A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport
A selective peroxisome proliferator-activated receptor δ agonist promotes reverse cholesterol transport
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DOI：
10.1073/pnas.091021198
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发表时间：
2001-04-24
影响因子：
11.1
通讯作者：
Willson, TM
中科院分区：
文献类型：
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作者：
Oliver, WR;Shenk, JL;Willson, TM
过氧化物酶体增殖物激活受体（PPARs）是调节脂肪酸和碳水化合物代谢的膳食脂质传感器。贝特类药物的降血脂作用和格列酮类药物的抗糖尿病作用是由于α（NR1C1）和γ（NR1C3）亚型的激活。分别相比之下，delta（NR1C2）亚型的治疗潜力是未知的，部分原因是缺乏选择性配体。我们使用组合化学和基于结构的药物设计来开发有效的和亚型选择性的PPAR δ激动剂，GW501516。在巨噬细胞、成纤维细胞和肠细胞中，GW 501516增加胆固醇反向转运蛋白ATP结合盒A1的表达，并诱导载脂蛋白A1特异性胆固醇流出。当给予胰岛素抵抗的中年肥胖恒河猴时，GW501516导致血清高密度脂蛋白胆固醇的显著剂量依赖性升高，同时降低小密度低密度脂蛋白、空腹甘油三酯和空腹胰岛素的水平。我们的研究结果表明，PPAR δ激动剂可能是增加胆固醇逆向转运和减少与代谢综合征X相关的心血管疾病的有效药物。
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 PPAR delta agonist, GW501516. In macrophages, fibroblasts, and intestinal cells, GW501516 increases expression of the reverse cholesterol transporter ATP-binding cassette Al and induces apolipoprotein Al-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 delta agonists may be effective drugs to increase reverse cholesterol transport and decrease cardiovascular disease associated with the metabolic syndrome X.