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

我正在进行的nserc资助的研究项目的长期目标是了解调节肌肉中甘油三酯（脂肪或脂质）代谢的哺乳动物酶/蛋白质的潜在机制和调节。我们知道，骨骼肌脂质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。***目前的建议集中在脂滴蛋白的perilipin家族在这些过程中发挥的潜在作用。Perilipin （PLIN）蛋白最早是在脂肪组织中发现的。发现的第一个基因（PLIN1）是唯一一个具有良好描述功能的基因。在脂肪组织中，PLIN1在调节脂滴中储存脂肪的分解和积累方面非常重要。虽然PLIN1含量很低，但骨骼肌中PLIN2、PLIN3、PLIN5含量丰富。因此，目前的建议概述了将探索这三种骨骼肌蛋白在脂质代谢中的潜在作用的实验。我们最近证明，在急性收缩（PLIN5）或耐力训练（PLIN3）的反应中，线粒体部分中的两种PLIN蛋白增加。有趣的是，这表明它们在线粒体中有不同的功能，线粒体负责氧化从肌内脂滴释放的脂肪酸。几个拟议的实验都集中在进一步探索这个重要的新功能。此外，我们之前的工作表明，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很重要。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。总之，这些研究将有望对我们对骨骼肌脂质代谢的理解产生影响，并为药物和/或替代疗法研究铺平道路

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.**