Regulation of mammalian skeletal muscle lipid metabolism: the role of perilipin proteins

我正在进行的NSERC资助的研究计划的长期目标是了解调节肌肉中甘油三酯(脂肪或脂肪)新陈代谢的哺乳动物酶/蛋白质的潜在机制和调节。我们知道，骨骼肌脂代谢的失调会导致细胞信号的恶化和细胞能量稳态的破坏，因此，了解这些过程的潜在调节机制将是确定治疗靶点和替代疗法(例如，运动)的第一步。*目前的提议集中在Perilipin脂滴蛋白家族在这些过程中扮演的潜在角色(S)。Perilipin(Plin)蛋白最早是在脂肪组织中发现的。第一个被发现的(PLIN1)是唯一一个具有良好描述功能的。在脂肪组织中，PLIN1在调节脂滴中储存的脂肪的分解和积累方面起着非常重要的作用。虽然PLIN1的含量很低，但PLIN2、PLIN3和PLIN5在骨骼肌中含量很高。因此，目前的提案概述了将探索这三种骨骼肌蛋白质在脂肪代谢中扮演的潜在角色的实验(S)。我们最近证实，其中两种plin蛋白在急性收缩(PLIN5)或耐力训练(PLIN3)时线粒体部分增加。这一有趣的发现表明，它们在线粒体中具有不同的功能，负责氧化从肌肉内脂滴中释放的脂肪酸。几个拟议的实验集中在进一步探索这一重要的新功能。此外，我们以前的工作表明，PLIN2不与脂肪分解的其他重要代谢调节因子(如脂肪酶和脂肪酶激活剂)相互作用，PLIN3可能参与细胞内运输，这在脂肪分解和合成中都是重要的。因此，我们建议开始探索PLIN2和PLIN3在脂肪积累/合成中的潜在作用。这些研究预计将对我们对骨骼肌脂代谢的理解产生影响，并为药物和/或替代疗法的研究铺平道路。

The long-term objective of my ongoing NSERC-funded research program is to understand the underlying mechanisms and the regulation of mammalian enzymes/proteins that regulate triglyceride (fat or lipid) metabolism in muscle. We know that dysregulation of skeletal muscle lipid metabolism results in deterioration of cell signaling and disruptions in cellular energy homeostasis, and therefore understanding the underlying mechanisms of regulation of these processes would be a first step to identifying therapeutic targets and alternate therapies (e.g., exercise).***The current proposal focuses on the potential role(s) that the perilipin family of lipid droplet proteins plays in these processes. Perilipin (PLIN) proteins were first discovered in adipose or fat tissue. The first one discovered (PLIN1) is the only one that has a well-described function. In adipose tissue, PLIN1 is very important in regulating the breakdown and accumulation of the stored fat in lipid droplets. Although PLIN1 content is very low, PLIN2, PLIN3, and PLIN5 are abundant in skeletal muscle. Therefore, the current proposal outlines experiments that will explore the potential role(s) that these three skeletal muscle proteins play in lipid metabolism. We recently demonstrated that two of these PLIN proteins increased in the mitochondrial fraction in response to acute contraction (PLIN5) or endurance training (PLIN3). This intriguingly suggests that they have disparate functions in the mitochondria that are responsible for oxidizing the fatty acids that are released from the intramuscular lipid droplets. Several of the proposed experiments are focused on exploring this important new function further. In addition, our previous work indicates that PLIN2 does not interact with other important metabolic regulators of fat breakdown (e.g., lipase and lipase activators) and that PLIN3 might be involved in intracellular trafficking, which would be important in both fat breakdown and synthesis. Therefore we propose to begin exploration of a potential role for PLIN2 and PLIN3 in fat accumulation/synthesis. Together these studies will be expected to make an impact on our understanding of skeletal muscle lipid metabolism and pave the way for pharmaceutical and/or alternate therapy research.**