title: Acute liver carnitine palmitoyltransferase I overexpression recapitulates reduced palmitate oxidation of cardiac hypertrophy.
abstract: BACKGROUND
  Muscle carnitine palmitoyltransferase I is predominant in the heart, but the liver isoform (liver carnitine palmitoyltransferase I [L-CPT1]) is elevated in hearts with low long chain fatty acid oxidation, such as fetal and hypertrophied hearts.
  
  
  OBJECTIVE
  This work examined the effect of acute L-CPT1 expression on the regulation of palmitate oxidation and energy metabolism in intact functioning rat hearts for comparison with findings in hypertrophied hearts.
  
  
  RESULTS
  L-CPT1 was expressed in vivo in rat hearts by coronary perfusion of Adv.cmv.L-CPT1 (L-CPT1, n=15) vs. phosphate-buffered saline (PBS) infusion (PBS, n=7) or empty virus (empty, n=5). L-CPT1 was elevated 5-fold at 72 hours after Adv.cmv.L-CPT1 infusion (P<0.05), but muscle carnitine palmitoyltransferase I was unaffected. Despite similar tricarboxylic acid cycle rates, palmitate oxidation rates were reduced with L-CPT1 (1.12 ± 0.29 μmol/min per gram of dry weight, mean±SE) vs. PBS (1.6 ± 0.34). Acetyl CoA production from palmitate was reduced with L-CPT1 (69 ± 0.02%; P<0.05; PBS=79 ± 0.01%; empty=81 ± 0.02%), similar to what occurs in hypertrophied hearts, and with no difference in malonyl CoA content. Glucose oxidation was elevated with L-CPT1 (by 60%). Surprisingly, L-CPT1 hearts contained elevated atrial natriuretic peptide, indicating induction of hypertrophic signaling.
  
  
  CONCLUSIONS
  The results link L-CPT1 expression to reduced palmitate oxidation in a nondiseased adult heart, recapitulating the phenotype of reduced long chain fatty acid oxidation in cardiac hypertrophy. The implications are that L-CPT1 expression induces metabolic remodeling hypertrophic signaling and that regulatory factors beyond malonyl CoA in the heart regulate long chain fatty acid oxidation via L-CPT1.
authors.affiliation: Center for Cardiovascular Research, UIC College of Medicine, 909 South Wolcott Ave, MC 801, Chicago, IL 60612, USA. dougl@uic.edu
authors.forename: E Douglas
authors.initials: ED
authors.lastname: Lewandowski
authors.forename: Susan K
authors.initials: SK
authors.lastname: Fischer
authors.forename: Matthew
authors.initials: M
authors.lastname: Fasano
authors.forename: Natasha H
authors.initials: NH
authors.lastname: Banke
authors.forename: Lori A
authors.initials: LA
authors.lastname: Walker
authors.forename: Alda
authors.initials: A
authors.lastname: Huqi
authors.forename: Xuerong
authors.initials: X
authors.lastname: Wang
authors.forename: Gary D
authors.initials: GD
authors.lastname: Lopaschuk
authors.forename: J Michael
authors.initials: JM
authors.lastname: O'Donnell
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D009320:Atrial Natriuretic Factor / Q000235:genetics / Q000378:metabolism; D002262:Carboxy-Lyases / Q000378:metabolism; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D004734:Energy Metabolism; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D005838:Genotype; D008099:Liver / Q000201:enzymology*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008316:Malonyl Coenzyme A / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology*; D010084:Oxidation-Reduction; D019308:Palmitic Acid / Q000378:metabolism*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015854:Up-Regulation
chemical_list: D012333:RNA, Messenger; D019308:Palmitic Acid; D008316:Malonyl Coenzyme A; D009320:Atrial Natriuretic Factor; D002334:Carnitine O-Palmitoyltransferase; D002262:Carboxy-Lyases; C021532:malonyl-CoA decarboxylase; D000103:Acetyl-CoA Carboxylase