Mechanisms of Fatty Acid Uptake by Cardiac Muscle

摘要 心脏是脂肪酸（FA）利用最多的器官，心力衰竭（HF）几乎总是 与心脏脂质代谢改变相关：糖尿病和肥胖增加FA使用;心脏衰竭 减少FA氧化（FAO）。在后负荷较大的情况下需要FA，但在其他情况下， 过量的脂质摄取导致HF，该过程有时称为脂毒性。该项目的重点是如何 脂肪酸是获得的心脏和用于能源的使用，以及为什么毒性发生时，过量的脂质 积累。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， 分化转运蛋白簇（CD）36在非酯化脂肪酸和脂蛋白衍生脂肪酸运动中的作用 植入到心脏中。我们发现内皮细胞CD 36是一个主要的调节因子， 心脏对FA的急性摄取。尽管内皮细胞或心肌细胞中CD 36的缺失导致 与禁食期间脂滴（LD）积聚显著减少相比，只有内皮细胞缺失导致 介导胰岛素信号传导和葡萄糖摄取的基因的mRNA水平增加。因此，CD 36的作用在以下方面不同： 这两种细胞类型。本次修订有三个目标，重点是心脏FA摄取和LD形成。在Aim中 1，我们将确定CD 36的变化如何影响脂质摄取和LD形成。目标2将比较 与甘油三酯的毒性和生理储存相关的LD组成。目标3将测试HF是否 由于脂肪甘油三酯脂酶（ATGL）缺乏，这是人类HF的一个原因，可以通过CD 36缺失来纠正 或抑制。我们研究的总体目标是确定心脏摄取FA所需的途径， 了解哪种形式的储存甘油三酯是否有益，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.