Inactivation of the hemochromatosis gene differentially regulates duodenal expression of iron-related mRNAs between mouse strains

Background & Aims: We knockout mice, like patients with hereditary hemochromatosis, have augmented duodenal iron absorption and increased iron deposition in hepatic parenchymal cells. The goals of the present study were to gain further insight into the control of iron absorption by comparing the transcript levels of iron-related genes in the duodenum of DBA/2 Hfe(-/-) mice, susceptible to iron loading, and wild-type controls, and to test whether variations in the duodenal expression of these messengers contribute to the DBA/2 and C57BL/6 strain differences in the severity of hepatic iron loading. Methods: Expression of the different transcripts was quantified by real-time polymerase chain reaction. Results: The 2 strains differ strikingly, not only in the severity of hepatic iron loading, but also in the duodenal expression of iron-related genes. In DBA/2 Hfe(-/-) mice, increased intestinal iron absorption results from the concomitant up-regulation of the Dcytb, DMT1, and FPN1. messengers. No increase in the expression of these messengers is seen in C57BL/6 Hfe(-/-) mice. Conclusions: The up-regulation of these transcripts suggests that an inappropriate iron-deficiency signal is sensed by the duodenal enterocytes, leading to an enhanced ferric reductase activity and the increase of duodenal iron uptake and transfer to the circulation. The genes modifying the hemochromatosis phenotype probably act by modifying the expression of these 3 messengers.