IDENTIFICATION OF AN ACTIVATOR HORMONE FOR A HEPATIC ORPHAN NUCLEAR RECEPTOR

一种名为OR2的孤儿核受体基因已被分离出来 与果蝇蜕皮激素受体关系最为密切。OR2是 仅在肝、肠、肾髓质和肾上腺皮质表达。 我们最初证明OR2是一种配体依赖的激活剂，通过其 对牛血清亲脂性提取物的反应。OR2活性为 用高效液相色谱和硅胶分离血清中的其他成分 测定分子活化剂结构的层析法。 同时，通过随机调查确定了OR2的活化子 亲脂性化合物。保幼激素(JH)III诱导OR2 转录活性的效价为15微摩尔。其他或2 通过与JH III的结构比较发现了激活剂，包括 法尼醇、法尼醇、金合欢酸、金合欢乙酸酯和 香叶醇。因此，我们将OR2称为法尼醇受体(FXR)。 有趣的是，OR2血清活性层析与甲基 法尼苏酸盐(MF)，也存在于尿液中。新陈代谢的前体 这些法尼醇代谢物就是法尼基焦磷酸(FPP)。FPP是 类异戊二烯的中心中间体，如胆固醇，胆汁酸， 泛苯二酚、多酚和类固醇激素。法尼醇类代谢物 从FPP形成生化分流。因为法尼斯类物质在 在发现FXR的组织中，我们假设 受体及其激活物构成一个内分泌信号系统。我们 建议循环中的MF代表一种排泄产物。自.以来 其中一些法尼醇类化合物与胆固醇调节有关。 我们推测，法尼醇类化合物存在于胆固醇生成组织中 FXR调节甲氧戊酸途径中的酶的基因。 对这些法尼醇调节基因的鉴定正在进行中 证实或反驳这一提议。

An orphan nuclear receptor gene called OR2 has been isolated which is most closely related to the Drosophila ecdysone receptor. OR2 is expressed only in the liver, intestine, renal medulla and adrenal cortex. We originally showed that OR2 was a ligand-dependent activator by its response to lipophilic extracts of bovine serum. The OR2 activity was separated from other serum components by HPLC and silica gel chromatography for determining the structure of the molecular activator. Concomitantly, an activator for OR2 was identified by randomly surveying lipophilic compounds. Juvenile hormone (JH) III induces OR2 transcriptional activity with a potency of 15 micromolar. Other OR2 activators were found by structural comparisons with JH III and include farnesol, farnesal, farnesoic acid, farnesyl acetate, and geranylgeraniol. We have therefore dubbed OR2 a farnesoid receptor (FXR). Interestingly, the OR2 serum activity chromatographs with methyl farnesoate (MF) which is also found in urine. The metabolic precursor for these farnesoid metabolites is farnesyl pyrophosphate (FPP). FPP is the central intermediate to isoprenoids such as cholesterol, bile acids, ubiquinone, dolichols, and steroid hormones. The farnesoid metabolites form a biochemical shunt from FPP. Since farnesoids accumulate in the isoprenoidogenic tissues where FXR is found, we hypothesize that the receptor and its activators comprise an intracrine signaling system. We propose that the circulating MF represents an excreted product. Since some of these farnesoids have been implicated in cholesterol regulation and the farnesoids are found in cholesterologenic tissues, we hypothesize that FXR regulates genes for enzymes in the mevalonate pathway. Identification of these farnesoid-regulated genes is underway to corroborate or dispute this proposal.