Gene expression profiling of Hfe-/- liver and duodenum in mouse strains with differing susceptibilities to iron loading:: identification of transcriptional regulatory targets of Hfe and potential hemochromatosis modifiers

Background: Hfe disruption in mouse leads to experimental hemochromatosis by a mechanism that remains elusive. Affymetrix GeneChip((R)) Mouse Genome 430 2.0 microarrays and bioinformatics tools were used to characterize patterns of gene expression in the liver and the duodenum of wild-type and Hfe- deficient B6 and D2 mice (two inbred mouse strains with divergent iron loading severity in response to Hfe disruption), to clarify the mechanisms of Hfe action, and to identify potential modifier genes. Results: We identified 1,343 transcripts that were upregulated or downregulated in liver and 370 in duodenum of Hfe(-/-) mice, as compared to wild- type mice of the same genetic background. In liver, Hfe disruption upregulated genes involved in antioxidant defense, reflecting mechanisms of hepatoprotection activated by iron overload. Hfe disruption also downregulated the expression of genes involved in fatty acid beta-oxidation and cholesterol catabolism, and of genes participating in mitochondrial iron traffic, suggesting a link between Hfe and the mitochondrion in regulation of iron homeostasis. These latter alterations may contribute to the inappropriate iron deficiency signal sensed by the duodenal enterocytes of these mice, and the subsequent upregulation of the genes encoding the ferrireductase Dcytb and several iron transporters or facilitators of iron transport in the duodenum. In addition, for several genes differentially expressed between B6 and D2 mice, expression was regulated by loci overlapping with previously mapped Hfe- modifier loci. Conclusion: The expression patterns identified in this study contribute novel insights into the mechanisms of Hfe action and potential candidate genes for iron loading severity.