Intestinal iron uptake determined by divalent metal transporter is enhanced in HFE-deficient mice with hemochromatosis

Background & Aims: Overexpression of duodenal divalent metal transporter (DMT1) messenger RNA occurs in hemochromatosis and HFE-knockout mice, suggesting that DMT1 mediates enhanced absorption of iron; however, increased expression of functional DMT1 protein has yet to be substantiated. We examined the role of DMT1 and the mucosal iron uptake defect in HFE-knockout mice. Methods: Unidirectional iron uptake of Fe-59 by small intestinal mucosa in vitro was compared between matched pairs of HFE-knockout and wild-type mice. DMT1-specific antibodies were used to block iron transport and to quantify duodenal protein expression. Results: Ferrous iron uptake at 3.5-450 mu mol/L was greatly enhanced in HFE-knockouts compared with wildtype, the apparent V-max for Fe2+ transport being doubled (P < 0.01), Supplied as Fe3+, uptake was only enhanced in HFE-knockouts at less than or equal to 18 mu mol/L, when the iron was almost completely converted to Fe2+ by mucosal ferrireductases, DMT1 antibody reduced the apparent V-max for mucosal Fe2+ transport in HFE-knockouts to below wildtype control values (P < 0.02); immunoreactive mucosal DMT1 protein was increased nearly 2-fold in HFE-knockouts (P < 0.01), Conclusions: Disruption of the HFE gene up-regulates functional DMT1 transporters and enhances uptake of ferrous iron by this mechanism; DMT1 also mediates increased uptake after reduction of ferric iron presented at physiological concentrations.