Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes

Juraj Koska,Hussein Yassine,Olgica Trenchevska,Shripad Sinari,Dawn C Schwenke,Frances T Yen,Dean Billheimer,Randall W Nelson,Dobrin Nedelkov,Peter D Reaven

doi:10.1194/jlr.p064816

Abstract

The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT NOW, a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. At baseline, higher relative apoC-III2 and apoC-III2/apoC-III1 ratios were associated with lower triglycerides and total cholesterol in both cohorts, and with lower small dense LDL in the RACED. Longitudinally, changes in apoC-III2/apoC-III1 were inversely associated with changes in triglycerides in both cohorts, and with total and small dense LDL in the RACED. apoC-III2/apoC-III1 was also higher in patients treated with PPAR-γ agonists and was associated with reduced cardiovascular events in the RACED control group. Ex vivo studies of apoC-III complexes with higher apoC-III2/apoC-III1 showed attenuated inhibition of VLDL uptake by HepG2 cells and LPL-mediated lipolysis, providing possible functional explanations for the inverse association between a higher apoC-III2/apoC-III1 and hypertriglyceridemia, proatherogenic plasma lipid profiles, and cardiovascular risk.

Highlights

The apoC-III proteoform containing two sialic acid residues has different in vitro effects on lipid metabolism compared with asialylated or the most abundant monosialylated proteoforms
It enhances binding of LDL particles to proteoglycans and, thereby, Abbreviations: CI, confidence interval; d, des-Alanine; DAPI, 4′,6-diamidino-2-phenylindole; Fuc, fucose; Gal, galactose; Gal-NAc, N-acetygalactosamine; HbA1c, hemoglobin A1c; Hi, high apoC-III2/ apoC-III1 ratio; HR, hazard ratio; Int, intensive glucose-lowering therapy; Lo, low apoC-III2/apoC-III1 ratio; LPL, lipoprotein lipase; lipolysis-stimulated receptor (LSR), lipolysisstimulated receptor; MACE, major adverse cardiovascular event; MSIA, mass spectrometric immunoassay; PBST, phosphate buffered saline with Tween-20; Pio, pioglitazone; Plc, placebo; RPA, relative peak area Std, standard glucose-lowering therapy; UKPDS, United Kingdom Prospective Diabetes Study
To examine whether the uniquely favorable associations of apoC-III2 with metabolic risk factors may have an impact on CVD, we explored its association with major adverse cardiovascular events (MACEs; myocardial infarction, stroke, or CVD death) in the RACED cohort

Summary

Introduction

The apoC-III proteoform containing two sialic acid residues (apoC-III2) has different in vitro effects on lipid metabolism compared with asialylated (apoC-III0) or the most abundant monosialylated (apoC-III1) proteoforms. Cross-sectional and longitudinal associations between plasma apoC-III proteoforms (by mass spectrometric immunoassay) and plasma lipids were tested in two randomized clinical trials: ACT a study of pioglitazone in subjects with impaired glucose tolerance (n = 531), and RACED (n = 296), a study of intensive glycemic control and atherosclerosis in type 2 diabetes patients. It enhances binding of LDL particles to proteoglycans and, thereby, Abbreviations: CI, confidence interval; d, des-Alanine; DAPI, 4′,6-diamidino-2-phenylindole; Fuc, fucose; Gal, galactose; Gal-NAc, N-acetygalactosamine; HbA1c, hemoglobin A1c; Hi, high apoC-III2/ apoC-III1 ratio; HR, hazard ratio; Int, intensive glucose-lowering therapy; Lo, low apoC-III2/apoC-III1 ratio; LPL, lipoprotein lipase; LSR, lipolysisstimulated receptor; MACE, major adverse cardiovascular event; MSIA, mass spectrometric immunoassay; PBST, phosphate buffered saline with Tween-20; Pio, pioglitazone; Plc, placebo; RPA, relative peak area Std, standard glucose-lowering therapy; UKPDS, United Kingdom Prospective Diabetes Study.

Methods

Results

Conclusion