Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin
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 transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the pept...
| Main Author: | |
|---|---|
| Format: | Journal article |
| Published: |
Springer Nature
2019
|
| _version_ | 1797087239995392000 |
|---|---|
| author | Drakesmith, A |
| author_facet | Drakesmith, A |
| author_sort | Drakesmith, A |
| collection | OXFORD |
| description | 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 transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal 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 homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders. |
| first_indexed | 2024-03-07T02:33:00Z |
| format | Journal article |
| id | oxford-uuid:a7de86ab-63a8-484f-a6a2-f9a6fff9734a |
| institution | University of Oxford |
| last_indexed | 2024-03-07T02:33:00Z |
| publishDate | 2019 |
| publisher | Springer Nature |
| record_format | dspace |
| spelling | oxford-uuid:a7de86ab-63a8-484f-a6a2-f9a6fff9734a2022-03-27T02:57:23ZNrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidinJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:a7de86ab-63a8-484f-a6a2-f9a6fff9734aSymplectic Elements at OxfordSpringer Nature2019Drakesmith, AIron 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 transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) orchestrates cell-intrinsic protective antioxidant responses, while the peptide hormone hepcidin maintains systemic iron homoeostasis, but is pathophysiologically decreased in haemochromatosis and β-thalassaemia. Here, we show that Nrf2 is activated by iron-induced, mitochondria-derived pro-oxidants and drives bone morphogenetic protein 6 (Bmp6) expression in liver sinusoidal 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 homoeostasis in haemochromatosis and counteracting the inhibition of Bmp6 by erythroferrone in β-thalassaemia. We propose that Nrf2 links cellular sensing of excess toxic iron to the control of systemic iron homoeostasis and antioxidant responses, and may be a therapeutic target for iron-associated disorders. |
| spellingShingle | Drakesmith, A Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin |
| title | Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin |
| title_full | Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin |
| title_fullStr | Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin |
| title_full_unstemmed | Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin |
| title_short | Nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via Bmp6 and hepcidin |
| title_sort | nrf2 controls iron homoeostasis in haemochromatosis and thalassaemia via bmp6 and hepcidin |
| work_keys_str_mv | AT drakesmitha nrf2controlsironhomoeostasisinhaemochromatosisandthalassaemiaviabmp6andhepcidin |