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Iron overload in adult Hfe-deficient mice independent of changes in the steady-state expression of the duodenal iron transporters DMT1 and Ireg1/ferroportin

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Abstract

Patients suffering from hereditary hemochromatosis (HH) show progressive iron overload as a consequence of increased duodenal iron absorption. It has been hypothesized that mutations in the HH gene HFE cause misprogramming of the duodenal enterocytes towards a paradoxical iron-deficient state, resulting in increased iron transporter expression. Previous reports concerning gene expression levels of the duodenal iron transporters DMT1 and IREG1 in HH patients and animal models are controversial, however, and in many cases only mRNA expression levels were investigated. To analyze the duodenal expression of DMT1, Ireg1, Dcytb, and hephaestin and the association with iron overload in adult Hfe −/− mice, an Hfe −/− mouse line was generated. Duodenal DMT1 and Ireg1 protein levels, duodenal DMT1, Ireg1, Dcytb, hephaestin, and TfR1 mRNA levels, and hepatic hepcidin mRNA levels were quantified and the correlation to liver iron contents was calculated. We report that duodenal DMT1 and Ireg1 mRNA levels and DMT1 and Ireg1 protein levels remained unaffected by the Hfe deletion. Furthermore, duodenal hephaestin and TfR1 mRNA expression and hepatic hepcidin mRNA expression remained unaltered, while the duodenal mRNA expression of the brush border ferric reductase Dcytb was significantly increased in Hfe −/− mice. We found no correlation between the expression level of any of the analyzed transcripts and the liver iron content. In conclusion, the lack of correlation between DMT1 and Ireg1 protein expression and the liver iron content suggests that elevated duodenal iron transporter expression is not required for high liver iron overload. Hfe −/− mice do not necessarily display features of iron deficiency in the duodenum, indicated by an increase in mRNA and protein levels of DMT1 and Ireg1. Rather, the duodenal ferric reductase Dcytb may act as a possible mediator of iron overload in Hfe deficiency.

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Abbreviations

Dcytb :

Duodenal cytochrome b

DMT1 :

Divalent metal ion transporter 1

Fatp4 :

Fatty acid transport protein 4

FRT :

FLP recombinase target

HH :

Hereditary hemochromatosis

IRE :

Iron-responsive element

Ireg1 :

Iron-regulated transporter 1

KLH :

Keyhole limpet hemocyanin

RT :

Reverse transcriptase

TfR1 :

Transferrin receptor 1

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Acknowledgements

We thank Kristina Vintersten for blastocyst injections, Petra Hornsberger for animal care, Anja Peter and Karin Bents for assistance with molecular analyses, Gabi Schmidt for assistance with histology, and Walter Heilmann for assistance with atomic absorption spectroscopy. This work was supported by grants from the Deutsche Forschungsgemeinschaft (STR 216/10-1) and the Dietmar-Hopp-Foundation to W.S. and from the Faculty of Medicine, University of Heidelberg, to T.H.. M.W.H. acknowledges generous support from funds of the Gottfried-Wilhelm-Leibniz award (He1442/6-1).

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Authors and Affiliations

  1. Department of Internal Medicine IV, University of Heidelberg, Bergheimer Strasse 58, 69115, Heidelberg, Germany

    Thomas Herrmann, Sven G. Gehrke, Iris Kaiser, Isabella Gosch, Hans-Dieter Riedel & Wolfgang Stremmel

  2. European Molecular Biology Laboratory, 69117, Heidelberg, Germany

    Martina Muckenthaler, Karen Brennan, Nadia Hubert & Matthias W. Hentze

  3. German Cancer Research Center, 69120, Heidelberg, Germany

    Frank van der Hoeven & Hermann-Josef Gröne

  4. Department of Paediatric Pathology, St. Michael’s University Hospital, Bristol, UK

    Consolato Sergi

  5. Central Laboratory, University of Heidelberg, 69115, Heidelberg, Germany

    Martin Volkmann

  6. Biotec, Technical University of Dresden, 01307, Dresden, Germany

    A. Francis Stewart

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  1. Thomas Herrmann
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Correspondence to Wolfgang Stremmel.

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Herrmann, T., Muckenthaler, M., van der Hoeven, F. et al. Iron overload in adult Hfe-deficient mice independent of changes in the steady-state expression of the duodenal iron transporters DMT1 and Ireg1/ferroportin. J Mol Med 82, 39–48 (2004). https://doi.org/10.1007/s00109-003-0508-x

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