Mechanism of ApoA1 Lipidation by ABCA1 in HDL biogenesis

 描述（由申请方提供）：流行病学研究表明，高水平的高密度脂蛋白胆固醇（HDL-C）与心血管疾病（CVD）风险降低相关。然而，最近的遗传和药物研究表明，HDL-C本身可能不是降低CVD风险的原因。相反，一个共识是HDL功能可以防止CVD，并且治疗HDL-C的生物标志物可能并不总是与增加HDL功能相一致。HDL在其保护作用中可能发挥作用的功能之一是其在胆固醇逆向转运（RCT）途径中的作用，其中胆固醇从外周组织中去除并转移到肝脏进行排泄。HDL及其主要蛋白质成分载脂蛋白A-I（apoA-I）是该过程的关键组分。在RCT途径的第一步中，贫脂apoA-I通过细胞膜蛋白ABCA 1作为细胞胆固醇和磷脂的受体，通过分子水平上尚不清楚的机制产生新生HDL。ABCA 1具有两种充分表征的活性，即磷脂酰丝氨酸的向外移位和其配体apoA-I的细胞表面结合。我们最近 ABCA 1的第三个活性是展开apoA-I的N-末端螺旋发夹的能力。在目标1中，我们探索了我们的新发现，即磷脂酰肌醇磷酸（PIP）在新生HDL生物合成中发挥作用。在目标2中，我们探索ABCA 1帮助apoA-I在细胞表面部分展开的机制，包括我们新发现的ABCA 1介导的apoA-I在细胞表面酸化的作用。成功完成拟议的研究将增加我们对从头HDL产生机制的了解，这可能会产生对增加HDL生物合成和HDL功能的新策略的见解，并有助于预防CVD。

 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.