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导致细胞信号传导的恶化和细胞能量稳态的破坏，因此理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，***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。周脂蛋白（PLIN）蛋白首先在脂肪或脂肪组织中发现。第一个发现的（PLIN 1）是唯一一个具有良好描述功能的。在脂肪组织中，PLIN 1在调节脂滴中储存的脂肪的分解和积累方面非常重要。虽然PLIN 1含量很低，但PLIN 2、PLIN 3和PLIN 5在骨骼肌中丰富。 因此，目前的提案概述了将探索这三种骨骼肌蛋白在脂质代谢中发挥的潜在作用的实验。我们最近证明，这些PLIN蛋白中的两种在线粒体组分中响应于急性收缩（PLIN 5）或耐力训练（PLIN 3）而增加。这有趣地表明，它们在线粒体中具有不同的功能，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一重要的新功能。此外，我们以前的工作表明PLIN 2不与脂肪分解的其他重要代谢调节剂相互作用（例如，脂肪酶和脂肪酶激活剂），PLIN 3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PLIN 2和PLIN 3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.**