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. 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)

Unbiased RNAi screen for hepcidin regulators links hepcidin suppression to proliferative Ras/RAF and nutrient-dependent mTOR signaling

“…34,36 Our independent data extend these findings by showing that upstream Ras/RAF-dependent signals, rather than downstream MEK1/ERK signaling, inhibit hepcidin mRNA expression. Together with the previous observation that ERK kinases activate hepcidin mRNA expression in response to holotransferrin, 65 these results suggest that other noncanonical signals initiated by Ras/RAF are involved in hepcidin inhibition.…”

“…32,33 More recently, inhibition of hepcidin messenger RNA (mRNA) expression was also linked to growth factors and testosterone. [34][35][36] Here we report data from a genome-wide screen that provides the first comprehensive list of putative hepatic hepcidin regulators. In secondary analyses of our screening hits, we uncover links between hepcidin suppression and the Ras/RAF MAPK and mTOR pathways, which are known to promote hepatocyte proliferation and cell growth, as well as play roles in the control of liver nutrient homeostasis.…”

Hemolytic anemia repressed hepcidin level without hepatocyte iron overload: lesson from Günther disease model

“…For acute hemolysis and heme-arginate experiments, BALB/c mice were provided by the Janvier laboratory (Janvier, Le Genest Saint Isle, France). Since in male mice the expression of hepcidin has been shown to be repressed by testosterone, 13 our experiments were performed on 12-to 14-week-old female mice, unless mentioned otherwise. For hematologic and biochemical analysis, mice were anesthetized by intraperitoneal (i.p.)…”

Erythroferrone contributes to hepcidin repression in a mouse model of malarial anemia

“…Since iron parameters and hepcidin levels differ significantly between male and female mice, 32,33 only male mice were used in this study. 9 week-old C57BL/6 wild-type (WT) mice (5 to 10 per time-point) were infected intraperitoneally with 10 6 PbK-infected RBCs, and given free access to tap water and standard laboratory mouse chow diet (250 mg iron/kg; SAFE, Augy, France) during the 18 days post-infection.…”