Hepatocyte Abca1, cholesterol trafficking, and lipid mobilization
肝细胞 Abca1、胆固醇运输和脂质动员
基本信息
- 批准号:10063950
- 负责人:
- 金额:$ 48.92万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-07-23 至 2022-11-30
- 项目状态:已结题
- 来源:
- 关键词:ADD-1 proteinATP binding cassette transporter 1ATP-Binding Cassette TransportersAcuteAddressAffectAnabolismApolipoprotein A-IAtherosclerosisBODIPYCardiometabolic DiseaseCardiovascular DiseasesCatabolismCell membraneCellsCholesterolCholesterol HomeostasisComplexDataDropsEndoplasmic ReticulumEndosomesExcretory functionFastingFatty LiverFecesFundingFutureGenetic TranscriptionGluconeogenesisHepaticHepatocyteHigh Density Lipoprotein CholesterolHigh Density LipoproteinsHigh Fat DietHomeostasisInsulinInsulin ResistanceKineticsKnock-outKnockout MiceKnowledgeLipid MobilizationLipidsLipoproteinsLiverLiver MitochondriaLocationLow Density Lipoprotein ReceptorLow-Density LipoproteinsLysophospholipidsLysosomesMass Spectrum AnalysisMeasuresMediatingMembrane FluidityMembrane ProteinsMessenger RNAMetabolicMetabolismMitochondriaModelingMusNPC1 geneNuclear ProteinOrganellesPathogenesisPhenotypePhospholipidsPlant RootsPlasmaProcessProductionProtein Export PathwayRecyclingRegulationResearchRespirationRoleSterolsStressTestingTissuesTransport ProcessUnited States National Institutes of HealthVery low density lipoproteinViralWorkbasecholesterol traffickingcholesteryl linoleatecholesteryl oleatefatty acid oxidationfluidityimprovedinsightinsulin signalinglipid biosynthesislipid metabolismmacrophagemitochondrial metabolismmouse modelmutantnovelparticleprogramspromoterreceptor expressionrespiratory enzymereverse cholesterol transporttraffickinguptakevery low density lipoprotein triglyceride
项目摘要
Abstract- This R01 renewal seeks to continue the PI's creative, productive, and significant research program,
which has enjoyed uninterrupted NIH funding since 1996, focused on lipid/lipoprotein metabolism in the
pathogenesis of cardiovascular disease (CVD) and cardiometabolic disease (CMD). For over 15 years, the PI's
research program has focused on ATP binding cassette transporter A1 (Abca1) and lipid and lipoprotein
metabolism using tissue/cell-specific Abca1 knockout mice. Studies in hepatocyte-specific Abca1 knockout
(HSKO) mice provided novel mechanistic insights into how hepatic Abca1 impacts the production and
catabolism of all three major classes of plasma lipoproteins (VLDL, LDL, HDL) that contribute to CVD and
CMD. Despite the massive (~80%) drop in plasma HDL relative to control mice, hyperlipidemic HSKO mice
maintained macrophage reverse cholesterol transport and had decreased aortic root atherosclerosis compared
to controls. HSKO mice also had increased plasma HDL cholesterol transport into the feces, decreased
hepatic insulin signaling and de novo lipogenesis (DNL), increased mitochondrial respiration, increased LDL
receptor expression, and increased hepatic VLDL triglyceride secretion. This unique phenotype was
associated with diminished antegrade trafficking of lysosomal free cholesterol (FC) to the plasma membrane of
hepatocytes, with no differences in total hepatic lipid mass between HSKO and control mice. Based on this
work, our global hypothesis is that targeted deletion of hepatocyte Abca1 enhances hepatocyte retrograde
FC redistribution from the plasma membrane to intracellular compartments, reprogramming insulin-mediated
anabolism towards a coordinated catabolic program that reduces hepatic DNL, improves mitochondrial
metabolism, and increases TG secretion, thereby decreasing hepatic steatosis when mice are stressed with a
high-fat diet. This metabolic reprogramming in the absence of hepatic Abca1 results in a novel form of
selective insulin resistance in HSKO mice, in which hepatic DNL is suppressed, but gluconeogenesis is
appropriately downregulated by insulin. Future studies will address gaps in knowledge and barriers to
progress, including: Specific aim 1) how Abca1 deletion alters FC distribution (or trafficking) among the
plasma membrane, endoplasmic reticulum, and other organelles; Specific aim 2a) how insulin signaling and
endoplasmic reticulum FC interact to activate Srebp1c; and Specific aim 2b) whether loss of Abca1 leads to
increased mitochondria FC and/or lysophospholipid that improves mitochondrial respiration. Our proposed
studies will build a more comprehensive and expansive model for Abca1 as a central control point of metabolic
homeostasis and propel our previous 5-year discoveries in new directions, thereby advancing the field.
Impact- Our studies will continue generating new discoveries regarding regulation of hepatic lipogenesis and
the emerging role of Abca1 and FC trafficking in reprogramming hepatic lipid metabolism, a key contributor to
CVD and CMD.
摘要-此次R01更新旨在继续PI的创造性,生产性和重要的研究计划,
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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JOHN S PARKS其他文献
JOHN S PARKS的其他文献
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{{ truncateString('JOHN S PARKS', 18)}}的其他基金
2016 Lipoprotein Metabolism Gordon Research Conference and Gordon Research Seminar
2016年脂蛋白代谢戈登研究会议暨戈登研究研讨会
- 批准号:
9119203 - 财政年份:2016
- 资助金额:
$ 48.92万 - 项目类别:
Regulation of ApoB Lipoprotein Expansion and Hepatic Lipid Efflux by ApoA-IV
ApoA-IV 对 ApoB 脂蛋白扩增和肝脂质流出的调节
- 批准号:
8772438 - 财政年份:2014
- 资助金额:
$ 48.92万 - 项目类别:
Regulation of ApoB Lipoprotein Expansion and Hepatic Lipid Efflux by ApoA-IV
ApoA-IV 对 ApoB 脂蛋白扩增和肝脂质流出的调节
- 批准号:
9302519 - 财政年份:2014
- 资助金额:
$ 48.92万 - 项目类别:
The Role of Hepatocyte ABCA1 in Lipid Mobilization and Transport
肝细胞 ABCA1 在脂质动员和运输中的作用
- 批准号:
8571018 - 财政年份:2013
- 资助金额:
$ 48.92万 - 项目类别:
The Role of Hepatocyte ABCA1 in Lipid Mobilization and Transport
肝细胞 ABCA1 在脂质动员和运输中的作用
- 批准号:
9301641 - 财政年份:2013
- 资助金额:
$ 48.92万 - 项目类别:
Hepatocyte Abca1, cholesterol trafficking, and lipid mobilization
肝细胞 Abca1、胆固醇运输和脂质动员
- 批准号:
10308037 - 财政年份:2013
- 资助金额:
$ 48.92万 - 项目类别:
The Role of Hepatocyte ABCA1 in Lipid Mobilization and Transport
肝细胞 ABCA1 在脂质动员和运输中的作用
- 批准号:
9081640 - 财政年份:2013
- 资助金额:
$ 48.92万 - 项目类别:
The Role of Hepatocyte ABCA1 in Lipid Mobilization and Transport
肝细胞 ABCA1 在脂质动员和运输中的作用
- 批准号:
8858676 - 财政年份:2013
- 资助金额:
$ 48.92万 - 项目类别:
Macrophage, ABCA1, Inflammation, and Atherosclerosis
巨噬细胞、ABCA1、炎症和动脉粥样硬化
- 批准号:
7901571 - 财政年份:2009
- 资助金额:
$ 48.92万 - 项目类别:
Macrophage, ABCA1, Inflammation, and Atherosclerosis
巨噬细胞、ABCA1、炎症和动脉粥样硬化
- 批准号:
8277087 - 财政年份:2009
- 资助金额:
$ 48.92万 - 项目类别:














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