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.

Saturated and unsaturated fatty acids differentially regulate in vitro and ex vivo placental antioxidant capacity

“…18 Maternal adiposity is strongly associated with an increased risk of essentially all maternal and fetal complications. [20][21][22] However, to our knowledge, our study is the first to in- Oxidative stress can be defined as an imbalance between free radical generation and antioxidant defense and is recognized as a key factor in the pathogenesis of adverse pregnancy outcomes. 19. Previous studies have shown that PA induces cytotoxicity in a diverse set of cells including trophoblasts, skeletal muscle, and liver cells.…”

“…19. Previous studies have shown that PA induces cytotoxicity in a diverse set of cells including trophoblasts, skeletal muscle, and liver cells. [20][21][22] However, to our knowledge, our study is the first to in- Oxidative stress can be defined as an imbalance between free radical generation and antioxidant defense and is recognized as a key factor in the pathogenesis of adverse pregnancy outcomes. 25 Although OS is a common feature of normal pregnancy, persistent, overwhelming OS leads to the consumption and decline of antioxidants, affecting placental antioxidant capacity and reducing systems.…”

Analysis of the PPARD gene expression level changes in football players in response to the training cycle

“…The highest expression level of PPARD mRNA is observed in Sertoli cells, intestine, heart, liver, brain and kidney tissues [ 2 , 3 , 4 , 5 ]. The most popular ligands of PPARβ/δ are: unsaturated fatty free acid (FFA) and their metabolites [ 1 , 2 , 5 , 6 ], GW0742 [ 7 , 8 , 9 ], ezetimibe [ 7 ], GW501516 [ 6 , 10 ], 15-HETE, 4-HNE, 4-HDDE and ATRA [ 2 ]. The PPAR activation plays a vital role in regulation of many physiological and pathological processes, such as energy consumption, inflammation, tissue repair, proliferation and differentiation of various types of cells [ 1 , 2 , 3 ].…”

“…The PPARβ/δ receptor exerts a pleiotropic impact on skeletal muscle physiology and metabolism. The use of cell cultures and animal models has revealed that PPARβ/δ activation results in a metabolic shift promoting lipid utilization (increased fatty acid uptake and oxidation) and reduced carbohydrate oxidation [ 6 , 11 , 13 ]. These modifications occur through upregulation of the expression of proteins implicated in myocyte energetic substrate preference, such as fat tissue (FAT)/CD36 [ 13 , 14 ], lipoprotein lipase, PDK4 or CPT1 [ 2 , 4 , 6 , 14 ].…”

“…The use of cell cultures and animal models has revealed that PPARβ/δ activation results in a metabolic shift promoting lipid utilization (increased fatty acid uptake and oxidation) and reduced carbohydrate oxidation [ 6 , 11 , 13 ]. These modifications occur through upregulation of the expression of proteins implicated in myocyte energetic substrate preference, such as fat tissue (FAT)/CD36 [ 13 , 14 ], lipoprotein lipase, PDK4 or CPT1 [ 2 , 4 , 6 , 14 ]. The PPARβ/δ also promotes mitochondrial biogenesis, angiogenesis and changes in fiber type composition from glycolytic to slow/fast oxidative fibers [ 11 , 13 , 15 , 16 ].…”