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

Lim, PJ; Duarte, TL; Arezes, J; Garcia-Santos, D; Hamdi, A; Pasricha, SR; Armitage, AE; Mehta, H; Wideman, S; Santos, AG; Santos-Goncalves, A; Morovat, A; Hughes, JR; Soilleux, E; Wang, CY; Bayer, AL; Klenerman, P; Willberg, CB; Hartley, RC; Murphy, MP; Babitt, JL; Ponka, P; Porto, G; Drakesmith, H

Author(s): Lim, PJ; Duarte, TL; Arezes, J; Garcia-Santos, D; Hamdi, A; Pasricha, SR; Armitage, AE; Mehta, H; Wideman, S; Santos, AG; Santos-Goncalves, A; Morovat, A; Hughes, JR; Soilleux, E; Wang, CY; Bayer, AL; Klenerman, P; Willberg, CB; Hartley, RC; Murphy, MP; Babitt, JL; Ponka, P; Porto, G; Drakesmith, H;
Details: Publication Year 2019-05,Volume 1,Issue #5,Page 519-531
Journal Title: Nature Metabolism
Publication Type: Journal Article
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.
Publisher: Springer Nature
Research Division(s): Population Health And Immunity
PubMed ID: 31276102
Link To PubMed Central Version: https://www,ncbi.nlm.nih.gov/pmc/articles/PMC6609153/
Publisher's Version: https://doi.org/10.1038/s42255-019-0063-6
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-07-17 01:31:56

Last Modified: 2020-02-03 08:23:40