DMT1 Facilitates Heme-iron Absorption in Rats and Mice

Mechanisms of heme-iron (HI) absorption remain uncertain. Heme is probably absorbed by receptor-mediated endocytosis; iron is then enzymatically liberated from heme within endosomes, or in the cytosol. If heme is catabolized in endosomes, a transporter, such as DMT1, would be required to export ionic iron into the cytosol. Here, we tested the hypothesis that intestinal DMT1 functions in the HI absorption pathway. The first experimental approach utilized Belgrade (b) rats, expressing dysfunctional DMT1 protein, and the second used conditional, intestine-specific DMT1 KO mice. HI absorption experiments were carried out with radiolabeled, donor rat RBCs, containing ~98% of iron as HI and with >94% of activity in 59Fe-heme. Iron-deficient, anemic +/b (control) rats absorbed 10.8% of a peroral dose of 59Fe-heme within 24 hours, while similarly anemic b/b rats absorbed 1.4% (an 8-fold reduction). Notably, serum hepcidin levels were invariable between both groups of rats (and 10x lower than controls). Moreover, ablation of intestinal DMT1 led to iron-restricted erythropoiesis and severe anemia in adolescent mice weaned on to nonheme iron (NHI) or HI diets. DMT1 was also required to upregulate 59Fe-heme absorption in iron-deficient, anemic mice. DMT1 thus facilitates the absorption of both main forms of dietary iron, NHI and HI.