Perilipin and cellular triacylglycerol metabolism

Perilipin 和细胞三酰甘油代谢

基本信息

  • 批准号:
    8297197
  • 负责人:
  • 金额:
    $ 6.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2000
  • 资助国家:
    美国
  • 起止时间:
    2000-08-15 至 2014-06-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Adipocytes store the body's major energy supply in the form of triacylglycerols (TAGs) packaged into perilipin- coated lipid droplets. Dysregulation of adipose TAG metabolism in obese individuals leads to release of excess fatty acids into circulation, which contributes to the development of health complications including peripheral insulin resistance and hepatic steatosis. The regulation of adipose TAG storage and hydrolysis is complex; our understanding of these processes is rudimentary and incomplete. The proposed studies investigate the molecular mechanisms by which perilipin controls and coordinates TAG metabolism and lipid droplet dynamics. The overarching hypothesis of these studies is that perilipin forms a scaffold at the surfaces of lipid droplets in adipocytes that serves as an organizing center for lipid metabolic enzymes and trafficking factors. Under basal conditions, when TAG storage predominates over a low level of basal lipolysis, the perilipin scaffold binds CGI- 58, a Coenzyme A-dependent lysophosphatidic acid acyltransferase and co-activator of adipose triglyceride lipase (ATGL). When cell surface ¿-adrenergic receptors are stimulated, cellular cAMP levels increase and protein kinase A (PKA) is activated. Perilipin is phosphorylated by PKA on as many as 6 serine residues; phosphorylation of these sites promotes lipolysis through several different mechanisms. Phosphorylation of PKA sites 1, 2, and 3 in the amino terminus of perilipin promotes the docking of PKA-phosphorylated hormone- sensitive lipase (HSL) on lipid droplets through a protein-protein interaction with perilipin, and HSL gains access to TAG and diacylglycerol substrates. Phosphorylation of carboxyl terminal PKA sites 4, 5, and 6 facilitates lipolysis by as yet poorly understood mechanisms, which include the promotion of lipid droplet fragmentation into myriad lipid micro-droplets with increased surface area for lipase (ATGL) binding. The goals of the proposed study are to 1) investigate the role of serine 517 (within PKA site 6) in lipid droplet association of perilipin and control of lipolysis using techniques of cellular and molecular biology, 2) investigate the role of PKA-mediated phosphorylation of serine 492 (within PKA site 5) in lipid droplet remodeling in a cultured cell model and lipolysis in both cells and mice, and 3) investigate the mechanisms by which CGI-58 co-activates ATGL, and perilipin serves as a platform for regulation of TAG hydrolysis by ATGL. Mutated variants of peri- lipin and CGI-58 will be studied in cultured cells and a novel transgenic mouse model of adipose-selective expression of mutated perilipin on a perilipin null background. The information gained from these studies will contribute to a long-term goal of defining lipid droplet-associated factors that control TAG metabolism in adipocytes. PUBLIC HEALTH RELEVANCE: Adipocytes (fat cells) in adipose tissue store the major energy reserves of the body as triacylglycerols in struc- tures called lipid droplets. Obese individuals have enlarged lipid droplets in adipocytes when compared to lean individuals. Lipid droplets are covered with perilipin, a protein which controls the metabolism of triacylglycerols, and hence, the release of fatty acids into the blood for use as a source of energy by various tissues of the body. Obesity is characterized by inappropriate and excessive release of fatty acids into circulation; these fatty acids are taken up by muscle and liver and contribute to the development of insulin resistance (which occurs in type II diabetes) and fatty liver. Our understanding of the mechanisms by which perilipin controls triacylglycerol (fat) metabolism in adipocytes is incomplete; the proposed research will increase understanding of these mechanisms, and identify potential new targets for therapeutic intervention to control release of fatty acids from adipose tissue.
描述(由申请人提供):脂肪细胞以三酰甘油(TAG)的形式储存身体的主要能量供应,这些三酰甘油被包装到包被有脂周蛋白的脂滴中。肥胖个体中脂肪TAG代谢的失调导致过量脂肪酸释放到循环中,这有助于健康并发症的发展,包括外周胰岛素抵抗和肝脂肪变性。脂肪TAG储存和水解的调节是复杂的,我们对这些过程的理解是初步和不完整的。拟议的研究调查的分子机制,其中perilipin控制和协调TAG代谢和脂滴动力学。这些研究的首要假设是,周脂蛋白在脂肪细胞中的脂滴表面形成支架,其充当脂质代谢酶和运输因子的组织中心。在基础条件下,当TAG储存超过低水平的基础脂解时,周脂蛋白支架结合CGI- 58,CGI-58是辅酶A依赖性溶血磷脂酸酰基转移酶和脂肪甘油三酯脂肪酶(ATGL)的共激活剂。当细胞表面的肾上腺素能受体受到刺激时,细胞内cAMP水平增加,蛋白激酶A(PKA)被激活。周磷脂被PKA在多达6个丝氨酸残基上磷酸化;这些位点的磷酸化通过几种不同的机制促进脂解。周脂蛋白氨基末端PKA位点1、2和3的磷酸化通过与周脂蛋白的蛋白质-蛋白质相互作用促进PKA-磷酸化激素敏感性脂肪酶(HSL)在脂滴上的对接,并且HSL获得对TAG和二酰基甘油底物的接近。羧基末端PKA位点4、5和6的磷酸化通过迄今尚不清楚的机制促进脂解,所述机制包括促进脂滴碎裂成具有增加的脂肪酶(ATGL)结合表面积的无数脂质微滴。这项研究的目的是:1)研究丝氨酸517的作用,利用细胞和分子生物学技术研究PKA介导的丝氨酸492磷酸化在脂滴结合和脂解调控中的作用(在PKA位点5内)在培养的细胞模型中的脂滴重塑和细胞和小鼠中的脂解中的作用,和3)研究CGI-58共激活ATGL的机制,并且外脂蛋白作为ATGL调节TAG水解的平台。将在培养的细胞和在周脂蛋白空白背景上脂肪选择性表达突变的周脂蛋白的新型转基因小鼠模型中研究β-脂蛋白和CGI-58的突变变体。从这些研究中获得的信息将有助于确定控制脂肪细胞中TAG代谢的脂滴相关因子的长期目标。 公共卫生相关性:脂肪组织中的脂肪细胞(脂肪细胞)以称为脂滴的结构中的三酰甘油形式储存身体的主要能量储备。肥胖的个体与瘦的个体相比,脂肪细胞中的脂滴增大。脂滴被脂周蛋白覆盖,脂周蛋白是一种控制三酰甘油代谢的蛋白质,因此,脂肪酸释放到血液中,用作身体各种组织的能量来源。肥胖的特征是脂肪酸不适当和过度释放到循环中;这些脂肪酸被肌肉和肝脏吸收,并导致胰岛素抵抗(发生在II型糖尿病中)和脂肪肝的发展。我们对perilipin控制脂肪细胞中三酰甘油(脂肪)代谢的机制的理解是不完整的;拟议的研究将增加对这些机制的理解,并确定潜在的新靶点,用于治疗干预,以控制脂肪组织中脂肪酸的释放。

项目成果

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DAWN L BRASAEMLE其他文献

DAWN L BRASAEMLE的其他文献

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{{ truncateString('DAWN L BRASAEMLE', 18)}}的其他基金

Perilipins and cellular triacyglycerol metabolism
Perilipins 和细胞三酰甘油代谢
  • 批准号:
    7996466
  • 财政年份:
    2010
  • 资助金额:
    $ 6.16万
  • 项目类别:
Lipid Droplets: Metabolic Consequences of Stored Neutral Lipids
脂滴:储存的中性脂质的代谢后果
  • 批准号:
    7329013
  • 财政年份:
    2007
  • 资助金额:
    $ 6.16万
  • 项目类别:
Perilipins and cellular triacyglycerol metabolism
Perilipins 和细胞三酰甘油代谢
  • 批准号:
    7389507
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
Perilipins and cellular triacyglycerol metabolism
Perilipins 和细胞三酰甘油代谢
  • 批准号:
    7031015
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
PERILIPINS AND CELLULAR TRIACYLGLYCEROL METABOLISM
周脂蛋白和细胞三酰甘油代谢
  • 批准号:
    6402590
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
Perilipin and cellular triacylglycerol metabolism
Perilipin 和细胞三酰甘油代谢
  • 批准号:
    8282929
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
PERILIPINS AND CELLULAR TRIACYLGLYCEROL METABOLISM
周脂蛋白和细胞三酰甘油代谢
  • 批准号:
    6603562
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
Perilipin and cellular triacylglycerol metabolism
Perilipin 和细胞三酰甘油代谢
  • 批准号:
    8470621
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
Perilipins and cellular triacyglycerol metabolism
Perilipins 和细胞三酰甘油代谢
  • 批准号:
    7214083
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:
Perilipin and cellular triacylglycerol metabolism
Perilipin 和细胞三酰甘油代谢
  • 批准号:
    8105109
  • 财政年份:
    2000
  • 资助金额:
    $ 6.16万
  • 项目类别:

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临床记录中缩写词的实时消歧
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