Peroxisomes contribute to the acylcarnitine production when the carnitine shuttle is deficient |
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Authors: | Sara Violante,Lodewijk IJlst,Heleen te Brinke,Janet Koster,Isabel Tavares de Almeida,Ronald J.A. Wanders,Fá tima V. Ventura,Sander M. Houten |
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Affiliation: | 1. Metabolism and Genetics Group, Research Institute for Medicines and Pharmaceutical Sciences, iMed.UL, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;2. Department of Biochemistry and Human Biology, Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisboa, Portugal;3. Laboratory Genetic Metabolic Diseases, Department Clinical Chemistry and Pediatrics, University of Amsterdam, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands |
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Abstract: | Fatty acid β-oxidation may occur in both mitochondria and peroxisomes. While peroxisomes oxidize specific carboxylic acids such as very long-chain fatty acids, branched-chain fatty acids, bile acids, and fatty dicarboxylic acids, mitochondria oxidize long-, medium-, and short-chain fatty acids. Oxidation of long-chain substrates requires the carnitine shuttle for mitochondrial access but medium-chain fatty acid oxidation is generally considered carnitine-independent. Using control and carnitine palmitoyltransferase 2 (CPT2)- and carnitine/acylcarnitine translocase (CACT)-deficient human fibroblasts, we investigated the oxidation of lauric acid (C12:0). Measurement of the acylcarnitine profile in the extracellular medium revealed significantly elevated levels of extracellular C10- and C12-carnitine in CPT2- and CACT-deficient fibroblasts. The accumulation of C12-carnitine indicates that lauric acid also uses the carnitine shuttle to access mitochondria. Moreover, the accumulation of extracellular C10-carnitine in CPT2- and CACT-deficient cells suggests an extramitochondrial pathway for the oxidation of lauric acid. Indeed, in the absence of peroxisomes C10-carnitine is not produced, proving that this intermediate is a product of peroxisomal β-oxidation. In conclusion, when the carnitine shuttle is impaired lauric acid is partly oxidized in peroxisomes. This peroxisomal oxidation could be a compensatory mechanism to metabolize straight medium- and long-chain fatty acids, especially in cases of mitochondrial fatty acid β-oxidation deficiency or overload. |
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Keywords: | C12:0, lauric acid CACT, carnitine/acylcarnitine translocase CPT1, carnitine palmitoyltranferase 1 CPT2, carnitine palmitoyltransferase 2 CrAT, carnitine acetyltranferase CrOT, carnitine octanoyltransferase l-AC, l-aminocarnitine LCFA, long-chain fatty acids MCFA, medium-chain fatty acids POCA, 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate |
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