title: Peroxisomes contribute to the acylcarnitine production when the carnitine shuttle is deficient.
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.
authors.affiliation: 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.
authors.forename: Sara
authors.initials: S
authors.lastname: Violante
authors.forename: Lodewijk
authors.initials: L
authors.lastname: Ijlst
authors.forename: Heleen
authors.initials: H
authors.lastname: Te Brinke
authors.forename: Janet
authors.initials: J
authors.lastname: Koster
authors.forename: Isabel
authors.initials: I
authors.lastname: Tavares de Almeida
authors.forename: Ronald J A
authors.initials: RJ
authors.lastname: Wanders
authors.forename: Fátima V
authors.initials: FV
authors.lastname: Ventura
authors.forename: Sander M
authors.initials: SM
authors.lastname: Houten
mesh_terms: D002331:Carnitine / Q000031:analogs & derivatives* / Q000378:metabolism*; D002333:Carnitine Acyltransferases / Q000172:deficiency / Q000378:metabolism / Q000502:physiology*; D002334:Carnitine O-Palmitoyltransferase / Q000502:physiology*; D002478:Cells, Cultured; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D007850:Lauric Acids / Q000737:chemistry; D008052:Lipid Metabolism, Inborn Errors / Q000378:metabolism* / Q000473:pathology; D010084:Oxidation-Reduction; D020675:Peroxisomes / Q000378:metabolism*; D012867:Skin / Q000166:cytology / Q000378:metabolism*
chemical_list: D007850:Lauric Acids; C116917:acylcarnitine; C030358:lauric acid; D002333:Carnitine Acyltransferases; D002334:Carnitine O-Palmitoyltransferase; D002331:Carnitine
keywords: 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate; C12:0; CACT; CPT1; CPT2; Carnitine palmitoyltransferase 1; Carnitine palmitoyltransferase 2; Carnitine/acylcarnitine translocase; CrAT; CrOT; Fatty acid β-oxidation; LCFA; MCFA; Medium-chain fatty acids; Mitochondria; POCA; carnitine acetyltranferase; carnitine octanoyltransferase; carnitine palmitoyltranferase 1; carnitine palmitoyltransferase 2; carnitine/acylcarnitine translocase; l-AC; l-aminocarnitine; lauric acid; long-chain fatty acids; medium-chain fatty acids