Deciphering Mechanisms for Triglyceride and Cholesterol Transport
甘油三酯和胆固醇运输的破译机制
基本信息
- 批准号:10613968
- 负责人:
- 金额:$ 65.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-05-01 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ANGPTL3 geneANGPTL4 geneATP binding cassette transporter 1AffinityAgonistAmino AcidsArterial Fatty StreakAutoantibodiesBindingBinding SitesBiochemicalBlood capillariesCell LineCell membraneCellsCholesterolCollaborationsComplexCoronary heart diseaseCrystallizationCytolysinsDiseaseDreamsEndothelial CellsFab ImmunoglobulinsFailureFutureGenerationsGeneticGenetic PolymorphismGoalsHealthHeparan Sulfate ProteoglycanHigh Density LipoproteinsHistopathologyHydrolaseImageInterventionInvestigationLipidsLipolysisLipoproteinsLiver X ReceptorMacrophageMainstreamingMediatingMetabolicMetabolismMethodologyMolecularMonoclonal AntibodiesMovementMutationPathogenesisPatientsPlasmaPositioning AttributePreparationPropertyProteinsProteomePublicationsReagentResearchResearch PersonnelRoleScanning Electron MicroscopyStarvationSterolsStructureTangier DiseaseTechnical ExpertiseTextbooksTriglyceride MetabolismTriglyceridesWorkcareerfallsgain of functionhuman diseaseimaging studyinsightinterestlipidomelipoprotein lipaseloss of function mutationmutantnovel strategiesparticlepharmacologicrecruitreverse cholesterol transport
项目摘要
Project 1: Deciphering Mechanisms for Triglyceride and Cholesterol Transport
SUMMARY/ABSTRACT
Project 1 investigators have devoted their careers to exploring basic mechanisms of lipoprotein metabolism in
health and disease. They discovered that an endothelial cell protein, GPIHBP1, is responsible for transporting
lipoprotein lipase (LPL) to the capillary lumen; that the LPL–GPIHBP1 complex is crucial for the margination of
triglyceride-rich lipoproteins (TRLs) along capillaries; and that GPIHBP1 protects LPL from spontaneous and
ANGPTL4-catalyzed unfolding/inactivation. Their efforts have resulted in >60 publications, many reflecting a
commitment to understanding human disease. For example, they identified GPIHBP1 mutations causing
chylomicronemia and uncovered a new human disease—chylomicronemia from GPIHBP1 autoantibodies.
Recently, Project 1 investigators and coworkers determined the structure of the LPL–GPIHBP1 complex. During
the next 5 years, Project 1 investigators will pursue two independent objectives. The first is to pursue ongoing
studies of intravascular lipolysis, building on insights from the structure of the GPIHBP1–LPL complex. That
structure, along with new reagents, new methodologies, and expert collaborators, have made intravascular
lipolysis more exciting than ever. Key goals include defining amino acid residues required for GPIHBP1–LPL
interactions, exploring mechanisms underlying specific “chylomicronemia mutations,” understanding a gain-of-
function polymorphism in LPL, defining the role of GPIHBP1’s acidic domain in stabilizing LPL from
unfolding/inactivation, examining the function of GPIHBP1’s acidic domain in recruiting LPL from heparan sulfate
proteoglycan binding sites in the subendothelial spaces, and investigating how ANGPTL4 initiates the unfolding
and inactivation of LPL. We will also determine the structure of GPIHBP1 and LPL in association with an Fab
fragment of the LPL–specific monoclonal antibody 5D2. Our second objective is to investigate the distribution of
cholesterol in macrophages and the mechanisms by which macrophages dispose of cholesterol. In preliminary
studies, Project 1 investigators found that macrophages release, by plasma membrane budding, numerous 30–
70-nm particles. By NanoSIMS imaging, these particles are highly enriched in cholesterol, including the
metabolically active “accessible cholesterol” detectable by bacterial cytolysins (e.g., ALO-D4). The finding that
cholesterol-rich particles “bud” from macrophages raises many questions. What is the function of particle
budding? What is the composition of these particles? Is particle budding regulated? In collaboration with projects
2 and 3, project 1 will investigate the numbers and composition of macrophage particles in different settings
(e.g., sterol starvation, cholesterol loading, LXR agonist treatment, and deficiencies of LXRs, ABCA1, or
ABCG1). Preliminary NanoSIMS imaging studies showed that high-density lipoproteins are effective in unloading
cholesterol from macrophage-derived particles, implying that macrophage particle budding could be relevant to
reverse cholesterol transport and the emergence of cholesterol-laden cells in atherosclerotic plaques.
项目1:甘油三酯和胆固醇转运的解码机制
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Stephen G. Young其他文献
Genetic abnormalities in apolipoprotein B.
载脂蛋白 B 基因异常。
- DOI:
- 发表时间:
1991 - 期刊:
- 影响因子:9.3
- 作者:
Stephen G. Young;M. F. Linton - 通讯作者:
M. F. Linton
APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries
APOA5 缺乏症通过减少毛细血管中脂蛋白脂肪酶的量导致高甘油三酯血症。
- DOI:
10.1016/j.jlr.2024.100578 - 发表时间:
2024-07-01 - 期刊:
- 影响因子:4.100
- 作者:
Ye Yang;Robert J. Konrad;Michael Ploug;Stephen G. Young - 通讯作者:
Stephen G. Young
Absence of VLDL secretion does not affect α-tocopherol content in peripheral tissues
- DOI:
10.1194/jlr.m600125-jlr200 - 发表时间:
2006-08-01 - 期刊:
- 影响因子:
- 作者:
Kaori Minehira-Castelli;Scott W. Leonard;Quinn M. Walker;Maret G. Traber;Stephen G. Young - 通讯作者:
Stephen G. Young
Using genetically modified mice to study apolipoprotein B.
使用转基因小鼠研究载脂蛋白 B。
- DOI:
- 发表时间:
1996 - 期刊:
- 影响因子:4.4
- 作者:
Stephen G. Young - 通讯作者:
Stephen G. Young
Apolipoprotein B gene expression in a series of human apolipoprotein B transgenic mice generated with recA-assisted restriction endonuclease cleavage-modified bacterial artificial chromosomes. An intestine-specific enhancer element is located between 54 and 62 kilobases 5' to the structural gene.
用recA辅助限制性内切酶切割修饰的细菌人工染色体产生的一系列人载脂蛋白B转基因小鼠中的载脂蛋白B基因表达。
- DOI:
- 发表时间:
1998 - 期刊:
- 影响因子:4.8
- 作者:
L. B. Nielsen;Debra Kahn;Thomas Duell;H. G. Weier;S. Taylor;Stephen G. Young - 通讯作者:
Stephen G. Young
Stephen G. Young的其他文献
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{{ truncateString('Stephen G. Young', 18)}}的其他基金
New approaches for understanding lipid movement in health and disease
了解健康和疾病中脂质运动的新方法
- 批准号:
10161848 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别:
Deciphering Mechanisms for Triglyceride and Cholesterol Transport
甘油三酯和胆固醇运输的破译机制
- 批准号:
10161851 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别:
Deciphering Mechanisms for Triglyceride and Cholesterol Transport
甘油三酯和胆固醇运输的破译机制
- 批准号:
10397413 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别:
New approaches for understanding lipid movement in health and disease
了解健康和疾病中脂质运动的新方法
- 批准号:
10613963 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别:
Understanding the Influence of Lipid Homeostasis on T cell Function
了解脂质稳态对 T 细胞功能的影响
- 批准号:
10336183 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别:
New approaches for understanding lipid movement in health and disease
了解健康和疾病中脂质运动的新方法
- 批准号:
9919622 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别:
New approaches for understanding lipid movement in health and disease
了解健康和疾病中脂质运动的新方法
- 批准号:
10397409 - 财政年份:2019
- 资助金额:
$ 65.02万 - 项目类别: