Project 2: Regulation of lipid and glucose metabolism by ANGPTL3 in humans

项目2：ANGPTL3对人体脂质和葡萄糖代谢的调节

• 批准号: 10450862
• 负责人: Nathan Oliver Stitziel
• 金额: $ 47.43万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10450862
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; ANGPTL3 gene; Address; Adipose tissue; Antisense Oligonucleotides; Atherosclerosis; Biological Assay; Biology; Cardiovascular Diseases; Cell Fractionation; Cells; Classification; Co-Immunoprecipitations; Collaborations; Complement; Data; Diabetes Mellitus; Dyslipidemias; Endoplasmic Reticulum; Epidemiology; Exhibits; Family; Fasting; Fatty Liver; Genetic Transcription; Glucose; Glucose Clamp; Goals; Golgi Apparatus; Health; Hepatic; Hepatocyte; High Density Lipoprotein Cholesterol; Human; Human Biology; Human Genetics; In Vitro; Insulin; Insulin Signaling Pathway; Insulin-Dependent Diabetes Mellitus; Kinetics; LDL Cholesterol Lipoproteins; LIPG gene; Lead; Link; Lipase; Lipids; Lipolysis; Lipoproteins; Liver; Low-Density Lipoproteins; Measures; Mendelian randomization; Metabolic; Metabolism; Mus; Mutation; Non-Insulin-Dependent Diabetes Mellitus; Participant; Particle Size; Pathway interactions; Patients; Pharmacology; Physiologic pulse; Physiological Adaptation; Plasma; Proteins; Proteomics; Randomized Clinical Trials; Regulation; Research Personnel; Risk; Role; Skeletal Muscle; Testing; Therapeutic; Tissue Harvesting; Tracer; Triglycerides; Very low density lipoprotein; basal insulin; cardiometabolism; cardiovascular disorder risk; extracellular; glucose metabolism; glucose production; glucose uptake; high risk; human pluripotent stem cell; imaging approach; improved; in vivo; induced pluripotent stem cell; inhibitor; insulin sensitivity; lipid biosynthesis; lipid metabolism; lipoprotein lipase; lipoprotein triglyceride; loss of function mutation; novel; novel therapeutic intervention; particle; programs; protective effect; recruit; side effect; subcutaneous; therapeutic target; transcriptome; transcriptome sequencing

Human genetic, epidemiologic, and randomized clinical trial data suggest that therapies that independently lower LDL-C and TRLs reduce the risk of CVD. Inhibiting ANGPTL3 recently emerged as a novel therapeutic approach for reducing both LDL-C and TRLs, which, unlike other lipid-lowering therapies, may protect against diabetes because ANGPTL3-deficient subjects have improved insulin sensitivity. However, the complete metabolic consequences of inhibiting ANGPTL3 in humans and the cellular mechanisms responsible for the cardiometabolic protective effect of ANGPTL3 deficiency remain unknown. In that context, Project 2’s aims will define the role of ANGPTL3 in lipid and glucose metabolism. Aim 1 will determine how ANGPTL3 deficiency alters lipoprotein and glucose metabolism in humans, using in vivo tracer kinetic studies in controls and in a previously recruited family with participants who have either single or biallelic ANGPTL3 loss of function mutations. We will determine how ANGPTL3 deficiency alters fasting and postprandial plasma lipoprotein particle number, size, and composition in addition to adipose tissue and skeletal muscle transcriptional programs related to glucose metabolism. Aim 2 will use subject-specific iPSCs from humans with complete ANGPTL3 deficiency along with corrected isogenic control iPSCs to determine the cellular mechanisms linking ANGPTL3 with lipoprotein (including RLP) and glucose metabolism. Unlike the therapeutic targets of APOB (mipomerson) and MTTP (lomitapide), ANGPTL3 deficiency appears to reduce hepatic VLDL secretion without leading to hepatic steatosis. In addition, unlike other approved LDL-lowering therapies (statins, PSCK9 inhibitors, etc), ANGPTL3 deficiency appears to reduce LDL cholesterol without worsening risk for T2DM. Together, these observations suggest that ANGPTL3 may be working through novel intracellular and extracellular pathways that are yet to be discovered which collectively modulate lipoprotein and glucose metabolism. The studies outlined here are poised to discover these cellular mechanisms which hold the promise to expand our understanding of human biology and identify additional therapeutic targets for the treatment of dyslipidemia while improving glucose levels.

人类遗传学、流行病学和随机临床试验数据表明，独立治疗 较低的低密度脂蛋白和高密度脂蛋白胆固醇可降低心血管疾病的风险。抑制血管紧张素转换酶3最近作为一种新的治疗方法出现 同时降低LDL-C和TRL的方法，与其他降脂疗法不同，这可能会预防 糖尿病是因为血管紧张素转换酶3缺乏的受试者改善了胰岛素敏感性。然而，完整的 抑制血管紧张素转换酶3在人体内的代谢后果以及导致血管紧张素转换酶3的细胞机制 血管紧张素转换酶3缺乏对心脏代谢的保护作用尚不清楚。在这种背景下，项目2的S目标将 明确Angptl3在脂肪和葡萄糖代谢中的作用。目标1将确定Angptl3缺乏症 改变人类的脂蛋白和葡萄糖代谢，使用体内示踪剂动力学研究在对照和在 先前招募的有单等位或双等位基因Angptl3功能丧失的参与者的家庭 突变。我们将确定血管紧张素转换酶3缺乏如何改变空腹和餐后血浆脂蛋白 除了脂肪组织和骨骼肌转录外，颗粒数量、大小和组成 与葡萄糖新陈代谢有关的项目。Aim 2将使用来自人类的特定主题的ipscs，并完成 血管紧张素转换酶3缺乏症和校正的等基因控制的ipscs确定细胞机制连接 血管紧张素转换酶3与脂蛋白(包括RLP)和糖代谢。与载脂蛋白B的治疗靶点不同 (美波松)和MTTP(洛米替普)，Angptl3缺乏似乎减少肝脏VLDL的分泌，而不是 导致肝脏脂肪变性。此外，与其他已批准的降低低密度脂蛋白疗法(他汀类药物、PSCK9)不同 血管紧张素转换酶抑制剂等)，血管紧张素转换酶3缺乏似乎可以降低低密度脂蛋白胆固醇，而不会恶化患2型糖尿病的风险。 综上所述，这些观察表明Angptl3可能通过新的细胞内和 共同调节脂蛋白和葡萄糖的尚未发现的细胞外途径 新陈代谢。这里概述的研究准备发现这些细胞机制，这些细胞机制持有 承诺扩大我们对人类生物学的理解，并确定更多的治疗靶点 在改善血糖水平的同时治疗血脂异常。