title: Very-long-chain acyl-coenzyme a dehydrogenase deficiency in mice.
abstract: Fatty acid oxidation (FAO) defects are inborn errors of metabolism clinically associated with cardiomyopathy and sudden infant death syndrome (SIDS). FAO disorders often present in infancy with myocardial dysfunction and arrhythmias after exposure to stresses such as fasting, exercise, or intercurrent viral illness. It is uncertain whether the heart, in the absence of stress, is normal. We generated very-long-chain acyl-coenzyme A dehydrogenase (VLCAD)-deficient mice by homologous recombination to define the onset and molecular mechanism of myocardial disease. We found that VLCAD-deficient hearts have microvesicular lipid accumulation, marked mitochondrial proliferation, and demonstrated facilitated induction of polymorphic ventricular tachycardia, without antecedent stress. The expression of acyl-CoA synthase (ACS1), adipophilin, activator protein 2, cytochrome c, and the peroxisome proliferator activated receptor gamma coactivator-1 were increased immediately after birth, preceding overt histological lipidosis, whereas ACS1 expression was markedly downregulated in the adult heart. We conclude that mice with VLCAD deficiency have altered expression of a variety of genes in the fatty acid metabolic pathway from birth, reflecting metabolic feedback circuits, with progression to ultrastructural and physiological correlates of the associated human disease in the absence of stress.
authors.affiliation: Division of Cardiology, Department of Pediatrics, Vanderbilt University School of Medicine, Nashville, TN, USA. vernat.exil@vanderbilt.edu
authors.forename: Vernat J
authors.initials: VJ
authors.lastname: Exil
authors.forename: Richard L
authors.initials: RL
authors.lastname: Roberts
authors.forename: Harold
authors.initials: H
authors.lastname: Sims
authors.forename: Jacquelin E
authors.initials: JE
authors.lastname: McLaughlin
authors.forename: Robert A
authors.initials: RA
authors.lastname: Malkin
authors.forename: Carla D
authors.initials: CD
authors.lastname: Gardner
authors.forename: Gemin
authors.initials: G
authors.lastname: Ni
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Rottman
authors.forename: Arnold W
authors.initials: AW
authors.lastname: Strauss
mesh_terms: D044942:Acyl-CoA Dehydrogenase, Long-Chain; D000818:Animals; D000831:Animals, Newborn; D001145:Arrhythmias, Cardiac / Q000503:physiopathology; D004452:Echocardiography; D044943:Fatty Acid Desaturases / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006339:Heart Rate / Q000187:drug effects / Q000502:physiology; D006352:Heart Ventricles / Q000201:enzymology / Q000503:physiopathology; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D018482:Muscle, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics; D016276:Ventricular Function
chemical_list: D012333:RNA, Messenger; D014157:Transcription Factors; C111264:peroxisome-proliferator-activated receptor-gamma coactivator-1; D044943:Fatty Acid Desaturases; D044942:Acyl-CoA Dehydrogenase, Long-Chain; D007545:Isoproterenol