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)

Huntington's disease resulting from huntingtin containing an expanded polyglutamine is associated with aggregates largely confined to neuronal inclusions, and with neuronal death. Inclusions are thought to originate from discrete N-terminal fragments of expanded huntingtin produced by specific endopeptidases. We have now purified the neuronal inclusions of Huntington's disease brain. When incubated in concentrated formic acid, purified inclusions release a polymer, an oligomer and a broad range of N-terminal fragments of expanded huntingtin. The fragments and the polymeric forms are linked to each other by non-covalent bonds as they are both released by formic acid, whereas the polymeric forms themselves are presumably stabilized by covalent bonds, as they are resistant to formic acid. We also demonstrate the presence in affected areas of the brain but not in unaffected areas of a broad range of soluble N-terminal fragments of expanded huntingtin not yet associated with the inclusions and which are likely to be the precursors of the inclusions. Fragmentation of expanded huntingtin in Huntington's disease must result from the operation of multiple proteolytic activities with little specificity and not from that of a specific endopeptidase; subsequent aggregation of the fragments by covalent and non-covalent bonds leads to the formation of the inclusions.

BPM-RE. In conclusion, our results suggest that a mutation in the BMP-RE of hepcidin promoter may impact on human iron metabolism.Key words: hepcidin, BMP, hemochromatosis, iron, gene expression. hemochromatosis. Haematologica 2009; 94:720-724. doi: 10.3324/haematol.2008 This is an open-access paper. Citation: Island M-L, Jouanolle A-M, Mosser A, Deugnier Y, David V, Brissot P, and Loréal O. A new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related ABSTRACTA new mutation in the hepcidin promoter impairs its BMP response and contributes to a severe phenotype in HFE related hemochromatosis © F e r r a t a S t o r t i F o u n d a t i o n Design and Methods Patient and genetic studiesIn 1994, the diagnosis of genetic hemochromatosis was established in a 37-year old man with massive hepatic iron overload (450 µmoL of iron/g dry liver weight, n<36) involving mainly hepatocytes and associated to liver fibrosis stage 2-3 in Metavir classification. 18 Iron depletive treatment based on weekly 400 mL phlebotomies was initiated. In 1997, the patient was demonstrated to be homozygous for the p.Cys282Tyr mutation. In 2004 (47 years), 468 venesections had been performed, corresponding to the removal of 85g of iron. However, the patient was always exhibiting abnormal iron parameters with 40 µmol/L for serum iron, 100% for transferrin saturation, and 2,066 µg/L for serum ferritin. In addition, hepatic iron concentration remained very high (close to 300 µmol/g dry liver weight) at MRI. Serum hepcidin level quantified by Elisa 19 was low (24 ng/L; 29

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