HDL superphospholipidation enhances key steps in reverse cholesterol transport
HDL superphospholipidation enhances key steps in reverse cholesterol transport
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DOI：
10.1016/j.atherosclerosis.2009.10.002
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发表时间：
2010-04-01
期刊：
影响因子：
5.3
通讯作者：
Pownall, Henry J.
中科院分区：
文献类型：
--
作者：
Tchoua, Urbain;Gillard, Baiba K.;Pownall, Henry J.
高密度脂蛋白磷脂（HDL-PL）在胆固醇逆向转运（RCT）中起重要作用。磷脂酰胆碱（PC）是RCT中最重要的磷脂，因为它是脂蛋白的必需胆固醇结合组分，并且是卵磷脂：胆固醇酰基转移酶（LCAT）酯化FC的酰基供体。FC向血清的流出是HDL-PL的积极抗动脉粥样硬化功能。虽然PC长期以来被认为是一种抗动脉粥样硬化剂，但基于PC的新HDL疗法的开发充满了疗效、成本和安全性问题。此外，一些增加HDL-PC的方法干扰HDL并释放无脂质载脂蛋白（apo）A-I。我们开发了一种新的方法，HDL SPLn（SPLn）使用改进的去污剂去除方法，消除了这些问题。SPLn可将PC掺入HDL中并使HDL-PC增加> 10倍。这在没有apo A-I损失的情况下实现。根据尺寸排阻色谱和天然梯度凝胶电泳，SPLn以剂量依赖性方式提高HDL颗粒重量，从接近120 kDa提高到接近350 kDa。FC流出到所得SPLn颗粒的动力学分析显示，SPLn HDL的Km和V-max分别低于和高于天然HDL。因此，催化效率V-max/K-m增加超过400%。临床上，血清HDL-PL的小幅增加与FC流出至血清的显著和深刻增加相关。通过SPLn处理相对少量的血浆是改善RCT中至少一个步骤的潜在方法。(C)2009爱思唯尔爱尔兰有限公司保留所有权利。
HDL-phospholipids (HDL-PL) play an important role in reverse cholesterol transport (RCT). Phosphatidylcholine (PC) is the most important phospholipid in RCT because it is the essential cholesterol-binding component of lipoproteins and is the acyl donor in the esterification of FC by lecithin: cholesterol acyltransferase (LCAT). FC efflux to sera is a positive anti-atherogenic function of HDL-PL. Although PC has long been recognized as an anti-atherogenic agent, development of new HDL therapies based on PC has been fraught with issues of efficacy, cost, and safety. Moreover, some methods to increase HDL-PC perturb HDL and release lipid-free apolipoproteins (apo) A-I. We developed a new method, HDL SPLn (SPLn) using a modified detergent removal method that obviates these concerns. SPLn can incorporate PC into HDL and increase HDL-PC > 10-fold. This is achieved with no loss of apo A-I. According to size exclusion chromatography and native gradient gel electrophoresis, SPLn raises the HDL particle weight in a dose-dependent way, from similar to 120 to similar to 350 kDa. Kinetic analysis of FC efflux to the resulting SPLn particles shows that K-m and V-max for SPLn HDL are lower and higher respectively than for native HDL. As a consequence, the catalytic efficiency, V-max/K-m, increases by more than 400%. Clinically, small increases in serum HDL-PL are associated with significant and profound increases in FC efflux to serum. Treatment of relatively small amounts of plasma by SPLn is a potential method of improving at least one step in RCT. (C) 2009 Elsevier Ireland Ltd. All rights reserved.