Abstract 023: Clearance of ApoC-III Glycoforms Associated With Triglyceride Metabolism

Abstract

Background: We previously reported an association between higher abundance of disialylated (apoC-III 2 ) over monosialylated (apoC-III 1 ) apoC-III and lower plasma triglyceride (TG) concentrations in three independent studies. Methods: The goal of this study was to get mechanistic insights in the metabolism of apoC-III 1 and apoC-III 2 . First, the relative abundances of human triglyceride-rich lipoproteins (TRL)-associated apoC-III glycoforms in plasma were assessed by mass spectrometric immunoassay (MSIA) over time after injecting human TRL in wild-type mice, mice lacking hepatic heparan sulfate proteoglycans (HSPG), and mice deficient for both low-density lipoprotein receptor (LDLR) and LDLR-Related Protein 1 (LRP-1). Secondly, the relative abundance of plasma apoC-III glycoforms was assessed by MSIA in 11 participants randomized to volanesorsen (apoC-III antisense drug; n=11) or placebo (n=6) treatment for 13 weeks. Results: Kinetic studies revealed that half of TRL-associated apoC-III (total) was rapidly cleared via LDLR and LRP1 (t 1/2 = 16.5 min), and the remaining half via the much slower but higher capacity HSPGs (t 1/2 = 55.5 min). After injection, a significant increase in the relative abundance of apoC-III 2 was observed in HSPG-deficient mice , while no increase in mice lacking LDLR and LRP-1. Clinically, the relative abundance of apoC-III 2 significantly increased (42% increase compared to placebo, p=0.05) and that of apoC-III 1 significantly decreased (15% decrease compared to placebo, p=0.007) in participants randomized to volanesorsen. The decrease in the relative abundance of apoC-III 1 after volanesorsen treatment was strongly correlated with the decrease in TG levels (r=0.63, p=0.006). Conclusions: Our results indicate slower clearance of apoC-III-containing particles through HSPGs, which preferentially clear apoC-III 2. In contrast, apoC-III 2 is less effectively cleared by LDLR/LRP-1 compared to apoC-III 1 . Clinically, the increase in the apoC-III 2 /apoC-III 1 ratio upon antisense lowering of apoC-III might reflect faster clearance of apoC-III 1 as it associates with improved TG levels.