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
• 负责人: Stephen G. Young
• 金额: $ 232.58万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10613963
• 关键词: ATP binding cassette transporter 1; Affect; Atherosclerosis; Binding; Biochemical; Biological Assay; Biology; Blood capillaries; Cardiometabolic Disease; Cardiovascular Diseases; Cardiovascular system; Cell membrane; Cells; Chemicals; Cholesterol; Cholesterol Homeostasis; Collaborations; Complex; Coronary heart disease; Disease; Dyslipidemias; Electron Microscopy; Electronic Mail; Endoplasmic Reticulum; Endothelial Cells; Esterification; Funding; Future; Genes; Goals; Health; High Density Lipoproteins; Homeostasis; Hour; Human; Human Resources; Hypertriglyceridemia; Image; Impairment; Inflammation; Inflammatory; Joints; Knowledge; Laboratories; Link; Lipids; Lipolysis; Macrophage; Metabolic; Metabolic Diseases; Microscopy; Molecular; Movement; Mutation; National Heart, Lung, and Blood Institute; Pathogenesis; Pathway interactions; Plasma; Play; Production; Program Research Project Grants; Proteins; Proteome; Proteomics; Public Health; Publications; Recombinant Proteins; Research; Research Personnel; Rest; Role; STING1 gene; Scanning; Seminal; Services; Shapes; Signal Transduction; Sterols; Structure; Structure-Activity Relationship; Telephone; Testing; Triglyceride Metabolism; Triglycerides; Up-Regulation; Visualization; Work; atherogenesis; biochemical tools; biophysical tools; cell type; chemoproteomics; data sharing; defined contribution; disorder risk; experience; fatty acid metabolism; imaging capabilities; in vivo; insight; interferon therapy; lipid metabolism; lipid transport; lipidome; lipoprotein lipase; member; novel; novel strategies; particle; response; reverse cholesterol transport; success; synergism; virtual

PPG Title: New Approaches for Understanding Lipid Movement in Health and Disease SUMMARY/ABSTRACT Our Program Project Grant (PPG) focuses on lipid metabolism and transport, with the goal of defining mechanisms for metabolic and cardiovascular disease. Our PPG team has made seminal discoveries in lipid metabolism and transport. We discovered an endothelial cell protein, GPIHBP1, that transports lipoprotein lipase (LPL) to the capillary lumen and stabilizes the structure of LPL. Recently, we defined the structure of the GPIHBP1–LPL complex, providing fresh insights into mutations causing hypertriglyceridemia and opening the door to understanding mechanisms that regulate intravascular lipolysis. In the realm of cholesterol metabolism, our PPG discovered that macrophages release, by plasma membrane (PM) budding, particles that are enriched in cholesterol. Our PPG uncovered a link between inflammatory signaling and cholesterol metabolism in macrophages, and we identified a new protein, Aster-B, that is critical for cholesterol movement between the PM and the endoplasmic reticulum (ER). A deficiency of Aster-B impairs cholesterol movement to the ER, causing a striking upregulation of lipid biosynthetic genes. These discoveries, all relevant to the pathogenesis of atherosclerosis, were utterly dependent on collaborations between our PPG leaders and the advanced molecular, biochemical, and imaging capabilities in their laboratories. As we look to the future, we will dig deeper into the molecules and mechanisms that we have uncovered. In project 1, Drs. Young and his PPG colleagues will use biochemical and biophysical tools to elucidate the functions of the LPL–GPIHBP1 complex, including the role of GPIHBP1’s acidic domain in stabilizing LPL activity and capturing LPL within the subendothelial spaces. They will also study, with electron microscopy and NanoSIMS imaging, the budding of cholesterol-rich particles from the macrophage PM. They will define the composition of the particles and explore their relevance to reverse cholesterol transport. In project 2, Dr. Bensinger and coworkers will determine how inflammatory signals modulate the lipidome of macrophages. They will also define mechanisms by which alterations in cholesterol homeostasis affect STING signaling and the impact of the STING pathway on dyslipidemia, inflammation, and atherogenesis. In Project 3, Dr. Tontonoz and his PPG coworkers will explore the role of Aster-B in cholesterol transport, efflux, and esterification and elucidate the function of Aster-B in sterol transport in vivo. They will also assess the contribution of the “macrophage Aster pathway” to atherosclerosis and screen for additional proteins required for the nonvesicular transport of cholesterol within cells. The three component projects will be supported by a single scientific core, led by Dr. Loren Fong and colleagues. They will produce recombinant proteins, provide advanced microscopy services, including NanoSIMS imaging of lipids. They will also work with Dr. Keriann Backus to provide chemical proteomics for investigating lipid metabolism. Our PPG is confident in success because we have exciting hypotheses and we work as a team at both scientific and technical levels.

PPG标题：理解健康和疾病中脂质运动的新方法 摘要/摘要 我们的计划项目赠款(PPG)专注于脂类代谢和运输，目标是定义 代谢和心血管疾病的机制。我们的PPG团队在脂质方面有了开创性的发现 新陈代谢和运输。我们发现了一种内皮细胞蛋白GPIHBP1，它可以运输脂蛋白脂肪酶 (LPL)到毛细管腔，稳定LPL的结构。最近，我们定义了 GPIHBP1-LPL复合体，为导致高甘油三酯血症的突变提供了新的见解，并打开了 了解调节血管内脂肪分解的机制。在胆固醇代谢领域， 我们的PPG发现，巨噬细胞通过质膜(PM)萌芽释放浓缩的颗粒 胆固醇。我们的PPG发现炎症信号和胆固醇代谢之间的联系 巨噬细胞，我们发现了一种新的蛋白质，Aster-B，它对PM之间的胆固醇运动至关重要 内质网(ER)。Aster-B的缺乏会损害胆固醇向内质网的移动，导致 脂类生物合成基因的显著上调。这些发现，都与霍乱的发病机制有关。 动脉粥样硬化，完全依赖于我们的PPG领导人和高级 他们实验室的分子、生化和成像能力。展望未来，我们将更深入地挖掘 我们已经发现的分子和机制。在项目1中，杨博士和他的PPG同事 将使用生化和生物物理工具来阐明LPL-GPIHBP1复合体的功能，包括 GPIHBP1‘S酸性结构域在稳定脂蛋白脂酶活性和捕获内皮下间隙脂蛋白中的作用 他们还将用电子显微镜和NanoSIMS成像技术研究富含胆固醇颗粒的萌芽 来自巨噬细胞PM他们将定义粒子的组成，并探索它们与反转的相关性 胆固醇的运输。在项目2中，本辛格博士和同事将确定炎症信号如何 调节巨噬细胞的脂质体。他们还将定义胆固醇变化的机制 动态平衡影响STING信号和STING通路对血脂异常、炎症和 动脉粥样硬化的形成。在项目3中，Tontonoz博士和他的PPG同事将探索Aster-B在胆固醇中的作用 转运、外排和酯化，阐明Aster-B在体内甾醇转运中的作用。他们还将 评估“巨噬细胞Aster途径”在动脉粥样硬化中的作用并筛选额外的蛋白质 胆固醇在细胞内的非囊泡运输所必需的。这三个组成部分项目将得到支持 由Loren Fong博士和他的同事领导的单一科学核心。它们将产生重组蛋白，提供 先进的显微镜服务，包括脂质的NanoSIMS成像。他们还将与克里安博士合作 Backus为研究脂代谢提供化学蛋白质组学。我们的PPG对成功充满信心 因为我们有令人兴奋的假设，我们作为一个团队在科学和技术层面上工作。

项目成果

Profiling of mouse macrophage lipidome using direct infusion shotgun mass spectrometry.

• DOI: 10.1016/j.xpro.2020.100235
• 发表时间: 2021-03-19
• 期刊: STAR protocols
• 作者: Hsieh WY;Williams KJ;Su B;Bensinger SJ
• 通讯作者: Bensinger SJ

Selective Aster inhibitors distinguish vesicular and nonvesicular sterol transport mechanisms.

选择性 Aster 抑制剂区分囊泡和非囊泡甾醇转运机制。

• DOI: 10.1073/pnas.2024149118
• 发表时间: 2021
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Xiao,Xu;Kim,Youngjae;Romartinez-Alonso,Beatriz;Sirvydis,Kristupas;Ory,DanielS;Schwabe,JohnWR;Jung,MichaelE;Tontonoz,Peter
• 通讯作者: Tontonoz,Peter