title: A selective peroxisome proliferator-activated receptor delta 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 alpha (NR1C1) and gamma (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the delta (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 PPARdelta agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette A1 and induces apolipoprotein A1-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. Our results suggest that PPARdelta agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.
authors: Metabolic Diseases Drug Discovery and Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
authors: W R
authors: WR
authors: Oliver
authors: J L
authors: JL
authors: Shenk
authors: M R
authors: MR
authors: Snaith
authors: C S
authors: CS
authors: Russell
authors: K D
authors: KD
authors: Plunket
authors: N L
authors: NL
authors: Bodkin
authors: M C
authors: MC
authors: Lewis
authors: D A
authors: DA
authors: Winegar
authors: M L
authors: ML
authors: Sznaidman
authors: M H
authors: MH
authors: Lambert
authors: H E
authors: HE
authors: Xu
authors: D D
authors: DD
authors: Sternbach
authors: S A
authors: SA
authors: Kliewer
authors: B C
authors: BC
authors: Hansen
authors: T M
authors: TM
authors: Willson
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D001786:Blood Glucose / Q000032:analysis; D002460:Cell Line; D002784:Cholesterol / Q000097:blood / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000097:blood; D015195:Drug Design; D005215:Fasting; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006946:Hyperinsulinism / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects; D008253:Macaca mulatta; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008659:Metabolic Diseases / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000378:metabolism; D013379:Substrate Specificity; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use; D014157:Transcription Factors / Q000819:agonists* / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D001786:Blood Glucose; D008076:Cholesterol, HDL; C425931:GW 501516; D007328:Insulin; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013844:Thiazoles; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol