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. 2001 Apr 24;98(9):5306-11.
doi: 10.1073/pnas.091021198. Epub 2001 Apr 17.

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

W R Oliver Jr  1 , J L Shenk, M R Snaith, C S Russell, K D Plunket, N L Bodkin, M C Lewis, D A Winegar, M L Sznaidman, M H Lambert, H E Xu, D D Sternbach, S A Kliewer, B C Hansen, T M Willson
Affiliations

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

W R Oliver Jr et al. Proc Natl Acad Sci U S A. .

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.

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Figures

Figure 1
Figure 1
GW501516 is a selective PPARδ agonist. Data are expressed as fold change compared with vehicle-treated cells and represent the mean of assays performed in triplicate ± SE. (A) Chemical structure of GW501516. (B) Activation of GAL4-PPAR ligand binding domain chimeras in transiently transfected CV-1 cells by GW501516. Dose–response curves are shown for human PPARδ (●), human PPARα (▵), and human PPARγ (□). (C) Activation of GAL4-nuclear receptor ligand binding domain chimeras in CV-1 cells. Transfected cells were treated with 1.0 μM GW501516.
Figure 2
Figure 2
Regulation of ABCA1 expression and cholesterol efflux from THP1 macrophages. Compounds were used at the following concentrations: LXRα (GW3965), 1.0 μM; PPARδ (GW501516), 100 nM; PPARα (GW7647), 100 nM; PPARγ (GW7845), 100 nM. Data are presented as the mean of assays performed in triplicate ± SD. (A) ABCA1 mRNA levels. (B) ApoA1-specific cholesterol efflux.
Figure 3
Figure 3
NMR analysis of serum lipoproteins from primates treated with GW501516. V = vehicle, GW = 3.0 mg/kg GW501516. Data are presented as mean ± SE for n = 5. *, P ≤ 0.05; **, P ≤ 0.01. (A) Lipid values determined by summation of the directly measured concentrations of HDL, LDL, and VLDL subclasses after conversion to cholesterol (c) or triglyceride (TG) units. (B) Number of LDL particles calculated from the LDL subclasses. (C) Relative compositions of the HDL, LDL, and VLDL subclasses.
Figure 4
Figure 4
Serum apo concentrations determined by immunoprecipitation. V = vehicle, GW = 3.0 mg/kg GW501516. Data are presented as mean ± SE for n = 5. *, P ≤ 0.05; **, P ≤ 0.01.
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