Lipid droplet morphology and triglyceride storage

脂滴形态和甘油三酯储存

• 批准号: 8539866
• 负责人: Vishwajeet Puri
• 金额: $ 20.35万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-14 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8539866
• 关键词: Adipocytes; Adipose tissue; Affect; Amino Acid Sequence; Biological Models; Biology; COS-7 Cell; Catabolism; Cells; Data; Disease; Fatty acid glycerol esters; Functional disorder; Goals; Health; Homeostasis; Hormonal; Human; Hydrolysis; Hypertriglyceridemia; In Vitro; Insulin; Insulin Resistance; Knowledge; Length; Lipase; Lipids; Lipodystrophy; Lipolysis; Maps; Measures; Mediating; Metabolic; Metabolic Diseases; Modeling; Molecular; Morphology; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organelles; Orthologous Gene; Pathogenesis; Pathway interactions; Physiology; Play; Process; Proteins; Protocols documentation; Regulation; Research; Role; Signal Transduction; Structure-Activity Relationship; Testing; Therapeutic; Translating; Triglycerides; Variant; base; fatty acid metabolism; glucose uptake; in vivo; insulin sensitivity; insulin signaling; lipid biosynthesis; lipid metabolism; mutant; novel; null mutation; overexpression; pandemic disease; perilipin; tool

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.

项目摘要 脂肪细胞中脂肪包装不良与高脂解、脂毒性和胰岛素抵抗有关。脂质 脂肪细胞中的液滴（LD）是不同的细胞内细胞器，其是脂肪细胞的主要储存介质， FFA作为甘油三酯（TG）。缺乏对LD的分子组分的了解， 测定其形态和脂肪细胞中TG的储存能力。因此，迫切需要 了解调节脂肪细胞中LD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，也称为CIDEC）与LD相关，并在LD中发挥作用。 在脂肪细胞的脂肪代谢中的作用。在细胞中表达FSP27导致TG积累增加， 更大的LD，而其消耗导致LD的片段化和增加的TG水解。我们也 鉴定了FSP27中的突变，该突变导致人类的部分脂肪代谢障碍和胰岛素抵抗（IR）。在 在另一项研究中，我们发现FSP27在胰岛素敏感的WAT中的表达高于胰岛素抵抗的WAT 肥胖的人类我们的研究表明FSP27是LD形态和功能的主要新调节剂。 基于我们强有力的初步数据，我们假设在人脂肪细胞中，FSP27是一个关键的 是LD形态的调节剂，并且是有效TG储存所需的。我们进一步假设FSP27 通过减少脂肪细胞中的基础脂解来调节TG储存。这些措施将共同保护 脂肪细胞从FFA介导的IR隔离FFA作为TG在LD。我们提出了一个详细的机制， FSP27作为LD组装多功能调节剂的构效关系研究 (Aim 1），TG储存（目标2）和胰岛素敏感性（目标3）在人脂肪细胞。我们的研究将推动 通过鉴定决定其形态的LD的分子组分，并阐明其分子结构， 参与脂肪细胞中TG周转的机制。此外，这些研究将提供工具， 鉴定可用作胰岛素抵抗治疗剂的特定氨基酸序列。