title: Protective Effect of Unsaturated Fatty Acids on Palmitic Acid-Induced Toxicity in Skeletal Muscle Cells is not Mediated by PPARδ Activation.
abstract: Unsaturated free fatty acids (FFA) are able to prevent deleterious effects of saturated FFA in skeletal muscle cells although the mechanisms involved are still not completely understood. FFA act as endogenous ligands of peroxisome proliferator-activated receptors (PPAR), transcription factors regulating the expression of genes involved in lipid metabolism. The aim of this study was to determine whether activation of PPARδ, the most common PPAR subtype in skeletal muscle, plays a role in mediating the protective effect of unsaturated FFA on saturated FFA-induced damage in skeletal muscle cells and to examine an impact on mitochondrial respiration. Mouse C2C12 myotubes were treated for 24 h with different concentrations of saturated FFA (palmitic acid), unsaturated FFA (oleic, linoleic and α-linolenic acid), and their combinations. PPARδ agonist GW501516 and antagonist GSK0660 were also used. Both mono- and polyunsaturated FFA, but not GW501516, prevented palmitic acid-induced cell death. Mono- and polyunsaturated FFA proved to be effective activators of PPARδ compared to saturated palmitic acid; however, in combination with palmitic acid their effect on PPARδ activation was blocked and stayed at the levels observed for palmitic acid alone. Unsaturated FFA at moderate physiological concentrations as well as GW501516, but not palmitic acid, mildly uncoupled mitochondrial respiration. Our results indicate that although unsaturated FFA are effective activators of PPARδ, their protective effect on palmitic acid-induced toxicity is not mediated by PPARδ activation and subsequent induction of lipid regulatory genes in skeletal muscle cells. Other mechanisms, such as mitochondrial uncoupling, may underlie their effect.
authors.affiliation: Department of Nutrition and Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Tumova
authors.affiliation: Department of Sport Medicine, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Malisova
authors.affiliation: Department of Nutrition and Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Andel
authors.affiliation: Department of Nutrition and Centre for Research on Diabetes, Metabolism and Nutrition, Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. jan.trnka@lf3.cuni.cz.
authors.forename: Jan
authors.identifier: http://orcid.org/0000-0002-1786-7562
authors.initials: J
authors.lastname: Trnka
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival; D004042:Dietary Fats, Unsaturated / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D051379:Mice; D032342:Muscle Cells / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D019308:Palmitic Acid / Q000633:toxicity*; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
chemical_list: D004042:Dietary Fats, Unsaturated; C529769:GSK0660; C425931:GW 501516; C091778:Ppard protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D013450:Sulfones; D013844:Thiazoles; D013876:Thiophenes; D019308:Palmitic Acid
keywords: Mitochondrial respiration; Mitochondrial uncoupling; PPARδ; PPARδ agonist; Saturated fatty acid; Skeletal muscle cells; Unsaturated fatty acids