MECHANISTIC INSIGHTS ON DIETARY IRON ABSORPTION: THE ROLES OF HEPCIDIN AND TRANSFERRIN

Hepcidin is a liver-derived peptide hormone that controls systemic iron homeostasis by inhibiting iron entry into plasma. Plasma iron is captured by transferrin for delivery to the bone marrow and other tissues. We studied the effects of hepcidin or transferrin injection on dietary iron absorption. First, wild type and Hjv-/- mice, a model of hemochromatosis, were injected with synthetic hepcidin. A dose of 2 g/kg synthetic hepcidin reached maximal plasma concentration of 1.3 μg/ml, with 90 min half-life. Hepcidin partially decreased levels of ferroportin and the apical metal transporter DMT1 in wild type duodenal enterocytes. Surprisingly, hepcidin profoundly suppressed duodenal DMT1 in Hjv-/- mice without affecting highly induced ferroportin. Nevertheless, the treatment triggered duodenal iron retention. Experiments in intestinal mouse organoids showed that ferroportin and DMT1 are sensitive to degradation by hepcidin or iron, respectively. Thus, hepcidin efficiently degrades basal duodenal ferroportin but appears limiting when ferroportin is overexpressed. Nevertheless, under these conditions, hepcidin occludes ferroportin’s iron-exporting channel and causes iron accumulation in enterocytes. Our data show that iron retention due to hepcidin-mediated ferroportin inactivation is the signal that drives DMT1 degradation in enterocytes. In a second set of experiments, iron-deficient wild type mice were injected with apo-transferrin and were switched to a high-iron diet. Unexpectedly, excess apo-transferrin enhanced dietary iron absorption and triggered accumulation of plasma non-transferrin bound iron (NTBI). Injected fluorescent-labeled transferrin colocalized with lamina propria macrophages. These data are consistent with a recently proposed iron absorption checkpoint involving macrophage-mediated transferrin degradation.