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 journalArticlepeer-review

965 Scopus citations


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
Issue number9
StatePublished - Apr 24 2001

ASJC Scopus subject areas

  • General


Dive into the research topics of 'A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport'. Together they form a unique fingerprint.

Cite this