title: Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Inserm, U1043, Toulouse, France; CNRS, U5282, Toulouse, France; Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors.forename: Chloé
authors.initials: C
authors.lastname: Latour
authors.forename: Léon
authors.initials: L
authors.lastname: Kautz
authors.forename: Céline
authors.initials: C
authors.lastname: Besson-Fournier
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Island
authors.forename: François
authors.initials: F
authors.lastname: Canonne-Hergaux
authors.forename: Olivier
authors.initials: O
authors.lastname: Loréal
authors.forename: Tomas
authors.initials: T
authors.lastname: Ganz
authors.forename: Hélène
authors.initials: H
authors.lastname: Coppin
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Roth
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D027682:Cation Transport Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D064451:Hepcidins / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D007501:Iron / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D010179:Pancreas / Q000378:metabolism; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D051785:Smad Proteins / Q000378:metabolism; D013739:Testosterone / Q000378:metabolism*; D000098742:Ferroportin
chemical_list: C525817:Bmp6 protein, mouse; D055418:Bone Morphogenetic Protein 6; D027682:Cation Transport Proteins; D064451:Hepcidins; D051785:Smad Proteins; D000098742:Ferroportin; D013739:Testosterone; D007501:Iron; D066246:ErbB Receptors