IDENTIFICATION OF ACTIVATOR HORMONE FOR HEPATIC ORPHAN NUCLEAR RECEPTOR

工作总结：FXR 是一种大鼠核受体，可响应法呢基二磷酸代谢物而激活转录。由于这些法呢酯是保幼激素 (JH) 激动剂，因此推测 FXR 可能与昆虫 JH 受体有关。这一假设现在得到了以下研究结果的支持：FXR 是由植物源性和合成的 JH 激动剂诱导的，并受到 JH 拮抗剂早熟期的特异性调节，从而诱导过早变态。 Precocene 与苯并[a]芘一样，是一种啮齿动物肝癌物质，两者均被小鼠肝微粒体代谢为 FXR 拮抗剂。 相反，早熟二聚体和四氢类似物诱导FXR。接下来的结构-活性研究确定了 3 种 α-羟基类固醇和胆汁酸作为内源性 FXR 效应物。尽管 DNA 合成和细胞生长需要一些甲羟戊酸衍生产物，但法尼醇会在转录后水平诱导细胞凋亡并抑制 HMG CoA 还原酶活性。 降胆固醇剂 SR-12813 类似地抑制还原酶，现在与金合欢醇一起作为 FXR 激活剂，该激活剂在该受体与甲羟戊酸途径的控制之间提供了潜在的联系。 最后，人们已经认识到包括天然和合成杀虫剂在内的多种外源 FXR 诱导剂，其对细胞生长的影响取决于它们扰乱这些类异戊二烯调节机制的能力。

Summary of Work: FXR is a rat nuclear receptor that activates transcription in response to metabolites of farnesyl diphosphate. Since these farnesoids are juvenile hormone (JH) agonists, it was postulated that FXR may be related to an insect JH receptor. This hypothesis is now supported by the findings that FXR is induced by plant-derived and synthetic JH agonists and specifically regulated by the JH antagonist precocene which induces premature metamorphosis. Precocene, like benzo[a]pyrene, is a rodent hepatocarcinogen and both were metabolized by mouse liver microsomes to FXR antagonists. In contrast, a precocene dimer and tetrahydrochrysene analogs induced FXR. Structure-activity studies next led to the identification of 3 alpha-hydroxysteroids and bile acids as endogenous FXR effectors. Even though some mevalonate-derived product is required for DNA synthesis and cell growth, farnesoids induce apoptosis and suppress HMG CoA reductase enzyme activity at the post-transcriptional level. The cholesterol-lowering agent SR-12813 similarly inhibits reductase and now joins farnesol as an FXR activator which provides a potential link between this receptor and control in the mevalonate pathway. Finally, a diverse group of xenobiotic FXR inducers including natural and synthetic insecticides has been discerned whose effects on cell growth are proposed to hinge on their abilities to perturb these isoprenoid regulatory mechanisms.