title: Fatty acid transport protein 1 (FATP1) localizes in mitochondria in mouse skeletal muscle and regulates lipid and ketone body disposal.
abstract: FATP1 mediates skeletal muscle cell fatty acid import, yet its intracellular localization and metabolic control role are not completely defined. Here, we examine FATP1 localization and metabolic effects of its overexpression in mouse skeletal muscle. The FATP1 protein was detected in mitochondrial and plasma membrane fractions, obtained by differential centrifugation, of mouse gastrocnemius muscle. FATP1 was most abundant in purified mitochondria, and in the outer membrane and soluble intermembrane, but not in the inner membrane plus matrix, enriched subfractions of purified mitochondria. Immunogold electron microscopy localized FATP1-GFP in mitochondria of transfected C2C12 myotubes. FATP1 was overexpressed in gastrocnemius mouse muscle, by adenovirus-mediated delivery of the gene into hindlimb muscles of newborn mice, fed after weaning a chow or high-fat diet. Compared to GFP delivery, FATP1 did not alter body weight, serum fed glucose, insulin and triglyceride levels, and whole-body glucose tolerance, in either diet. However, fatty acid levels were lower and β-hydroxybutyrate levels were higher in FATP1- than GFP-mice, irrespective of diet. Moreover, intramuscular triglyceride content was lower in FATP1- versus GFP-mice regardless of diet, and β-hydroxybutyrate content was unchanged in high-fat-fed mice. Electroporation-mediated FATP1 overexpression enhanced palmitate oxidation to CO2, but not to acid-soluble intermediate metabolites, while CO2 production from β-hydroxybutyrate was inhibited and that from glucose unchanged, in isolated mouse gastrocnemius strips. In summary, FATP1 was localized in mitochondria, in the outer membrane and intermembrane parts, of mouse skeletal muscle, what may be crucial for its metabolic effects. Overexpressed FATP1 enhanced disposal of both systemic fatty acids and intramuscular triglycerides. Consistently, it did not contribute to the high-fat diet-induced metabolic dysregulation. However, FATP1 lead to hyperketonemia, likely secondary to the sparing of ketone body oxidation by the enhanced oxidation of fatty acids.
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Institut de Biomedicina de la UB, Barcelona, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Guitart
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Institut de Biomedicina de la UB, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Osorio-Conles
authors.affiliation: Hospital Sant Joan de Déu, Endocrinology, Esplugues, Barcelona, Spain.
authors.forename: Thais
authors.initials: T
authors.lastname: Pentinat
authors.affiliation: Hospital Sant Joan de Déu, Endocrinology, Esplugues, Barcelona, Spain.
authors.forename: Judith
authors.initials: J
authors.lastname: Cebrià
authors.affiliation: Sección de Errores Congénitos del Metabolismo (IBC), Servicio de Bioquímica y Genética Molecular, Hospital Clínico, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain.
authors.forename: Judit
authors.initials: J
authors.lastname: García-Villoria
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Institut de Biomedicina de la UB, Barcelona, Spain; Institute for Research in Biomedicine, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sala
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Institut de Biomedicina de la UB, Barcelona, Spain; Institute for Research in Biomedicine, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Sebastián
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Institut de Biomedicina de la UB, Barcelona, Spain; Institute for Research in Biomedicine, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Zorzano
authors.affiliation: Sección de Errores Congénitos del Metabolismo (IBC), Servicio de Bioquímica y Genética Molecular, Hospital Clínico, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; CIBER de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Spain.
authors.forename: Antonia
authors.initials: A
authors.lastname: Ribes
authors.affiliation: Hospital Sant Joan de Déu, Endocrinology, Esplugues, Barcelona, Spain.
authors.forename: Josep C
authors.initials: JC
authors.lastname: Jiménez-Chillarón
authors.affiliation: Departament de Patologia i Terapèutica Experimental, UB, Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: García-Martínez
authors.affiliation: Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona (UB), Institut de Biomedicina de la UB, Barcelona, Spain; CIBER de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Spain.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Gómez-Foix
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002460:Cell Line; D015256:Coenzyme A-Transferases / Q000235:genetics; D059305:Diet, High-Fat / Q000009:adverse effects; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006904:Hydroxymethylglutaryl-CoA Synthase / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007657:Ketone Bodies / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D032342:Muscle Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology* / Q000187:drug effects; D010084:Oxidation-Reduction; D010168:Palmitates / Q000378:metabolism; D011494:Protein Kinases / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D050612:Fatty Acid Transport Proteins; D005227:Fatty Acids; D007328:Insulin; D007657:Ketone Bodies; D010168:Palmitates; C493569:Slc27a1 protein, mouse; D014280:Triglycerides; D006904:Hydroxymethylglutaryl-CoA Synthase; D011494:Protein Kinases; C403287:pyruvate dehydrogenase kinase 4; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase; D020155:3-Hydroxybutyric Acid