FATTY-ACIDS ACTIVATE A CHIMERA OF THE CLOFIBRIC ACID-ACTIVATED RECEPTOR AND THE GLUCOCORTICOID RECEPTOR
FATTY-ACIDS ACTIVATE A CHIMERA OF THE CLOFIBRIC ACID-ACTIVATED RECEPTOR AND THE GLUCOCORTICOID RECEPTOR
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DOI：
10.1073/pnas.89.10.4653
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发表时间：
1992-05-15
影响因子：
11.1
通讯作者：
GUSTAFSSON, JA
中科院分区：
文献类型：
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作者：
GOTTLICHER, M;WIDMARK, E;GUSTAFSSON, JA
过氧化物酶体增殖剂如环丙沙酸、奈非诺平和WY-14,643已被证明能激活PPAR(Peroxisome增殖物激活受体)，PPAR是类固醇核受体超家族的成员。我们已经从大鼠中克隆了与小鼠[IsSemann，I.&Green，S.(1990)Nature(London)347,645-650]同源的基因，其编码的蛋白有97%的相似性，具有一个特别保守的假定配体结合结构域。为了寻找生理上发生的激活剂，我们建立了一种转录反式激活实验，在CHO细胞中稳定表达大鼠PPAR和人糖皮质激素受体的嵌合体，该嵌合体在小鼠乳腺肿瘤病毒启动子的控制下激活胎盘碱性磷酸酶报告基因的表达。对与脂质代谢或过氧化体增殖相关的化合物的测试表明，150 mU-M的花生四烯酸或亚油酸，而不是脱氢表雄酮、胆固醇或25-羟基-胆固醇，激活了受体嵌合体。此外，饱和脂肪酸还诱导了报告基因。将链长缩短到n=6或引入欧米伽末端的羧基取消了脂肪酸的活化潜力。综上所述，本研究结果表明，脂肪酸可以调节类固醇核受体超家族成员所介导的基因表达。
Peroxisome proliferators such as clofibric acid, nafenopin, and WY-14,643 have been shown to activate PPAR (peroxisome proliferator-activated receptor), a member of the steroid nuclear receptor superfamily. We have cloned the cDNA from the rat that is homologous to that from the mouse [Issemann, I. & Green, S. (1990) Nature (London) 347, 645-650], which encodes a 97% similar protein with a particularly well-conserved putative ligand-binding domain. To search for physiologically occurring activators, we established a transcriptional transactivation assay by stably expressing in CHO cells a chimera of rat PPAR and the human glucocorticoid receptor that activates expression of the placental alkaline phosphatase reporter gene under the control of the mouse mammary tumor virus promoter. Testing of compounds related to lipid metabolism or peroxisomal proliferation revealed that 150-mu-M concentrations of arachidonic or linoleic acid but not of dehydroepiandrosterone, cholesterol, or 25-hydroxy-cholesterol, activate the receptor chimera. In addition, saturated fatty acids induce the reporter gene. Shortening the chain length to n = 6 or introduction of an omega-terminal carboxylic group abolished the activation potential of the fatty acid. In conclusion, the present results indicate that fatty acids can regulate gene expression mediated by a member of the steroid nuclear receptor superfamily.