Lipid Droplet Metabolism

脂滴代谢

• 批准号: 8803241
• 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/8803241
• 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 analysis; granulosa cell; in vitro Assay; in vivo; interest; knock-down; lipid metabolism; macrophage; monolayer; neuronal cell body; physical property; 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）： 在过去的几年中，人们对细胞内脂质液滴（LDS）的生物学产生了兴趣，这引起了人们的意识，即LDS不仅是脂质储存的静态存储库，而且是动态的细胞内“细胞器”，它们参与了相互作用并与细胞的机器进行交互并相互作用。通过多种方法，包括显微镜，蛋白质组学和全基因组筛查，我们对LD代谢的理解的进步已经取得了进步。 LDS与脂肪细胞最突出，其中三酰甘油（TAG）存储。脂肪组织对全身代谢的主要贡献是以TAG的形式储存能量，并动员了这种存储的能量，导致游离脂肪酸释放，该过程称为脂肪分解。但是，LD并非仅在脂肪细胞中发生，而是在许多（包括大多数（如果不是大多数））中发现的，包括肝脏，骨骼肌，心脏肌肉，肠细胞和白细胞，在某些生理和病理生理条件下，其中LDS通常用作能量repository。此外，在生理条件下，在病理生理条件下，在生理条件和巨噬细胞泡沫细胞中，在肾上腺和卵巢中显着发现了主要由胆固醇酯（CE）组成的LD。肾上腺和卵巢中的CE富含LDS是胆固醇底物的重要来源，用于类固醇激素的产生。该提案的总体目标是促进我们对LD的细胞生物学的理解，鉴于生物学的重要性，这可能对健康具有广泛的影响 LD胆固醇利用用于类固醇激素的产生以及脂质中脂质过量积聚是肥胖，2型糖尿病，肝脂肪变性，动脉粥样硬化和其他代谢性疾病的标志，这些疾病在全球范围内普遍存在，尤其是普遍存在。总体目标将通过测试两个主要假设来实现。首先，我们假设LD的物理特性在定义的方式上通过特定的液滴相关蛋白质明显改变，这些物理特性促进了LD大小（生长和融合）和代谢。该假设将使用专用设备进行测试，以测量正常脂肪细胞和脂肪细胞内LDS的粘弹性特性（粘度，表面张力等），其中特定的LD相关蛋白已通过基因靶向来操纵。其次，我们假设CE丰富的LDS的形成与富含TAG的LDS的重要和可识别的方式不同，并且CE富的LDS具有与液滴相关的蛋白质的补充，这些蛋白质专门促进了它们对类固醇生成的利用。该假设将通过探索特异性LD相关蛋白在LD稳态和胆固醇转运的功能中进行检验。这些研究的结果应确定LD生物学中关键分子的途径和功能，其中一些人有望成为治疗靶标，这些靶标应有助于遏制与LD积累过多相关的病态。