PHYTOL METABOLITES ARE DIETARY FACTORS THAT ACTIVATE THE NUCLEAR RECEPTOR RXR

工作总结：RXR是一种核受体，通过与一系列其他受体配对，在细胞信号转导中发挥核心作用。以前，全反式维甲酸和9-顺式维甲酸被认为是RXR效应。相反，通过跟踪RXR依赖的转录活性，我们已经从牛血清的氯仿提取物中鉴定出植酸和植酸是循环支链脂肪酸。对活性组份中物质的质谱分析表明，这些饱和的二萜酸在4和微米之间的浓度范围内诱导了RXR依赖的活性。虽然9cRA的效力是植酸的200倍，但在等量的提取物中检测不到9cRA，而且不能在可以解释活性的浓度下存在。另一种植物酚代谢物植酸被合成并刺激RXR，其效力和效果与植酸相似。这些代谢物特异性地取代RXR上的[~3H]-9cRA，Ki值为4um，表明它们的转录效应是由直接受体相互作用介导的。植物酚代谢物是引人注目的生理效应物，因为它们的RXR结合亲和力和激活潜力与它们的微摩尔循环量相匹配。鉴于其独特的饮食来源，这些叶绿素代谢物可能代表着通过RXR依赖的信号通路协调细胞代谢的必要营养物质。通过比较用植酸缺乏的饲料饲养的小鼠和大鼠的生长情况，以及用补充植酸的饲料喂养的动物组，这一假说正在得到验证。综上所述，这些发现引导我们提出，植物酚代谢物可能是通过核受体RXR将动物的饮食状态与各种内分泌和内分泌信号通路联系起来的营养信号。

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, all-trans-retinoic acid and 9-cis-retinoic acid were characterized as RXR effectors. In contrast, we have identified phytenic acid and phytanic acid as circulating branched chain fatty acids from chloroform extracts of bovine serum by following RXR-dependent transcriptional activity. Mass spectrometric analyses of material in active fractions pointed to these saturated diterpenoid acids, which induced RXR-dependent activity 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 Ki 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 amounts. 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 mice and 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.