What is the clinical evidence from this study?

Study design: Other. Population: Cardiac metabolism. Intervention: Cardiac-specific overexpression of PPARalpha (MHC-PPARalpha) vs. Normal mice (nontransgenic). Primary outcome: Palmitoyl turnover within triacylglyceride (micromol/min per gram dry weight) (p=<0.05).

June 4, 2010Open Access

Preferential Oxidation of Triacylglyceride-Derived Fatty Acids in Heart Is Augmented by the Nuclear Receptor PPARα

Q: What are the key findings of this study?

Cardiac-specific overexpression of PPARalpha augmented triacylglyceride turnover 3-fold over nontransgenic hearts (16.2 vs 4.5 micromol/min per gram dry weight, P<0.05).

Key Result

Cardiac-specific overexpression of PPARalpha augmented triacylglyceride turnover 3-fold over nontransgenic hearts (16.2 vs 4.5 micromol/min per gram dry weight, P<0.05).

Structured PICO

Population

Isolated hearts from normal mice (nontransgenic) and mice with cardiac-specific overexpression of PPARalpha (MHC-PPARalpha)

Intervention

Cardiac-specific overexpression of PPARalpha (MHC-PPARalpha)

Comparator

Normal mice (nontransgenic)

Outcome

Palmitoyl turnover within TAG and palmitate oxidation ratessurrogate

Chronic PPARalpha activation in the heart accelerates palmitoyl turnover in triacylglycerides, demonstrating that endogenous lipolysis provides the bulk of long-chain fatty acids for cardiac beta-oxidation.

Main Result

Absolute Event Rate: 16.2% vs 4.5%

p-value: p=<0.05

Abstract

RATIONALE: 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. METHODS AND 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.