Identification of molecular mechanisms underlying hereditary hemo
Current project members: Maja Vujić Spasić (Postdoc), Richard Sparla (Technical assistant)
Previous project members: Judit Kiss (PhD student), Sonja Lück (Technical Assistance), Regina Kessler (Technical Assistance); Stefanie Martinache (Technical Assistance)
Iron is essential for fundamental metabolic processes in cells and organisms. Regulation of systemic iron homeostasis evolved to maintain a plasma iron concentration that secures adequate supplies while preventing organ iron overload. The homeostatic system must react to signals from pathways that consume iron (e.g. the erythropoiesis) and send signals to cells that supply iron (e.g. duodenal enterocytes, which absorb iron from the diet; macrophages which recycle iron from senescent erythrocytes, and hepatocytes which are the major iron storage site). The small hepatic peptide hormone hepcidin (Hamp, LEAP1) orchestrates these iron fluxes and controls the amount of available extracellular iron by interacting with the iron exporter ferroportin: binding of hepcidin induces ferroportin internalization and degradation.
Systemic iron homeostasis is disrupted in the common iron overload disorder, hereditary hemochromatosis (HH). HH is most frequently caused by mutations in the HFE/Hfe gene. Mice homozygous with respect to an HFE null allele or the orthologous, murine Hfe mutation recapitulate the HH phenotype observed in humans confirming that HH arises from a loss of Hfe function. Since the discovery of the HFE gene, different models have been proposed to explain how HFE/Hfe malfunction causes increased intestinal iron absorption, hepatic iron overload and relative iron deficiency in macrophages, the main features of HH. Lack of functional Hfe in intestinal cells was initially suggested to affect serosal iron uptake mediated by transferrin receptor 1 (TfR1) and to increase intestinal iron transporter expression. However, enterocyte-specific Hfe ablation in mice recently excluded a primary role for duodenal Hfe in the pathogenesis of HH, as hepatic and plasma iron parameters as well as hepcidin mRNA expression remained unaffected in this mouse model. An inappropriately low expression of Hamp is largely accepted to play a central role in the pathogenesis of HH. However, it is unclear how Hfe affects Hamp expression in the liver and whether Hfe does so via its expression in hepatocytes, liver macrophages and/or other cell types. To answer this fundamental question for the understanding of Hfe function and HH, we generated mice with tissue-specific ablations of the Hfe. Analysis of these models uncovered that a lack of Hfe in hepatocytes (but not macrophages or duodenal enterocytes) explains all the anomalies within iron metabolism parameters observed in constitutive Hfe knock-out mice and HH patients. Using our conditional Hfe knock-out mouse line we now will investigate additional functions of the broadly expressed Hfe protein.
Project-related publications:
- Maja Vujić Spasić*, Judit Kiss*, Thomas Herrmann*, Bruno Galy, Stefanie Martinache, Jens Stolte, Hermann-Josef Gröne, Wolfgang Stremmel, Matthias W. Hentze and Martina U. Muckenthaler. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metabolism, Feb;7(2):173-8, 2008 (* equal contribution)
- Maja Vujić Spasić*, Judit Kiss*, Thomas Herrmann*, Regina Kessler, Jens Stolte, Bruno Galy, Birgit Rathkolb, Eckhard Wolf, Wolfgang Stremmel, Matthias W. Hentze, and Martina U. Muckenthaler. Physiologic systemic iron metabolism in mice deficient for duodenal Hfe. Blood 109 (10): 4511-4517, 2007 (* equal contribution)
Richard Sparla (Technical assistant)
