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

载脂蛋白（apo）A-II是一种丰富的人血浆蛋白，主要以高密度形式存在。 脂蛋白（HDL），但也在极低密度脂蛋白（VLDL）和乳糜微粒。尽管 虽然有大量文献记载，但其生理功能仍然模糊不清，并引起广泛争论。为 例如，它已被假定在心血管疾病中发挥有益和有害的作用， 疾病（CVD）的发展。我们认为apoA-II的功能与其他基因完全不同， 载脂蛋白，其倾向于直接充当辅因子或配体。我们假设载脂蛋白A- II通过改变脂蛋白质组间接影响HDL和VLDL代谢 和/或影响共存蛋白质的构象和功能。我们的工作表明， apoA-II可以刺激HDL促进胆固醇流出细胞，但只有当apoA-I 礼物这一点很重要，因为HDL胆固醇流出能力是一个更好的预测因子， 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/或受体的基础。 当apoA-II升高时介导清除。高脂血症和迟发性 餐后残留物清除是一个重要的CVD危险因素。我们将定义以下机制： apoA-II对HDL介导的胆固醇流出的增强作用及其对apoA-I的影响 结构使用创新的结构技术，包括低温电子显微镜。一个 一个重要的目标是确定apoA-II序列， 开发促进胆固醇流出的疗法。使用人血浆中的人蛋白质- 基于实验，我们还将确定apoA-II如何影响组成和结构 的其他VLDL蛋白质和评估的后果方面的活化脂蛋白 脂肪酶和与负责其血浆清除的细胞表面受体的结合。与一个完整 这些影响的机制的理解，它可能是可能的，推导出apoA-II的基础上， 最大限度地减少蛋白质的有害作用，同时优化 对心血管疾病和其他可能的代谢疾病有好处。

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.