Testosterone perturbs systemic iron balance through activation of EGFR signaling in the liver and repression of hepcidin.
Résumé
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 showed that testosterone robustly represses hepcidin transcription by enhancing Egfr signaling in the liver and that selective 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: These data indicate that 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. They 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 2013;).