IDENTIFICATION OF ACTIVATOR HORMONE FOR HEPATIC ORPHAN NUCLEAR RECEPTOR

工作总结：FXR是一种大鼠核受体，由 微摩尔量的金合欢醇、金合欢酸、保幼激素(JH) 和其他法尼基二磷酸的代谢物。这些法尼酮 定义一种共同调节FXR依赖基因的代谢分流 表情。具有JH生物活性的合成化合物，如 甲氧基丁二烯也刺激FXR，强化了FXR可能是 与昆虫的JH受体有关。这一假设得到了 发现FXR被羟基化衍生物特异性激活 JH拮抗剂预可林，可诱导早熟变态。 前烯是一种肝脏致癌物质，与苯并(A)芘和其他 多环芳烃，必须经过环氧化才能发挥其毒性作用。 二聚化的前驱体和结构相关的黄原烯衍生物也 刺激FXR的还有肝脏生长诱导剂水飞蓟宾和 抗癌物质鱼藤酮和柠檬烯。FXR也受到以下因素的刺激 Forskolin，但8-溴-环AMP和共转染法都没有。 PKA催化亚基的作用与此相似。的模拟控制 Forskolin偶联ITS表达细胞色素P450 3A基因 由药理剂量的糖皮质激素诱导促使我们 将细胞色素P3A作为FXR调控的基因靶点进行研究。我们发现了那颗微小的磨牙 皮质醇代谢产物水平触发FXR依赖的转录 通过特定的CYP3A启动子元件发挥活性。其他人已经展示了 甲氧戊酸衍生产品是刺激DNA所必需的 合成和法尼醇类物质在细胞的G1期施加了阻碍 周而复始。

Summary of Work: FXR is a rat nuclear receptor that is activated by micromolar amounts of farnesol, farnesoic acid, juvenile hormone (JH) III, and other metabolites of farnesyl diphosphate. These farnesoids define a metabolic shunt that together may regulate FXR-dependent gene expression. Synthetic compounds with JH biological activity such as methoprene also stimulated FXR, strengthening the notion that FXR may be related to an insect JH receptor. This hypothesis is supported by the finding that FXR is specifically activated by hydroxylated derivatives of the JH antagonist precocene, which induces premature metamorphosis. Precocene is a hepatic carcinogen that, like benzo(a)pyrene and other polyaromatic hydrocarbons, must be epoxidated to exert its toxic effects. Dimerized precocene and structurally-related chrysene derivatives also stimulated FXR as did the liver growth inducer silybin and metabolites of the anticarcinogens rotenone and limonene. FXR was also stimulated by forskolin, but neither 8-Br-cyclic AMP nor cotransfection of the catalytic subunit of PKA mimicked this effect. Analogous control of cytochrome P450 3A (CYP3A) gene expression by forskolin coupled with its induction by pharmacological doses of glucocorticoids prompted us to examine CYP3A as an FXR-regulated gene target. We found that micromolar levels of cortisol metabolites triggered FXR-dependent transcriptional activity through a specific CYP3A promoter element. Others have shown that a mevalonate-derived product is required for stimulating DNA synthesis and that farnesoids impose a block in the G1 phase of the cell cycle.