title: Cardiac peroxisome proliferator-activated receptor-alpha activation causes increased fatty acid oxidation, reducing efficiency and post-ischaemic functional loss.
abstract: OBJECTIVE
  Myocardial fatty acid (FA) oxidation is regulated acutely by the FA supply and chronically at the transcriptional level owing to FA activation of peroxisome proliferator-activated receptor-alpha (PPARalpha). However, in vivo administration of PPARalpha ligands has not been shown to increase cardiac FA oxidation. In this study we have examined the cardiac response to in vivo administration of tetradecylthioacetic acid (TTA, 0.5% w/w added to the diet for 8 days), a PPAR agonist with primarily PPARalpha activity.
  
  
  RESULTS
  Despite the fact that TTA treatment decreased plasma concentrations of lipids [FA and triacylglycerols (TG)], hearts from TTA-treated mice showed increased mRNA expression of PPARalpha target genes. Cardiac substrate utilization, ventricular function, cardiac efficiency, and susceptibility to ischaemia-reperfusion were examined in isolated perfused hearts. In accordance with the mRNA changes, myocardial FA oxidation was increased 2.5-fold with a concomitant reduction in glucose oxidation. This increase in FA oxidation was abolished in PPARalpha-null mice. Thus, it appears that the metabolic effects of TTA on the heart must be owing to a direct stimulatory effect on cardiac PPARalpha. Hearts from TTA-treated mice also showed a marked reduction in cardiac efficiency (because of a two-fold increase in unloaded myocardial oxygen consumption) and decreased recovery of ventricular contractile function following low-flow ischaemia.
  
  
  CONCLUSIONS
  This study for the first time observed that in vivo administration of a synthetic PPARalpha ligand elevated FA oxidation, an effect that was also associated with decreased cardiac efficiency and reduced post-ischaemic functional recovery.
authors.affiliation: Department of Medical Physiology, Institute of Medical Biology, University of Tromsø, Tromsø N-9037, Norway.
authors.forename: Anne D
authors.initials: AD
authors.lastname: Hafstad
authors.forename: Ahmed M
authors.initials: AM
authors.lastname: Khalid
authors.forename: Martin
authors.initials: M
authors.lastname: Hagve
authors.forename: Trine
authors.initials: T
authors.lastname: Lund
authors.forename: Terje S
authors.initials: TS
authors.lastname: Larsen
authors.forename: David L
authors.initials: DL
authors.lastname: Severson
authors.forename: Kieran
authors.initials: K
authors.lastname: Clarke
authors.forename: Rolf K
authors.initials: RK
authors.lastname: Berge
authors.forename: Ellen
authors.initials: E
authors.lastname: Aasum
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004734:Energy Metabolism / Q000187:drug effects; D005227:Fatty Acids / Q000097:blood / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D047493:PPAR alpha / Q000819:agonists* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020127:Recovery of Function; D013440:Sulfides / Q000008:administration & dosage / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood; D016276:Ventricular Function / Q000187:drug effects
chemical_list: D001786:Blood Glucose; D002317:Cardiovascular Agents; D005227:Fatty Acids; D047493:PPAR alpha; D012333:RNA, Messenger; D013440:Sulfides; D014280:Triglycerides; C062078:1-(carboxymethylthio)tetradecane