Relationship of Plasma ApolipoproteinC3 with Plasma Lipoprotein(a)

Abstract

Introduction ApoliproteinC3 (ApoC3) is a small (~8.8kDa) protein, made in the liver. It is an inhibitor of lipoprotein lipase as well as the uptake of triglyceride (TG) rich lipoproteins and remnants by the liver. Overexpression contributes to atherosclerosis by increasing plasma concentration of TG-rich lipoproteins. Recent genetic studies suggest that ApoC3-lowering treatments may have cardiovascular benefit. ApoC3 is also known to participate in the inflammation cascade; it facilitates the interaction between monocytes and endothelial cells leading to their activation and monocyte adhesion, promoting further development of atherosclerosis. A recent study reported the presence of ApoC3 on lipoprotein(a) [Lp(a)] particles in subjects with mild to moderate aortic stenosis. Lp(a) is an ApoB100 containing lipoprotein and a causal factor of ASCVD. Most individuals have two isoforms of Apo(a), varying in the number of KIV2 repeats, and hence, have two different circulating Lp(a) molecules. High levels of Lp(a) are inversely associated with the isoform size. Our goal was to investigate relationships between ApoC3 and Lp(a) in a racially diverse healthy population. Methods We analyzed data from 39 healthy subjects who completed studies of lipoprotein metabolism at the Columbia University Medical Center. Subjects were 18 – 75 years old, and 49% were female. Fifty-one percent were Black, 23% Hispanic, 21% White, and 5% mixed race. Lipids (total Cholesterol (C), TG, HDLC, LDLC) were measured by a CDC standardized automatic analyzer. Plasma ApoC3 and Lp(a) levels were measured via validated ELISA assays. Lp(a) particles were isolated from plasma by immunoprecipitation (IP) with a monoclonal antibody (Abcam). Isolated Lp(a) samples were processed for proteomic analysis at the CUIMC – Proteomics Core. We calculated iBAQ value (total intensities/identified peptides for one protein). Excel and R-program were used for statistical analysis. Results Unlikeprevious studies, our group of healthy volunteers did not have an association between Lp(a) and ApoC3 levels. Previous studies were completed in subjects with high Lp(a). In a sub-group analysis of participants (N=15) in our study, with Lp(a) levels >100nmol/L, we found a trend in the association of ApoC3 and Lp(a) plasma concentration (R = -0.48, p=0.068). However, unlike in previous reports, it was not a positive correlation. Based on the proteomic analysis of our IP Lp(a) particles from 2 subjects with high (~ 128nmol/L) and 2 subjects with low (~ 23nmol/L) Lp(a), ApoC3/Apo(a) iBAQ ratios were similar in subjects with low Lp(a) levels, however there was not a clear relationship between ApoC3/Apo(a) ratios in subjects with high Lp(a). Conclusion and Future Direction In healthy subjects, there is no association of ApoC3 with Lp(a) plasma levels. In a subset of subjects (high Lp(a)), we observed a trend towards lower ApoC3 levels associated with high Lp(a). Our small data set suggests possible distinct roles for ApoC3 in healthy individuals with high Lp(a) level. ApoC3 may be associated with specific circulating isoform sizes of Lp(a). Future studies will focus on analysis of larger cohorts, examining the ApoC3 and Apo(a) relationships.