Lipolysis

脂肪分解

• 批准号: 8258644
• 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 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258644
• 关键词: Address; Adenosine; Adipocytes; Adipose tissue; Adrenergic Agonists; Atherosclerosis; Biology; Blood Circulation; Caring; Cells; Cerebrovascular Disorders; Complex; Coronary Arteriosclerosis; Corticotropin; Cytoplasm; Cytoskeleton; Cytosol; Data; Degenerative polyarthritis; Development; Diabetes Mellitus; Diet; Disease; Event; Fatty Liver; Fatty acid glycerol esters; Gene Expression; General Population; Gout; Healthcare; Heart failure; Hormonal; Hormones; Hydrolysis; Hyperlipidemia; Hypertension; In Vitro; Insulin; Insulin Resistance; Intermediate Filament Proteins; Intermediate Filaments; Knockout Mice; Lipase; Lipids; Lipolysis; Location; Lung diseases; Malignant Neoplasms; Medical; Metabolism; Methods; Microscopy; Molecular; Motor; Movement; Myocardial Infarction; Non obese; Nonesterified Fatty Acids; Nutritional; Obesity; Organism; Outcome; Patients; Peripheral Vascular Diseases; Phospholipids; Physiological; Play; Process; Proteins; Proteomics; Receptor Signaling; Regulation; Research; Role; Signal Pathway; Stroke; Techniques; Testing; Triglycerides; Veterans; Vimentin; Work; abstracting; base; carbohydrate metabolism; cell type; feeding; lipid metabolism; perilipin; public health relevance; repository; research study; sterol esterase; synthetic enzyme

DESCRIPTION (provided by applicant): 6. Project Summary/Abstract Objectives: For fat to be utilized for energy, it is necessary for the triacylglycerols (TAG) in adipose tissue to be mobilized to free fatty acids (FFA) and then released into the circulation, i.e., lipolysis. The control of lipolysis is complex and involves multiple mechanisms. The counterpoint to lipolysis is lipid droplet formation, a process that is also not fully understood. The objective of this proposal is to understand the cellular and molecular mechanisms regulating lipolysis and lipid droplet metabolism. We will test 2 hypotheses: 1) A physical interaction between hormone sensitive lipase (HSL) and vimentin participates in the translocation of HSL to the lipid droplet, thus facilitating lipolysis. 2) Vimentin has a dual function in adipose lipid metabolism, facilitating lipid droplet formation by allowing droplets to enlarge via the fusion of small droplets, while also facilitating the hydrolysis of lipid droplets. Research Plan and Methods: To test the first hypothesis, the location of the cellular compartment where the interaction between HSL and vimentin occurs will be determined using microscopy and biophysical techniques, the physiological importance of the HSL-vimentin interaction will be examined using vimentin knockout mice and in vitro knockdown, and the determinants of the HSL-vimentin interaction will be identified using mutational analyses. To test the second hypothesis, the dynamics of lipid droplet formation will be compared by microscopy in wild-type cells and cells lacking vimentin, and the interaction of droplet-associated proteins with vimentin will be examined by biophysical techniques. In addition, wild-type and vimentin null mice will be fed normal or high fat diets and the effects on adiposity, carbohydrate and lipid metabolism and adipose gene expression will be determined. Potential Impact on Veterans Health Care: A large proportion of patients for whom care is provided by the VA are obese. These obese veterans tend to have more complicated medical courses, and to have worse medical outcomes than nonobese patients. The obese patients within the VA have multiple medical problems, including hypertension, diabetes mellitus, hyperlipidemia, pulmonary disease, osteoarthritis, gout, and cancer. These conditions contribute to the development of atherosclerosis, with coronary artery disease (angina, myocardial infarction or cardiac failure), peripheral vascular disease and cerebrovascular disease (stroke) being extremely prevalent. Patients with all of these conditions are characterized by abnormal regulation of FFA flux. Understanding the basic mechanisms regulating FFA release and how lipolysis impacts the overall biology of adipose cells will have implications for delineating the abnormalities contributing to the accelerated atherosclerosis seen in obesity and in other conditions characterized by abnormal levels of circulating FFA. PUBLIC HEALTH RELEVANCE: 7. Project Narrative Just as observed in the general population, a large proportion of patients who are medically evaluated and for whom care is provided by the VA are obese. These obese veterans tend to have more complicated medical courses, and to have worse medical outcomes than nonobese patients. The obese patients within the VA have multiple medical problems, including hypertension, diabetes mellitus, hyperlipidemia, pulmonary disease, osteoarthritis, gout, and cancer. These conditions contribute to the development of atherosclerosis, with coronary artery disease (angina, myocardial infarction or cardiac failure), peripheral vascular disease and cerebrovascular disease (stroke) being extremely prevalent. Patients with all of these conditions are characterized by abnormal regulation of free fatty acids (FFA). Understanding the basic mechanisms regulating FFA release and how this impacts the overall biology of adipose cells will have implications for delineating the abnormalities contributing to the accelerated atherosclerosis seen in obesity and in other conditions characterized by abnormal levels of circulating FFA.

描述（由申请人提供）： 6。项目摘要/抽象目标：为了使脂肪用于能量，脂肪组织中的三酰基甘油（TAG）必须动员至游离脂肪酸（FFA），然后释放到循环中，即脂解。脂解的控制很复杂，涉及多种机制。脂解的对立面是脂质液滴的形成，这一过程也尚未完全理解。该提议的目的是了解调节脂解和脂质液滴代谢的细胞和分子机制。我们将检验2个假设：1）激素灵敏脂肪酶（HSL）和波形蛋白之间的物理相互作用参与HSL转移到脂质液滴，从而促进脂解。 2）波形蛋白在脂肪脂质代谢中具有双重功能，通过允许液滴通过小滴来促进脂质液滴的形成，同时还可以促进脂质液滴的水解。研究计划和方法：为了检验第一个假设，将使用显微镜和生物物理技术来确定细胞隔室的位置，其中将使用Vimentin敲除小鼠以及识别易于识别的HS viments peiments peiment of the virents peiment of the viments ventiins peiment peiment opins opins opins of the virents peiment peiment peiment peiment peiment peiments opins opins peiments opins opins opins contins contigin，将确定HSL与波形蛋白之间的相互作用的生理重要性。为了检验第二个假设，将通过野生型细胞和缺乏波形蛋白的细胞的显微镜比较脂质液滴形成的动力学，并且将通过生物物理技术检查液滴相关蛋白与波形蛋白的相互作用。此外，将确定野生型和波形蛋白空小鼠的正常或高脂肪饮食，并确定对脂肪，碳水化合物和脂质代谢以及脂肪基因表达的影响。对退伍军人卫生保健的潜在影响：VA提供护理的大部分患者肥胖。这些肥胖的退伍军人倾向于拥有更复杂的医疗课程，并且比非肥胖患者的医疗结果更糟糕。 VA中的肥胖患者有多个医学问题，包括高血压，糖尿病，高脂血症，肺部疾病，骨关节炎，痛风和癌症。这些疾病有助于动脉粥样硬化的发展，冠状动脉疾病（心绞痛，心肌梗塞或心脏衰竭），周围血管疾病和脑血管疾病（中风）极为普遍。所有这些疾病的患者的特征是FFA通量异常调节。了解调节FFA释放的基本机制以及脂解如何影响脂肪细胞的整体生物学将对描述造成肥胖症和其他以异常循环FFA水平为特征的有助于加速的动脉粥样硬化的异常。 公共卫生相关性： 7。正如在普通人群中所观察到的那样，项目叙述是对医学评估并为VA提供护理的大部分患者肥胖。这些肥胖的退伍军人倾向于拥有更复杂的医疗课程，并且比非肥胖患者的医疗结果更糟糕。 VA中的肥胖患者有多个医学问题，包括高血压，糖尿病，高脂血症，肺部疾病，骨关节炎，痛风和癌症。这些疾病有助于动脉粥样硬化的发展，冠状动脉疾病（心绞痛，心肌梗塞或心脏衰竭），周围血管疾病和脑血管疾病（中风）极为普遍。所有这些疾病的患者的特征是自由脂肪酸（FFA）异常调节。了解调节FFA释放的基本机制，以及这如何影响脂肪细胞的整体生物学，对描述造成肥胖症和其他以循环FFA水平异常为特征的加速动脉粥样硬化的异常有影响。