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ANGPTL8: function and mechanism of action

ANGPTL8：功能和作用机制

基本信息

批准号：
9381308
负责人：
Ren Zhang
金额：
$ 39.73万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9381308
关键词：
ANGPTL3 gene Address Adipose tissue Alleles Alpha Cell Antibodies Binding Blood Circulation Blood capillaries CRISPR/Cas technology Cardiac Cardiomyopathies Cell Culture System Cell surface Clinical Trials Complex Data Disease Dyslipidemias Endonuclease I Endothelial Cells Epitope Mapping Exhibits Fasting Fatty Acids Goals Health Heart Hepatic High Fat Diet Hypertriglyceridemia Injectable Injection of therapeutic agent Insulin Resistance Isotope Labeling Knockout Mice Lead Liver Mediating Metabolism Methodology Methods Modeling Molecular Monoclonal Antibodies Morbidity - disease rate Mus Muscle Mutagenesis Myocardium Nonesterified Fatty Acids Nutritional Obesity Palmitates Peptide Library Peripheral Physiological Processes Plasma Positioning Attribute Proteins Regulation Research Role Route Serum Skeletal Muscle Solid Surface Technology Testing Therapeutic Tissues Triglyceride Metabolism Triglycerides United States Wild Type Mouse base capillary cardiovascular disorder risk disorder risk feeding insulin sensitivity lipoprotein lipase mortality new therapeutic target novel novel strategies overexpression tool trafficking uptake

项目摘要

Elevated plasma triglycerides (TG) increase the risk of cardiovascular disease, a leading cause of morbidity and mortality in the United States. As the primary determinant of plasma TG levels, lipoprotein lipase (LPL), anchored by the endothelial cell protein GPIHBP1 to the capillary luminal surface, hydrolyzes circulating TG into free fatty acids that are taken up by peripheral tissues. LPL activity is tightly regulated to enable circulating TG be routed into cardiac and skeletal muscles to generate energy during fasting and into white adipose tissue (WAT) for storage in the fed state. However, the molecular mechanisms for regulating tissue-specific LPL activity during the fed-fast cycle are largely unknown. ANGPTL8 (lipasin) is a recently described TG metabolism regulator, which is specifically expressed in liver and adipose tissues. In the liver, which secretes ANGPTL8 into the circulation, ANGPTL8 expression is reduced by fasting and dramatically increased by feeding. In mice, ANGPTL8 deficiency causes hypotriglyceridemia, whereas its hepatic overexpression causes hypertriglyceridemia. Despite having great therapeutic potential in treating dyslipidemia, ANGPTL8’s functions and mechanism of action remain elusive. Based on our solid preliminary data, we propose to study the functional roles of ANGPTL8 and the mechanism by which it regulates TG metabolism. In Aim 1, we will determine functional roles of ANGPTL8 in regulating TG trafficking, by performing fluxomics analysis with isotope-labeled TG in ANGPTL8 KO mice, wild-type mice with injection of an ANGPTL8 monoclonal TG- lowering antibody, as well as liver and adipose-specific KO mice. In Aim 2, we will elucidate mechanisms of ANGPTL8-mediated inhibition of GPIHBP1-bound LPL. By using a novel cell-culture system to examine LPL complexed with GPIHBP1 on the endothelial cell surface, we will examine the interactions among ANGPTL8, ANGPTL3, and LPL-GPIHBP1 complexes. Upon completion, we will have revealed the molecular mechanism by which ANGPTL8 regulates LPL to direct TG trafficking to specific tissues during the fed-fast cycle, a physiological process of fundamental importance.

血浆甘油三酯 (TG) 升高会增加心血管疾病的风险，而心血管疾病是美国发病率和死亡率的主要原因。作为血浆 TG 水平的主要决定因素，脂蛋白脂肪酶 (LPL) 通过内皮细胞蛋白 GPIHBP1 锚定在毛细血管腔表面，将循环中的 TG 水解成被外周组织吸收的游离脂肪酸。 LPL 活性受到严格调节，使循环 TG 能够进入心脏和骨骼肌，在禁食期间产生能量，并进入白色脂肪组织 (WAT)，在进食状态下储存。然而，在禁食周期中调节组织特异性 LPL 活性的分子机制在很大程度上尚不清楚。 ANGPTL8（lipasin）是最近描述的TG代谢调节剂，在肝脏和脂肪组织中特异性表达。在将 ANGPTL8 分泌到循环中的肝脏中，ANGPTL8 的表达因禁食而减少，并因进食而急剧增加。在小鼠中，ANGPTL8 缺乏会导致低甘油三酯血症，而其肝脏过度表达则会导致高甘油三酯血症。尽管 ANGPTL8 在治疗血脂异常方面具有巨大的治疗潜力，但其功能和作用机制仍然难以捉摸。基于我们扎实的初步数据，我们建议研究ANGPTL8的功能作用及其调节TG代谢的机制。在目标 1 中，我们将通过在 ANGPTL8 KO 小鼠、注射 ANGPTL8 单克隆 TG 降低抗体的野生型小鼠以及肝脏和脂肪特异性 KO 小鼠中使用同位素标记的 TG 进行通量组学分析，确定 ANGPTL8 在调节 TG 运输中的功能作用。在目标 2 中，我们将阐明 ANGPTL8 介导的 GPIHBP1 结合 LPL 抑制的机制。通过使用新型细胞培养系统来检查内皮细胞表面上 LPL 与 GPIHBP1 的复合物，我们将检查 ANGPTL8、ANGPTL3 和 LPL-GPIHBP1 复合物之间的相互作用。完成后，我们将揭示 ANGPTL8 调节 LPL 的分子机制，以在禁食周期（一个至关重要的生理过程）中引导 TG 运输至特定组织。