HDL subclass proteomic analysis and functional implication of protein dynamic change during HDL maturation
HDL subclass proteomic analysis and functional implication of protein dynamic change during HDL maturation
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DOI：
10.1016/j.redox.2019.101222
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发表时间：
2019-06-01
期刊：
影响因子：
11.4
通讯作者：
Wang, Hong
中科院分区：
文献类型：
--
作者：
Zhang, Yuling;Gordon, Scott M.;Wang, Hong
最近的临床试验报道，增加高密度脂蛋白胆固醇（HDL-C）水平并不能改善心血管结局。我们假设HDL蛋白质组动力学决定HDL心脏保护功能。在这项研究中，我们的特点是蛋白质组的高密度脂蛋白亚类，并建立其功能的连接。用快速蛋白质液相色谱法分离小鼠血浆，测定蛋白质、磷脂、甘油三酯含量。收集小、中和大（S/M/L）-HDL亚类用于通过质谱法进行蛋白质组学分析。鉴定了51种HDL蛋白（S-HDL中39种，M-HDL中27种，L-HDL中29种），并将其分为4个功能类别（脂质代谢，免疫反应，凝血和其他）。在所有HDL亚类中鉴定了11种HDL共同蛋白。仅在S-HDL、M-HDL和L-HDL中分别发现16、3和7个蛋白质。建立了S/M/L-HDL中HDL蛋白质的动态分布，并建立了HDL成熟过程中蛋白质组成变化的模型。我们发现，胆固醇流出和免疫反应是所有HDL颗粒的基本功能，氨基酸代谢是S-HDL的特殊功能，而抗凝是M-HDL的特殊功能。Pon 1被募集到M/L-HDL中以提供其抗氧化功能。ApoE被掺入L-HDL中以优化其动脉清除功能。接下来，我们从Pubmed获得HDL蛋白质组数据，并在人和小鼠HDL颗粒中鉴定了12个复制蛋白。最后，我们提取了所有HDL颗粒的3个共享的顶级分子通路（LXR/RXR、FXR/RXR和急性期反应）和与S/M/L-HDL亚类差异相关的5个顶级疾病/生物功能，并为每个HDL亚类呈现了一个顶级网络。结论：HDL成熟过程中，除了胆固醇流出和免疫应答的基本功能外，还通过募集Pon 1和ApoE来获得抗氧化和胆固醇清除功能。
Recent clinical trials reported that increasing high-density lipoprotein-cholesterol (HDL-C) levels does not improve cardiovascular outcomes. We hypothesize that HDL proteome dynamics determine HDL cardioprotective functions. In this study, we characterized proteome profiles in HDL subclasses and established their functional connection. Mouse plasma was fractionized by fast protein liquid chromatography, examined for protein, cholesterial, phospholipid and trigliceride content. Small, medium and large (S/M/L)-HDL subclasseses were collected for proteomic analysis by mass spectrometry. Fifty-one HDL proteins (39 in S-HDL, 27 in M-HDL and 29 in L-HDL) were identified and grouped into 4 functional categories (lipid metabolism, immune response, coagulation, and others). Eleven HDL common proteins were identified in all HDL subclasses. Sixteen, 3 and 7 proteins were found only in S-HDL, M-HDL and L-HDL, respectively. We established HDL protein dynamic distribution in S/M/L-HDL and developed a model of protein composition change during HDL maturation. We found that cholesterol efflux and immune response are essential functions for all HDL particles, and amino acid metabolism is a special function of S-HDL, whereas anti-coagulation is special for M-HDL. Pon1 is recruited into M/L-HDL to provide its antioxidative function. ApoE is incorporated into L-HDL to optimize its cholesterial clearance function. Next, we acquired HDL proteome data from Pubmed and identified 12 replicated proteins in human and mouse HDL particle. Finally, we extracted 3 shared top moleccular pathways (LXR/RXR, FXR/RXR and acute phase response) for all HDL particles and 5 top disease/bio-functions differentially related to S/M/L-HDL subclasses, and presented one top net works for each HDL subclass. We conclude that beside their essencial functions of cholesterol efflux and immune response, HDL aquired antioxidative and cholesterol clearance functions by recruiting Pon1 and ApoE during HDL maturation.