Long-term sequelae of HFE deletion in C57BL/6 × 129/O1a mice, an animal model for hereditary haemochromatosis

Authors


  • Pathologisches Institut, Ludwig-Maximilians-Universität, München, Germany (A. Lebeau); Institut für Biologische Chemie und Ernährungswissenschaft, Universität Hohenheim, Stuttgart, Germany (J. Frank, H. K. Biesalski); Abteilung für Interne Medizin, Universitätskrankenhaus Innsbruck, Austria (G. Weiss); Department of Molecular Biology, Royal Free Hospital School of Medicine, London, UK (S. K. S. Srai); Department of Endocrinology, Diabetes and Internal Medicine (R. J. Simpson), Department of Molecular Medicine, King's College, London, UK (A. T. McKie); INSERM-CReS, Centre de Recherche d’Immunologie et d’Hématologie, Faculté de Médecine, Strasbourg, France (S. Bahram); Basel Institut for Immunology, Basel, Switzerland (S. Gilfillan); Walther-Straub-Institut für Pharmakologie und Toxikologie, Ludwig-Maximilians-Universität, München, Germany (K. Schümann).

Prof. Dr Klaus Schümann, Walther-Straub-Institut für Pharmakologie und Toxikologie, Nussbaumstrasse 26, 80336 München, Germany. Tel.: + 49 89 5160 7223; fax: + 49 89 5160 7207; e-mail: K.Schuemann@lrz.uni-muenchen.de

Abstract

Background  HFE knockout mice (C57BL/6 × 129/Ola strain) mimic the functional aberrations of human hereditary haemochromatosis (HH) in short-term experiments. The present study investigates functional and morphological long-term changes.

Methods HFEo/o, HFE+/o and HFE+/+ mice were maintained on iron-rich and control diets for 2 weeks, 3, 12 and 18 months. Light microscopic tissue iron distribution, pathomorphological alterations, tissue iron content and oxidative stress were analysed in liver, pancreas, spleen, gastrointestinal tract, kidneys and myocardium. Additionally, duodenal 59Fe absorption and 59Fe whole body loss were measured.

Results Iron distribution between organs and microscopic iron deposition in the tissues resembled the patterns described in HH. After 3 months of iron-rich feeding duodenal 59Fe absorption decreased to ∼15% of iron-adequate controls but remained about twice as high in HFEo/o as in HFE+/+ mice. Hepatic iron concentrations reached only half the values known to induce hepatic fibrosis in rats and humans, while whole body 59Fe loss was about twice as high. Consequently no hepatic fibrosis developed, although massive hepatocellular iron deposition and indication for oxidative stress were observed.

Conclusion C57BL/6 × 129/O1a HFEo/o mice mimic HH iron distribution and the regulation of intestinal iron absorption after long-term feeding. However, characteristic morphological late changes in untreated HH are not modelled.

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