Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes

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• dc.contributor.author Rodríguez-Calvo, Ricardoca
• dc.contributor.author Chanda, Dipanjanca
• dc.contributor.author Oligschlaeger, Yvonneca
• dc.contributor.author Miglianico, Marieca
• dc.contributor.author Coumans, Will A.ca
• dc.contributor.author Barroso, Emmaca
• dc.contributor.author Tajes Orduña, Martaca
• dc.contributor.author Luiken, Joost J. F. P.ca
• dc.contributor.author Glatz, Jan F.C.ca
• dc.contributor.author Vázquez-Carrera, Manuelca
• dc.contributor.author Neumann, Dietbertca
• dc.date.accessioned 2017-11-22T08:44:58Z
• dc.date.issued 2017
• dc.description.abstract Small heterodimer partner (SHP) is an atypical nuclear receptor expressed in heart that has been shown to inhibit the hypertrophic response. Here, we assessed the role of SHP in cardiac metabolism and inflammation. Mice fed a high-fat diet (HFD) displayed glucose intolerance accompanied by increased cardiac mRNA levels of Shp. In HL-1 cardiomyocytes, SHP overexpression inhibited both basal and insulin-stimulated glucose uptake and impaired the insulin signalling pathway (evidenced by reduced AKT and AS160 phosphorylation), similar to insulin resistant cells generated by high palmitate/high insulin treatment (HP/HI; 500μM/100nM). In addition, SHP overexpression increased Socs3 mRNA and reduced IRS-1 protein levels. SHP overexpression also induced Cd36 expression (~6.2 fold; p<0.001) linking to the observed intramyocellular lipid accumulation. SHP overexpressing cells further showed altered expression of genes involved in lipid metabolism, i.e., Acaca, Acadvl or Ucp3, augmented NF-κB DNA-binding activity and induced transcripts of inflammatory genes, i.e., Il6 and Tnf mRNA (~4-fold induction, p<0.01). Alterations in metabolism and inflammation found in SHP overexpressing cells were associated with changes in the mRNA levels of Ppara (79% reduction, p<0.001) and Pparg (~58-fold induction, p<0.001). Finally, co-immunoprecipitation studies showed that SHP overexpression strongly reduced the physical interaction between PPARα and the p65 subunit of NF-κB, suggesting that dissociation of these two proteins is one of the mechanisms by which SHP initiates the inflammatory response in cardiac cells. Overall, our results suggest that SHP upregulation upon high-fat feeding leads to lipid accumulation, insulin resistance and inflammation in cardiomyocytes.
• dc.description.sponsorship This study was partially supported by funds from The Netherlands Organization for Scientific Research (NWO) (VIDI grant number 864.10.007 to DN), the Spanish Ministerio de Economía y Competitividad (SAF2015-64146-R to MVC) and Fundació la Marató TV3 2014 (to MVC). DC was supported by a Marie Curie fellowship (PIIFGA-2012-332230).
• dc.format.mimetype application/pdfca
• dc.identifier.citation Rodríguez-Calvo R, Chanda D, Oligschlaeger Y, Miglianico M, Coumans WA, Barroso E. et al. Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes. Biochim Biophys Acta. 2017 May;1862(5):541-551. DOI: 10.1016/j.bbalip.2017.02.006
• dc.identifier.doi http://dx.doi.org/10.1016/j.bbalip.2017.02.006
• dc.identifier.issn 0006-3002
• dc.identifier.uri http://hdl.handle.net/10230/33306
• dc.language.iso eng
• dc.publisher Elsevierca
• dc.relation.ispartof Biochimica et Biophysica Acta. 2017 May;1862(5):541-51
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-64146-R
• dc.rights © Elsevier http://dx.doi.org/10.1016/j.bbalip.2017.02.006
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.subject.keyword Diabetic cardiomyopathy
• dc.subject.keyword Insulin resistance
• dc.subject.keyword Nuclear receptors
• dc.subject.keyword Small heterodimer partner
• dc.subject.other Insulina
• dc.subject.other Diabetis
• dc.title Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytesca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/acceptedVersion