Mechanisms of Fatty Acid Uptake by Cardiac Muscle

摘要 心脏是利用脂肪酸(FA)最多的器官，心力衰竭(HF)几乎总是 与心脏脂质代谢改变有关：糖尿病和肥胖增加FA的使用；心脏衰竭 减少了FA的氧化(粮农组织)。在后载较大的情况下，但在其他情况下，需要使用FA 过量的脂肪摄取会导致心力衰竭，这个过程有时被称为脂毒性。本项目的重点是如何 Fas是由心脏获得并用于能量使用的，这就是为什么当过多的脂肪时会产生毒性 积累起来。我们研究了甘油三酯脂解酶脂蛋白脂酶(LPL)和脂肪酸的作用。 非酯化脂肪酸和脂蛋白来源脂肪酸运动中的分化转运体簇(CD)36 通过将每种蛋白质的基因漂浮到心脏中。我们发现内皮细胞CD36是一种主要的调节因子 心脏对FA的急性摄取。尽管内皮细胞或心肌细胞中CD36的缺失会导致 为了显著减少禁食期间脂滴(LD)的堆积，只有内皮细胞的缺失才会导致 调节胰岛素信号和葡萄糖摄取的基因的mRNA水平增加。因此，CD36操作的不同之处 这两种细胞类型。这次修订有三个目标，重点是心脏FA摄取和LD的形成。在AIM 1，我们将确定CD36的变化如何影响脂质摄取和LD的形成。Aim 2将比较 低密度脂蛋白的组成与甘油三酯的毒性和生理储存有关。目标3将测试心力衰竭 由于脂肪甘油三酯脂肪酶(ATGL)缺乏，人类心力衰竭的原因之一，可以通过CD36缺失来纠正 或者是抑制。我们研究的总体目标是确定心脏摄取FA所需的途径，以 了解储存的甘油三酯的哪种形式是否有益，并确定治疗脂毒性的方法 心脏病。

Abstract The heart is the organ with the greatest fatty acid (FA) utilization and heart failure (HF) is almost always associated with alterations in cardiac lipid metabolism: diabetes and obesity increase FA use; failing hearts have reduced FA oxidation (FAO). FAs are needed in conditions of greater afterload, but in other situations excess lipid uptake leads to HF, a process sometimes referred to as lipotoxicity. This project focuses on how FAs are acquired by the heart and used for energy use, and why toxicity occurs when excess lipid accumulates. We have studied the roles of the triglyceride lipolysis enzyme lipoprotein lipase (LpL) and the FA transporter cluster of differentiation (CD) 36 in the movement of non-esterified FAs and lipoprotein-derived FAs into hearts by floxing the genes of each of these proteins. We found that endothelial CD36 is a major regulator of acute FA uptake by the heart. Although deletion of CD36 in either endothelial cells or cardiomyocytes leads to a marked reduction in lipid droplet (LD) accumulation during fasting, only the endothelial deletion led to an increase in mRNA levels of genes mediating insulin signaling and glucose uptake. Thus, CD36 actions differ in these two cell types. This revision has three aims that focuses on cardiac FA uptake and LD formation. In Aim 1, we will determine how changes in CD36 affect lipid uptake and LD formation. Aim 2 will compare the composition of LDs associated with toxicity and physiologic storage of triglyceride. Aim 3 will test whether HF due to adipose triglyceride lipase (ATGL) deficiency, a cause of human HF, can be corrected by CD36 deletion or inhibition. The overall objective of our studies is define the pathways required for FA uptake by the heart, to understand whether which forms of stored triglyceride are beneficial, and to define methods to treat lipotoxic heart disease.