The molecular basis for the role of apolipoprotein A-II in cholesterol and triglyceride metabolism

载脂蛋白 A-II 在胆固醇和甘油三酯代谢中作用的分子基础

• 批准号: 10318588
• 负责人: W Sean Davidson
• 金额: $ 49.82万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10318588
• 关键词: ATP-Binding Cassette Transporters; Affect; Agreement; Animal Model; Animals; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Blood Circulation; Cardiovascular Diseases; Cell Surface Receptors; Cells; Chemosensitization; Cholesterol; Cholesterol Homeostasis; Chylomicrons; Complex; Consensus; Cryoelectron Microscopy; Data; Development; Disease; Equilibrium; Experimental Models; Eye; Fatty acid glycerol esters; Genetic; Genetic Polymorphism; Goals; Hepatocyte; High Density Lipoprotein Cholesterol; High Density Lipoproteins; Human; Hypertriglyceridemia; Incubated; Inflammatory; Knowledge; Ligands; Lipids; Lipolysis; Lipoprotein (a); Lipoprotein Binding; Lipoproteins; Literature; Mediating; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Molecular Conformation; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Oxides; Physiological; Plasma; Plasma Proteins; Play; Predisposition; Process; Proteins; Proteome; Proteomics; Public Health; Resolution; Risk Factors; Role; Scaffolding Protein; Scientist; Structure; Techniques; Technology; Testing; Therapeutic; Time; Triglyceride Metabolism; Triglycerides; Vascular Diseases; Very low density lipoprotein; Work; atherogenesis; atheroprotective; base; cardiovascular disorder risk; design; experimental study; improved; in vivo; innovation; lipoprotein lipase; novel; particle; receptor; residence; uptake

Apolipoprotein (apo)A-II is an abundant human plasma protein primarily in high-density lipoproteins (HDL) but also in very low density lipoproteins (VLDL) and chylomicrons. Despite a large literature, its physiological functions remain ambiguous and widely debated. For example, it has been postulated to play both beneficial and detrimental roles in cardiovascular disease (CVD) development. We believe that apoA-II functions quite differently than other apolipoproteins, which tend to act directly as a co-factor or ligand. We hypothesize that apoA- II impacts both HDL and VLDL metabolism indirectly by altering the lipoprotein proteome and/or affecting the conformation and function of co-residing proteins. Our work shows that apoA-II can stimulate HDL to promote cholesterol efflux from cells, but only when apoA-I is present. This is important because HDL cholesterol efflux proficiency is a better predictor of cardiovascular disease (CVD) than its plasma levels. We also found that apoA-II impacts the VLDL proteome and suspect that this underlies delayed VLDL lipolysis and/or receptor mediated clearance when apoA-II is elevated. Hypertriglyceridemia and delayed post- prandial remnant clearance is an important CVD risk factor. We will define the mechanism for apoA-II’s potentiation of HDL-mediated cholesterol efflux by testing its effects on apoA-I structure using innovative structural techniques including cryo-electron microscopy. An important goal will be to identify the apoA-II sequences responsible with an eye toward developing cholesterol efflux boosting therapeutics. Using human proteins in human plasma- based experiments, we will also determine how apoA-II affects the composition and structure of other VLDL proteins and assess the consequences with respect to activation of lipoprotein lipase and binding to cell surface receptors responsible for its plasma clearance. With a full mechanistic understanding of these effects, it may be possible to derive apoA-II based therapeutic approaches that minimize the protein’s deleterious effects while optimizing benefits for CVD and possibly other metabolic diseases.

载脂蛋白（APO）A-II是高密度的丰富人血浆蛋白。 脂蛋白（HDL），但也以非常低的密度脂蛋白（VLDL）和乳糜微粒。尽管 大量文献，其身体功能仍然模棱两可，并广泛争论。为了 例如，已经假定在心血管中扮演有益和有害角色 疾病（CVD）发育。我们认为，apoa-II的功能与其他方面有很大不同 载脂蛋白倾向于直接充当副因素或配体。我们假设apoa- II通过改变脂蛋白蛋白质组间接影响HDL和VLDL代谢 和/或影响共同替代蛋白的构象和功能。我们的工作表明 ApoA-II可以刺激HDL以促进细胞的胆固醇外排，但只有当ApoA-I为 展示。这很重要，因为HDL胆固醇外排水平是更好的预测指标 心血管疾病（CVD）比其血浆水平。我们还发现Apoa-II影响 VLDL蛋白质组，并怀疑这是延迟的VLDL脂解和/或接收器的基础 ApoA-II升高时介导的清除率。高甘油三酯血症和延迟 培养基残留清除是重要的CVD风险因素。我们将定义机制 APOA-II通过测试其对APOA-I的影响来对HDL介导的胆固醇外排的增强 使用包括冷冻电子显微镜在内的创新结构技术的结构。一个 重要的目标是确定负责的apoa-II序列 发展胆固醇外排疗法。在人血浆中使用人蛋白 基于实验，我们还将确定ApoA-II如何影响组成和结构 其他VLDL蛋白质和评估脂蛋白激活的后果 脂肪酶并与负责其血浆清除率的细胞表面受体结合。充满 对这些效果的机械理解，可能会得出基于ApoA-II 优化蛋白质的有害效果的治疗方法 CVD以及可能其他代谢疾病的好处。