Preferential oxidation of triacylglyceride-derived fatty acids in heart is augmented by the nuclear receptor PPARalpha.
BACKGROUND
Long chain fatty acids (LCFAs) are the preferred substrate for energy provision in hearts. However, the contribution of endogenous triacylglyceride (TAG) turnover to LCFA oxidation and the overall dependence of mitochondrial oxidation on endogenous lipid is largely unstudied.


OBJECTIVE
We sought to determine the role of TAG turnover in supporting LCFA oxidation and the influence of the lipid-activated nuclear receptor, proliferator-activated receptor (PPAR)alpha, on this balance.


RESULTS
Palmitoyl turnover within TAG and palmitate oxidation rates were quantified in isolated hearts, from normal mice (nontransgenic) and mice with cardiac-specific overexpression of PPARalpha (MHC-PPARalpha). Turnover of palmitoyl units within TAG, and thus palmitoyl-coenzyme A recycling, in nontransgenic (4.5+/-2.3 micromol/min per gram dry weight) was 3.75-fold faster than palmitate oxidation (1.2+/-0.4). This high rate of palmitoyl unit turnover indicates preferential oxidation of palmitoyl units derived from TAG in normal hearts. PPARalpha overexpression augmented TAG turnover 3-fold over nontransgenic hearts, despite similar fractions of acetyl-coenzyme A synthesis from palmitate and oxygen use at the same workload. Palmitoyl turnover within TAG of MHC-PPARalpha hearts (16.2+/-2.9, P<0.05) was 12.5-fold faster than oxidation (1.3+/-0.2). Elevated TAG turnover in MHC-PPARalpha correlated with increased mRNA for enzymes involved in both TAG synthesis, Gpam (glycerol-3-phosphate acyltransferase, mitochondrial), Dgat1 (diacylglycerol acetyltransferase 1), and Agpat3 (1-acylglycerol-3-phospate O-acyltransferase 3), and lipolysis, Pnliprp1 (pancreatic lipase related protein 1).


CONCLUSIONS
The role of endogenous TAG in supporting beta-oxidation in the normal heart is much more dynamic than previously thought, and lipolysis provides the bulk of LCFA for oxidation. Accelerated palmitoyl turnover in TAG, attributable to chronic PPARalpha activation, results in near requisite oxidation of LCFAs from TAG.
Program in Integrative Cardiac Metabolism, Center for Cardiovascular Research, University of Illinois at Chicago College of Medicine, Chicago, IL 60612, USA.
Natasha H
NH
Banke
Adam R
AR
Wende
Teresa C
TC
Leone
J Michael
JM
O'Donnell
E Dale
ED
Abel
Daniel P
DP
Kelly
E Douglas
ED
Lewandowski
D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000105:Acetyl Coenzyme A / Q000378:metabolism; D000818:Animals; D002316:Cardiotonic Agents / Q000494:pharmacology; D051048:Diacylglycerol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic; D005992:Glycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D006439:Hemodynamics; D007545:Isoproterenol / Q000494:pharmacology; D008049:Lipase / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D019308:Palmitic Acid / Q000378:metabolism*; D010171:Palmitoyl Coenzyme A / Q000378:metabolism; D010477:Perfusion; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014280:Triglycerides / Q000378:metabolism*
D002316:Cardiotonic Agents; D047493:PPAR alpha; D012333:RNA, Messenger; D014280:Triglycerides; D010171:Palmitoyl Coenzyme A; D019308:Palmitic Acid; D000105:Acetyl Coenzyme A; D005992:Glycerol-3-Phosphate O-Acyltransferase; C494882:Dgat1 protein, mouse; D051048:Diacylglycerol O-Acyltransferase; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase; D008049:Lipase; C075987:pancreatic lipase-related protein 1; D007545:Isoproterenol