Abstract 9496: Multiphasic Triacylglycerol Dynamics in the Intact Heart During Acute In Vivo Overexpression of CD36

Abstract

The cardiac triacylglycerol (TAG) pool is a dynamic buffer for the intracellular availability of long chain fatty acid (LCFA), a critically important source of nuclear receptor ligand and oxidative fuel for the beating heart. In addition, the TAG pool prevents the accumulation of potentially toxic LCFA derivatives. However, specific kinetics of LCFA incorporation into TAG in the intact, beating heart are largely uncharacterized, and the mechanisms linking uptake and storage dynamics have until now remained elusive. This work examines TAG dynamics in the intact rat heart, under normal conditions and in response to acute, gene expression-induced changes in in vivo protein-mediated lipid uptake. Dynamic mode 13C NMR of beating rat hearts elucidated multiple kinetic processes in 13C-palmitate incorporation into TAG: an initial saturable exponential component and a slower linear rate. While previous work indicates the linear component to reflect TAG turnover, we hypothesized the saturable exponential to reflect transport of LCFA across the sarcolemma. Thus, we overexpressed the LCFA transporter, CD36 through cardiac-specific adenoviral infection (adv.CD36) in vivo. Within 72 hours, CD36 expression was increased 40% in intact hearts, accelerating the exponential phase (highlighted in Figure 1) with a 60% reduction in the time constant relative to PBS infused hearts (adv.CD36: 1.29±0.24, PBS: 3.18±0.53 min, n=5, p<0.05). CD36 overexpression also increased TAG turnover rates and the corresponding expression of key a TAG synthase, DGAT1, and lipase, ATGL. The results demonstrate coupling LCFA uptake across the sarcolemma to intracellular TAG dynamics and coordination of these events by reciprocal control of gene expression in the heart. Thus, a model system of reciprocal regulation between altered LCFA uptake, and TAG synthesis / lipolysis is elucidated that buffers potentially reactive free fatty acids while maintaining ligands and high energy fuel capacity.