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: 10096569
• 负责人: W Sean Davidson
• 金额: $ 49.55万
• 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/10096569
• 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A-II是一种含量丰富的人血浆蛋白，主要以高密度 脂蛋白(HDL)也存在于极低密度脂蛋白(VLDL)和乳糜粒中。尽管 作为一部大型文献，它的生理功能仍然模棱两可，并引发了广泛的争论。为 例如，它被认为在心血管疾病中既有有益的作用也有有害的作用 疾病(CVD)的发展。我们认为载脂蛋白A-II的功能与其他 载脂蛋白，倾向于直接作为辅助因子或配体。我们假设apoA- II通过改变脂蛋白蛋白质组间接影响高密度脂蛋白和极低密度脂蛋白的代谢 和/或影响共存蛋白质的构象和功能。我们的工作表明 载脂蛋白A-II可以刺激高密度脂蛋白促进胆固醇从细胞外流，但只有当载脂蛋白A-I 现在时。这一点很重要，因为高密度脂蛋白流出的熟练程度是更好的预测 心血管疾病(CVD)的水平高于其血浆水平。我们还发现载脂蛋白A-II影响了 VLDL蛋白质组，并怀疑这是延迟的VLDL脂解和/或受体的基础 载脂蛋白A-II升高时介导的清除。高甘油三酯血症和迟发性后遗症 膳食残留物清除是心血管疾病的重要危险因素。我们将定义以下机制： 载脂蛋白A-II通过检测其对载脂蛋白A-I的影响增强高密度脂蛋白介导的胆固醇外流 使用创新的结构技术，包括冷冻电子显微镜。一个 重要的目标将是识别apoA-II序列，并着眼于 开发促进胆固醇外流的治疗药物。利用人类血浆中的人类蛋白质- 在实验的基础上，我们还将确定apoA-II如何影响组成和结构 并评估与脂蛋白激活有关的后果 脂肪酶和与细胞表面受体的结合负责其血浆清除。带着完整的 从机理上理解这些影响，可能会得出基于载脂蛋白A-II的 治疗方法，将蛋白质的有害影响降至最低，同时优化 对心血管疾病和可能的其他代谢性疾病的好处。