Abstract 5382: Accelerated Triacylglyceride Dynamics Induced by Cardiac PPARα Overexpression are Potentiated by Adrenergic Stress to Reveal Increased Reliance on Endogenous Lipid Stores

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is a nuclear receptor involved in regulating fatty acid utilization and is implicated in the pathogenesis of diabetic cardiomyopathy. However, the involvement of PPARα in the specific utilization of endogenous lipid stores and the consequences for triacylglyceride (TAG) formation in the cardiomyocyte remain unknown. Thus, we examined TAG dynamics in isolated perfused hearts of transgenic mice exhibiting cardiac-specific over-expression of PPARα under normal and stressed conditions. Hearts from MHC-PPARα overexpressing mice (PPAR) and non-transgenic (NTG) littermates were isolated and retrogradely perfused in a 14.1 T NMR magnet with buffer containing 0.4 mM [2,4,6,8,10,12,14,16]-13C palmitate, as a source of long chain fatty acids (LCFA) + 10 mM glucose. Dynamic 13C NMR observations of the beating heart and endpoint mass spectrometry provided TAG turnover at baseline work (PPAR, n=12; NTG, n=7) and adrenergic stress (10–7 M isoproterenol, ISO) (PPAR ISO, n=5; NTG ISO, n=6). ISO elevated rate pressure product by 27% and 25% in NTG and PPAR, respectively (P<0.05). At baseline workloads, PPAR contained 45% more TAG than NTG (P <0.05) and TAG turnover was elevated in PPARα mice by 191% over NTG. ISO did not affect TAG content in either NTG or PPAR. However, ISO induced large increases in TAG turnover in PPAR from 1454 ± 232 to 2532 ±334 nanomoles/mg prot/min (P<0.05), without affecting TAG turnover in NTG. The near doubling of TAG turnover with elevated content in MHC-PPARα hearts indicates upregulated baseline lipid metabolism via both utilization and storage pathways. Surprisingly, the adrenergic stress response potentiates the already elevated TAG dynamics in MHC-PPARα hearts, indicating persistence in matching LCFA storage rates to maintain this elevated endogenous lipid pool. Elevated TAG content in PPAR was maintained during ISO, despite increased reliance on endogenous TAG to meet the increased energy demand as compared to NTG. Therefore, activation of LCFA oxidation enzymes by PPARα is coupled in complementary fashion to the activation of LCFA storage kinetics, suggesting an expanded role for PPARα in the induction of TAG turnover.