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Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
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Luke Davies ,
Victoria J. Tyrrell,
Patricia R. S. Rodrigues ,
Gloria A. Benavides,
Christine Hinz,
Robert C. Murphy,
Paul Kennedy,
Philip R. Taylor ,
Marcela Rosas,
Simon A. Jones,
James E. McLaren ,
Sumukh Deshpande,
Robert Andrews,
Nils Helge Schebb,
Magdalena A. Czubala,
Mark Gurney ,
Maceler Aldrovandi,
Sven W. Meckelmann,
Peter Ghazal ,
Victor Darley-Usmar,
Daniel A. White ,
Valerie B. O’Donnell
Nature Communications, Volume: 13, Issue: 1
Swansea University Author:
Luke Davies
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DOI (Published version): 10.1038/s41467-021-27766-8
Abstract
Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological...
| Published in: | Nature Communications |
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| ISSN: | 2041-1723 |
| Published: |
Springer Science and Business Media LLC
2022
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| Online Access: |
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa61681 |
| Abstract: |
Oxylipins are potent biological mediators requiring strict control, but how they are removed en masse during infection and inflammation is unknown. Here we show that lipopolysaccharide (LPS) dynamically enhances oxylipin removal via mitochondrial β-oxidation. Specifically, genetic or pharmacological targeting of carnitine palmitoyl transferase 1 (CPT1), a mitochondrial importer of fatty acids, reveal that many oxylipins are removed by this protein during inflammation in vitro and in vivo. Using stable isotope-tracing lipidomics, we find secretion-reuptake recycling for 12-HETE and its intermediate metabolites. Meanwhile, oxylipin β-oxidation is uncoupled from oxidative phosphorylation, thus not contributing to energy generation. Testing for genetic control checkpoints, transcriptional interrogation of human neonatal sepsis finds upregulation of many genes involved in mitochondrial removal of long-chain fatty acyls, such as ACSL1,3,4, ACADVL, CPT1B, CPT2 and HADHB. Also, ACSL1/Acsl1 upregulation is consistently observed following the treatment of human/murine macrophages with LPS and IFN-γ. Last, dampening oxylipin levels by β-oxidation is suggested to impact on their regulation of leukocyte functions. In summary, we propose mitochondrial β-oxidation as a regulatory metabolic checkpoint for oxylipins during inflammation. |
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| College: |
Faculty of Medicine, Health and Life Sciences |
| Funders: |
Funding from Wellcome Trust (094143/Z/10/Z) and European Research Foundation
(LipidArrays) is gratefully acknowledged (V. B. O.). V. B. O. is a Royal Society Wolfson
Research Merit Award Holder and acknowledges funding for LIPID MAPS from
Wellcome Trust (203014/Z/16/Z). Ser Cymru Project Sepsis grant funded by WG/EUERDF (P. G., V. B. O.). P. R. T. is funded by a Wellcome Trust Investigator Award
(107964/Z/15/Z) and the UK Dementia Research Institute. M. A. C. is funded by BBSRC
Discovery Fellowship (BB/T009543/1). V.D.-U. acknowledges The Nathan Shock Center
P30 AG05088. Kidney Research UK (RP-024-20160304, S.A.J.), Versus Arthritis (Reference 20770 awarded to S.A.J., V.O.D.). M.A.C. is supported by BBSRC Discovery Fellowship (BB/T009543/1). |
| Issue: |
1 |