Journal article

Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin

Pei Jin Lim, Tiago L Duarte, Joao Arezes, Daniel Garcia-Santos, Amel Hamdi, Sant-Rayn Pasricha, Andrew E Armitage, Hema Mehta, Sarah Wideman, Ana G Santos, Andreia Santos-Goncalves, Alireza Morovat, Jim R Hughes, Elizabeth Soilleux, Chia-Yu Wang, Abraham L Bayer, Paul Klenerman, Christian B Willberg, Richard C Hartley, Michael P Murphy Show all



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 Nrf2 transcription factor orchestrates cell-intrinsic protective antioxidant responses, and the peptide hormone hepcidin maintains systemic iron homeostasis, but is pathophysiologically decreased in haemochromatosis and beta-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives Bmp6 expression in liver sinusoid endothelial cells, which in turn increases hepcidin synthesis by neighbouring hepatocytes. In Nrf2 knockout mice, the Bmp6-hepcidin response to oral and parenteral iron is impa..

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Awarded by UK Medical Research Council (MRC Human Immunology Unit)

Awarded by Fundacao para a Ciencia e Tecnologia

Awarded by Norte 2020 Portugal Regional Operational Programme

Awarded by National Institutes of Health

Awarded by Medical Research Council UK

Awarded by Wellcome Trust

Awarded by Canadian Institutes of Health Research

Awarded by MRC

Awarded by Fundação para a Ciência e a Tecnologia

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).