Genetic and structure-function studies of missense mutations in human endothelial lipase.
Genetic and structure-function studies of missense mutations in human endothelial lipase.
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DOI：
10.1371/journal.pone.0055716
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Churchill ME
中科院分区：
文献类型：
--
作者：
Razzaghi H;Tempczyk-Russell A;Haubold K;Santorico SA;Shokati T;Christians U;Churchill ME
内皮脂肪酶(EL)在高密度脂蛋白代谢中起着关键作用。我们试图从基因、功能和结构上描述EL及其与高密度脂蛋白及其天然变体的相互作用。我们对我们的双族人群样本(n = 802)进行了筛选，以寻找选定的错义突变(n = 5)，并确定T111I是唯一常见的变异。西班牙裔受试者的多元线性回归分析显示，T111I与升高的低密度脂蛋白(p值 = 0.012)和总胆固醇(p值 = 0.004)存在意想不到的关联。我们检测了选定的错义突变体(n = 10)的脂肪酶活性，发现从正常到完全丧失活性对EL功能有不同的影响。EL-高密度脂蛋白脂体组分析表明，EL在不耗尽底物的情况下具有明确的高密度脂蛋白重塑，并且对几种脂肪酸具有明显的偏好，这些脂肪酸是脂质介质，以其强大的促炎和抗炎特性而闻名。同源建模结构研究发现，在C-结构域有一个新的α/β基序，是EL所特有的。EL二聚体被发现具有膨胀和结合不同大小的高密度脂蛋白颗粒的灵活性。所有已知的错义突变(n = 18)对EL结构的可能影响通过分子模拟以及它们可能对EL脂肪酶活性的影响使用基于它们的结构自由能差异的新的结构-功能斜率来检测。这一多学科方法的结果描绘了EL及其变体对高密度脂蛋白的影响。此外，这些结果表明EL有能力通过其在基于脂肪酸的信号通路中的作用来调节血管健康。
Endothelial lipase (EL) plays a pivotal role in HDL metabolism. We sought to characterize EL and its interaction with HDL as well as its natural variants genetically, functionally and structurally. We screened our biethnic population sample (n = 802) for selected missense mutations (n = 5) and identified T111I as the only common variant. Multiple linear regression analyses in Hispanic subjects revealed an unexpected association between T111I and elevated LDL-C (p-value = 0.012) and total cholesterol (p-value = 0.004). We examined lipase activity of selected missense mutants (n = 10) and found different impacts on EL function, ranging from normal to complete loss of activity. EL-HDL lipidomic analyses indicated that EL has a defined remodeling of HDL without exhaustion of the substrate and a distinct and preference for several fatty acids that are lipid mediators and known for their potent pro- and anti-inflammatory properties. Structural studies using homology modeling revealed a novel α/β motif in the C-domain, unique to EL. The EL dimer was found to have the flexibility to expand and to bind various sizes of HDL particles. The likely impact of the all known missense mutations (n = 18) on the structure of EL was examined using molecular modeling and the impact they may have on EL lipase activity using a novel structure-function slope based on their structural free energy differences. The results of this multidisciplinary approach delineated the impact of EL and its variants on HDL. Moreover, the results suggested EL to have the capacity to modulate vascular health through its role in fatty acid-based signaling pathways.
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影响因子：
2.9
作者：
Eydoux, Cecilia;Spinelli, Silvia;Carriere, Frederic
通讯作者：
Carriere, Frederic
影响因子：
3.7
作者：
Barter, Philip J;Puranik, Rajesh;Rye, Kerry-Anne
通讯作者：
Rye, Kerry-Anne
DOI：
10.1016/j.bbalip.2007.08.001
发表时间：
2007-10-01
影响因子：
4.8
作者：
Chen, Su;Subbaiah, Papasani V.
通讯作者：
Subbaiah, Papasani V.
影响因子：
20.1
作者：
Ahmed, W;Orasanu, G;Plutzky, J
通讯作者：
Plutzky, J
影响因子：
15.9
作者：
Besler, Christian;Heinrich, Kathrin;Landmesser, Ulf
通讯作者：
Landmesser, Ulf