Magnetic Resonance of Cardiac C13 Flux & Metabolism Rate

心脏 C13 通量的磁共振

• 批准号: 9194522
• 负责人: E DOUGLAS LEWANDOWSKI
• 金额: $ 76.66万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9194522
• 关键词: Address; Adipose tissue; Affect; Affinity; Animal Model; Animals; Carbon Isotopes; Cardiac; Cardiac Myocytes; Cardiac health; Cell Nucleus; Cells; Ceramides; Data; Deltastab; Detection; Diet; Dietary Fats; Diglycerides; Disease; Enzymes; Equilibrium; Esterification; Event; Fatty acid glycerol esters; Fingerprint; Gene Activation; Genetic Transcription; Health; Hearing problem; Heart; Heart Hypertrophy; Human; Insulin Resistance; Kinetics; Knock-out; Left Ventricular Function; Length; Ligands; Link; Lipase; Lipids; Lipolysis; Magnetic Resonance; Mediating; Metabolic; Metabolic stress; Metabolism; Mitochondria; Modeling; Mus; Myocardial; Nature; Nuclear Magnetic Resonance; Nuclear Receptors; Obesity; PPAR alpha; Palmitates; Performance; Perfusion; Peroxisome Proliferator-Activated Receptors; Physiological; Plasma; Process; Production; Protocols documentation; Rattus; Receptor Activation; Research; Rodent; Sarcolemma; Source; Specificity; Testing; Therapeutic; Transcriptional Activation; Transferase; Transgenic Mice; Triglycerides; Ventricular Function; Work; base; diacylglycerol O-acyltransferase; fatty acid oxidation; heart function; heart metabolism; insulin sensitivity; long chain fatty acid; mouse model; overexpression; oxidation; prognostic; research study; response; therapeutic target; uptake; western diet

 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.

 描述（申请人提供）：心脏中的甘油三酯（TG）的中性脂质池，曾经被认为是未使用脂肪的静态、非活性储存库，最近被认为是酯化长链脂肪酸（LCFA）的动态池，其不断翻转以提供LCFA作为PPAR-a的核受体活化的配体，以及随后的代谢酶表达的转录活化，和线粒体β-氧化的重要燃料源。在动物模型和肥胖或胰岛素抵抗的人中，心脏脂质动力学的失调与心室功能的最终下降相关。因此，将改变的心脏TG动力学与收缩性能联系起来，有望作为潜在的治疗靶点，用于预后指征和疾病机制的鉴定。我们的研究结果已经阐明了心脏TG的这种动态性质和TG富集率从13 C-LCFA的不同动力学成分，如通过啮齿动物心脏的动态模式13 C NMR所观察到的。这些动力学对应于载体介导的心肌细胞摄取或细胞内TG库内的周转。初步数据表明，两个主要的饮食LCFA丰富的血浆，棕榈酸和油酸，诱导不同的TG周转率。拟议的研究利用这些发现来研究LCFA对完整大鼠细胞内脂质摄取、储存和利用动力学的影响， 小鼠心脏，可决定生理活性和潜在脂毒性酰基中间体、神经酰胺和二酰基甘油酯（DAG）的形成。脂质动力学将在TG合酶和脂肪酶表达改变的模型中以及在饮食诱导的代谢应激期间进行探索。重要的是，大鼠心脏的动态模式13 C NMR将评估脂质动力学对与脂毒性和潜在心肌病相关的西方饮食的反应。我们假设：1）在油酸酯和棕榈酸酯的生理混合物中，每种LCFA对TG合成和脂解的不同亲和力可以通过13 C NMR辨别，并且这些动力学影响并限定DAG和不同神经酰胺的形成; 2）富含油酸酯或富含棕榈酸酯的正常和西方饮食介导心脏脂质动力学，影响PPAR-a的活化和酰基衍生物的形成; 3）改变的TG合成或脂解可以在心脏中TG的13 C动力学曲线内区分。目的1确定油酸和棕榈酸酯对大鼠心脏TG周转和低水平酰基衍生物形成的竞争亲和力。目的2确定在富含高油酸或高棕榈酸的西方饮食期间大鼠心脏中的TG周转率、LCFA氧化速率、PPAR-a活化和酰基衍生物，以及对心脏功能的潜在影响。目的3评价转基因小鼠心脏TG合成酶和脂肪酶活性的动态模式13 C NMR的特异性。总体目标是测试TG 13 C富集动力学对TG酯化和去酯化的特异性，并鉴定13 C富集速率的13 C富集动力学，所述13 C富集速率用作在心肌病代谢应激期间产生脂毒性神经酰胺和DAG的改变的脂质储存动力学的特征。