IDENTIFICATION OF ACTIVATOR HORMONE FOR HEPATIC ORPHAN NUCLEAR RECEPTOR

肝孤儿核受体激活激素的鉴定

• 批准号: 6162295
• 负责人: C WEINBERGER
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6162295
• 关键词: complementary DNA; cytochrome P450; embryonic stem cell; farnesyl compound; gene induction /repression; genetic promoter element; hormone receptor; hormone regulation /control mechanism; laboratory mouse; nucleic acid sequence; oligonucleotides; polymerase chain reaction; reporter genes; tissue /cell culture; transcription factor; transfection /expression vector

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.

工作概述：FXR是一种大鼠核受体，由 微摩尔量的法呢醇、法呢酸、保幼激素（JH） III和法呢基二磷酸的其他代谢物。 这些法尼醇 定义一种代谢分流， 表情 具有JH生物活性的合成化合物，例如 methoprene也刺激了FXR，加强了FXR可能是 与昆虫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precocene，诱导过早变态。 前新世是一种肝脏致癌物，与苯并（a）芘和其他致癌物一样， 多环芳烃必须被环氧化以发挥其毒性作用。 二聚的前茂和结构相关的二茂衍生物还 刺激FXR，如肝生长诱导剂水飞蓟宾和代谢产物 抗癌剂鱼藤酮和柠檬烯。 FXR也受到刺激， 毛喉素，但既没有8-Br-环AMP，也没有共转染的 PKA的催化亚基模拟了这种效应。 类比控制 细胞色素P450 3A（CYP 3A）基因表达的毛喉素耦合其 药理剂量的糖皮质激素诱导促使我们 检查CYP 3A作为FXR调节的基因靶点。 我们发现微摩尔 皮质醇代谢物水平触发FXR依赖的转录 通过特定的CYP 3A启动子元件的活性。 其他人已经表明 甲羟戊酸衍生产物是刺激DNA 合成和法尼醇类化合物在细胞G1期施加阻滞 周期