학술논문
Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.
Document Type
Academic Journal
Author
Lim PJ; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Duarte TL; Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Arezes J; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Garcia-Santos D; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Department of Physiology, McGill University, Montreal, QC, Canada.; Hamdi A; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Department of Physiology, McGill University, Montreal, QC, Canada.; Pasricha SR; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Armitage AE; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Mehta H; Peter Medawar Building for Pathogen Research, University of Oxford, Oxford, Oxfordshire, UK.; Wideman S; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Santos AG; Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Santos-Gonçalves A; Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Morovat A; Department of Clinical Biochemistry, Oxford University Hospitals NHS Foundation Trust, UK.; Hughes JR; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine. University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Soilleux E; Department of Cellular Pathology, Oxford University Hospitals NHS Trust, John Radcliffe Hospital, Oxford, UK.; Wang CY; Nephrology Division, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Bayer AL; Nephrology Division, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Klenerman P; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Oxford NIHR Biomedical Research Centre, The John Radcliffe Hospital, Oxford, UK.; Willberg CB; The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.; Hartley RC; WestCHEM School of Chemistry, University of Glasgow, Glasgow, G12 8QQ, UK.; Murphy MP; MRC Mitochondrial Biology Unit, University of Cambridge, Cambridge, CB2 0XY, UK.; Babitt JL; Nephrology Division, Program in Membrane Biology, Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.; Ponka P; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC, Canada.; Department of Physiology, McGill University, Montreal, QC, Canada.; Porto G; Instituto de Biologia Molecular e Celular & Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal.; Drakesmith H; MRC Human Immunology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, OX3 9DS, UK.; Haematology Theme Oxford Biomedical Research Centre, Oxford, UK.
Source
Publisher: Springer Nature Country of Publication: Germany NLM ID: 101736592 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2522-5812 (Electronic) Linking ISSN: 25225812 NLM ISO Abbreviation: Nat Metab
Subject
Language
English
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 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 impaired and iron accumulation and hepatic damage are increased. Pharmacological activation of Nrf2 stimulates the Bmp6-hepcidin axis, improving iron homeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in beta-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to control of systemic iron homeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders.
Competing Interests: Competing financial interests The authors declare no competing financial interests.
Competing Interests: Competing financial interests The authors declare no competing financial interests.