Role of cholesteryl ester transfer protein in cellular lipid homeostasis
Role of cholesteryl ester transfer protein in cellular lipid homeostasis
批准号:
8197866
负责人:
RICHARD E MORTON
金额:
$39.25万
依托单位国家:
美国
项目类别:
财政年份:
2000
资助国家:
美国
项目状态:
已结题
起止时间:
2000-02-25 至 2014-11-30
关键词:
AcuteAdipocytesAdipose tissueAffectAlternative SplicingAmino AcidsApplications GrantsAtherosclerosisBiochemicalBiological ProcessCell Culture TechniquesCell physiologyCell secretionCellsCholesterolCholesterol Ester Transfer ProteinsCholesterol EstersCholesterol HomeostasisCytoplasmDataDepositionDevelopmentDiseaseEndoplasmic ReticulumEnterocytesExonsExtrahepaticFailureFatty acid glycerol estersGenerationsGeneticHamstersHeart DiseasesHepatocyteHomeostasisHormonesIn VitroInflammationInflammatory ResponseInsulin ResistanceIntestinesKineticsLearningLengthLinkLipidsLipoproteinsLiverMeasuresMediatingMessenger RNAMetabolicMetabolismMicroscopyMicrosomesMiningMolecularMovementOrganellesPathway interactionsPharmaceutical PreparationsPlasmaPlayProcessProtein BiosynthesisProtein DeficiencyProtein InhibitionProtein IsoformsProtein OverexpressionProteinsRegulationRoleSiteStructureTechniquesTestingTissuesTriglyceridesVariantabsorptionadipokinesatherogenesiscell typedensityglucose metabolismin vivoinsightlipid metabolismlipid transportnovelprotein expressionprotein metabolismprotein structureprotein transportsugar
中文摘要
项目总结/摘要
胆固醇酯转移蛋白(CETP)在胆固醇和甘油三酯之间交换胆固醇酯(CE)和甘油三酯(TG)。
脂蛋白,并且被公认为血浆脂蛋白代谢的调节剂。CETP还驻留在
存在两种同种型的细胞:全长(FL)和外显子9(E9)缺失的CETP。CETP内部的功能
细胞中CETP的生物合成尚不清楚,但显然是必要的,因为抑制脂肪细胞中CETP的生物合成会损害脂质
存储.我们假设这是因为细胞内CETP是CE和TG从细胞内转运所必需的。
从合成点到储存点为了验证这一假设,我们提出了三个具体目标。要求1
- 确定促进细胞脂质储存的CETP亚型,并定义CETP的结构特征
对它的细胞内功能至关重要。该目的测试了E9缺失的CETP促进了E9缺失的CETP的表达的假设。
细胞内脂质转运直接或通过与FL CETP相互作用,并检查这种细胞活性如何
取决于CETP结构。目的2 -确定CETP在细胞脂质代谢中的作用。解开
CETP缺乏破坏细胞脂质代谢的机制,这一目的是量化代谢
改变并定义当CETP同种型表达改变时发生的脂滴形成的变化。
目的3 -确定CETP在脂蛋白中脂质储存滴的形成和利用中的作用-
合成细胞与初步研究一致,我们提出,在脂蛋白合成细胞中,CETP
有助于脂滴的形成和储存的脂质向微粒体的反向转运,
组装件.基因和腺病毒方法将改变SW 872中FL和/或E9缺失的CETP的表达
脂肪细胞、Caco-2肠上皮细胞和仓鼠中。这些分子的后果
对脂质合成、细胞器间脂质转运、脂滴形成和脂蛋白组装的操纵
将通过生物化学和显微镜技术进行研究。这些研究将描述一种新的功能,
CETP和推进我们对细胞脂质运输和储存机制的理解。脂质储存
脂肪细胞与它们分泌调节葡萄糖和脂质代谢的激素有关,
影响炎症和动脉粥样硬化形成等过程。
英文摘要
PROJECT SUMMARY/ABSTRACT
Cholesteryl ester transfer protein (CETP) exchanges cholesteryl ester (CE) and triglyceride (TG) between
lipoproteins and is well recognized as a regulator of plasma lipoprotein metabolism. CETP also resides inside
cells where two isoforms exist: full-length (FL) and exon 9 (E9)-deleted CETP. The function of CETP inside
cells is not understood, but it is clearly essential since inhibiting CETP biosynthesis in adipocytes impairs lipid
storage. We postulate this occurs because intracellular CETP is required for CE and TG transport from their
site of synthesis to their site of storage. To test this general hypothesis, we propose three specific aims. Aim 1
- Determine the CETP isoform(s) that promote cellular lipid storage, and define the structural features of CETP
that are essential to its intracellular function. This aim tests the hypothesis that E9-deleted CETP facilitates
intracellular lipid transport directly or by interacting with FL CETP, and also examines how this cellular activity
depends on CETP structure. Aim 2 - Define the role of CETP in cellular lipid metabolism. To unravel the
mechanisms by which CETP deficiency disrupts cellular lipid metabolism, this aim quantifies metabolic
alterations and defines changes in lipid droplet formation that occur when CETP isoform expression is altered.
Aim 3 - Define the role of CETP in the formation and utilization of lipid storage droplets in lipoprotein-
synthesizing cells. Consistent with preliminary studies, we propose that in lipoprotein-synthesizing cells CETP
assists in both lipid droplet formation and the reverse transport of stored lipids to microsomes for lipoprotein
assembly. Genetic and adenoviral approaches will alter expression of FL and/or E9-deleted CETPs in SW872
adipocytes, Caco-2 intestinal enterocytes, and in hamster. The consequences of these molecular
manipulations on lipid synthesis, interorganelle lipid transport, lipid droplet formation and lipoprotein assembly
will be studied through biochemical and microscopy techniques. These studies will describe a novel function for
CETP and advance our understanding of cellular lipid transport and storage mechanisms. Lipid storage in
adipocytes is linked to their secretion of hormones that regulate glucose and lipid metabolism, which directly
affect processes such as inflammation and atherogenesis.
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国内基金
海外基金
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依托单位: