title: Increased mitochondrial fatty acid oxidation is sufficient to protect skeletal muscle cells from palmitate-induced apoptosis.
abstract: The mechanisms underlying the protective effect of monounsaturated fatty acids (e.g. oleate) against the lipotoxic action of saturated fatty acids (e.g. palmitate) in skeletal muscle cells remain poorly understood. This study aimed to examine the role of mitochondrial long-chain fatty acid (LCFA) oxidation in mediating oleate's protective effect against palmitate-induced lipotoxicity. CPT1 (carnitine palmitoyltransferase 1), which is the key regulatory enzyme of mitochondrial LCFA oxidation, is inhibited by malonyl-CoA, an intermediate of lipogenesis. We showed that expression of a mutant form of CPT1 (CPT1mt), which is active but insensitive to malonyl-CoA inhibition, in C2C12 myotubes led to increased LCFA oxidation flux even in the presence of high concentrations of glucose and insulin. Furthermore, similar to preincubation with oleate, CPT1mt expression protected muscle cells from palmitate-induced apoptosis and insulin resistance by decreasing the content of deleterious palmitate derivates (i.e. diacylglycerols and ceramides). Oleate preincubation exerted its protective effect by two mechanisms: (i) in contrast to CPT1mt expression, oleate preincubation increased the channeling of palmitate toward triglycerides, as a result of enhanced diacylglycerol acyltransferase 2 expression, and (ii) oleate preincubation promoted palmitate oxidation through increasing CPT1 expression and modulating the activities of acetyl-CoA carboxylase and AMP-activated protein kinase. In conclusion, we demonstrated that targeting mitochondrial LCFA oxidation via CPT1mt expression leads to the same protective effect as oleate preincubation, providing strong evidence that redirecting palmitate metabolism toward oxidation is sufficient to protect against palmitate-induced lipotoxicity.
authors.affiliation: Institut Cochin, Université Paris Descartes UMRS1016, CNRS (UMR 8104), 75014 Paris, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Henique
authors.forename: Abdelhak
authors.initials: A
authors.lastname: Mansouri
authors.forename: Gwladys
authors.initials: G
authors.lastname: Fumey
authors.forename: Veronique
authors.initials: V
authors.lastname: Lenoir
authors.forename: Jean
authors.initials: J
authors.lastname: Girard
authors.forename: Frederic
authors.initials: F
authors.lastname: Bouillaud
authors.forename: Carina
authors.initials: C
authors.lastname: Prip-Buus
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cohen
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000473:pathology*; D019301:Oleic Acid / Q000737:chemistry* / Q000378:metabolism; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D010168:Palmitates / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D010168:Palmitates; D012333:RNA, Messenger; D019301:Oleic Acid; D002334:Carnitine O-Palmitoyltransferase