IDENTIFICATION OF ACTIVATOR HORMONE FOR HEPATIC ORPHAN NUCLEAR RECEPTOR

工作概述：FXR是一种大鼠核受体，对法呢基二磷酸的代谢产物起反应，激活转录。由于这些法尼醇是保幼激素（JH）激动剂，因此推测FXR可能与昆虫JH受体相关。这一假设现在得到以下发现的支持：FXR由植物来源的和合成的JH激动剂诱导，并由诱导过早变态的JH拮抗剂precocene特异性调节。 与苯并[a]芘一样，前茂是一种啮齿类动物肝癌原，两者均通过小鼠肝微粒体代谢为FXR拮抗剂。 与此相反，前二聚体和tetrahydrochyrrhythm类似物诱导FXR。结构-活性研究接下来导致鉴定3 α-羟基类固醇和胆汁酸作为内源性FXR效应物。尽管一些甲羟戊酸衍生的产物是DNA合成和细胞生长所需的，但法尼醇类化合物诱导细胞凋亡并在转录后水平抑制HMG CoA还原酶活性。 降胆固醇剂SR-12813同样抑制还原酶，现在加入法尼醇作为FXR激活剂，在甲羟戊酸途径中提供该受体和控制之间的潜在联系。 最后，已经识别出包括天然和合成杀虫剂的异生素FXR诱导剂的不同组，其对细胞生长的影响被提出取决于其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.