Fatty acids are a major energy source for skeletal muscle. They are transported into the cell via a protein-mediated mechanism, involving fatty acid translocase/CD36 (FAT/ CD36), plasma-membrane-associated fatty acid binding protein, and fatty acid transport protein (FATP1-6)

Journal of Lipid Research Volume 50, 2009 1789 Copyright © 2009 by the American Society for Biochemistry and Molecular Biology, Inc. Fatty acids are a major energy source for skeletal muscle. They are transported into the cell via a protein-mediated mechanism, involving fatty acid translocase/CD36 (FAT/ CD36), plasma-membrane-associated fatty acid binding protein, and fatty acid transport protein (FATP1-6) ( 1 ). Once inside the cell, fatty acids can be esterifi ed, metabolized to lipid second messengers, such as leukotrienes and eicosanoids, or -oxidized in the mitochondrion. The fi rst step of the oxidative pathway is the transport of fatty acids into the mitochondrial matrix. This step is controlled by the carnitine palmitoyltransferase (CPT) system, consisting of CPT1, acylcarnitine translocase, and CPT2 ( 2 ). CPT1 catalyzes the conversion of long-chain fatty acylCoAs to acylcarnitines in the presence of L -carnitine and is the rate-limiting step in the transport of long-chain fatty acids (LCFAs) from the cytoplasm to the mitochondrial matrix, where they undergo -oxidation. CPT1 is tightly regulated by its physiological inhibitor malonyl-CoA. This regulation allows CPT1 to signal the availability of lipid and carbohydrate fuels to the cell ( 2 ). Mammalian tissues express three isoforms: CPT1A (liver), CPT1B (muscle and heart), and CPT1C (brain) ( 3–5 ). Owing to the metabolic peculiarities of muscle, the regulation of CPT1B by malonyl-CoA is more complex than that of CPT1A in liver. The regulation of muscle CPT1 by malonylCoA cannot fully explain changes in mitochondrial fatty acid import. Thus, malonyl-CoA is not responsible for the increase in fatty acid oxidation during the transition from low to moderate aerobic exercise or for the decrease in fatty Abstract Carnitine palmitoyltransferase 1 (CPT1) catalyzes the fi rst step in long-chain fatty acid import into mitochondria, and it is believed to be rate limiting for  -oxidation of fatty acids. However, in muscle, other proteins may collaborate with CPT1. Fatty acid translocase/CD36 (FAT/ CD36) may interact with CPT1 and contribute to fatty acid import into mitochondria in muscle. Here, we demonstrate that another membrane-bound fatty acid binding protein, fatty acid transport protein 1 (FATP1), collaborates with CPT1 for fatty acid import into mitochondria. Overexpression of FATP1 using adenovirus in L6E9 myotubes increased both fatty acid oxidation and palmitate esterifi cation into triacylglycerides. Moreover, immunocytochemistry assays in transfected L6E9 myotubes showed that FATP1 was present in mitochondria and coimmunoprecipitated with CPT1 in L6E9 myotubes and rat skeletal muscle in vivo. The cooverexpression of FATP1 and CPT1 also enhanced mitochondrial fatty acid oxidation, similar to the cooverexpression of FAT/CD36 and CPT1. However, etomoxir, an irreversible inhibitor of CPT1, blocked all these effects. These data reveal that FATP1, like FAT/CD36, is associated with mitochondria and has a role in mitochondrial oxidation of fatty acids. —Sebastián, D., M. Guitart, C. García-Martínez, C. Mauvezin, J. M. Orellana-Gavaldà, D. Serra, A. M. GómezFoix, F. G. Hegardt, and G. Asins. Novel role of FATP1 in mitochondrial fatty acid oxidation in skeletal muscle cells. J. Lipid Res. 2009. 50: 1789–1799.