A. Cabrero, M. Alegret, R. Sánchez
Mar 22, 2002
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Journal
The Journal of Biological Chemistry
Abstract
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 α (PPARα) mRNA expression, achieving an 87% reduction at 80 μm etomoxir. The mRNA levels of most of the PPARα target genes studied were reduced at 100 μm etomoxir. By using several inhibitors of de novo ceramide synthesis and C2-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 PPARα 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-κB. In the presence of the pyrrolidine dithiocarbamate, a potent antioxidant and inhibitor of NF-κB activity, etomoxir did not down-regulate PPARα mRNA in C2C12 skeletal muscle cells. These results indicate that ROS generation and NF-κB activation are responsible for the down-regulation of PPARα and may provide a new mechanism by which intracellular lipid accumulation occurs in skeletal muscle cells.