Magnetic Resonance of Cardiac C13 Flux & Metabolism Rate

心脏 C13 通量的磁共振

基本信息

批准号：
8906110
负责人：
E DOUGLAS LEWANDOWSKI
金额：
$ 62.74万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2015-12-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8906110
关键词：
1,2-diacylglycerol Address Adipose tissue Affect Affinity Animal Model Animals Carbon Isotopes Cardiac Cardiac Myocytes 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 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 public health relevance research study response therapeutic target uptake western diet

项目摘要

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（由申请人提供）：心脏中甘油三酯（TG）的中性脂质池曾经被认为是未使用的脂肪的静态、非活性仓库，最近被认为是酯化长链脂肪酸的动态池（LCFA），不断转变以提供 LCFA 作为 PPAR-a 核受体激活的配体，随后代谢酶表达的转录激活，以及线粒体的重要燃料来源β-氧化。在肥胖或胰岛素抵抗的动物模型和人类中，心脏脂质动态的失调与心室功能的最终下降有关，因此将改变的心脏 TG 动态与收缩性能联系起来，为预后指标和疾病机制的识别带来了希望。作为潜在的治疗靶点，我们的研究结果阐明了心脏 TG 的这种动态性质以及 13C-LCFA 的 TG 富集率的独特动力学成分，如通过动态模式 13C NMR 观察到的。这些动力学与载体介导的心肌细胞摄取或细胞内 TG 池内的周转相对应，初步数据表明，血浆中富含的两种主要膳食 LCFA（棕榈酸酯和油酸酯）可诱导不同的 TG 周转率。研究结果调查了 LCFA 对完整大鼠和细胞内脂质摄取、储存和利用动态的影响小鼠心脏可能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，将在改变的 TG 合酶和脂肪酶表达模型以及饮食诱导的代谢应激期间探索脂质动力学。大鼠心脏的核磁共振将评估与脂毒性和潜在的心肌病相关的西方饮食的脂质动态，我们解决了这个问题：1）在生理混合物中。油酸和棕榈酸，每种 LCFA 对 TG 合成和脂肪分解的不同亲和力，可以通过 13C NMR 辨别，这些动力学影响和定义 DAG 和不同神经酰胺的形成 2) 富含油酸或富含棕榈酸，正常和西方饮食，介导心脏脂质动力学，影响 PPAR-a 的激活和酰基衍生物的形成 3) 可以在 TG 合成或脂肪分解中区分；心脏中 TG 的 13C 动力学曲线确定油酸和棕榈酸对大鼠心脏中 TG 周转和低水平酰基衍生物形成的竞争亲和力。西方饮食期间大鼠心脏中富含高油酸或高棕榈酸的衍生物，以及对心脏功能的潜在影响。评估转基因小鼠心脏中 TG 合酶和脂肪酶活性的动态模式 13C NMR 的特异性总体目标是测试 TG 酯化和脱酯化的 TG 13C 富集动力学的特异性，并确定 13C 的 13C 富集动力学。富集率作为改变脂质储存动力学的标志，在心肌病代谢应激期间产生脂毒性神经酰胺和 DAG。