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dc.contributor.authorSobczak, Amelie Isabelle Sylvie
dc.contributor.authorKatundu, Kondwani George Happy
dc.contributor.authorPhoenix, Fladia A.
dc.contributor.authorKhazaipoul, Siavash
dc.contributor.authorYu, Ruitao
dc.contributor.authorLampiao, Fanuel
dc.contributor.authorStefanowicz, Fiona
dc.contributor.authorBlindauer, Claudia A.
dc.contributor.authorPitt, Samantha J.
dc.contributor.authorSmith, Terry K
dc.contributor.authorAjjan, Ramzi A.
dc.contributor.authorStewart, Alan J.
dc.date.accessioned2021-02-11T10:30:21Z
dc.date.available2021-02-11T10:30:21Z
dc.date.issued2021-03-21
dc.identifier.citationSobczak , A I S , Katundu , K G H , Phoenix , F A , Khazaipoul , S , Yu , R , Lampiao , F , Stefanowicz , F , Blindauer , C A , Pitt , S J , Smith , T K , Ajjan , R A & Stewart , A J 2021 , ' Albumin-mediated alteration of plasma zinc speciation by fatty acids modulates blood clotting in type-2 diabetes ' , Chemical Science , vol. 12 , no. 11 , pp. 4079-4093 . https://doi.org/10.1039/D0SC06605Ben
dc.identifier.issn2041-6520
dc.identifier.otherPURE: 272597645
dc.identifier.otherPURE UUID: 04aad9e0-a571-4ba0-aa05-819209e7bfa8
dc.identifier.otherORCID: /0000-0003-4580-1840/work/88730942
dc.identifier.otherORCID: /0000-0003-2257-1595/work/88731037
dc.identifier.otherScopus: 85103354138
dc.identifier.otherWOS: 000632580200025
dc.identifier.urihttp://hdl.handle.net/10023/21412
dc.descriptionThis work was supported by the British Heart Foundation (grant numbers PG/15/9/31270, FS/15/42/31556) and travel grants from the Commonwealth Scholarship Commission (grant number MWCN-2017-294) and the International Co-operation project of Qinghai Province (grant number 2021-HZ-806).en
dc.description.abstractZn2+ is an essential regulator of coagulation and is released from activated platelets. In plasma, free Zn2+ concentration is fine-tuned through buffering by human serum albumin (HSA). Importantly, the ability of HSA to bind/buffer Zn2+ is compromised by co-transported non-esterified fatty acids (NEFAs). Given the role of Zn2+ in blood clot formation, we hypothesise that Zn2+ displacement from HSA by NEFAs in certain conditions (such as type 2 diabetes mellitus, T2DM) impacts on the cellular and protein arms of coagulation. To test this hypothesis, we assessed the extent to which increasing concentrations of a range of medium- and long-chain NEFAs reduced Zn2+-binding ability of HSA. Amongst the NEFAs tested, palmitate (16:0) and stearate (18:0) were the most effective at suppressing zinc-binding, whilst the mono-unsaturated palmitoleate (16:1c9) was markedly less effective. Assessment of platelet aggregation and fibrin clotting parameters in purified systems and in pooled plasma suggested that the HSA-mediated impact of the model NEFA myristate on zinc speciation intensified the effects of Zn2+ alone. The effects of elevated Zn2+ alone on fibrin clot density and fibre thickness in a purified protein system were mirrored in samples from T2DM patients, who have derranged NEFA metabolism. Crucially, T2DM individuals had increased total plasma NEFAs compared to controls, with the concentrations of key saturated (myristate, palmitate, stearate) and mono-unsaturated (oleate, cis-vaccenate) NEFAs positively correlating with clot density. Collectively, these data strongly support the concept that elevated NEFA levels contribute to altered coagulation in T2DM through dysregulation of plasma zinc speciation.
dc.format.extent15
dc.language.isoeng
dc.relation.ispartofChemical Scienceen
dc.rightsCopyright © 2021 the Author(s). This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.en
dc.subjectQD Chemistryen
dc.subjectQH301 Biologyen
dc.subjectRC Internal medicineen
dc.subjectDASen
dc.subject.lccQDen
dc.subject.lccQH301en
dc.subject.lccRCen
dc.titleAlbumin-mediated alteration of plasma zinc speciation by fatty acids modulates blood clotting in type-2 diabetesen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews.School of Medicineen
dc.contributor.institutionUniversity of St Andrews.Centre for Biophotonicsen
dc.contributor.institutionUniversity of St Andrews.Cellular Medicine Divisionen
dc.contributor.institutionUniversity of St Andrews.Biomedical Sciences Research Complexen
dc.contributor.institutionUniversity of St Andrews.School of Biologyen
dc.contributor.institutionUniversity of St Andrews.Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews.Institute of Behavioural and Neural Sciencesen
dc.identifier.doihttps://doi.org/10.1039/D0SC06605B
dc.description.statusPeer revieweden


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