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

摘要

Hereditary hemochroinatosis (HH) is a common autosomal recessive disorder characterized by tissue iron deposition secondary to excessitve dietary iron absorption. We recently reported that HFE, the protein defective in HH, was physically associated with the trausferrin receptor (TfR) in duodenal crypt cells and proposed that mutations in HFE attenuate the uptake of transferrin-bound iron from plasma by duodenal crypt cells, leading to up-regulation of transporters for dietary iron. Here, we tested the hypothesis that HFE-/- mice have increased duodenal expression of the divalent metal transporter (DMTI). By 4 weeks of age, the HFE-/- mice demonstrated iron loading when compared with HFE+/+ littermates, with elevated transferrin saturations (68.4 vs. 49.8) and elevated liver iron concentrations (985 mu g/g vs. 381 mug/g). By using Northern blot analyses, we quantitated duodenal expression of both classes of DMTI transcripts: one containing an iron responsive element (IRE), called DMTI(IRE), and one containing no IRE, called DMTI(non-IRE). The positive control for DMTI up- regulation was a murine model of dietary iron deficiency that demonstrated greatly increased levels of duodenal DMTI(IRE) mRNA. HFE-/- mice also demonstrated an increase in duodenal DMTI(IRE) mRNA (average 7.7-fold), despite their elevated transferrin saturation and hepatic iron content. Duodenal expression of DMTI(non-IRE) was not incrtased, nor was hepatic expression of DMTI increased. These data support the model for HH in which HFE mutations lead to inappropriately low crypt cell iron, with resultant