Mechanisms of fatty acid uptake by cardiac muscle

描述（由申请人提供）： 递送至组织的脂肪酸可源自三个来源：1）通过内皮结合脂蛋白脂肪酶（LpL）水解脂蛋白甘油三酯产生的脂肪酸，2）与白蛋白相关的循环脂肪酸，3）作为脂蛋白中未水解甘油三酯的组分的脂肪酸。这项提案将重点关注脂肪酸通常是如何被心脏积累的，以及多余的脂肪如何导致心脏功能障碍。这类似于患有脂毒性心肌病的肥胖模型中出现的心脏功能障碍。这两个具体目标将评估与心肌细胞相关的甘油三酯脂解减少或LpL增加的心脏中的脂质摄取和心脏功能。目的1将确定局部脂肪分解在心脏摄取脂肪酸中的作用。LpL将被抑制或从其内皮结合位点解离，或者将研究心肌细胞LpL表达缺陷的遗传改变小鼠。 我们的初步结果表明，LpL是心脏摄取TG的中心，其损失可能会改变其他热量来源的代谢。使用新创建的Floxed LpL小鼠，我们将特异性地从心肌细胞中消除LpL，并评估脂解的慢性损失对心脏能量学的影响。目的2是研究不能从细胞上分离并转移到内皮表面的脂蛋白L是否介导组织脂质。为了做到这一点，我们将研究在心肌细胞中表达GPI锚定LpL的转基因小鼠的脂质摄取。我们的初步结果表明，这些小鼠发展为心肌病和过量的脂质积累，并过早死亡。心脏功能的缺陷将被详细研究，并提出使用遗传杂交、饮食和药物来纠正它的方法。这两个目标都包括研究心脏功能、底物氧化和基因表达的实验。我们的总体目标是了解心脏如何从脂肪中获得能量，它如何补偿脂肪摄取的缺陷，以及多余的脂肪如何导致心脏功能障碍和过早死亡。

DESCRIPTION (provided by applicant): Fatty acids delivered to tissues may be derived from three sources: 1) fatty acids generated by hydrolysis of lipoprotein triglyceride by endothelial bound lipoprotein lipase (LpL), 2) fatty acids circulating associated with albumin, 3) fatty acids that are a component of unhydrolyzed triglyceride in lipoproteins. This proposal will focus on how fatty acids are normally accumulated by the heart and how excess fat leads to cardiac dysfunction. This is analogous to the cardiac dysfunction that is seen in models of obesity that have lipotoxic cardiomyopathy. The two specific aims will assess lipid uptake and cardiac function in hearts that have reduced triglyceride lipolysis or increased LpL associated with cardiomyocytes. Aim 1 will determine the role of localized lipolysis in cardiac uptake of fatty acids. LpL will be inhibited or dissociated from its endothelial binding site, or genetically altered mice that have are defective in cardiomyocyte expression of LpL will be studied. Our Preliminary Results suggest that LpL is central to cardiac uptake of TG and its loss is likely to alter the metabolism of other caloric sources. Using newly created Floxed LpL mice we will specifically eliminate LpL from the cardiomycyte and assess the effect of chronic loss of lipolysis on heart energetics. Aim 2 includes experiments to study whether LpL that is unable to dissociate from the cells and transfer to the endothelial surface mediates tissue lipid. To do this, we will study lipid uptake in transgenic mice that express GPI-anchored LpL in cardiomyocytes. Our Preliminary Results show that these mice develop a cardiomypathy and excess lipid accumulation and have premature death. The defect in heart function will be studied in detail and methods to correct it using genetic crosses, diets and drugs are proposed. Both aims include experiments to study cardiac function, substrate oxidation, and gene expression. Our overall objective is to understand how the heart derived energy from fat, how it compensates for a defect in fat uptake, and how excess fat leads to cardiac dysfunction and premature death.