IDENTIFICATION OF ACTIVATOR HORMONE FOR HEPATIC ORPHAN NUCLEAR RECEPTOR

工作总结：FXR是一种大鼠核受体，它能激活转录，对法尼基二磷酸的代谢物做出反应。由于这些法尼醇类化合物是保幼激素(JH)激动剂，推测FXR可能与昆虫的JH受体有关。这一假说现在得到了以下发现的支持：FXR是由植物来源的和合成的JH激动剂诱导的，并由JH拮抗剂preocene特异性地调节，它诱导早熟变态。前烯和苯并[a]芘一样，都是啮齿动物肝癌的致癌物，两者都被小鼠肝微粒体代谢成FXR拮抗剂。相反，前驱体二聚体和四氢黄烷类似物诱导FXR。结构-活性研究随后确定了3个α-羟基类固醇和胆汁酸为内源性FXR效应物质。尽管甲氧戊酸衍生的产物是DNA合成和细胞生长所必需的，但法尼醇类化合物在转录后水平诱导细胞凋亡并抑制HMG CoA还原酶的活性。降胆固醇药物SR-12813类似地抑制还原酶，现在加入法尼醇作为FXR激活剂，这在该受体和甲氧戊酸途径中的对照之间提供了潜在的联系。最后，包括天然和合成杀虫剂在内的各种异生FXR诱导剂已经被识别出来，它们对细胞生长的影响被认为取决于它们扰乱这些异戊二烯类调控机制的能力。

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.