PHYTOL METABOLITES ARE DIETARY FACTORS THAT ACTIVATE THE NUCLEAR RECEPTOR RXR

RXR是一种核受体，通过与其他受体配对，在细胞信号传导中起核心作用。以前，全反式维甲酸和9顺式维甲酸被定性为RXR效应物。相反，我们已经确定植酸和植酸作为循环支链脂肪酸从牛血清氯仿提取物通过跟踪rxr依赖的转录活性。活性组分的质谱分析表明，这些饱和二萜酸在浓度为4至64 μ m时诱导了依赖rxr的活性。尽管9cRA的效力是植酸的200倍，但在等量的提取物中检测不到9cRA，并且不能以可以解释其活性的浓度存在。合成另一叶绿醇代谢物植酸，刺激RXR，其效价与功效与植酸相似。这些代谢物特异性取代RXR中的[3H]-9cRA， Ki值为4 uM，表明它们的转录作用是由受体直接相互作用介导的。叶绿醇代谢物是生理效应物的有力候选者，因为它们的RXR结合亲和力和激活能力与其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通过rxr依赖的信号通路协调细胞代谢的必需营养素。通过比较在缺乏植酸的饮食中饲养的小鼠和大鼠与在补充植酸的饮食中饲养的动物的生长情况，这一假设得到了验证。综上所述，这些发现使我们提出叶绿醇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.