Human apoA-I[Lys107del] mutation affects lipid surface behavior of apoA-I and its ability to form large nascent HDL.
Human apoA-I[Lys107del] mutation affects lipid surface behavior of apoA-I and its ability to form large nascent HDL.
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DOI：
10.1016/j.jlr.2022.100319
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发表时间：
2023-02
影响因子：
6.5
通讯作者：
Atkinson, David
中科院分区：
文献类型：
--
作者：
Gorshkova, Irina N.;Meyers, Nathan L.;Herscovitz, Haya;Mei, Xiaohu;Atkinson, David
关键词：
人群研究发现，人类apoA-I的一个自然变异，apoA-I[K107del]，与低HDLc但正常的血浆apoA-I水平密切相关。我们的目的是揭示这种变异的特性，从而导致其与动脉粥样硬化相关的不同寻常的表型。我们的油滴张力计研究表明，与WT相比，重组apoA-I[K107del]以更快的速度吸附到POPC包被的三油酸脂液滴的表面，在更大程度上重塑了表面，并在较高的表面压力下被挤出表面，压缩了脂滴。这些特性可能促使apoA-I[K107del]与大的富含甘油三酯的脂蛋白结合增加，并更好地保留它，从而增加这些脂蛋白上的变异体的含量。虽然K107del不影响apoA-I促进ABCA1介导的胆固醇从J774细胞外流的能力，但它损害了大的新生高密度脂蛋白颗粒的生物发生，导致形成主要较小的新生高密度脂蛋白。自发重组的1，2-二肉豆蔻基磷脂酰胆碱-apoA-I络合物的尺寸排斥层析表明，apoA-I[K107del]形成较大的络合物的能力受到阻碍，但有效地形成较小的络合物。CD分析表明，apoA-I[K107del]与1，2-二肉豆蔻基磷脂酰胆碱结合或在三氟乙醇存在下增加α-螺旋结构的能力降低。这一特性可能会阻碍含有大的apoA-I[K107del]的盘状和球形高密度脂蛋白的形成，但不会阻碍较小的高密度脂蛋白的形成。这两个因素，富含甘油三酯的脂蛋白上apoA-I[K107del]含量的增加，以及该变异体稳定大的高密度脂蛋白颗粒的能力减弱，导致高密度脂蛋白中脂质与蛋白质的比例降低，可能导致正常的血浆载脂蛋白-I水平以及低高密度脂蛋白-C和增加心血管疾病的风险。
Population studies have found that a natural human apoA-I variant, apoA-I[K107del], is strongly associated with low HDL-C but normal plasma apoA-I levels. We aimed to reveal properties of this variant that contribute to its unusual phenotype associated with atherosclerosis. Our oil-drop tensiometry studies revealed that compared to WT, recombinant apoA-I[K107del] adsorbed to surfaces of POPC-coated triolein drops at faster rates, remodeled the surfaces to a greater extent, and was ejected from the surfaces at higher surface pressures on compression of the lipid drops. These properties may drive increased binding of apoA-I[K107del] to and its better retention on large triglyceride-rich lipoproteins, thereby increasing the variant’s content on these lipoproteins. While K107del did not affect apoA-I capacity to promote ABCA1-mediated cholesterol efflux from J774 cells, it impaired the biogenesis of large nascent HDL particles resulting in the formation of predominantly smaller nascent HDL. Size-exclusion chromatography of spontaneously reconstituted 1,2-dimyristoylphosphatidylcholine-apoA-I complexes showed that apoA-I[K107del] had a hampered ability to form larger complexes but formed efficiently smaller-sized complexes. CD analysis revealed a reduced ability of apoA-I[K107del] to increase α-helical structure on binding to 1,2-dimyristoylphosphatidylcholine or in the presence of trifluoroethanol. This property may hinder the formation of large apoA-I[K107del]-containing discoidal and spherical HDL but not smaller HDL. Both factors, the increased content of apoA-I[K107del] on triglyceride-rich lipoproteins and the impaired ability of the variant to stabilize large HDL particles resulting in reduced lipid:protein ratios in HDL, may contribute to normal plasma apoA-I levels along with low HDL-C and increased risk for CVD.
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