A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

William R. Oliver, Jennifer L. Shenk, Mike R. Snaith, Caroline S. Russell, Kelli D. Plunket, Noni L. Bodkin, Michael C. Lewis, Deborah A. Winegar, Marcos L. Sznaidman, Millard H. Lambert, H. Eric Xu, Daniel D. Sternbach, Steven A. Kliewer, Barbara C. Hansen, Timothy M. Willson

Research output: Contribution to journalArticle

897 Citations (Scopus)

Abstract

The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein Al-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Out results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Original languageEnglish (US)
Pages (from-to)5306-5311
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume98
Issue number9
DOIs
StatePublished - Apr 24 2001

Fingerprint

Peroxisome Proliferator-Activated Receptors
Cholesterol
Fasting
Metabolic Syndrome X
Insulin
Fibric Acids
Thiazolidinediones
ATP-Binding Cassette Transporters
Drug Design
Apolipoprotein A-I
Carbohydrate Metabolism
Macaca mulatta
Hypoglycemic Agents
Pharmaceutical Preparations
HDL Cholesterol
Cardiovascular Diseases
Fatty Acids
Fibroblasts
Macrophages
Ligands

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. / Oliver, William R.; Shenk, Jennifer L.; Snaith, Mike R.; Russell, Caroline S.; Plunket, Kelli D.; Bodkin, Noni L.; Lewis, Michael C.; Winegar, Deborah A.; Sznaidman, Marcos L.; Lambert, Millard H.; Xu, H. Eric; Sternbach, Daniel D.; Kliewer, Steven A.; Hansen, Barbara C.; Willson, Timothy M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 98, No. 9, 24.04.2001, p. 5306-5311.

Research output: Contribution to journalArticle

Oliver, WR, Shenk, JL, Snaith, MR, Russell, CS, Plunket, KD, Bodkin, NL, Lewis, MC, Winegar, DA, Sznaidman, ML, Lambert, MH, Xu, HE, Sternbach, DD, Kliewer, SA, Hansen, BC & Willson, TM 2001, 'A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport', Proceedings of the National Academy of Sciences of the United States of America, vol. 98, no. 9, pp. 5306-5311. https://doi.org/10.1073/pnas.091021198
Oliver, William R. ; Shenk, Jennifer L. ; Snaith, Mike R. ; Russell, Caroline S. ; Plunket, Kelli D. ; Bodkin, Noni L. ; Lewis, Michael C. ; Winegar, Deborah A. ; Sznaidman, Marcos L. ; Lambert, Millard H. ; Xu, H. Eric ; Sternbach, Daniel D. ; Kliewer, Steven A. ; Hansen, Barbara C. ; Willson, Timothy M. / A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport. In: Proceedings of the National Academy of Sciences of the United States of America. 2001 ; Vol. 98, No. 9. pp. 5306-5311.
@article{0dc81ec7edc340edae2daa2354cceb7b,
title = "A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport",
abstract = "The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein Al-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Out results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.",
author = "Oliver, {William R.} and Shenk, {Jennifer L.} and Snaith, {Mike R.} and Russell, {Caroline S.} and Plunket, {Kelli D.} and Bodkin, {Noni L.} and Lewis, {Michael C.} and Winegar, {Deborah A.} and Sznaidman, {Marcos L.} and Lambert, {Millard H.} and Xu, {H. Eric} and Sternbach, {Daniel D.} and Kliewer, {Steven A.} and Hansen, {Barbara C.} and Willson, {Timothy M.}",
year = "2001",
month = "4",
day = "24",
doi = "10.1073/pnas.091021198",
language = "English (US)",
volume = "98",
pages = "5306--5311",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "9",

}

TY - JOUR

T1 - A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport

AU - Oliver, William R.

AU - Shenk, Jennifer L.

AU - Snaith, Mike R.

AU - Russell, Caroline S.

AU - Plunket, Kelli D.

AU - Bodkin, Noni L.

AU - Lewis, Michael C.

AU - Winegar, Deborah A.

AU - Sznaidman, Marcos L.

AU - Lambert, Millard H.

AU - Xu, H. Eric

AU - Sternbach, Daniel D.

AU - Kliewer, Steven A.

AU - Hansen, Barbara C.

AU - Willson, Timothy M.

PY - 2001/4/24

Y1 - 2001/4/24

N2 - The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein Al-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Out results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

AB - The peroxisome proliferator-activated receptors (PPARs) are dietary lipid sensors that regulate fatty acid and carbohydrate metabolism. The hypolipidemic effects of the fibrate drugs and the antidiabetic effects of the glitazone drugs in humans are due to activation of the α (NR1C1) and γ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the δ (NR1C2) subtype is unknown, due in part to the lack of selective ligands. We have used combinatorial chemistry and structure-based drug design to develop a potent and subtype-selective PPARδ agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein Al-specific cholesterol efflux. When dosed to insulin-resistant middle-aged obese rhesus monkeys, GW501516 causes a dramatic dose-dependent rise in serum high density lipoprotein cholesterol while lowering the levels of small-dense low density lipoprotein, fasting triglycerides, and fasting insulin. Out results suggest that PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

UR - http://www.scopus.com/inward/record.url?scp=0035942162&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0035942162&partnerID=8YFLogxK

U2 - 10.1073/pnas.091021198

DO - 10.1073/pnas.091021198

M3 - Article

C2 - 11309497

AN - SCOPUS:0035942162

VL - 98

SP - 5306

EP - 5311

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 9

ER -