Department of Biosystems Science and Engineering, Swiss Federal Institute of Technology in Zurich (ETH Zurich), Basel, Switzerland.
Swiss Institute of Bioinformatics (SIB), Basel, Switzerland.
JCI Insight. 2020 Jan 16;5(1):131491. doi: 10.1172/jci.insight.131491.
High-density lipoproteins (HDL) contain hundreds of lipid species and proteins and exert many potentially vasoprotective and antidiabetogenic activities on cells. To resolve structure-function-disease relationships of HDL, we characterized HDL of 51 healthy subjects and 98 patients with diabetes (T2DM), coronary heart disease (CHD), or both for protein and lipid composition, as well as functionality in 5 cell types. The integration of 40 clinical characteristics, 34 nuclear magnetic resonance (NMR) features, 182 proteins, 227 lipid species, and 12 functional read-outs by high-dimensional statistical modeling revealed, first, that CHD and T2DM are associated with different changes of HDL in size distribution, protein and lipid composition, and function. Second, different cellular functions of HDL are weakly correlated with each other and determined by different structural components. Cholesterol efflux capacity (CEC) was no proxy of other functions. Third, 3 potentially novel determinants of HDL function were identified and validated by the use of artificially reconstituted HDL, namely the sphingadienine-based sphingomyelin SM 42:3 and glycosylphosphatidylinositol-phospholipase D1 for the ability of HDL to inhibit starvation-induced apoptosis of human aortic endothelial cells and apolipoprotein F for the ability of HDL to promote maximal respiration of brown adipocytes.
高密度脂蛋白 (HDL) 含有数百种脂质和蛋白质，对细胞具有多种潜在的血管保护和抗糖尿病作用。为了阐明 HDL 的结构-功能-疾病关系，我们对 51 名健康受试者和 98 名糖尿病（T2DM）、冠心病（CHD）或两者均有的患者的 HDL 进行了蛋白质和脂质组成以及 5 种细胞类型功能的特征分析。通过高维统计建模，将 40 项临床特征、34 项核磁共振（NMR）特征、182 种蛋白质、227 种脂质和 12 种功能读数进行整合，结果首先表明，CHD 和 T2DM 与 HDL 大小分布、蛋白质和脂质组成以及功能的不同变化相关。其次，HDL 的不同细胞功能彼此弱相关，由不同的结构成分决定。胆固醇流出能力（CEC）不能作为其他功能的替代指标。第三，通过使用人工再构建的 HDL，鉴定并验证了 3 种潜在的 HDL 功能决定因素，即基于鞘氨醇的鞘磷脂 SM 42:3 和糖基磷脂酰肌醇-磷脂酶 D1 可抑制人主动脉内皮细胞饥饿诱导的细胞凋亡，载脂蛋白 F 可促进棕色脂肪细胞的最大呼吸能力。
