Mechanism of Action of a Peroxisome Proliferator-Activated Receptor (PPAR)-δ Agonist on Lipoprotein Metabolism in Dyslipidemic Subjects with Central Obesity

• Published in: The journal of clinical endocrinology and metabolism Vol. 96; no. 10; pp. E1568 - E1576
• Main Authors: Ooi, Esther M. M., Watts, Gerald F., Sprecher, Dennis L., Chan, Dick C., Barrett, P. Hugh R.
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01.10.2011; Copyright by The Endocrine Society
• Subjects: Adult; Agonists; Apolipoprotein A-I - blood; Apolipoprotein A-II - blood; Apolipoproteins; Apolipoproteins B - blood; Apolipoproteins C - blood; Blood; Cardiorespiratory; Cardiovascular diseases; Cholesterol; Cholesterol - blood; Cholesteryl ester transfer protein; Cross-Over Studies; Double-Blind Method; Dyslipidemia; Dyslipidemias - blood; High density lipoprotein; Humans; Kinetics; Lipid metabolism; Lipids; Lipids - blood; Lipoproteins; Lipoproteins (very low density); Lipoproteins - blood; Lipoproteins, HDL - blood; Lipoproteins, LDL - blood; Lipoproteins, VLDL - blood; Low density lipoprotein; Male; Measurement; Men; Metabolic disorders; Metabolism; Middle Aged; Obesity; Obesity, Abdominal - blood; Peroxisome proliferator-activated receptors; Placebos; PPAR delta - agonists; Proteins; Receptor density; Thiazoles - pharmacology; Triglycerides; Triglycerides - blood
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2011-1131

Context: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.Participants:We recruited 13 dyslipidemic men with central obesity from the general community.Main Outcome Measures: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.