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

WR Oliver Jr, JL Shenk, MR Snaith… - Proceedings of the …, 2001 - National Acad Sciences
WR Oliver Jr, JL Shenk, MR Snaith, CS Russell, KD Plunket, NL Bodkin, MC Lewis…
Proceedings of the national academy of sciences, 2001National Acad Sciences
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 …
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.
National Acad Sciences