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: 10533294
• 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/10533294
• 关键词: ATP-Binding Cassette Transporters; Affect; Agreement; Animal Model; Animals; Apolipoprotein A-I; Apolipoprotein A-II; Apolipoproteins; Cardiovascular Diseases; Cell Surface Receptors; Cells; Chemosensitization; Cholesterol; Cholesterol Homeostasis; Chylomicrons; Circulation; Complex; Consensus; Cryoelectron Microscopy; Data; Development; Disease; Equilibrium; Experimental Models; 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; Low-Density Lipoproteins; Mediating; Metabolic Diseases; Metabolic syndrome; Metabolism; Molecular; Molecular Conformation; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; 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; cardiovascular disorder risk; cofactor; design; experimental study; improved; in vivo; innovation; lipoprotein lipase; novel; overexpression; 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 是一种丰富的人类血浆蛋白，主要以高密度形式存在 脂蛋白（HDL），也存在于极低密度脂蛋白（VLDL）和乳糜微粒中。 虽然文献很多，但其生理功能仍然含糊不清并受到广泛争论。 例如，它被认为在心血管方面发挥着有益和有害的作用 我们认为 apoA-II 的功能与其他疾病有很大不同。 载脂蛋白，它往往直接作为辅助因子或配体，我们追逐的是apoA-。 II 通过改变脂蛋白蛋白质组间接影响 HDL 和 VLDL 代谢 和/或影响共存蛋白质的构象和功能。 apoA-II 可以刺激 HDL 促进胆固醇从细胞流出，但前提是 apoA-I 存在 这很重要，因为 HDL 胆固醇流出能力是更好的预测指标。 我们还发现 apoA-II 对心血管疾病 (CVD) 的影响大于其血浆水平。 VLDL 蛋白质组并怀疑这是 VLDL 脂解延迟和/或受体的基础 当 apoA-II 升高且高甘油三酯血症时介导清除。 膳食残渣清除是一个重要的 CVD 危险因素，我们将明确其机制。 通过测试 apoA-II 对 apoA-I 的影响来增强 HDL 介导的胆固醇流出 使用包括冷冻电子显微镜在内的创新结构技术进行结构。 重要的目标是确定 apoA-II 序列，着眼于 使用人类血浆中的人类蛋白质开发胆固醇流出促进疗法。 基于实验，我们还将确定 apoA-II 如何影响组成和结构 其他 VLDL 蛋白并评估脂蛋白激活的后果 脂肪酶并与细胞表面受体结合，负责其血浆清除。 如果了解了这些效应的机制，就有可能推导出基于 apoA-II 的 在优化的同时最大限度地减少蛋白质的有害影响的治疗方法 对心血管疾病和可能的其他代谢疾病有好处。