Apolipoprotein Proteoforms: Exploring Their Relationships with Cardiometabolic Health and Coronary Heart Disease Events

ABSTRACT Cholesterol concentration in the blood is one of the primary determinants of coronary heart disease (CHD) events. Human apolipoproteins (APO) serve as binding ligands as well as cofactors for enzymatic interactions that mediate cholesterol metabolism. Apolipoproteins are also central to the pathobiology of atherosclerosis through direct effects on lipid metabolism as well as atherosclerosis initiation, propagation, inflammation, and plaque instability. Human APOs are frequently post-translationally modified, which alters protein function and human phenotype. For example, post-translational modifications (PTMs) such as glycosylation of apoB may increase the synthesis and excretion of apoB lipoproteins and lead to adverse cholesterol profiles. Our prior work strongly suggests that PTMs of human APOs may be a biologic pathway through which adiposity and insulin resistance modify cholesterol concentrations and downstream CHD events. Further, preliminary data from our group indicates that the relative abundance of APO PTMs in atherosclerotic plaque varies substantially from APO PTMs found in plasma, suggesting that PTM of human APOs may partially mediate of atherosclerosis propagation. Our group has identified 18 PTM’s of apoA-I, 9 of apoA-II, 2 of apoA4, 32 glycosylated PTMs of apoB-100, 13 of apoC1, 14 of apoC2, and 23 of apoCIII, and 18 of apoE. However, we have not quantified the associations of these APO PTMs with adiposity, insulin resistance, downstream atherogenic lipid concentrations and CHD events. Nor have we comprehensively characterized APO PTMs found in atherosclerotic plaque and plasma. Therefore, the overall objective of this study is to characterize the full spectrum of APO PTMs in human plasma and to quantify their associations with upstream adiposity and insulin resistance and downstream atherogenic lipid levels and CHD endpoints (fatal/non-fatal MI) in the population-based Multi-Ethnic Study of Atherosclerosis Cohort. We will also explore differences in APO PTMs across paired samples of human carotid and femoral atherosclerotic plaque and plasma. Characterization and cataloguing of apolipoprotein PTMs and understanding their associations with prior exposures to adiposity and insulin resistance and subsequent lipid levels and CHD endpoints will lead to novel insights into lipid metabolism and atherogenesis and may provide novel targets for therapy.