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

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

doi:10.1038/s41467-021-27766-8

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

Mariya Misheva, Konstantinos Kotzamanis

, 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...

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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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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. 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spelling	2023-09-13T14:58:10.0165881 v2 61681 2022-10-31 Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation ff080296775381560053d5e3a6e81745 0000-0001-7767-4060 Luke Davies Luke Davies true false 2022-10-31 MEDS 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. Journal Article Nature Communications 13 1 Springer Science and Business Media LLC 2041-1723 10 1 2022 2022-01-10 10.1038/s41467-021-27766-8 COLLEGE NANME Medical School COLLEGE CODE MEDS Swansea University 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). 2023-09-13T14:58:10.0165881 2022-10-31T11:59:17.8030704 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Mariya Misheva 1 Konstantinos Kotzamanis 0000-0002-6846-7761 2 Luke Davies 0000-0001-7767-4060 3 Victoria J. Tyrrell 4 Patricia R. S. Rodrigues 0000-0003-0768-0013 5 Gloria A. Benavides 6 Christine Hinz 7 Robert C. Murphy 8 Paul Kennedy 9 Philip R. Taylor 0000-0003-0163-1421 10 Marcela Rosas 11 Simon A. Jones 12 James E. McLaren 0000-0002-7021-5934 13 Sumukh Deshpande 14 Robert Andrews 15 Nils Helge Schebb 16 Magdalena A. Czubala 17 Mark Gurney 0000-0003-1119-6638 18 Maceler Aldrovandi 19 Sven W. Meckelmann 20 Peter Ghazal 0000-0003-0035-2228 21 Victor Darley-Usmar 22 Daniel A. White 0000-0002-7588-8935 23 Valerie B. O’Donnell 0000-0003-4089-8460 24 61681__25768__4b714a39093d4cd38c426b1b4c48ecaa.pdf 61681.pdf 2022-11-14T15:26:12.7424406 Output 3825988 application/pdf Version of Record true This article is licensed under a Creative Commons Attribution 4.0 International License true eng http://creativecommons.org/licenses/by/4.0/
title	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
spellingShingle	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation Luke Davies
title_short	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
title_full	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
title_fullStr	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
title_full_unstemmed	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
title_sort	Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation
author_id_str_mv	ff080296775381560053d5e3a6e81745
author_id_fullname_str_mv	ff080296775381560053d5e3a6e81745_***_Luke Davies
author	Luke Davies
author2	Mariya Misheva Konstantinos Kotzamanis 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
format	Journal article
container_title	Nature Communications
container_volume	13
container_issue	1
publishDate	2022
institution	Swansea University
issn	2041-1723
doi_str_mv	10.1038/s41467-021-27766-8
publisher	Springer Science and Business Media LLC
college_str	Faculty of Medicine, Health and Life Sciences
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hierarchy_top_title	Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id	facultyofmedicinehealthandlifesciences
hierarchy_parent_title	Faculty of Medicine, Health and Life Sciences
department_str	Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
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description	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.
published_date	2022-01-10T14:24:57Z
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Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation

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