title: Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity.
abstract: BACKGROUND
  Dyslipidemia increases the risk of cardiovascular disease in obesity. Peroxisome proliferator-activated receptor (PPAR)-δ agonists decrease plasma triglycerides and increase high-density lipoprotein (HDL)-cholesterol in humans.
  
  
  OBJECTIVE
  The aim of the study was to examine the effect of GW501516, a PPAR-δ agonist, on lipoprotein metabolism. Design, Setting, and Intervention: We conducted a randomized, double-blind, crossover trial of 6-wk intervention periods with placebo or GW501516 (2.5 mg/d), with 2-wk placebo washout between treatment periods.
  
  
  METHODS
  We recruited 13 dyslipidemic men with central obesity from the general community.
  
  
  METHODS
  We measured the kinetics of very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein-, and low-density lipoprotein (LDL)-apolipoprotein (apo) B-100, plasma apoC-III, and high-density lipoprotein (HDL) particles (LpA-I and LpA-I:A-II).
  
  
  RESULTS
  GW501516 decreased plasma triglycerides, fatty acid, apoB-100, and apoB-48 concentrations. GW501516 decreased the concentrations of VLDL-apoB by increasing its fractional catabolism and of apoC-III by decreasing its production rate (P < 0.05). GW501516 reduced VLDL-to-LDL conversion and LDL-apoB production. GW501516 increased HDL-cholesterol, apoA-II, and LpA-I:A-II concentrations by increasing apoA-II and LpA-I:A-II production (P < 0.05). GW501516 decreased cholesteryl ester transfer protein activity, and this was paralleled by falls in the triglyceride content of VLDL, LDL, and HDL and the cholesterol content of VLDL and LDL.
  
  
  CONCLUSIONS
  GW501516 increased the hepatic removal of VLDL particles, which might have resulted from decreased apoC-III concentration. GW501516 increased apoA-II production, resulting in an increased concentration of LpA-I:A-II particles. This study elucidates the mechanism of action of this PPAR-δ agonist on lipoprotein metabolism and supports its potential use in treating dyslipidemia in obesity.
authors.affiliation: Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, GPO Box X2213, Perth, Western Australia 6847, Australia.
authors.forename: Esther M M
authors.initials: EM
authors.lastname: Ooi
authors.forename: Gerald F
authors.initials: GF
authors.lastname: Watts
authors.forename: Dennis L
authors.initials: DL
authors.lastname: Sprecher
authors.forename: Dick C
authors.initials: DC
authors.lastname: Chan
authors.forename: P Hugh R
authors.initials: PH
authors.lastname: Barrett
mesh_terms: D000328:Adult; D016632:Apolipoprotein A-I / Q000097:blood; D016633:Apolipoprotein A-II / Q000097:blood; D001055:Apolipoproteins B / Q000097:blood; D001056:Apolipoproteins C / Q000097:blood; D002784:Cholesterol / Q000097:blood; D018592:Cross-Over Studies; D004311:Double-Blind Method; D050171:Dyslipidemias / Q000097:blood*; D006801:Humans; D007700:Kinetics; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D056128:Obesity, Abdominal / Q000097:blood*; D047494:PPAR delta / Q000819:agonists*; D013844:Thiazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000097:blood
chemical_list: D016632:Apolipoprotein A-I; D016633:Apolipoprotein A-II; D001055:Apolipoproteins B; D001056:Apolipoproteins C; C425931:GW 501516; D008055:Lipids; D008074:Lipoproteins; D008075:Lipoproteins, HDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D047494:PPAR delta; D013844:Thiazoles; D014280:Triglycerides; D002784:Cholesterol