Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay
Fatty acids, eicosanoids, and hypolipidemic agents identified as ligands of peroxisome proliferator-activated receptors by coactivator-dependent receptor ligand assay
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DOI：
10.1210/me.11.6.779
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发表时间：
1997-06-01
影响因子：
--
通讯作者：
Wahli, W
中科院分区：
文献类型：
--
作者：
Krey, G;Braissant, O;Wahli, W
过氧化物酶体增殖激活受体（PPARs）是核激素受体，控制参与脂质稳态的基因表达。ppar激活基因转录以响应多种化合物，包括降血脂药物和天然脂肪酸。从过多的PPAR激活剂中，Scatchard对受体-配体相互作用的分析迄今为止仅鉴定出四种配体，它们是趋化剂白三烯B-4和降脂药物wy14643。基于与PPAR结合的配体会诱导受体与转录共激活因子的相互作用的假设，我们开发了一种新的配体传感器检测方法，称为共激活因子依赖性受体配体检测（CARLA）。通过CARLA，我们筛选了几种天然的和合成的候选配体，并鉴定了天然存在的脂肪酸和代谢物以及降血脂药物作为非洲爪蟾三种PPAR亚型的真正配体。表明ppar通过与多种结构不同的化合物相互作用的能力，在核受体超家族中获得了与其生物活性相容的独特配体结合特性。
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors controlling the expression of genes involved in lipid homeostasis. PPARs activate gene transcription in response to a variety of compounds including hypolipidemic drugs as well as natural fatty acids. From the plethora of PPAR activators, Scatchard analysis of receptor-ligand interactions has thus far identified only four ligands, These are the chemotactic agent leukotriene B-4 and the hypolipidemic drug Wy 14,643 for. the alpha-subtype and a prostaglandin J2 metabolite and synthetic antidiabetic thiazolidinediones for the gamma-subtype, Based on the hypothesis that ligand binding to PPAR would induce interactions of the receptor with transcriptional coactivators, we have developed a novel ligand sensor assay, termed coactivator-dependent receptor ligand assay (CARLA), With CARLA we have screened several natural and synthetic candidate ligands and have identified naturally occurring fatty acids and metabolites as well as hypolipidemic drugs as bona fide ligands of the three PPAR subtypes from Xenopus laevis, Our results;suggest that PPARs, by their ability to interact with a number of structurally diverse compounds, have acquired unique ligand-binding properties among the superfamily of nuclear receptors that are compatible with their biological activity.