title: Small heterodimer partner (SHP) contributes to insulin resistance in cardiomyocytes.
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.
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands. Electronic address: rrodriguez080480@yahoo.es.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Rodríguez-Calvo
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Dipanjan
authors.initials: D
authors.lastname: Chanda
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Oligschlaeger
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Marie
authors.initials: M
authors.lastname: Miglianico
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Will A
authors.initials: WA
authors.lastname: Coumans
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Pediatrica-Hospital Sant Joan de Déu, and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Pharmacy, Diagonal 643, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Emma
authors.initials: E
authors.lastname: Barroso
authors.affiliation: Heart Diseases Biomedical Research Group, Inflammatory and Cardiovascular Disorders Program, Hospital del Mar Medical Research Institute (IMIM), Parc de Salut Mar, Dr. Aiguader 88, E-08003, Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Tajes
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Joost Jfp
authors.initials: JJ
authors.lastname: Luiken
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands.
authors.forename: Jan Fc
authors.initials: JF
authors.lastname: Glatz
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutic Chemistry, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Institut de Recerca Pediatrica-Hospital Sant Joan de Déu, and Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM)-Instituto de Salud Carlos III, Faculty of Pharmacy, Diagonal 643, University of Barcelona, E-08028 Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Vázquez-Carrera
authors.affiliation: Department of Molecular Genetics, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, 6200 MD Maastricht, Netherlands. Electronic address: d.neumann@maastrichtuniversity.nl.
authors.forename: Dietbert
authors.initials: D
authors.lastname: Neumann
mesh_terms: D000818:Animals; D005786:Gene Expression Regulation; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction
chemical_list: D007328:Insulin; D016328:NF-kappa B; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; C099713:nuclear receptor subfamily 0, group B, member 2; D005947:Glucose
keywords: Diabetic cardiomyopathy; Insulin resistance; Nuclear receptors; Small heterodimer partner