Journal article
Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin
PJ Lim, TL Duarte, J Arezes, D Garcia-Santos, A Hamdi, SR Pasricha, AE Armitage, H Mehta, S Wideman, AG Santos, A Santos-Gonçalves, A Morovat, JR Hughes, E Soilleux, CY Wang, AL Bayer, P Klenerman, CB Willberg, RC Hartley, MP Murphy Show all
Nature Metabolism | NATURE RESEARCH | Published : 2019
Abstract
Iron is critical for life but toxic in excess because of iron-catalysed formation of pro-oxidants that cause tissue damage in a range of disorders. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf..
View full abstractGrants
Awarded by UK Research and Innovation
Funding Acknowledgements
The authors thank the staff of the University of Oxford Department of Biomedical Services for animal husbandry, M. Nairz (Medical University of Innsbruck) for assistance with flow cytometry and A. Townsend (Weatherall Institute of Molecular Medicine) for helpful advice and discussions. This work was supported by the UK Medical Research Council (MRC Human Immunology Unit core funding to H.D., award no. MC_UU_12010/10) and Radcliffe Department of Medicine (RDM Scholars Program to P.J.L.). The work conducted at the Instituto de Biologia Molecular e Celular was supported by FEDER funds through COMPETE and by Portuguese funds through Fundacao para a Ciencia e Tecnologia (grant nos. PTDC/BIM-MET/0739/2012 and SFRH/BPD/108207/2015 to T.L.D.), and the Norte 2020 Portugal Regional Operational Programme (grant no. Norte-01-0145-FEDER-000012). J.L.B. was supported by the National Institutes of Health (grant no. RO1-DK087727) and Massachusetts General Hospital (Howard Goodman Award). Work in M.P.M.'s lab is supported by the Medical Research Council UK (grant no. MC_U105663142) and by a Wellcome Trust Investigator award (no. 110159/Z/15/Z). A.M.H., D.G.S. and P.P. were funded by grants from the Canadian Institutes of Health Research (grant nos. MOP-14100 and MOP-126064).