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Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity.
J Clin Endocrinol Metab. 2011 Oct; 96(10):E1568-76.JC

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.

Authors+Show Affiliations

Metabolic Research Centre, School of Medicine and Pharmacology, University of Western Australia, GPO Box X2213, Perth, Western Australia 6847, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21816786

Citation

Ooi, Esther M M., et al. "Mechanism of Action of a Peroxisome Proliferator-activated Receptor (PPAR)-delta Agonist On Lipoprotein Metabolism in Dyslipidemic Subjects With Central Obesity." The Journal of Clinical Endocrinology and Metabolism, vol. 96, no. 10, 2011, pp. E1568-76.
Ooi EM, Watts GF, Sprecher DL, et al. Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. J Clin Endocrinol Metab. 2011;96(10):E1568-76.
Ooi, E. M., Watts, G. F., Sprecher, D. L., Chan, D. C., & Barrett, P. H. (2011). Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. The Journal of Clinical Endocrinology and Metabolism, 96(10), E1568-76. https://doi.org/10.1210/jc.2011-1131
Ooi EM, et al. Mechanism of Action of a Peroxisome Proliferator-activated Receptor (PPAR)-delta Agonist On Lipoprotein Metabolism in Dyslipidemic Subjects With Central Obesity. J Clin Endocrinol Metab. 2011;96(10):E1568-76. PubMed PMID: 21816786.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mechanism of action of a peroxisome proliferator-activated receptor (PPAR)-delta agonist on lipoprotein metabolism in dyslipidemic subjects with central obesity. AU - Ooi,Esther M M, AU - Watts,Gerald F, AU - Sprecher,Dennis L, AU - Chan,Dick C, AU - Barrett,P Hugh R, Y1 - 2011/08/03/ PY - 2011/8/6/entrez PY - 2011/8/6/pubmed PY - 2011/12/13/medline SP - E1568 EP - 76 JF - The Journal of clinical endocrinology and metabolism JO - J Clin Endocrinol Metab VL - 96 IS - 10 N2 - 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. SN - 1945-7197 UR - https://www.unboundmedicine.com/medline/citation/21816786/Mechanism_of_action_of_a_peroxisome_proliferator_activated_receptor__PPAR__delta_agonist_on_lipoprotein_metabolism_in_dyslipidemic_subjects_with_central_obesity_ L2 - https://academic.oup.com/jcem/article-lookup/doi/10.1210/jc.2011-1131 DB - PRIME DP - Unbound Medicine ER -