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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
2019-05
Nature Metabolism
Journal Article
1
5
519-531
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.
Springer Nature
Population Health and Immunity
10.1038/s42255-019-0063-6
31276102
Refer to copyright notice on published article.

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Creation Date 2019-07-17 01:31:56 Last Modified 2020-02-03 08:23:40