Magnetic Resonance of Cardiac C13 Flux & Metabolism Rate

Ohio State University, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): The neutral lipid pool of triglyceride (TG) in the heart, once thought to be a static, inactive depot for unused fat, has more recently been recognized to instead be a dynamic pool of esterified long chain fatty acid (LCFA), constantly turning over to provide LCFA as both a ligand for nuclear receptor activation of PPAR-a, with subsequent transcriptional activation of metabolic enzyme expression, and a significant fuel-source for mitochondrial ß-oxidation. The dysregulation of cardiac lipid dynamics is associated with eventual decline in ventricular function in both animal models and humans with obesity or insulin resistance. Linking altered cardiac TG dynamics to contractile performance therefore holds promise for both prognostic indications and identification of disease mechanisms as potential therapeutic targets. Our findings have elucidated both this dynamic nature of cardiac TG and the distinct kinetic components of TG enrichment rates from 13C-LCFA, as observed by dynamic-mode 13C NMR of the rodent heart. These kinetics correspond to either carrier-mediated uptake into the cardiomyocyte or turnover within the intracellular TG pool. Preliminary data demonstrate that two primary dietary LCFA abundant in plasma, palmitate and oleate, induce different TG turnover rates. The proposed research exploits these findings to investigate LCFA effects on intracellular lipid uptake, storage, and utilization dynamics in the intact rat and mouse heart that may determine formation of physiologically active and potentially lipotoxic acyl intermediates, ceramides and diacylglyceride (DAG). Lipid dynamics will be explored in models of altered TG synthase and lipase expression and during diet-induced metabolic stress. Importantly, dynamic-mode 13C NMR of rat hearts will assess lipid dynamics in response to a Western diet that is associated with lipotoxicity and potentially cardiomyopathic. We hypothesize that: 1) Within a physiological mixture of oleate and palmitate, the different affinities of each LCFA for TG synthesis and lipolysis, can be discerned by 13C NMR and these dynamics influence and define formation of DAG and different ceramides; 2) Either oleate-rich or palmitate-rich, normal and Western diets, mediate cardiac lipid dynamics, affecting activation of PPAR-a and acyl-derivative formation; 3) altered TG synthesis or lipolysis can be distinguished within the 13C kinetic profile of TG in the heart. Aim 1 determines competing affinities of oleate and palmitate for TG turnover and low-level acyl derivative formation in rat hearts. Aim 2 determines TG turnover, LCFA oxidation rates, PPAR-a activation, and acyl-derivatives in rat hearts during a Western diet, enriched with either high oleate or high palmitate, and potential effects on cardiac function. Aim 3 assesses specificity of dynamic-mode 13C NMR for TG synthase and lipase activity in transgenic mouse hearts. The overall objectives are to test the specificity of TG 13C-enrichment kinetics for TG esterification and de-esterification and to identify 13C-enrichment kinetics of the 13C enrichment rates that serve as signatures for altered lipid storage dynamics that produce lipotoxic ceramides and DAG during cardiomyopathic metabolic stress.