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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

基本信息

批准号：
10642750
负责人：
Nathan Oliver Stitziel
金额：
$ 47.64万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
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/10642750
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A ANGPTL3 gene Address Adipose tissue Alleles 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 Hyperinsulinism In Vitro Insulin Insulin Signaling Pathway 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 Oxidoreductase Participant Particle Size Pathway interactions Patients Physiologic pulse Physiological Adaptation Plasma Proteins Proteomics Regulation Research Personnel Risk Risk Reduction Role Skeletal Muscle Testing Therapeutic Tissue Harvesting Tracer Triglycerides Very low density lipoprotein cardiometabolism cardiovascular disorder risk extracellular glucose metabolism glucose production glucose uptake high risk human stem cells 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 pharmacologic programs protective effect randomized, clinical trials recruit side effect subcutaneous therapeutic target transcriptome transcriptome sequencing

项目摘要

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，治疗独立