A selective peroxisome proliferator-activated receptor δ 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 ␣ (NR1C1) and ␥ (NR1C3) subtypes, respectively. By contrast, the therapeutic potential of the ␦ (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 PPAR␦ 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 PPAR␦ agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.

Synthesis, biological evaluation and molecular modeling studies of the PPARβ/δ antagonist CC618

“…In the PPARβ/δ-expressing cells, CC618 antagonized the effects of 4 nM of GW501516 with an IC50 = 10.0 μM. In this assay, the previously reported antagonist GSK3787 (9) displayed an IC50 = 5.0 μM (Figure 2A). The analog 10b, lacking the 5-trifluoromethyl group, did not display any antagonistic effects (see Supporting Information, Figure S1).…”

“…We envisioned that combining the arylthiazole moiety found in the potent and selective PPARβ/δ agonist GW501516 (1) with the 5-trifluoromethyl-2-pyridylsulfone moiety of GSK3787 (9) would result in antagonism against PPARβ/δ [28].…”

“…In the early days of PPAR research, the use of selective agonists against the three known PPAR subtypes was particularly important [8]. In the context of PPARβ/δ, the carboxylic acid GW501516 (1, Figure 1) [9,10] has seen widespread use as a pharmacological tool. Later, potent and selective PPARα and PPARγ antagonists, such as GW6471 (2) [11] and GW9662 (3) [12], were introduced ( Figure 1).…”

Features of the metabolic syndrome are modulated by an interaction between the peroxisome proliferator-activated receptor-delta −87T>C polymorphism and dietary fat in French-Canadians

“…8,10 Therefore, carriers of the À87C allele might be protected from deleterious effects of a highfat diet on the lipid metabolism in comparison to the general population. It has also been demonstrated by Oliver et al 7 that PPAR-delta increases cholesterol efflux from macrophage, fibroblast and intestinal cells, in part through an increase in the expression of the ABCA1 reverse cholesterol transporter.…”

“…In addition, it has been previously shown that plasma HDL-C levels of db/db mice and obese rhesus monkeys increase after treatment with PPAR-delta agonists. 6, 7 The fatty acid utilization in the skeletal muscle could be enhanced in À87C carriers through a greater activation by PPAR-delta of genes involved in long chain fatty acids b-oxidation. 8,10 Therefore, carriers of the À87C allele might be protected from deleterious effects of a highfat diet on the lipid metabolism in comparison to the general population.…”