Department of Medicine, Knight Cardiovascular Institute, Oregon Health and Science University, Portland, OR
Departments of Genetics University of California at Los Angeles, Los Angeles, CA.
J Lipid Res. 2019 Mar;60(3):594-608. doi: 10.1194/jlr.M090555. Epub 2019 Jan 8.
HDLs are nanoparticles with more than 80 associated proteins, phospholipids, cholesterol, and cholesteryl esters. The potential inverse relation of HDL to coronary artery disease (CAD) and the effects of HDL on myriad other inflammatory conditions warrant a better understanding of the genetic basis of the HDL proteome. We conducted a comprehensive genetic analysis of the regulation of the proteome of HDL isolated from a panel of 100 diverse inbred strains of mice (the hybrid mouse diversity panel) and examined protein composition and efflux capacity to identify novel factors that affect the HDL proteome. Genetic analysis revealed widely varied HDL protein levels across the strains. Some of this variation was explained by local -acting regulation, termed -protein quantitative trait loci (QTLs). Variations in apoA-II and apoC-3 affected the abundance of multiple HDL proteins, indicating a coordinated regulation. We identified modules of covarying proteins and defined a protein-protein interaction network that describes the protein composition of the naturally occurring subspecies of HDL in mice. Sterol efflux capacity varied up to 3-fold across the strains, and HDL proteins displayed distinct correlation patterns with macrophage and ABCA1-specific cholesterol efflux capacity and cholesterol exchange, suggesting that subspecies of HDL participate in discrete functions. The baseline and stimulated sterol efflux capacity phenotypes were associated with distinct QTLs with smaller effect size, suggesting a multigenetic regulation. Our results highlight the complexity of HDL particles by revealing the high degree of heterogeneity and intercorrelation, some of which is associated with functional variation, and support the concept that HDL-cholesterol alone is not an accurate measure of HDL's properties, such as protection against CAD.
高密度脂蛋白（HDL）是一种含有 80 多种相关蛋白、磷脂、胆固醇和胆固醇酯的纳米颗粒。HDL 与冠状动脉疾病（CAD）之间潜在的反比关系，以及 HDL 对无数其他炎症状态的影响，都需要更好地了解 HDL 蛋白质组的遗传基础。我们对从 100 种不同近交系小鼠（杂交小鼠多样性panel）分离的 HDL 蛋白质组的调节进行了全面的遗传分析，并检查了蛋白质组成和流出能力，以鉴定影响 HDL 蛋白质组的新的因素。遗传分析显示，在不同的品系中，HDL 蛋白水平存在广泛的差异。这种变异的一部分可以用局部作用的调节来解释，称为 - 蛋白质数量性状位点（QTLs）。载脂蛋白 A-II 和载脂蛋白 C-3 的变异影响了多种 HDL 蛋白的丰度，表明存在协调调节。我们鉴定了共变蛋白模块，并定义了一个蛋白质 - 蛋白质相互作用网络，描述了在小鼠中自然存在的 HDL 亚种的蛋白质组成。胆固醇流出能力在不同品系之间变化高达 3 倍，HDL 蛋白与巨噬细胞和 ABCA1 特异性胆固醇流出能力和胆固醇交换表现出不同的相关模式，表明 HDL 亚种参与了不同的功能。基线和刺激后的胆固醇流出能力表型与具有较小效应大小的不同 QTL 相关，表明存在多基因调节。我们的研究结果通过揭示高密度脂蛋白颗粒的高度异质性和相互关联性，突出了高密度脂蛋白颗粒的复杂性，其中一些与功能变化有关，并支持 HDL-胆固醇本身不是高密度脂蛋白特性的准确衡量标准，如对 CAD 的保护作用的概念。
