No Cover Image

Journal article 525 views 54 downloads

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

  • 61681.pdf

    PDF | Version of Record

    This article is licensed under a Creative Commons Attribution 4.0 International License

    Download (3.65MB)

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...

Full description

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
Tags: Add Tag
No Tags, Be the first to tag this record!
first_indexed 2022-11-14T15:28:28Z
last_indexed 2023-01-13T19:22:35Z
id cronfa61681
recordtype SURis
fullrecord <?xml version="1.0" encoding="utf-8"?><rfc1807 xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:xsd="http://www.w3.org/2001/XMLSchema"><bib-version>v2</bib-version><id>61681</id><entry>2022-10-31</entry><title>Oxylipin metabolism is controlled by mitochondrial β-oxidation during bacterial inflammation</title><swanseaauthors><author><sid>ff080296775381560053d5e3a6e81745</sid><ORCID>0000-0001-7767-4060</ORCID><firstname>Luke</firstname><surname>Davies</surname><name>Luke Davies</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-10-31</date><deptcode>BMS</deptcode><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.</abstract><type>Journal Article</type><journal>Nature Communications</journal><volume>13</volume><journalNumber>1</journalNumber><paginationStart/><paginationEnd/><publisher>Springer Science and Business Media LLC</publisher><placeOfPublication/><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic>2041-1723</issnElectronic><keywords/><publishedDay>10</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-01-10</publishedDate><doi>10.1038/s41467-021-27766-8</doi><url/><notes/><college>COLLEGE NANME</college><department>Biomedical Sciences</department><CollegeCode>COLLEGE CODE</CollegeCode><DepartmentCode>BMS</DepartmentCode><institution>Swansea University</institution><apcterm/><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).</funders><projectreference/><lastEdited>2023-09-13T14:58:10.0165881</lastEdited><Created>2022-10-31T11:59:17.8030704</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>Mariya</firstname><surname>Misheva</surname><order>1</order></author><author><firstname>Konstantinos</firstname><surname>Kotzamanis</surname><orcid>0000-0002-6846-7761</orcid><order>2</order></author><author><firstname>Luke</firstname><surname>Davies</surname><orcid>0000-0001-7767-4060</orcid><order>3</order></author><author><firstname>Victoria J.</firstname><surname>Tyrrell</surname><order>4</order></author><author><firstname>Patricia R. S.</firstname><surname>Rodrigues</surname><orcid>0000-0003-0768-0013</orcid><order>5</order></author><author><firstname>Gloria A.</firstname><surname>Benavides</surname><order>6</order></author><author><firstname>Christine</firstname><surname>Hinz</surname><order>7</order></author><author><firstname>Robert C.</firstname><surname>Murphy</surname><order>8</order></author><author><firstname>Paul</firstname><surname>Kennedy</surname><order>9</order></author><author><firstname>Philip R.</firstname><surname>Taylor</surname><orcid>0000-0003-0163-1421</orcid><order>10</order></author><author><firstname>Marcela</firstname><surname>Rosas</surname><order>11</order></author><author><firstname>Simon A.</firstname><surname>Jones</surname><order>12</order></author><author><firstname>James E.</firstname><surname>McLaren</surname><orcid>0000-0002-7021-5934</orcid><order>13</order></author><author><firstname>Sumukh</firstname><surname>Deshpande</surname><order>14</order></author><author><firstname>Robert</firstname><surname>Andrews</surname><order>15</order></author><author><firstname>Nils Helge</firstname><surname>Schebb</surname><order>16</order></author><author><firstname>Magdalena A.</firstname><surname>Czubala</surname><order>17</order></author><author><firstname>Mark</firstname><surname>Gurney</surname><orcid>0000-0003-1119-6638</orcid><order>18</order></author><author><firstname>Maceler</firstname><surname>Aldrovandi</surname><order>19</order></author><author><firstname>Sven W.</firstname><surname>Meckelmann</surname><order>20</order></author><author><firstname>Peter</firstname><surname>Ghazal</surname><orcid>0000-0003-0035-2228</orcid><order>21</order></author><author><firstname>Victor</firstname><surname>Darley-Usmar</surname><order>22</order></author><author><firstname>Daniel A.</firstname><surname>White</surname><orcid>0000-0002-7588-8935</orcid><order>23</order></author><author><firstname>Valerie B.</firstname><surname>O’Donnell</surname><orcid>0000-0003-4089-8460</orcid><order>24</order></author></authors><documents><document><filename>61681__25768__4b714a39093d4cd38c426b1b4c48ecaa.pdf</filename><originalFilename>61681.pdf</originalFilename><uploaded>2022-11-14T15:26:12.7424406</uploaded><type>Output</type><contentLength>3825988</contentLength><contentType>application/pdf</contentType><version>Version of Record</version><cronfaStatus>true</cronfaStatus><documentNotes>This article is licensed under a Creative Commons Attribution 4.0 International License</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language><licence>http://creativecommons.org/licenses/by/4.0/</licence></document></documents><OutputDurs/></rfc1807>
spelling 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 BMS 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 Biomedical Sciences COLLEGE CODE BMS 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
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
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
document_store_str 1
active_str 0
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 2022-01-10T14:58:11Z
_version_ 1776931036993683456
score 11.016794