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Enhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.

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cam.issuedOnline2021-12-15
dc.contributor.authorO'Brien, Katie
dc.contributor.authorMcNally, Ben D
dc.contributor.authorSowton, Alice P
dc.contributor.authorMurgia, Antonio
dc.contributor.authorArmitage, James
dc.contributor.authorThomas, Luke W
dc.contributor.authorKrause, Fynn N
dc.contributor.authorMaddalena, Lucas A
dc.contributor.authorFrancis, Ian
dc.contributor.authorKavanagh, Stefan
dc.contributor.authorWilliams, Dominic P
dc.contributor.authorAshcroft, Margaret
dc.contributor.authorGriffin, Julian L
dc.contributor.authorLyon, Jonathan J
dc.contributor.authorMurray, Andrew
dc.contributor.orcidO'Brien, Katie [0000-0002-0189-1971]
dc.contributor.orcidAshcroft, Margaret [0000-0002-0066-3707]
dc.contributor.orcidMurray, Andrew [0000-0002-0929-9315]
dc.date.accessioned2022-01-05T10:47:00Z
dc.date.available2022-01-05T10:47:00Z
dc.date.issued2021-12-15
dc.date.submitted2021-02-08
dc.date.updated2022-01-05T10:46:59Z
dc.descriptionFunder: GlaxoSmithKline; doi: http://dx.doi.org/10.13039/100004330
dc.description.abstractBACKGROUND: Tissue hypoxia is a key feature of several endemic hepatic diseases, including alcoholic and non-alcoholic fatty liver disease, and organ failure. Hypoxia imposes a severe metabolic challenge on the liver, potentially disrupting its capacity to carry out essential functions including fuel storage and the integration of lipid metabolism at the whole-body level. Mitochondrial respiratory function is understood to be critical in mediating the hepatic hypoxic response, yet the time-dependent nature of this response and the role of the respiratory chain in this remain unclear. RESULTS: Here, we report that hepatic respiratory capacity is enhanced following short-term exposure to hypoxia (2 days, 10% O2) and is associated with increased abundance of the respiratory chain supercomplex III2+IV and increased cardiolipin levels. Suppression of this enhanced respiratory capacity, achieved via mild inhibition of mitochondrial complex III, disrupted metabolic homeostasis. Hypoxic exposure for 2 days led to accumulation of plasma and hepatic long chain acyl-carnitines. This was observed alongside depletion of hepatic triacylglycerol species with total chain lengths of 39-53 carbons, containing palmitic, palmitoleic, stearic, and oleic acids, which are associated with de novo lipogenesis. The changes to hepatic respiratory capacity and lipid metabolism following 2 days hypoxic exposure were transient, becoming resolved after 14 days in line with systemic acclimation to hypoxia and elevated circulating haemoglobin concentrations. CONCLUSIONS: The liver maintains metabolic homeostasis in response to shorter term hypoxic exposure through transient enhancement of respiratory chain capacity and alterations to lipid metabolism. These findings may have implications in understanding and treating hepatic pathologies associated with hypoxia.
dc.description.sponsorshipGlaxoSmithKline
dc.identifier.doi10.17863/CAM.79437
dc.identifier.eissn1741-7007
dc.identifier.issn1741-7007
dc.identifier.others12915-021-01192-0
dc.identifier.other1192
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/331989
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectResearch Article
dc.subjectHypoxia
dc.subjectHepatic mitochondria
dc.subjectMitochondrial respiratory chain
dc.subjectMitochondrial supercomplexes
dc.subjectDe novo lipogenesis
dc.titleEnhanced hepatic respiratory capacity and altered lipid metabolism support metabolic homeostasis during short-term hypoxic stress.
dc.typeArticle
dcterms.dateAccepted2021-11-12
prism.issueIdentifier1
prism.publicationNameBMC Biol
prism.volume19
pubs.funder-project-idBritish Heart Foundation (FS/17/61/33473D)
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1186/s12915-021-01192-0

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