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：了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）侧重于脂质代谢和运输，目的是定义 代谢和心血管疾病的机制。我们的PPG团队已经在脂质中发现了半数发现 代谢和运输。我们发现了一种传输脂蛋白脂肪酶的内皮细胞蛋白GPIHBP1 （LPL）到毛细管腔并稳定LPL的结构。最近，我们定义了 GPIHBP1 – LPL复合物，提供有关引起高甘油三酯血症的突变的新见解并打开 了解调节血管内脂解的机制。在胆固醇代谢领域， 我们的PPG发现巨噬细胞通过质膜（PM）发芽，富集的颗粒释放 在胆固醇中。我们的PPG发现了炎症信号传导与胆固醇代谢之间的联系 巨噬细胞，我们确定了一种新蛋白Aster-B，这对于PM之间的胆固醇运动至关重要 和内质网（ER）。 Aster-B缺乏会损害ER的胆固醇运动，导致 脂质生物合成基因的惊人上调。这些发现与 动脉粥样硬化完全取决于我们的PPG领导者与高级领导者之间的合作 其实验室中的分子，生化和成像功能。当我们展望未来时，我们将更深入地挖掘 进入我们发现的分子和机制。在项目1中，博士。 Young和他的PPG同事 将使用生化和生物物理工具来阐明LPL – GPIHBP1复合物的功能，包括 GPIHBP1的酸性结构域在稳定LPL活性并捕获LPL的作用。 他们还将通过电子显微镜和纳米示象研究，富含胆固醇的颗粒的萌芽 从巨噬细胞PM。他们将定义粒子的组成，并探索它们与反向的相关性 胆固醇运输。在项目2中，Bensinger博士和同事将确定炎症信号如何 调节巨噬细胞的脂肪组。他们还将定义胆固醇改变的机制 稳态会影响刺激信号传导以及刺激途径对血脂异常，注射和 动脉粥样硬化。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 运输，外排和酯化并阐明了体内固醇转运中Aster-B的功能。他们也会 评估“巨噬细胞途径”对动脉粥样硬化的贡献和其他蛋白质的筛查 胆固醇在细胞内的非维化运输所必需的。这三个组件项目将得到支持 由Loren Fong博士及其同事领导的单一科学核心。它们将产生重组蛋白，提供 高级显微镜服务，包括脂质的纳米sims成像。他们还将与Keriann博士合作 Backus提供化学蛋白质组学用于研究脂质代谢。我们的PPG对成功充满信心 因为我们有令人兴奋的假设，并且我们在科学和技术层面上都是一个团队。

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