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: 6106764
• 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/6106764
• 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 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 has been discerned whose effects on cell growth are proposed to hinge on their abilities to perturb these isoprenoid regulatory mechanisms.

FXR是一种大鼠核受体 激活转录以响应法呢基的代谢物 二磷酸盐由于这些法尼醇是保幼激素（JH） 激动剂，推测FXR可能与昆虫JH 受体的这一假设现在得到以下研究结果的支持， FXR由植物衍生的和合成的JH激动剂诱导， 由JH拮抗剂precocene特异性调节， 过早变态。像苯并[a]芘一样， 啮齿类动物肝癌的致癌物质，两者都被小鼠肝脏代谢 微粒体与FXR拮抗剂。相比之下，前茂二聚体和 四氢金鱼草类似物诱导FXR。结构-活性研究 接下来导致了3 α-羟基类固醇和胆汁的鉴定 酸作为内源性FXR效应物。即使有些 甲羟戊酸衍生产物是DNA合成和细胞增殖所必需的。 生长，法尼醇类诱导细胞凋亡并抑制HMG CoA 在转录后水平的还原酶活性。的 降胆固醇剂SR-12813类似地抑制还原酶 现在加入法尼醇作为FXR激活剂， 甲羟戊酸中该受体和对照之间的潜在联系 通路最后，一组不同的异生素FXR诱导剂， 已经发现，其对细胞生长的影响被认为与 干扰这些类异戊二烯调节机制的能力。