OBJECTIVE: ApoC-III (apolipoprotein C-III) glycosylation can predict 
cardiovascular disease risk. Higher abundance of disialylated (apoC-III2) over 
monosialylated (apoC-III1) glycoforms is associated with lower plasma 
triglyceride levels. Yet, it remains unclear whether apoC-III glycosylation 
impacts TRL (triglyceride-rich lipoprotein) clearance and whether apoC-III 
antisense therapy (volanesorsen) affects distribution of apoC-III glycoforms. 
Approach and Results: To measure the abundance of human apoC-III glycoforms in 
plasma over time, human TRLs were injected into wild-type mice and mice lacking 
hepatic TRL clearance receptors, namely HSPGs (heparan sulfate proteoglycans) or 
both LDLR (low-density lipoprotein receptor) and LRP1 (LDLR-related protein 1). 
ApoC-III was more rapidly cleared in the absence of HSPG (t1/2=25.4 minutes) 
than in wild-type animals (t1/2=55.1 minutes). In contrast, deficiency of LDLR 
and LRP1 (t1/2=56.1 minutes) did not affect clearance of apoC-III. After 
injection, a significant increase in the relative abundance of apoC-III2 was 
observed in HSPG-deficient mice, whereas the opposite was observed in mice 
lacking LDLR and LRP1. In patients, abundance of plasma apoC-III glycoforms was 
assessed after placebo or volanesorsen administration. Volanesorsen treatment 
correlated with a statistically significant 1.4-fold increase in the relative 
abundance of apoC-III2 and a 15% decrease in that of apoC-III1. The decrease in 
relative apoC-III1 abundance was strongly correlated with decreased plasma 
triglyceride levels in patients.
CONCLUSIONS: Our results indicate that HSPGs preferentially clear apoC-III2. In 
contrast, apoC-III1 is more effectively cleared by LDLR/LRP1. Clinically, the 
increase in the apoC-III2/apoC-III1 ratio on antisense lowering of apoC-III 
might reflect faster clearance of apoC-III1 because this metabolic shift 
associates with improved triglyceride levels.