Lipid Droplet Metabolism

脂滴代谢

• 批准号: 8538217
• 负责人: FREDRIC B. KRAEMER
• 金额: --
• 依托单位: VETERANS ADMIN PALO ALTO HEALTH CARE SYS
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8538217
• 关键词: Adipocytes; Adipose tissue; Adrenal Glands; Affect; Arterial Fatty Streak; Atherosclerosis; Biochemical; Biological; Biology; Blood Glucose; Cells; Cellular biology; Cholesterol; Cholesterol Esters; Cholesterol Homeostasis; Complement; Diabetes Mellitus; Disease; Eating; Enterocytes; Equipment; Estrogens; Explosion; Fatty Liver; Fatty acid glycerol esters; Foam Cells; Gene Targeting; Gland; Goals; Growth; Health; Homeostasis; Hormones; Hydrocortisone; In Vitro; Knockout Mice; Leukocytes; Light; Lipids; Lipolysis; Liquid substance; Liver; Liver diseases; Mass Spectrum Analysis; Measurement; Measures; Mechanics; Metabolic Diseases; Metabolism; Microscopy; Mitochondria; Molecular Biology; Morbidity - disease rate; Movement; Myocardial Infarction; Myocardium; Non-Insulin-Dependent Diabetes Mellitus; Nonesterified Fatty Acids; Obesity; Organelles; Ovary; Pathway interactions; Physiological; Population; Positioning Attribute; Process; Production; Property; Protein Overexpression; Proteins; Proteome; Proteomics; SNAP receptor; Skeletal Muscle; Small Interfering RNA; Source; Steroid biosynthesis; Stroke; Surface Tension; Testing; Testis; Testosterone; Tissues; Triglycerides; Veterans; Vimentin; Viscosity; design; disorder control; genome wide association study; granulosa cell; in vitro Assay; in vivo; interest; knock-down; lipid metabolism; macrophage; monolayer; neuronal cell body; physical property; public health relevance; repository; response; steroid hormone; therapeutic target; tool

DESCRIPTION (provided by applicant): There has been an explosion of interest in the biology of intracellular lipid droplets (LDs) over the past several years that has been fueled by the realization that LDs are not simply static repositories for lipid storage, but are dynamic intracellular "organelles" that participate in interactions and interplay with much of the cell's machinery. Advances in our understanding of LD metabolism have been made through a variety of approaches, including microscopy, proteomics, and genome-wide screens. LDs are most prominently associated with adipose cells, where triacylglycerol (TAG) is stored. The major contribution of adipose tissue to whole body metabolism is the storage of energy in the form of TAG and the mobilization of this stored energy leading to the release of free fatty acids, the process known as lipolysis. However, LDs do not occur exclusively in adipose cells, but can be found in many, if not most, tissues and cells, including liver, skeletal muscle, cardiac muscle, enterocytes, and leukocytes, under certain physiological and pathophysiological conditions where the LDs generally serve as an energy repository. In addition, LDs that are primarily composed of cholesteryl esters (CEs) are prominently found in adrenals and ovaries under physiological conditions and in macrophage foam cells in atherosclerotic lesions under pathophysiological conditions. The CE-rich LDs in the adrenal and ovary serve as important sources of cholesterol substrate for steroid hormone production. The overall goal of this proposal is to advance our understanding of the cell biology of LDs, which is likely to have broad implications for health in light of the biological importance of LD cholesterol utilization for steroid hormone production and the fact that excessive accumulation of lipids in droplets is a hallmark of obesity, type 2 diabetes, hepatic steatosis, atherosclerosis, and other metabolic diseases that are prevalent worldwide and particularly prevalent among the population of veterans. The overall goal will be accomplished by testing 2 major hypotheses. First, we hypothesize that the physical properties of LDs are distinctively altered in quantifiably defined ways by specific droplet-associated proteins and these physical properties contribute to LD size (growth and fusion) and metabolism. This hypothesis will be tested using specialized equipment to measure the viscoelastic properties (viscosity, surface tension, etc.) of LDs within normal adipocytes and within adipocytes in which specific LD-associated proteins have been manipulated by gene targeting. Second, we hypothesize that the formation of CE-rich LDs differs in important and identifiable ways from TAG-rich LDs and that CE-rich LDs have a complement of droplet-associated proteins that specifically facilitates their utilization for steroidogenesis. This hypothesis will be tested through the exploration of the function of specific LD-associated proteins on LD homeostasis and cholesterol transport for steroidogenesis. The results from these studies should identify pathways and functions of key molecules in LD biology, some of which are expected to emerge as therapeutic targets that should help curb the morbidities associated with excessive LD accumulation.

描述（由申请人提供）： 在过去的几年里，人们对细胞内脂滴（LD）的生物学产生了极大的兴趣，这是由于人们认识到LD不仅仅是脂质储存的静态储存库，而是动态的细胞内“细胞器”，它们参与相互作用并与细胞的许多机制相互作用。我们对LD代谢的理解已经通过各种方法取得了进展，包括显微镜，蛋白质组学和全基因组筛选。LD最显著地与脂肪细胞相关，其中储存三酰甘油（TAG）。脂肪组织对全身代谢的主要贡献是以TAG的形式储存能量，并动员这种储存的能量，导致释放游离脂肪酸，该过程称为脂解。然而，LD并不专门存在于脂肪细胞中，而是在LD通常用作能量储存库的某些生理和病理生理条件下，可以在许多（如果不是大多数）组织和细胞中发现，包括肝脏、骨骼肌、心肌、肠细胞和白细胞。此外，主要由胆固醇酯（CE）组成的LD在生理条件下主要存在于肾上腺和卵巢中，在病理生理条件下主要存在于动脉粥样硬化病变的巨噬细胞泡沫细胞中。肾上腺和卵巢中富含CE的LD是类固醇激素产生的胆固醇底物的重要来源。本提案的总体目标是促进我们对LD细胞生物学的理解，鉴于其生物学重要性，这可能对健康产生广泛影响。 这些研究表明，LD胆固醇用于类固醇激素生产的可能性很大，并且液滴中脂质的过度积累是肥胖、2型糖尿病、肝脂肪变性、动脉粥样硬化和其他代谢疾病的标志，这些疾病在世界范围内普遍存在，尤其是在退伍军人群体中普遍存在。总体目标将通过检验2个主要假设来实现。首先，我们假设LD的物理性质通过特定的液滴相关蛋白以定量定义的方式明显改变，并且这些物理性质有助于LD的大小（生长和融合）和代谢。将使用专门的设备测试该假设，以测量粘弹性（粘度、表面张力等）。在正常脂肪细胞内和脂肪细胞内的LD，其中特定的LD相关蛋白已通过基因靶向操作。第二，我们假设，CE丰富的LD的形成不同的重要和可识别的方式从TAG丰富的LD和CE丰富的LD有一个小滴相关的蛋白质，特别是促进其利用类固醇激素的补充。这一假设将通过探索特定的LD相关蛋白对LD稳态和胆固醇转运类固醇生成的功能进行测试。这些研究的结果应该确定LD生物学中关键分子的途径和功能，其中一些有望成为治疗靶点，有助于抑制与LD过度积累相关的发病率。