PHYTOL METABOLITES ARE DIETARY FACTORS THAT ACTIVATE THE NUCLEAR RECEPTOR RXR

植醇代谢物是激活核受体 RXR 的饮食因素

• 批准号: 6162299
• 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/6162299
• 关键词: 13 cis retinoate; chlorophyll; dietary constituent; laboratory rat; mass spectrometry; nutrition related tag; receptor expression; retinoid binding proteins; terpenes; transcription factor

Summary of Work: RXR is a nuclear receptor which plays a central role in cell signalling by pairing with a host of other receptors. Previously, 9-cis-retinoic acid was from chloroform extracts of bovine serum by following RXR-dependent transcriptional activity. Mass spectrometric analyses of material in active fractions pointed to the saturated diterpenoid acid, which induced RXR-dependent transcription at concentrations between 4 and 64 uM. Although 200 times more potent than phytanic acid, 9cRA was undetectable in equivalent amounts of extract and cannot be present at a concentration that could account for the activity. Phytenic acid, another phytol metabolite, was synthesized and stimulated RXR with a potency and efficacy similar to phytanic acid. These metabolites specifically displaced [3H]-9cRA from RXR with k1 values of 4 uM, indicating that their transcriptional effects are mediated by direct receptor interactions. Phytol metabolites are compelling candidates for physiological effectors, because their RXR binding affinities and activation potencies match their micromolar circulating concentrations. Given their exclusive dietary origin, these chlorophyll metabolites may represent essential nutrients that coordinate cellular metabolism through RXR-dependent signalling pathways. This hypothesis is being tested by comparing the growth of rats raised on phytanic acid-deficient diets with groups of animals fed diets supplemented with phytanic acid. In summary, these findings lead us to propose that phytol metabolites may be nutritional signals linking the animal's dietary state with a variety of endocrine and intracrine signalling pathways through the nuclear receptor RXR.

工作概述：RXR是一种核受体，在细胞内起着核心作用， 通过与其他受体配对来传递细胞信号。 在此之前， 从牛血清氯仿提取物中， RXR依赖的转录活性。 质谱 活性组分中的物质分析表明， 二萜酸，诱导RXR依赖的转录， 浓度在4和64 μ M之间。 虽然比普通的 植烷酸，9 cRA在等量的提取物中检测不到， 不可能以可以解释活性的浓度存在。 合成并刺激另一种植醇代谢产物--植烯酸 RXR的效力和功效与植烷酸相似。 这些 代谢物特异性取代RXR中的[3 H]-9cRA，k1值为4 uM，表明它们的转录作用是由直接的 受体相互作用 植醇代谢物是植物生长调节剂的令人信服的候选者。 生理效应物，因为它们的RXR结合亲和力和 活化效力与它们的微摩尔循环浓度相匹配。 鉴于其独特的饮食来源，这些叶绿素代谢物可能 代表着协调细胞代谢的必需营养素， RXR依赖的信号通路。 这一假设正在接受 比较用植烷酸缺乏的饮食饲养的大鼠的生长情况， 动物组喂食补充植烷酸的饮食。 总的说来， 这些发现使我们提出植醇代谢物可能是 营养信号将动物的饮食状态与各种 通过核受体的内分泌和内分泌信号通路 RXR。