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dc.contributor.authorHazlehurst, Jonathan M
dc.contributor.authorLim, Teegan Reina
dc.contributor.authorCharlton, Catriona
dc.contributor.authorMiller, Jack J
dc.contributor.authorGathercole, Laura L
dc.contributor.authorCornfield, Thomas
dc.contributor.authorNikolaou, Nikolaos
dc.contributor.authorHarris, Shelley E
dc.contributor.authorMoolla, Ahmad
dc.contributor.authorOthonos, Nantia
dc.contributor.authorHeather, Lisa C
dc.contributor.authorMarjot, Thomas
dc.contributor.authorTyler, Damian J
dc.contributor.authorCarr, Carolyn
dc.contributor.authorHodson, Leanne
dc.contributor.authorMcKeating, Jane
dc.contributor.authorTomlinson, Jeremy W
dc.date.accessioned2022-06-06T23:30:22Z
dc.date.available2022-06-06T23:30:22Z
dc.date.issued2022-06
dc.identifier.issn2589-9368
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337707
dc.description.abstractBACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic de novo lipogenesis (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease. METHODS: Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms. RESULTS: Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms. CONCLUSIONS: These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained in vivo models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD.
dc.format.mediumElectronic-eCollection
dc.publisherElsevier BV
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectHIF
dc.subjectHypoxia
dc.subjectLipid metabolism
dc.subjectNAFLD
dc.titleAcute intermittent hypoxia drives hepatic de novo lipogenesis in humans and rodents.
dc.typeArticle
dc.publisher.departmentDepartment of Pathology
dc.date.updated2022-06-03T13:30:10Z
prism.number100177
prism.publicationDate2022
prism.publicationNameMetabol Open
prism.startingPage100177
prism.volume14
dc.identifier.doi10.17863/CAM.85116
dcterms.dateAccepted2022-03-12
rioxxterms.versionofrecord10.1016/j.metop.2022.100177
rioxxterms.versionVoR
dc.contributor.orcidNikolaou, Nikolaos [0000-0002-8789-8436]
dc.identifier.eissn2589-9368
rioxxterms.typeJournal Article/Review
cam.issuedOnline2022-03-14
cam.depositDate2022-06-03
pubs.licence-identifierapollo-deposit-licence-2-1
pubs.licence-display-nameApollo Repository Deposit Licence Agreement


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International