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The NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytes

2017-11-01Artigo científico Acesso aberto
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dc.contributor.authorLemos, Vera
dc.contributor.authorde Oliveira, Rita M
dc.contributor.authorNaia, Luana
dc.contributor.authorSzegö, Éva
dc.contributor.authorRamos, Elisabete
dc.contributor.authorPinho, Sónia
dc.contributor.authorMagro, Fernando
dc.contributor.authorCavadas, Cláudia
dc.contributor.authorCristina Rego, A.
dc.contributor.authorCosta, Vítor
dc.contributor.authorOuteiro, Tiago F.
dc.contributor.authorGomes, Pedro
dc.contributor.institutionNOVA Medical School|Faculdade de Ciências Médicas (NMS|FCM)
dc.contributor.institutionCentro de Estudos de Doenças Crónicas (CEDOC)
dc.contributor.pblOxford University Press
dc.date.accessioned2023-02-16T22:23:38Z
dc.date.available2023-02-16T22:23:38Z
dc.date.issued2017-11-01
dc.descriptionFunding Information: European Regional Development Fund (ERDF), Centro 2020 Regional Operational Programme (CENTRO-01-0145-FEDER-000012: HealthyAging2020); COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation and Portuguese national funds via FCT – Fundação para a Ciência e a Tecnologia (POCI-01-0145-FEDER-007440, SFRH/BPD/109347/ 2015 to R.M.O., SFRH/BD/86655/2012 to L.N. and SFRH/BPD/ 111815/2015 to P.G.); FLAD Life Science 2020 Grant to A.C.R.; European Molecular Biology Organization (EMBO Installation Grant to T.F.O.); DFG Center for Nanoscale Microscopy and Molecular Physiology of the Brain (CNMPB) to T.F.O.
dc.description.abstractInsulin resistance is a major predictor of the development of metabolic disorders. Sirtuins (SIRTs) have emerged as potential targets that can be manipulated to counteract age-related diseases, including type 2 diabetes. SIRT2 has been recently shown to exert important metabolic effects, but whether SIRT2 regulates insulin sensitivity in hepatocytes is currently unknown. The aim of this study is to investigate this possibility and to elucidate underlying molecular mechanisms. Here, we show that SIRT2 is downregulated in insulin-resistant hepatocytes and livers, and this was accompanied by increased generation of reactive oxygen species, activation of stress-sensitive ERK1/2 kinase, and mitochondrial dysfunction. Conversely, SIRT2 overexpression in insulin-resistant hepatocytes improved insulin sensitivity, mitigated reactive oxygen species production and ameliorated mitochondrial dysfunction. Further analysis revealed a reestablishment of mitochondrial morphology, with a higher number of elongated mitochondria rather than fragmented mitochondria instigated by insulin resistance. Mechanistically, SIRT2 was able to increase fusion-related protein Mfn2 and decrease mitochondrial-associated Drp1. SIRT2 also attenuated the downregulation of TFAM, a key mtDNA-associated protein, contributing to the increase in mitochondrial mass. Importantly, we found that SIRT2 expression in PBMCs of human subjects was negatively correlated with obesity and insulin resistance. These results suggest a novel function for hepatic SIRT2 in the regulation of insulin sensitivity and raise the possibility that SIRT2 activators may offer novel opportunities for preventing or treating insulin resistance and type 2 diabetes.en
dc.description.versionpublishersversion
dc.description.versionpublished
dc.format.extent13
dc.format.extent1032329
dc.identifier.doi10.1093/hmg/ddx298
dc.identifier.issn0964-6906
dc.identifier.otherPURE: 53478878
dc.identifier.otherPURE UUID: 08bca82d-c05a-4526-a159-c3ea4ecfa384
dc.identifier.otherScopus: 85034211658
dc.identifier.otherPubMed: 28973648
dc.identifier.otherWOS: 000413453900002
dc.identifier.urihttp://hdl.handle.net/10362/149358
dc.identifier.urlhttps://www.scopus.com/pages/publications/85034211658
dc.language.isoeng
dc.peerreviewedyes
dc.subjectMolecular Biology
dc.subjectGenetics
dc.subjectGenetics(clinical)
dc.subjectSDG 3 - Good Health and Well-being
dc.titleThe NAD+-dependent deacetylase SIRT2 attenuates oxidative stress and mitochondrial dysfunction and improves insulin sensitivity in hepatocytesen
dc.typejournal article
degois.publication.firstPage4105
degois.publication.issue21
degois.publication.lastPage4117
degois.publication.titleHuman molecular genetics
degois.publication.volume26
dspace.entity.typePublication
rcaap.rightsopenAccess

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