Abstract 3721: In vivo Delivery and Overexpression of LCPT1 in Rat Hearts Recapitulates the Hypertrophic Phenotype of Reduced Palmitate Oxidation
Reduced long chain fatty acid (LCFA) oxidation in cardiac hypertrophy is associated with an isoform shift of carnitine palmitoyltransferse I (CPT1). While muscle (M) CPT1 is predominant in heart, the liver (L) isoform is upregulated in hypertrophy. Less responsive to malonyl CoA inhibition, LCPT1 is elevated in heart models of low LCFA oxidation, such as neonatal and hypertrophied hearts. Although suggested as an adaptation to maintain LCFA oxidation, LCPT1 has never been associated with increased LCFA oxidation in cardiomyocytes. Therefore, we examined the consequences of LCPT1 expression on LCFA oxidation in rat heart. LCPT1 was expressed in in vivo rat hearts by coronary perfusion of Adv.cmv.LCPT1 (LCPT1, n=15) for comparison to rats with PBS infusion (PBS, n=5). Hearts were excised 3 days post-infusion and perfused with 0.4 mM [2,4,6,8,10,12,14,16] 13C palmitate + 10 mM glucose in a NMR magnet for dynamic 13C NMR, and then frozen for in vitro analysis. LCPT1 was low in PBS, but elevated 4.4 fold in LCPT1 hearts (P<0.05). MCPT1 levels were unaffected by LCPT1. Despite similar TCA cycle rates, flux of palmitate through CPT1 was lower in LCPT1 (1.12±0.24 micromole/min/g dw, mean±SD) than PBS (1.6±0.41). LCPT1 reduced the oxidation of palmitate versus other substrates by 12% compared to PBS: LCPT1=0.79±0.01; PBS=0.69±0.02, P<0.05), a reduction similar to the reported 12% drop in hypertrophied rat hearts. Unlike hypertrophy, non-diseased LCPT1 hearts, showed no changes in anaplerosis and cardiac function. These data are the first to link LCPT1 expression to reduced palmitate oxidation in a non-diseased, adult heart, recapitulating the phenotype of reduced LCFA oxidation in cardiac hypertrophy. The implications are that LCPT1 expression is responsible for reduced LCFA oxidation in cardiac hypertrophy and that additional regulatory factors beyond malonyl-CoA determine LCFA oxidation via the L isoform of CPT1.