A conditional mouse model to study murine hemochromatosis

Abstract

Aims: Hereditary hemochromatosis (HH) is a common iron overload disorder that is most frequently caused by mutations in the HFE gene. Work from our lab and others demonstrates that HFE is required for appropriate hepatic expression of the iron hormone and anti-microbial peptide hepcidin: expression of this negative regulator of duodenal iron absorption is decreased and cannot be adjusted in response to elevated hepatic iron levels in Hfe-deficient mice and HH patients. These findings further our understanding of the molecular mechanism of HFE function and suggest that the primary locus of HFE function is the liver and not the duodenum, as was previously hypothesized. It is currently not understood in which cell type HFE functions to direct appropriate hepcidin expression. Methods: Based on a mouse line with generalized Hfe deficiency [1] we generated a mouse line with a „floxed“, functionally active Hfe allele. This mouse line was crossed with transgenic mouse lines with Cre expression restricted to duodenal enterocytes, macrophages, and hepatocytes, respectively. Results and Conclusions: We have established a mouse line with a floxed Hfe allele. Based on this mouse line, we generated mouse lines with Hfe deletions in duodenal enterocytes, macrophages (incl. Kupffer cells), and hepatocytes, respectively. Experiments are ongoing to assess the efficiency and specificity of Hfe recombination in the targeted cells, the effect of Hfe deletion on hepatic iron content and hepcidin expression as well as cell type specific gene regulation elicited by the specific Hfe deletions.