title: Disialylated apolipoprotein C-III proteoform is associated with improved lipids in prediabetes and type 2 diabetes.
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.
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ juraj.koska@va.gov.
authors.forename: Juraj
authors.initials: J
authors.lastname: Koska
authors.affiliation: University of Southern California, Los Angeles, CA.
authors.forename: Hussein
authors.initials: H
authors.lastname: Yassine
authors.affiliation: Arizona State University, Tempe, AZ.
authors.forename: Olgica
authors.initials: O
authors.lastname: Trenchevska
authors.affiliation: University of Arizona, Tucson, AZ.
authors.forename: Shripad
authors.initials: S
authors.lastname: Sinari
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ.
authors.forename: Dawn C
authors.initials: DC
authors.lastname: Schwenke
authors.affiliation: Université de Lorraine, URAFPA, INSERM, Vandoeuvre-lès-Nancy, France.
authors.forename: Frances T
authors.initials: FT
authors.lastname: Yen
authors.affiliation: University of Arizona, Tucson, AZ.
authors.forename: Dean
authors.initials: D
authors.lastname: Billheimer
authors.affiliation: Arizona State University, Tempe, AZ.
authors.forename: Randall W
authors.initials: RW
authors.lastname: Nelson
authors.affiliation: Arizona State University, Tempe, AZ.
authors.forename: Dobrin
authors.initials: D
authors.lastname: Nedelkov
authors.affiliation: Phoenix Veterans Affairs Health Care System, Phoenix, AZ.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Reaven
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D053305:Apolipoprotein C-III / Q000097:blood*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006031:Glycosylation; D056945:Hep G2 Cells; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood; D000077205:Pioglitazone; D011236:Prediabetic State / Q000097:blood* / Q000188:drug therapy; D020033:Protein Isoforms / Q000097:blood; D011499:Protein Processing, Post-Translational; D016032:Randomized Controlled Trials as Topic; D012794:Sialic Acids / Q000097:blood; D045162:Thiazolidinediones / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D053305:Apolipoprotein C-III; D007004:Hypoglycemic Agents; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D020033:Protein Isoforms; D012794:Sialic Acids; D045162:Thiazolidinediones; D000077205:Pioglitazone
keywords: lipoproteins; mass spectrometry; proteomics; triglycerides; very low density lipoprotein