Proceedings of the National Academy of Sciences - PNAS, 2001-04, Vol.98 (9), p.5306-5311
2001
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- Autor(en) / Beteiligte
- Titel
- A Selective Peroxisome Proliferator-Activated Receptor δ Agonist Promotes Reverse Cholesterol Transport
- Ist Teil von
- Proceedings of the National Academy of Sciences - PNAS, 2001-04, Vol.98 (9), p.5306-5311
- Ort / Verlag
- United States: National Academy of Sciences
- Erscheinungsjahr
- 2001
- Quelle
- MEDLINE
- Beschreibungen/Notizen
- 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 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 PPARδ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0027-8424eISSN: 1091-6490DOI: 10.1073/pnas.091021198Titel-ID: cdi_pnas_primary_98_9_5306
- Format
- –
- Schlagworte
- Agonists, Animals, Apolipoprotein A-I - metabolism, ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters - genetics, ATP-Binding Cassette Transporters - metabolism, Biological Sciences, Biological Transport - drug effects, Blood Glucose - analysis, Cell Line, Cholesterol, Cholesterol - blood, Cholesterol - metabolism, Cholesterol, HDL - blood, Cholesterols, Drug Design, Fasting, Fatty acids, Fibroblasts - drug effects, Fibroblasts - metabolism, HDL lipoproteins, Humans, Hyperinsulinism - blood, Hyperinsulinism - drug therapy, Hyperinsulinism - metabolism, Insulin - blood, Insulin Resistance, Intestines - cytology, Intestines - drug effects, Intestines - metabolism, Lipids, Lipoproteins, Macaca mulatta, Macrophages, Macrophages - drug effects, Macrophages - metabolism, Male, Metabolic Diseases - blood, Metabolic Diseases - drug therapy, Metabolic Diseases - metabolism, Metabolism, Neurotransmitters, Obesity, Obesity - blood, Obesity - drug therapy, Obesity - metabolism, Pharmacology, Primates, Receptors, Receptors, Cytoplasmic and Nuclear - agonists, Receptors, Cytoplasmic and Nuclear - metabolism, RNA, Messenger - genetics, RNA, Messenger - metabolism, Substrate Specificity, Thiazoles - pharmacology, Thiazoles - therapeutic use, Transcription Factors - agonists, Transcription Factors - metabolism, Triglycerides, Triglycerides - blood