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

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