Regulation of GPIHBP1-dependent and independent triglyceride clearance
GPIHBP1 依赖性和独立性甘油三酯清除率的调节
基本信息
- 批准号:9895855
- 负责人:
- 金额:$ 38.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-06-01 至 2022-03-31
- 项目状态:已结题
- 来源:
- 关键词:ANGPTL3 geneANGPTL4 geneAddressAngiopoietinsBindingBinding ProteinsBiological AssayBlood VesselsBlood capillariesCapillary Endothelial CellCardiacCell Culture SystemCell Culture TechniquesClinicalComplexDataDepositionDyslipidemiasEndothelial CellsFatty AcidsFenestrated CapillaryFibratesGPI Membrane AnchorsGoalsHigh Density LipoproteinsHumanHydrolysisHyperlipidemiaHypertriglyceridemiaIn VitroIndividualInflammatory ResponseInjectionsInsulin ResistanceKnockout MiceKnowledgeLeadLifeLipaseLipidsLipolysisLiverMediatingMetabolic DiseasesMetabolic syndromeMethodsMissionModelingMusN-terminalNon-Insulin-Dependent Diabetes MellitusObesityPathway interactionsPharmaceutical PreparationsPhenotypePlasmaProcessProteinsPublic HealthRecombinant ProteinsRegulationResearchSerumSkeletal MuscleSurfaceTestingTherapeuticTissuesTriglyceride MetabolismTriglyceridesUnited States National Institutes of Healthbaseburden of illnesscardiovascular risk factordesignimprovedin vivoin vivo Modelinnovationlipoprotein lipaselipoprotein triglyceridemouse modelnovelnovel strategiesnovel therapeutic interventionpreventrestorationuptake
项目摘要
PROJECT SUMMARY
Clinical hypertriglyceridemia is common and is only partially responsive to available drugs. Conversely,
excess triglyceride delivery to individual tissues can lead to skeletal muscle insulin resistance, cardiac
lipotoxicity, or severe inflammatory responses. Given the importance of proper triglyceride delivery, it is
imperative that we understand the mechanisms that regulate this process. Two proteins normally
required for triglyceride clearance are lipoprotein lipase (LPL) and GPIHBP1. LPL is required for the
actual hydrolysis of plasma triglyceides, liberating fatty acids for tissue uptake. The endothelial cell
protein GPIHBP1 is required to properly localize LPL to the vascular lumen where lipolysis takes place.
The long term goal of the proposed research is to understand and ultimately modulate the delivery of
triglyceride-derived fatty acids to specific tissues. The objectives in this application are to advance our
understanding of how the angiopoietin-like (ANGPTL) proteins, ANGPTL3 and ANGPTL4, modulate
triglyceride clearance. ANGPTL3 and ANGPTL4 can both inhibit LPL in vitro, and ANGPTL3 or
ANGPTL4 deficiency leads to lower plasma triglyceride levels. However, if and how ANGPTL3 and
ANGPTL4 directly modulate LPL/GPIHBP1-mediated triglyceride clearance is not clear. Moreover, the
plasma triglyceride levels in mice deficient in both GPIHBP1 and ANGPTL4 indicate that ANGPTL4 may
regulate an uncharacterized, GPIHBP1-independent triglyceride clearance pathway. These issues will be
addressed by pursuing two specific aims: 1) Define the mechanisms by which ANGPTL3 and ANGPTL4
modulate GPIHBP1-dependent triglyceride clearance; and 2) Identify novel mechanisms of GPIHBP1-
independent triglyceride clearance. The studies in aim 1 employ cell culture–based binding and lipase
activity assays, as well as in vivo injection of recombinant proteins and tissue-specific knockout mice to
investigate how ANGPTL proteins interact with GPIHBP1/LPL complexes on the surface of endothelial
cells. The second aim will address the remarkably lower triglycerides in Angptl4–/–Gpihbp1–/– mice.
Triglyceride clearance and fatty acid uptake assays will be used to identify the tissues to which
triglycerides get cleared. Expression, protein, and lipase activity analysis will be used to identify the
proteins responsible for this clearance. The approaches in the proposed research are innovative
because they combine standard methods with novel mouse models to address previously untested
questions about how triglyceride clearance is regulated. The proposed studies are significant because
they will elucidate how and where ANGPTL3 and ANGPTL4 modulate levels of functional LPL to
influence triglyceride delivery and will uncover novel mechanisms of triglyceride clearance that do not
require vascular LPL, ultimately permitting new strategies designed to prevent or treat dyslipidemia.
项目摘要
临床高甘油三酯血症很常见,仅部分响应可用的药物。反过来,
甘油三酸酯过多地递送到单个组织会导致骨骼肌胰岛素抵抗,心脏
脂肪毒性或严重的炎症反应。考虑到适当甘油三酸酯的重要性,这是
我们必须了解调节这一过程的机制。通常两种蛋白质
甘油三酸酯清除所需的是脂蛋白脂肪酶(LPL)和GPIHBP1。 LPL是需要的
血浆triglyces的实际水解,使脂肪酸释放了组织摄取。内皮细胞
需要蛋白质GPIHBP1正确将LPL定位到发生脂解的血管内腔。
拟议研究的长期目标是了解并最终调节交付
甘油三酸酯衍生的脂肪酸到特定的组织。此应用程序中的对象是推动我们的
了解血管生成素样(Angptl)蛋白的ANGPTL3和ANGPTL4如何调节
甘油三酸酯的间隙。 angptl3和angptl4既可以在体外抑制LPL,angptl3或
ANGPTL4缺乏导致血浆甘油三酸酯水平较低。但是,如果以及如何angptl3和
ANGPTL4直接调节LPL/GPIHBP1介导的甘油三酸酯间隙尚不清楚。而且,
在GPIHBP1和ANGPTL4中,小鼠中的血浆甘油三酸酯水平表明Angptl4可能
调节一个未示范的GPIHBP1独立甘油三酸酯清除途径。这些问题将是
通过追求两个具体目标来解决:1)定义Angptl3和angptl4的机制
调节GPIHBP1依赖性甘油三酸酯间隙; 2)确定GPIHBP1-的新型机制
独立的甘油三酸酯清除率。 AIM 1员工细胞培养的结合和脂肪酶的研究
活性以及体内注入重组蛋白和组织特异性基因敲除小鼠
研究ANGPTL蛋白如何与内皮表面上的GPIHBP1/LPL复合物相互作用
细胞。第二个目标将解决Angptl4 - / - GPIHBP1 - / - 小鼠中较低的甘油三酸酯。
甘油三酸酯清除率和脂肪酸摄取测定将用于识别组织
清除甘油三酸酯。表达,蛋白质和脂肪酶活性分析将用于识别
蛋白质负责此清除。拟议研究中的方法是创新的
因为它们将标准方法与新型鼠标模型相结合以解决以前未经测试的
有关如何调节甘油三酸酯清除的问题。拟议的研究很重要,因为
他们将阐明如何和何处angptl3和angptl4调节功能LPL的水平
影响甘油三酸酯的递送,并会发现甘油三酸酯清除的新机制
需要血管LPL,最终允许旨在预防或治疗血脂异常的新策略。
项目成果
期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A novel NanoBiT-based assay monitors the interaction between lipoprotein lipase and GPIHBP1 in real time.
一种基于 NanoBiT 的新型检测实时监测脂蛋白脂肪酶和 GPIHBP1 之间的相互作用。
- DOI:10.1194/jlr.d119000388
- 发表时间:2020
- 期刊:
- 影响因子:6.5
- 作者:Shetty,ShwethaK;Walzem,RosemaryL;Davies,BrandonSJ
- 通讯作者:Davies,BrandonSJ
Regulation of plasma triglyceride partitioning by adipose-derived ANGPTL4 in mice.
- DOI:10.1038/s41598-021-87020-5
- 发表时间:2021-04-12
- 期刊:
- 影响因子:4.6
- 作者:Spitler KM;Shetty SK;Cushing EM;Sylvers-Davie KL;Davies BSJ
- 通讯作者:Davies BSJ
Chronic high-fat feeding and prolonged fasting in liver-specific ANGPTL4 knockout mice.
肝脏特异性 ANGPTL4 基因敲除小鼠的长期高脂肪喂养和长时间禁食。
- DOI:10.1152/ajpendo.00144.2021
- 发表时间:2021
- 期刊:
- 影响因子:0
- 作者:Spitler,KathrynM;Shetty,ShwethaK;Cushing,EmilyM;Sylvers-Davie,KelliL;Davies,BrandonSJ
- 通讯作者:Davies,BrandonSJ
ANGPTL8 promotes the ability of ANGPTL3 to bind and inhibit lipoprotein lipase.
- DOI:10.1016/j.molmet.2017.06.014
- 发表时间:2017-10
- 期刊:
- 影响因子:8.1
- 作者:Chi X;Britt EC;Shows HW;Hjelmaas AJ;Shetty SK;Cushing EM;Li W;Dou A;Zhang R;Davies BSJ
- 通讯作者:Davies BSJ
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
BRANDON Scott Joseph DAVIES其他文献
BRANDON Scott Joseph DAVIES的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('BRANDON Scott Joseph DAVIES', 18)}}的其他基金
Regulation of Endothelial Lipase and HDL Metabolism by ANGPTL3
ANGPTL3 对内皮脂肪酶和 HDL 代谢的调节
- 批准号:
10582972 - 财政年份:2023
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of GPIHBP1-dependent and independent triglyceride clearance
GPIHBP1 依赖性和独立性甘油三酯清除率的调节
- 批准号:
9276103 - 财政年份:2016
- 资助金额:
$ 38.13万 - 项目类别:
相似国自然基金
高原低氧上调肝脏ANGPTL4基因的表达导致巨噬细胞M1/M2比例失衡从而促进肝脂肪化的机制研究
- 批准号:82360333
- 批准年份:2023
- 资助金额:32 万元
- 项目类别:地区科学基金项目
利用条件性基因敲除小鼠研究ANGPTL4在肝癌发生中的作用及机制
- 批准号:81372192
- 批准年份:2013
- 资助金额:75.0 万元
- 项目类别:面上项目
PPARγ和ANGPTL4基因表达在急性胰腺炎肺损伤发病机制中的作用及清胰汤的干预作用
- 批准号:81173452
- 批准年份:2011
- 资助金额:65.0 万元
- 项目类别:面上项目
相似海外基金
Deep Phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 Human Knockouts and Population Based Studies
ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究
- 批准号:
10186801 - 财政年份:2019
- 资助金额:
$ 38.13万 - 项目类别:
Deep phenotyping of ANGPTL3, ANGPTL4 and ANGPTL8 human knockouts and population based studies
ANGPTL3、ANGPTL4 和 ANGPTL8 人类基因敲除的深度表型分析和基于人群的研究
- 批准号:
10528964 - 财政年份:2019
- 资助金额:
$ 38.13万 - 项目类别:
Regulation of GPIHBP1-dependent and independent triglyceride clearance
GPIHBP1 依赖性和独立性甘油三酯清除率的调节
- 批准号:
9276103 - 财政年份:2016
- 资助金额:
$ 38.13万 - 项目类别:
Investigation of the Molecular Mechanisms of Lipoprotein Lipase Inhibitors
脂蛋白脂肪酶抑制剂的分子机制研究
- 批准号:
9102237 - 财政年份:2015
- 资助金额:
$ 38.13万 - 项目类别:
HDL metabolism: Influence of extracellular lipases
HDL 代谢:细胞外脂肪酶的影响
- 批准号:
9312963 - 财政年份:1996
- 资助金额:
$ 38.13万 - 项目类别: