1. ApoC-III Glycoforms Are Differentially Cleared by Hepatic TRL (Triglyceride-Rich Lipoprotein) Receptors.
- Author
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Kegulian NC, Ramms B, Horton S, Trenchevska O, Nedelkov D, Graham MJ, Lee RG, Esko JD, Yassine HN, and Gordts PLSM
- Subjects
- Animals, Apolipoprotein C-III drug effects, Disease Models, Animal, Glycosylation drug effects, Humans, Hypertriglyceridemia blood, Male, Mice, Molecular Targeted Therapy methods, Receptors, LDL drug effects, Reference Values, Apolipoprotein C-III blood, Hypertriglyceridemia drug therapy, Lipoproteins, HDL3 metabolism, Oligonucleotides administration & dosage, Receptors, LDL metabolism
- Abstract
Objective: ApoC-III (apolipoprotein C-III) glycosylation can predict cardiovascular disease risk. Higher abundance of disialylated (apoC-III
2 ) 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.- Published
- 2019
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