HDL Quality Features Revealed by Proteome-Lipidome Connectivity Are Associated with Atherosclerotic Disease

Abstract

Background: The protein-lipid composition, namely the “quality” of lipoprotein particles, has been shown to be increasingly associated with cardiovascular disease (CVD). The high heterogeneity of lipoproteins makes it necessary to study the “quality” of each high-resolution subgroup. However, the targeted separation, detection, and exploration of the heterogeneous on omic-scale for lipoprotein remain challenging and rarely touched. Methods: We established a high-resolution proteomics and lipidomics (HiPL) method. Briefly, the lipoprotein particles were separated into nine fractions (Lipo-HiPL) using anion-exchange chromatography (AEC), in which HDL, LDL, and VLDL were fractionated into three more fractions respectively. Furthermore, the HDL subclasses were delicately purified within nine fractions (HDL-HiPL), covering diverse protein-lipid heterogeneity. Then the integration of proteomic and lipidomic analysis of these high-resolution subgroups revealed proteome-lipidome connectivity (PLC) in lipoprotein and HDL particles. Findings: We used the high fat high cholesterol (HFHC)-fed rabbit model before atherosclerotic lesions occurred to evaluate the applicability of our method preliminarily, and then we applied Lipo-HiPL and HDL-HiPL methods to acute coronary syndrome (ACS) patients before and after PCI and standardized drug treatment. We found that LiPL-HiPL method had enough sensitivity to illustrate dramatic changes of lipoproteins in HFHC died rabbits. However, in ACS patients, the HDL-HiPL method with a higher resolution could better reflect the molecular dynamics and PLC features of HDL than Lipo-HiPL. Moreover, the HDL “quality” revealed by PLC related more closely to clinical status in ACS patients than direct proteome and lipidome quantification. Interpretation: Proteome-lipidome connectivity (PLC) as novel HDL “quality” features could be highly associated with atherosclerotic cardiovascular diseases. Funding Statement: This work was supported by a grant from the Ministry of Science and Technology (2017YFA0505500), and grants from the National Natural Science Foundation of China (81561128018, 81670426 and 81870336). Declaration of Interests: None. Ethics Approval Statement: The study was approved by the Medical Ethics Committee of the Second Xiangya Hospital of Central South University. All patients gave written informed consent before blood sample collection. Rabbit studies were performed according to animal protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the University of Michigan.