Nrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.

TitleNrf2 controls iron homeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin.
Publication TypeJournal Article
Year of Publication2019
AuthorsLim, PJin, Duarte, TL, Arezes, J, Garcia-Santos, D, Hamdi, A, Pasricha, S-R, Armitage, AE, Mehta, H, Wideman, S, Santos, AG, Santos-Gonçalves, A, Morovat, A, Hughes, JR, Soilleux, E, Wang, C-Y, Bayer, AL, Klenerman, P, Willberg, CB, Hartley, RC, Murphy, MP, Babitt, JL, Ponka, P, Porto, G, Drakesmith, H
JournalNat Metab
Volume1
Issue5
Pagination519-531
Date Published2019 May
ISSN2522-5812
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.

DOI10.1038/s42255-019-0063-6
Alternate JournalNat Metab
Citation Key10.1038/s42255-019-0063-6
PubMed ID31276102
PubMed Central IDPMC6609153
Grant List / / Wellcome Trust / United Kingdom
R01 DK087727 / DK / NIDDK NIH HHS / United States