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

• Published in: Journal of lipid research Vol. 57; no. 5; pp. 894 - 905
• Main Authors: Koska, Juraj, Yassine, Hussein, Trenchevska, Olgica, Sinari, Shripad, Schwenke, Dawn C, Yen, Frances T, Billheimer, Dean, Nelson, Randall W, Nedelkov, Dobrin, Reaven, Peter D
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 01.05.2016
• Subjects: Adolescent; Adult; Aged; Apolipoprotein C-III - blood; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - drug therapy; Female; Glycosylation; Hep G2 Cells; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Life Sciences; Lipoproteins, LDL - blood; Lipoproteins, VLDL - blood; Male; Middle Aged; Obesity - blood; Pioglitazone; Prediabetic State - blood; Prediabetic State - drug therapy; Protein Isoforms - blood; Protein Processing, Post-Translational; Randomized Controlled Trials as Topic; Sialic Acids - blood; Thiazolidinediones - pharmacology; Thiazolidinediones - therapeutic use; Treatment Outcome; mass spectrometry; very low density lipoprotein; triglycerides; proteomics; lipoproteins
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.P064816

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.