Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: Increased duodenal expression of the iron transporter DMT1

Hereditary hemochromatosis (HEI) is a common autosomal recessive disorder c haracterized by tissue iron deposition secondary to excessive dietary iron absorption. We recently reported that HFE, the protein defective in HEI, wa s physically associated with the transferrin receptor (TfR) in duodenal cry pt cells and proposed that mutations in HFE attenuate the uptake of transfe rrin-bound iron from plasma by duodenal crypt cells, leading to up-regulati on of transporters for dietary iron. sere, we tested the hypothesis that HF E-/- mice have increased duodenal expression of the divalent metal transpor ter (DMT1). By 4 weeks of age, the HFE-/- mice demonstrated iron loading wh en compared with HFE+/+ littermates, with elevated transferrin saturations (68.4% vs. 49.8%) and elevated liver iron concentrations (985 mu g/g vs. 38 1 mu g/g). By using Northern blot analyses, we quantitated duodenal express ion of both classes of DMT1 transcripts: one containing an iron responsive element (IRE), called DMT1(IRE), and one containing no IRE, called DMT1(non -IRE). The positive control for DMT1 upregulation was a murine model of die tary iron deficiency that demonstrated greatly increased levels of duodenal DMT1(IRE) mRNA. HFE-/- mice also demonstrated an increase in duodenal DMT1 (IRE) mRNA (average 7.7-fold), despite their elevated transferrin saturatio n and hepatic iron content. Duodenal expression of DMT1(non-IRE) was not in creased, nor was hepatic expression of DMT1 increased. These data support t he model for HH in which HFE mutations lead to inappropriately low crypt ce ll iron, with resultant stabilization of DMT1(IRE) mRNA, up-regulation of D MT1, and increased absorption of dietary iron.