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）：