Human plasma high-density lipoproteins are stabilized by kinetic factors
Human plasma high-density lipoproteins are stabilized by kinetic factors
复制标题
DOI：
10.1016/s0022-2836(03)00155-4
复制
发表时间：
2003-04-18
影响因子：
5.6
通讯作者：
Gursky, O
中科院分区：
文献类型：
--
作者：
Mehta, R;Gantz, DL;Gursky, O
高密度脂蛋白（HDL）是介导胆固醇从体内排出的蛋白质和脂质的异质复合物。我们的热和化学变性研究的成熟的球形HDL从人血浆中分离出的结果表明，与广泛持有的假设，颗粒的稳定性有动力学，而不是热力学的起源。用圆二色性（CD）在222 nm处监测的盐酸胍（GdmHCl）在25 ℃的浓度跃变揭示了HDL变性的两个主要的不可逆动力学阶段。在1-6 M GdmHCl中观察到较慢的相（弛豫时间tau（1）类似于2 × 10（4）秒），在3-6 M GdmHCl中检测到较快的相（tau（2）类似于2 × 10（3）秒）。与这些相相关的自由能垒的比较，DeltaG* = 16-17 kcalmol（-1），与22 ℃下在0-6 M GdmHCl中长时间孵育后从光谱测量推断的接近零的表观热力学稳定性表明动力学来源HDL稳定化。在0-6 M GdmHCl中孵育的HDL的电子显微镜分析表明，较慢的动力学阶段涉及HDL融合，而较快的阶段涉及颗粒破裂和非极性脂质核心的释放。热变性实验表明，可能会出现从脂质和/或蛋白质包装的相互作用的瞬时破坏的颗粒破裂的高介电屏障。这些结果证实了我们早期对模型盘状HDL的分析，并表明动力学机制为脂蛋白稳定提供了一种普遍的天然策略。这种机制可能有助于异质性脂蛋白颗粒的结构完整性，减缓它们的自发相互转化，从而调节脂蛋白的寿命和功能。(C)2003爱思唯尔科技有限公司版权所有。
High-density lipoproteins (HDL) are heterogeneous complexes of proteins and lipids that mediate cholesterol removal from the body. Our thermal and chemical denaturation studies of mature spherical HDL isolated from human plasma show that, contrary to the widely held assumption, the particle stability has a kinetic rather than thermodynamic origin. Guanidinum hydrochloride (GdmHCl) concentration jumps at 25degreesC monitored by circular dichroism (CD) at 222 nm reveal two dominant irreversible kinetic phases in HDL denaturation. The slower phase (relaxation time tau(1) similar to 2 x 10(4) seconds) is observed in 1-6 M GdmHCl, and the faster phase (tau(2) similar to 2 x 10(3) seconds) is detected in 3-6 M GdmHCl. Comparison of the free energy barriers associated with these phases, DeltaG* = 16-17 kcal mol(-1), with the near-zero apparent thermodynamic stability inferred from the spectroscopic measurements after prolonged incubation in 0-6 M GdmHCl at 22degreesC indicates the kinetic origin for HDL stabilization. Electron microscopic analysis of HDL incubated in 0-6 M GdmHCl suggests that the slower kinetic phase involves HDL fusion, while the faster phase involves particle rupture and release of the apolar lipid core. Thermal denaturation experiments indicate high enthalpic barriers for the particle rupture that may arise from the transient disruption of lipid and/or protein packing interactions. These results corroborate our earlier analysis of model discoidal HDL and indicate that a kinetic mechanism provides a universal natural strategy for lipoprotein stabilization. Such a mechanism may facilitate structural integrity of the heterogeneous lipoprotein particles, slow their spontaneous interconversions, and thereby modulate lipoprotein lifetime and functions. (C) 2003 Elsevier Science Ltd. All rights reserved.