ApoC-III Glycoforms Are Differentially Cleared by Hepatic TRL (Triglyceride-Rich Lipoprotein) Receptors

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 (t_1/2=25.4 minutes) than in wild-type animals (t_1/2=55.1 minutes). In contrast, deficiency of LDLR and LRP1 (t_1/2=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.

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.