CPT I overexpression protects L6E9 muscle cells from fatty acid-induced insulin resistance.
Oversupply of lipids to skeletal muscle causes insulin resistance by promoting the accumulation of lipid-derived metabolites that inhibit insulin signaling. In this study, we tested the hypothesis that overexpression of carnitine palmitoyltransferase I (CPT I) could protect myotubes from fatty acid-induced insulin resistance by reducing lipid accumulation in the muscle cell. Incubation of L6E9 myotubes with palmitate caused accumulation of triglycerides, diacylgycerol, and ceramide, produced an activation of PKCtheta and PKCzeta, and blocked insulin-stimulated glucose metabolism, reducing insulin-stimulated PKB activity by 60%. Transduction of L6E9 myotubes with adenoviruses encoding for liver CPT I (LCPT I) wild-type (WT), or a mutant form of LCPT I (LCPT I M593S), which is insensitive to malonyl-CoA, produced a twofold increase in palmitate oxidation when LCPT I activity was increased threefold. LCPT I WT and LCPT I M593S-overexpressing L6E9 myotubes showed normal insulin-stimulated glucose metabolism and an improvement in PKB activity when pretreated with palmitate. Moreover, LCPT I WT- and LCPT I M593S-transduced L6E9 myotubes were protected against the palmitate-induced accumulation of diacylglycerol and ceramide and PKCtheta and -zeta activation. These results suggest that LCPT I overexpression protects L6E9 myotubes from fatty acid-induced insulin resistance by inhibiting both the accumulation of lipid metabolites and the activation of PKCtheta and PKCzeta.
Sebastián
David
D
Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, Diagonal 643, E-08028, Spain.
Herrero
Laura
L
Serra
Dolors
D
Asins
Guillermina
G
Hegardt
Fausto G
FG
D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism / Q000494:pharmacology*; D007333:Insulin Resistance / Q000235:genetics; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000201:enzymology; D008316:Malonyl Coenzyme A / Q000494:pharmacology; D032342:Muscle Cells / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D014162:Transfection
D005227:Fatty Acids; D008316:Malonyl Coenzyme A; D002334:Carnitine O-Palmitoyltransferase; D011493:Protein Kinase C