LDL and apoB
PPAR-delta agonist GW501516 lowers CETP activity alongside broad apoB and apoC-III kinetic changes in obese dyslipidemic men (J Clin Endocrinol Metab 2011)
Original title: Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity
In a randomized, double-blind, crossover trial, 13 dyslipidemic men with central obesity received 6-week periods of placebo or GW501516 (2.5 mg/day), a PPAR-delta agonist, separated by a 2-week washout, with apolipoprotein kinetics measured using stable-isotope tracers. GW501516 lowered triglycerides, fatty acids, and apoB-100/apoB-48 concentrations, reduced VLDL-apoB by increasing its fractional catabolism, and reduced apoC-III by decreasing its production rate (P less than 0.05), while cutting VLDL-to-LDL conversion and LDL-apoB production. It raised HDL cholesterol, apoA-II, and LpA-I:A-II particle concentrations by increasing apoA-II and LpA-I:A-II production (P less than 0.05), and decreased CETP activity, paralleled by falls in triglyceride content across VLDL, LDL, and HDL and cholesterol content in VLDL and LDL, elucidating a CETP-linked mechanism for this PPAR-delta agonist's lipid-modifying effects.
Original abstract
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.
HDL biologyLDL and apoBmechanisms
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 19 August 2026. Methods.