title: Transgenic expression of fatty acid transport protein 1 in the heart causes lipotoxic cardiomyopathy.
abstract: Evidence is emerging that systemic metabolic disturbances contribute to cardiac myocyte dysfunction and clinically apparent heart failure, independent of associated coronary artery disease. To test the hypothesis that perturbation of lipid homeostasis in cardiomyocytes contributes to cardiac dysfunction, we engineered transgenic mice with cardiac-specific overexpression of fatty acid transport protein 1 (FATP1) using the alpha-myosin heavy chain gene promoter. Two independent transgenic lines demonstrate 4-fold increased myocardial free fatty acid (FFA) uptake that is consistent with the known function of FATP1. Increased FFA uptake in this model likely contributes to early cardiomyocyte FFA accumulation (2-fold increased) and subsequent increased cardiac FFA metabolism (2-fold). By 3 months of age, transgenic mice have echocardiographic evidence of impaired left ventricular filling and biatrial enlargement, but preserved systolic function. Doppler tissue imaging and hemodynamic studies confirm that these mice have predominantly diastolic dysfunction. Furthermore, ambulatory ECG monitoring reveals prolonged QT(c) intervals, reflecting reductions in the densities of repolarizing, voltage-gated K+ currents in ventricular myocytes. Our results show that in the absence of systemic metabolic disturbances, such as diabetes or hyperlipidemia, perturbation of cardiomyocyte lipid homeostasis leads to cardiac dysfunction with pathophysiological findings similar to those in diabetic cardiomyopathy. Moreover, the MHC-FATP model supports a role for FATPs in FFA import into the heart in vivo.
authors.affiliation: Center for Cardiovascular Research, Washington University School of Medicine, St Louis, Mo 63110, USA.
authors.forename: Hsiu-Chiang
authors.initials: HC
authors.lastname: Chiu
authors.forename: Attila
authors.initials: A
authors.lastname: Kovacs
authors.forename: Robert M
authors.initials: RM
authors.lastname: Blanton
authors.forename: Xianlin
authors.initials: X
authors.lastname: Han
authors.forename: Michael
authors.initials: M
authors.lastname: Courtois
authors.forename: Carla J
authors.initials: CJ
authors.lastname: Weinheimer
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Yamada
authors.forename: Sylvain
authors.initials: S
authors.lastname: Brunet
authors.forename: Haodong
authors.initials: H
authors.lastname: Xu
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Nerbonne
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Welch
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Fettig
authors.forename: Terry L
authors.initials: TL
authors.lastname: Sharp
authors.forename: Nandakumar
authors.initials: N
authors.lastname: Sambandam
authors.forename: Krista M
authors.initials: KM
authors.lastname: Olson
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Ory
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
mesh_terms: D000818:Animals; D001692:Biological Transport; D009202:Cardiomyopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D048429:Cell Size; D003971:Diastole; D004562:Electrocardiography; D050612:Fatty Acid Transport Proteins; D005230:Fatty Acids, Nonesterified / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006984:Hypertrophy; D026901:Membrane Transport Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D018408:Patch-Clamp Techniques; D049268:Positron-Emission Tomography; D024642:Potassium Channels, Voltage-Gated / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000502:physiology
chemical_list: D050612:Fatty Acid Transport Proteins; D005230:Fatty Acids, Nonesterified; D026901:Membrane Transport Proteins; D024642:Potassium Channels, Voltage-Gated; D011993:Recombinant Fusion Proteins; C493569:Slc27a1 protein, mouse; C493572:Slc27a4 protein, mouse; D005947:Glucose