Lipid droplet morphology and triglyceride storage

项目总结 脂肪细胞对脂肪的包装不良与高脂解、脂毒性和胰岛素抵抗有关。脂类 脂肪细胞中的液滴(LDs)是不同的细胞内细胞器，是 游离脂肪酸为甘油三酯(TGS)。对LDS的分子组成缺乏了解，这是 测定其形态及在脂肪细胞中的储甘油三酯能力。因此，迫切需要 了解参与调节脂肪细胞中LDS和TG积累的途径。我们和其他人 最近发现，脂肪特异性蛋白(FSP27，又称CIDEC)与腰椎管狭窄症有关，并发挥着一种 脂肪细胞在脂肪代谢中的作用。在细胞中表达FSP27会导致TG蓄积增加和 较大的LDS，而它的耗尽导致LDS的碎裂和TG水解率的增加。我们也 发现了FSP27的一个突变，它会导致人类部分脂肪营养不良和胰岛素抵抗(IR)。在……里面 另一项研究发现，胰岛素敏感组与胰岛素抵抗组相比，FSP27的表达更高 肥胖的人类。我们的研究表明，FSP27是一种主要的新的LD形态和功能调节剂。 基于我们强大的初步数据，我们假设在人类脂肪细胞中，FSP27是一个关键的 LD形态调节剂，是高效TG存储所必需的。我们进一步假设FSP27 通过减少脂肪细胞的基础脂解来调节甘油三酯的储存。这些措施加在一起将保护 FFA来源的脂肪细胞通过将FFA以TGS的形式滞留在LDS中而介导IR。我们提出了一个详细的机制 FSP27作为LD组装多功能调节子的结构与功能关系研究 (目标1)、甘油三酯储存(目标2)和胰岛素敏感性(目标3)。我们的研究将推动 通过鉴定决定其形态的LDS的分子成分，并阐明 参与脂肪细胞甘油三酯转化的机制(S)。此外，这些研究将通过以下方式提供工具 确定可用于治疗胰岛素抵抗的特定氨基酸序列。

PROJECT SUMMARY Poor packaging of fat in adipocytes is associated with high lipolysis, lipotoxicity and insulin resistance. Lipid droplets (LDs) in adipocytes are distinct intracellular organelles that are the primary storage medium for FFAs as triglycerides (TGs). There is a lack of knowledge of the molecular components of LDs which determine their morphology and TG storing capacity in adipocytes. Thus, there is an urgent need to understand the pathways involved in regulating LDs and TG accumulation in adipocytes. We and others recently identified that fat specific protein (FSP27, also called CIDEC), is associated with LDs and plays a role in fat metabolism in adipocytes. Expressing FSP27 in cells causes increased TG accumulation and larger LDs whereas its depletion results in fragmentation of LDs and increased TG hydrolysis. We also identified a mutation in FSP27 which causes partial lipodystrophy and insulin resistance (IR) in humans. In another study, we found that FSP27 expression was higher in WAT of insulin sensitive vs. insulin resistant obese humans. Our studies show that FSP27 is a major new modulator of LD morphology and function. Based upon our strong preliminary data, we hypothesize that in human adipocytes FSP27 is a critical regulator of LD morphology and is required for efficient TG storage. We further hypothesize that FSP27 regulates TG storage by decreasing basal lipolysis in adipocytes. Together, these steps will protect adipocytes from FFA mediated IR by sequestering FFAs as TGs in LDs. We propose a detailed mechanistic study of structure-function relationships by which FSP27 acts as a multifunctional regulator of LD assembly (Aim 1), TG storage (Aim 2) and insulin sensitivity (Aim 3) in human adipocytes. Our studies will advance the field by identifying the molecular components of LDs that determine their morphology, and elucidating the mechanism(s) involved in TG turnover in adipocytes. Furthermore, these studies will provide tools by identifying the specific amino acid sequences that could be used as therapeutics for insulin resistance.