such as hypoxia and erythropoiesis. Overall, the identification of the proteins supports earlier physiological studies on the site of iron absorption and also the fact that uptake and transfer processes were distinct, involving different proteins. Several of the proteins have been implicated in genetic disease, such as the rodent anemias in the case of DMT1 and hephaestin and a rare form of autosomal dominant hemochromatosis in the case of Ireg1. The challenge now is to figure out how these genes and proteins are regulated.