Mechanism of ApoA1 Lipidation by ABCA1 in HDL biogenesis

 描述(由申请人提供)：流行病学研究表明，高密度脂蛋白胆固醇(高密度脂蛋白-胆固醇)水平高与心血管疾病(CVD)风险降低有关。然而，最近的遗传和药物研究表明，高密度脂蛋白胆固醇本身可能并不是降低心血管疾病风险的原因。相反，一个共识是，高密度脂蛋白的功能可以预防心血管疾病，而治疗高密度脂蛋白-C的生物标志物可能并不总是与高密度脂蛋白功能的增加相一致。高密度脂蛋白可能在其保护作用中发挥作用的功能之一是它在反向胆固醇运输(RCT)途径中的作用，在RCT途径中，胆固醇从周围组织中被清除，并被转移到肝脏进行排泄。高密度脂蛋白及其主要蛋白质成分载脂蛋白A-I(apoA-I)是这一过程的关键成分。在RCT途径的第一步，低脂的apoA-I通过细胞膜蛋白ABCA1作为细胞胆固醇和磷脂的受体，通过一种在分子水平上不被理解的机制产生新生的高密度脂蛋白。ABCA1有两个很有特点的活性，即磷脂酰丝氨酸的向外转运和其配体apoA-I的细胞表面结合。我们最近 表征了ABCA1的第三个活性，即展开apoA-I的N端螺旋毛发的能力。在目标1中，我们探索了我们的新发现，即磷脂酰肌醇磷酸盐(PIP)在新生高密度脂蛋白的生物发生中发挥作用。在目标2中，我们探索ABCA1帮助部分解开细胞表面apoA-I的机制，包括我们新发现的ABCA1介导的apoA-I在细胞表面酸化的作用。这些研究的成功完成将增加我们对从头产生高密度脂蛋白的机制的了解，这可能为提高高密度脂蛋白的生物发生和高密度脂蛋白的功能提供新的策略，并有助于预防心血管疾病。

 DESCRIPTION (provided by applicant): High levels of high density lipoprotein-cholesterol (HDL-C) are associated with lowered risk for cardiovascular disease (CVD) in epidemiological studies. However, recent genetic and drug studies have shown that HDL-C itself is probably not causal in reducing CVD risk. Instead, a consensus is building that HDL functions may protect against CVD, and that treating for the biomarker of HDL-C may not always coincide with increased HDL function. One of the functions of HDL that may play a role in its protective effect is its role in the reverse cholesterol transport (RCT) pathway, in which cholesterol is removed from peripheral tissues and transferred to the liver for excretion. HDL and its major protein constituent, apolipoprotein A-I (apoA-I), are critical components of this process. In the first ste of the RCT pathway, lipid-poor apoA-I acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCA1, generating nascent HDL through a mechanism which is not understood at the molecular level. ABCA1 has two well characterized activities, the outward translocation of phosphatidylserine, and the cell surface binding of its ligand apoA-I. We recently characterized a third activity of ABCA1, the ability to unfold apoA-I's N-terminal helical hairpin.In Aim 1, we explore our novel finding that phosphatidylinositol phosphates (PIPs) play a role in nascent HDL biogenesis. In Aim 2, we explore the mechanism by which ABCA1 helps partially unfold apoA-I on the cell surface, including the role of our novel finding of ABCA1 mediated acidification of apoA-I on the cell surface. Successful completion of the proposed studies will increase our knowledge of the mechanism of de novo HDL production, which may yield insights into new strategies to increase HDL biogenesis and HDL function, and aid in the prevention of CVD.