title: Mitochondrial remodeling in mice with cardiomyocyte-specific lipid overload.
abstract: BACKGROUND
  Obesity leads to metabolic heart disease (MHD) that is associated with a pathologic increase in myocardial fatty acid (FA) uptake and impairment of mitochondrial function. The mechanism of mitochondrial dysfunction in MHD, which results in oxidant production and decreased energetics, is poorly understood but may be related to excess FAs. Determining the effects of cardiac FA excess on mitochondria can be hindered by the systemic sequelae of obesity. Mice with cardiomyocyte-specific overexpression of the fatty acid transport protein FATP1 have increased cardiomyocyte FA uptake and develop MHD in the absence of systemic lipotoxicity, obesity or diabetes. We utilized this model to assess 1) the effect of cardiomyocyte lipid accumulation on mitochondrial structure and energetic function and 2) the role of lipid-driven transcriptional regulation, signaling, toxic metabolite accumulation, and mitochondrial oxidative stress in lipid-induced MHD.
  
  
  METHODS
  Cardiac lipid species, lipid-dependent signaling, and mitochondrial structure/function were examined from FATP1 mice. Cardiac structure and function were assessed in mice overexpressing both FATP1 and mitochondrial-targeted catalase.
  
  
  RESULTS
  FATP1 hearts exhibited a net increase (+12%) in diacylglycerol, with increases in several very long-chain diacylglycerol species (+160-212%, p<0.001) and no change in ceramide, sphingomyelin, or acylcarnitine content. This was associated with an increase in phosphorylation of PKCα and PKCδ, and a decrease in phosphorylation of AKT and expression of CREB, PGC1α, PPARα and the mitochondrial fusion genes MFN1, MFN2 and OPA1. FATP1 overexpression also led to marked decreases in mitochondrial size (-49%, p<0.01), complex II-driven respiration (-28.6%, p<0.05), activity of isolated complex II (-62%, p=0.05), and expression of complex II subunit B (SDHB) (-60% and -31%, p<0.01) in the absence of change in ATP synthesis. Hydrogen peroxide production was not increased in FATP1 mitochondria, and cardiac hypertrophy and diastolic dysfunction were not attenuated by overexpression of catalase in mitochondria in FATP1 mice.
  
  
  CONCLUSIONS
  Excessive delivery of FAs to the cardiac myocyte in the absence of systemic disorders leads to activation of lipid-driven signaling and remodeling of mitochondrial structure and function.
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Aly
authors.initials: A
authors.lastname: Elezaby
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sverdlov
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Vivian H
authors.initials: VH
authors.lastname: Tu
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Kanupriya
authors.initials: K
authors.lastname: Soni
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Ivan
authors.initials: I
authors.lastname: Luptak
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Fuzhong
authors.initials: F
authors.lastname: Qin
authors.affiliation: Boston University School of Medicine, Obesity and Nutrition Section, Department of Medicine, Boston, MA 02118, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Liesa
authors.affiliation: Boston University School of Medicine, Obesity and Nutrition Section, Department of Medicine, Boston, MA 02118, United States.
authors.forename: Orian S
authors.initials: OS
authors.lastname: Shirihai
authors.affiliation: Washington University School of Medicine, Diabetic Cardiovascular Disease Center, St Louis, MO 63110, United States.
authors.forename: Jamie
authors.initials: J
authors.lastname: Rimer
authors.affiliation: Washington University School of Medicine, Diabetic Cardiovascular Disease Center, St Louis, MO 63110, United States.
authors.forename: Jean E
authors.initials: JE
authors.lastname: Schaffer
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States.
authors.forename: Wilson S
authors.initials: WS
authors.lastname: Colucci
authors.affiliation: Boston University School of Medicine, Whitaker Cardiovascular Institute, Section of Cardiovascular Medicine, Boston, MA 02118, United States. Electronic address: ejmiller@bu.edu.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Miller
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002331:Carnitine / Q000031:analogs & derivatives / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D002518:Ceramides / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D042963:Electron Transport Complex II / Q000378:metabolism; D050612:Fatty Acid Transport Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006861:Hydrogen Peroxide / Q000378:metabolism; D008055:Lipids / Q000009:adverse effects*; D051379:Mice; D008929:Mitochondria, Heart / Q000378:metabolism* / Q000648:ultrastructure; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D032383:Myocytes, Cardiac / Q000378:metabolism*; D009928:Organ Specificity; D010101:Oxygen Consumption; D047493:PPAR alpha / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013109:Sphingomyelins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D002518:Ceramides; D017362:Cyclic AMP Response Element-Binding Protein; D004075:Diglycerides; D050612:Fatty Acid Transport Proteins; D008055:Lipids; D047493:PPAR alpha; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D012333:RNA, Messenger; C493569:Slc27a1 protein, mouse; D013109:Sphingomyelins; D014157:Transcription Factors; C116917:acylcarnitine; D000255:Adenosine Triphosphate; D006861:Hydrogen Peroxide; D002374:Catalase; D042963:Electron Transport Complex II; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D002331:Carnitine
keywords: Lipid excess; Metabolic heart disease; Mitochondria; Obesity