ApoC-III Glycoforms Are Differentially Cleared by Hepatic TRL (Triglyceride-Rich Lipoprotein) Receptors
| Autor: | Kegulian, Natalie C, Ramms, Bastian, Horton, Steven, Trenchevska, Olgica, Nedelkov, Dobrin, Graham, Mark J, Lee, Richard G, Esko, Jeffrey D, Yassine, Hussein N, Gordts, Philip LSM |
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| Rok vydání: | 2019 |
| Předmět: |
Male
Glycosylation Lipoproteins Clinical Sciences Oligonucleotides Cardiorespiratory Medicine and Haematology Cardiovascular LDL Mice Reference Values Receptors Animals Humans Molecular Targeted Therapy triglycerides glycoproteins HDL3 mass spectrometry Hypertriglyceridemia Apolipoprotein C-III Animal cardiovascular diseases Heart Disease Cardiovascular System & Hematology Disease Models lipids (amino acids peptides and proteins) apolipoproteins |
| Zdroj: | Arteriosclerosis, thrombosis, and vascular biology, vol 39, iss 10 |
| Popis: | ObjectiveApoC-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.ConclusionsOur 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. |
| Databáze: | OpenAIRE |
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