Apolipoprotein Proteoforms and Their Association with Cardiovascular Metabolism

dos Santos Seckler, Henrique

doi:https://doi.org/10.21985/n2-xnem-h240

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Apolipoprotein Proteoforms and Their Association with Cardiovascular Metabolism

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Despite prevention and treatment, substantial risk for cardiovascular disease(CVD) remains in the population and CVD has been the leading global cause-of-death in past years.While high-density lipoprotein (HDL) markers such as HDL cholesterol (HDL-C) and HDL efflux (a cholesterol-transport-function assay) are associated with decreased risk of CVD, the mechanism of this association remains unexplained. Understanding inter-individual HDL heterogeneity is essential towards unveiling HDL’s atheroprotective mechanism and may lead to new markers and intervention targets in CVD. While some associations of chemical variation in apolipoproteins – such as alleles and post-translational modifications (PTMs) – to changes in lipoprotein metabolism have been reported, studies of these associations have been sparse and hindered by the shortcomings of traditional proteomic technology, which prohibits reconstruction of full protein molecular forms (or proteoforms). We hypothesize that a more comprehensive study of apolipoprotein proteoform variation and its association with differences in human cardiometabolism may lead to novel cardiometabolic markers and insights into metabolic pathways of cardiovascular health. With that goal, we herein present novel top-down proteomic methodologies for more streamlined and comprehensive characterization and quantification of apolipoprotein proteoform variation between and within humans.We employ these techniques to describe a panel of proteoforms of apolipoproteins (Apo) A-I, A-II and C-III and quantify associations of proteoforms with differences in human phenotype and HDL particle morphology. We report on: 15 proteoforms of ApoA-I, differing by backbone length, glycation, oxidation and covalent fatty-acid modifications (acylations); 9 proteoforms of ApoA-II, either cysteinylated monomers or disulfide-linked dimers of differing chain lengths; and 22 different glycoforms of ApoC-III. Significant associations of proteoform variation to phenotype were observed. Acylations of ApoA-I were more abundant in individuals with higher HDL efflux (n=8) and were associated with higher HDL-C and lower indices of obesity (n=150). Acylations were also more abundant in larger HDL particles and not present in HDL-unbound ApoA-I, suggesting acylation is a marker of ApoA-I’s HDL-scaffolding function. Dimeric and singly-truncated ApoA-II was associated with higher HDL-C and efflux (n=150) and lower obesity indices. Finally, ApoC-III modified by HexNAc was associated with higher obesity indices (n=25).These results show potential for proteoform markers of cardiometabolic health.

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