IDENTIFICATION OF ACTIVATOR HORMONE FOR HEPATIC ORPHAN NUCLEAR RECEPTOR

工作概述：FXR是一种大鼠核受体，可激活二磷酸法尼酯代谢产物的转录。由于这些类法内酯是幼体激素（JH）激动剂，因此推测FXR可能与昆虫的JH受体有关。这一假设现在得到了一些研究结果的支持，即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precocene的特异性调控，后者诱导过早变态。与苯并[a]芘一样，早熟素也是一种啮齿动物的肝癌致癌物，两者均可通过小鼠肝微粒体代谢为FXR拮抗剂。相比之下，早熟二聚体和四氢chrysene类似物诱导FXR。结构-活性研究随后确定了3种α -羟基类固醇和胆汁酸作为内源性FXR效应器。尽管一些甲羟戊酸衍生的产物是DNA合成和细胞生长所必需的，但类法内酯在转录后水平诱导细胞凋亡并抑制HMG辅酶a还原酶活性。降胆固醇剂SR-12813同样抑制还原酶，现在作为FXR激活剂加入法尼醇，这在该受体和甲羟戊酸途径的控制之间提供了潜在的联系。最后，多种多样的外源FXR诱导剂（包括天然和合成杀虫剂）已经被发现，它们对细胞生长的影响取决于它们干扰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.