Increased Reactive Oxygen Species Production Down-regulates Peroxisome Proliferator-activated α Pathway in C2C12 Skeletal Muscle Cells
| Autor: | Marta Alegret, Manuel Vázquez Carrera, Rosa M. Sánchez, Tomás Adzet, Àgatha Cabrero, Juan C. Laguna |
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| Rok vydání: | 2002 |
| Předmět: |
Time Factors
Down-Regulation Receptors Cytoplasmic and Nuclear Biology Polymerase Chain Reaction Biochemistry Cell Line Mice chemistry.chemical_compound Pyrrolidine dithiocarbamate Sphingosine Thiocarbamates medicine Animals RNA Messenger Enzyme Inhibitors Muscle Skeletal Molecular Biology Cells Cultured Flavonoids chemistry.chemical_classification Reactive oxygen species Dose-Response Relationship Drug Fatty Acids NF-kappa B Skeletal muscle Increased reactive oxygen species production Cell Biology Peroxisome Flow Cytometry medicine.anatomical_structure chemistry Epoxy Compounds RNA Carnitine palmitoyltransferase I Triazenes Reactive Oxygen Species Etomoxir Intracellular Protein Binding Transcription Factors |
| Zdroj: | Journal of Biological Chemistry. 277:10100-10107 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m110321200 |
| Popis: | Generation of reactive oxygen species may contribute to the pathogenesis of diseases involving intracellular lipid accumulation. To explore the mechanisms leading to these pathologies we tested the effects of etomoxir, an inhibitor of carnitine palmitoyltransferase I which contains a fatty acid-derived structure, in C2C12 skeletal muscle cells. Etomoxir treatment for 24 h resulted in a down-regulation of peroxisome proliferator-activated receptor alpha (PPARalpha) mRNA expression, achieving an 87% reduction at 80 microm etomoxir. The mRNA levels of most of the PPARalpha target genes studied were reduced at 100 microm etomoxir. By using several inhibitors of de novo ceramide synthesis and C(2)-ceramide we showed that they were not involved in the effects of etomoxir. Interestingly, the addition of triacsin C, a potent inhibitor of acyl-CoA synthetase, to etomoxir-treated C2C12 skeletal muscle cells did not prevent the down-regulation in PPARalpha mRNA levels, suggesting that the active form of the drug, etomoxir-CoA, was not involved. Given that saturated fatty acids may generate reactive oxygen species (ROS), we determined whether the addition of etomoxir resulted in ROS generation. Etomoxir increased ROS production and the activity of the well known redox transcription factor NF-kappaB. In the presence of the pyrrolidine dithiocarbamate, a potent antioxidant and inhibitor of NF-kappaB activity, etomoxir did not down-regulate PPARalpha mRNA in C2C12 skeletal muscle cells. These results indicate that ROS generation and NF-kappaB activation are responsible for the down-regulation of PPARalpha and may provide a new mechanism by which intracellular lipid accumulation occurs in skeletal muscle cells. |
| Databáze: | OpenAIRE |
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