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 - Tập 98 Số 9 - Trang 5306-5311 - 2001
William R. Oliver1, Jennifer L. Shenk1, Mike R. Snaith1, CAROLINE S. RUSSELL1, Kelli D. Plunket1, Noni L. Bodkin1, Michael C. Lewis1, Deborah A. Winegar1, Marcos L. Sznaidman1, Millard H. Lambert1, H. Eric Xu1, Daniel D. Sternbach1, Steven A. Kliewer1, Barbara C. Hansen1, Timothy M. Willson1
1Metabolic Diseases Drug Discovery and Nuclear Receptor Discovery Research, GlaxoSmithKline, Research Triangle Park, NC 27709; Cardiovascular Diseases Drug Discovery, GlaxoSmithKline, Stevenage, Hertfordshire SG1 2NY, United Kingdom; and Obesity and Diabetes Research Center, University of Maryland School of Medicine, Baltimore, MD 21201

Tóm tắt

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.

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Tài liệu tham khảo

10.1021/jm990554g

10.1016/S1097-2765(00)80467-0

10.1016/0092-8674(95)90200-7

10.1210/endo.137.1.8536636

10.1111/j.1753-4887.1998.tb01728.x

10.1016/S0002-9149(98)00033-2

10.1172/JCI10762

10.1097/00041433-200012000-00005

10.1172/JCI11538

10.1097/00041433-200012000-00010

10.1097/00041433-200010000-00007

10.1038/11905

10.1038/11914

10.1038/11921

10.1172/JCI10727

10.1126/science.289.5484.1524

10.1016/S1074-5521(97)90299-4

10.1021/jm9804127

B C Hansen Obesity: Pathology and Therapy, eds D H Lockwood, T G Heffner (Springer-Verlag, Berlin), pp. 461–489 (2000).

J D Otvos Handbook of Lipoprotein Testing, eds N Rifai, G Warnick, M H Dominiczak (Am. Assoc. Clin. Chem. Press, Washington, DC), pp. 497–508 (1997).

10.1074/jbc.274.10.6718

10.1073/pnas.94.9.4312

10.1073/pnas.200367697

10.1074/jbc.M003337200

10.1021/jm980414r

10.1093/jnci/56.4.843

N L Bodkin, B L Metzger, B C Hansen Am J Physiol 256, E676–E681 (1989).

10.1210/jcem-72-5-1067

10.2337/diab.43.2.204

10.1007/BF00870281

10.3109/07853899808999405

10.2165/00003088-199937020-00001

10.1002/clc.4960221405

10.2165/00003495-199400472-00003

10.1161/01.ATV.19.3.472

10.1161/01.CIR.98.19.2088

10.1016/S0014-5793(00)01554-4

10.1128/MCB.20.14.5119-5128.2000

10.1016/S0022-2275(20)35728-X

10.1016/0163-7827(93)90002-E

10.1056/NEJM199908053410604

10.1038/83348

10.1016/S1097-2765(01)00164-2

10.1172/JCI117717

10.1074/jbc.270.22.13470

10.1021/jm9903601

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

Tập 98 Số 9

5306-5311

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