Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112: Effects on Cholesterol Efflux, Anti-Inflammatory and Antioxidative Activity.
Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112: Effects on Cholesterol Efflux, Anti-Inflammatory and Antioxidative Activity.
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DOI：
10.1161/circresaha.116.308685
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发表时间：
2016-09-02
影响因子：
20.1
通讯作者：
Wright SD
中科院分区：
文献类型：
--
作者：
Didichenko SA;Navdaev AV;Cukier AM;Gille A;Schuetz P;Spycher MO;Thérond P;Chapman MJ;Kontush A;Wright SD
补充数字内容可在正文中找到。CSL112，人载脂蛋白A-I(apoA-I)，由磷脂酰胆碱重组而成，可引起小分子高密度脂蛋白(HDL1)的显著升高。探讨CSL112诱导高密度脂蛋白小颗粒形成的机制。将CSL112注入人体后，2个小直径高密度脂蛋白组分和1个大直径高密度脂蛋白组分升高。体外研究表明，这种重塑不依赖于脂转移蛋白或脂肪酶。相反，CSL112与纯化的高密度脂蛋白相互作用自发地产生了3个高密度脂蛋白物种：一个大的球形物种，由天然高密度脂蛋白和CSL112的apoA-I组成；一个小的盘状物种，由CSL112的apoA-I组成，但由于磷脂的损失而变小；以及最小的物种，低脂的apoA-I，由高密度脂蛋白和CSL112的apoA-I组成。时间-过程研究表明，重塑发生在CSL112与高密度脂蛋白的初始融合和随后的裂变导致较小的形式。功能研究表明，ATP结合盒转运体1依赖的胆固醇流出和全血中的抗炎作用是由2个小物种携带的，而在大物种中活性很小。相比之下，氧化型低密度脂蛋白中脂质氢过氧化的失活能力主要由两个最大的物种携带，而在缺乏脂质的载脂蛋白A-I中较低。我们已经描述了一种形成小的、高功能的高密度脂蛋白物种的机制，包括盘状高密度脂蛋白与球形高密度脂蛋白的自发融合以及随后的分裂。在体内apoA-I的生命周期中也可能发生类似的重塑。
Supplemental Digital Content is available in the text. CSL112, human apolipoprotein A-I (apoA-I) reconstituted with phosphatidylcholine, is known to cause a dramatic rise in small high-density lipoprotein (HDL). To explore the mechanisms by which the formation of small HDL particles is induced by CSL112. Infusion of CSL112 into humans caused elevation of 2 small diameter HDL fractions and 1 large diameter fraction. Ex vivo studies showed that this remodeling does not depend on lipid transfer proteins or lipases. Rather, interaction of CSL112 with purified HDL spontaneously gave rise to 3 HDL species: a large, spherical species composed of apoA-I from native HDL and CSL112; a small, disc-shaped species composed of apoA-I from CSL112, but smaller because of the loss of phospholipids; and the smallest species, lipid-poor apoA-I composed of apoA-I from HDL and CSL112. Time-course studies suggest that remodeling occurs by an initial fusion of CSL112 with HDL and subsequent fission leading to the smaller forms. Functional studies showed that ATP-binding cassette transporter 1–dependent cholesterol efflux and anti-inflammatory effects in whole blood were carried by the 2 small species with little activity in the large species. In contrast, the ability to inactivate lipid hydroperoxides in oxidized low-density lipoprotein was carried predominantly by the 2 largest species and was low in lipid-poor apoA-I. We have described a mechanism for the formation of small, highly functional HDL species involving spontaneous fusion of discoidal HDL with spherical HDL and subsequent fission. Similar remodeling is likely to occur during the life cycle of apoA-I in vivo.