These authors contributed equally to this work.
Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin
Article first published online: 16 DEC 2013
© 2013 by the American Association for the Study of Liver Diseases
Volume 59, Issue 2, pages 683–694, February 2014
How to Cite
Latour, C., Kautz, L., Besson-Fournier, C., Island, M.-L., Canonne-Hergaux, F., Loréal, O., Ganz, T., Coppin, H. and Roth, M.-P. (2014), Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin. Hepatology, 59: 683–694. doi: 10.1002/hep.26648
Supported in part by a grant from the French National Research Agency (ANR, programme Genopat, project ANR-09-GENO-016).
Potential conflict of interest: Nothing to report.
- Issue published online: 29 JAN 2014
- Article first published online: 16 DEC 2013
- Accepted manuscript online: 1 AUG 2013 05:20AM EST
- Manuscript Accepted: 18 JUL 2013
- Manuscript Received: 1 MAY 2013
Gender-related disparities in the regulation of iron metabolism may contribute to the differences exhibited by men and women in the progression of chronic liver diseases associated with reduced hepcidin expression, e.g., chronic hepatitis C, alcoholic liver disease, or hereditary hemochromatosis. However, their mechanisms remain poorly understood. In this study we took advantage of the major differences in hepcidin expression and tissue iron loading observed between Bmp6-deficient male and female mice to investigate the mechanisms underlying this sexual dimorphism. We found that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective epidermal growth factor receptor (Egfr) inhibition by gefitinib (Iressa) in males markedly increases hepcidin expression. In males, where the suppressive effects of testosterone and Bmp6-deficiency on hepcidin expression are combined, hepcidin is more strongly repressed than in females and iron accumulates massively not only in the liver but also in the pancreas, heart, and kidneys. Conclusion: Testosterone-induced repression of hepcidin expression becomes functionally important during homeostatic stress from disorders that result in iron loading and/or reduced capacity for hepcidin synthesis. These findings suggest that novel therapeutic strategies targeting the testosterone/EGF/EGFR axis may be useful for inducing hepcidin expression in patients with iron overload and/or chronic liver diseases. (Hepatology 2014;59:683–694)