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Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation

Mariya Misheva, Konstantinos Kotzamanis Orcid Logo, Luke Davies Orcid Logo, Victoria J. Tyrrell, Patricia R. S. Rodrigues Orcid Logo, Gloria A. Benavides, Christine Hinz, Robert C. Murphy, Paul Kennedy, Philip R. Taylor Orcid Logo, Marcela Rosas, Simon A. Jones, James E. McLaren Orcid Logo, Sumukh Deshpande, Robert Andrews, Nils Helge Schebb, Magdalena A. Czubala, Mark Gurney Orcid Logo, Maceler Aldrovandi, Sven W. Meckelmann, Peter Ghazal Orcid Logo, Victor Darley-Usmar, Daniel A. White Orcid Logo, Valerie B. O’Donnell Orcid Logo

Nature Communications, Volume: 13, Issue: 1

Swansea University Author: Luke Davies Orcid Logo

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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...

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Published in: Nature Communications
ISSN: 2041-1723
Published: Springer Science and Business Media LLC 2022
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa61681
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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.
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