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: 6432401
• 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/6432401
• 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, 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.

RXR是一种核受体，通过与其他受体配对在细胞信号传导中发挥核心作用。 以前，全反式视黄酸和9-顺式视黄酸被表征为RXR效应物。 与此相反，我们已经确定植烯酸和植烷酸循环支链脂肪酸从氯仿提取物的牛血清通过以下RXR依赖的转录活性。 活性组分中物质的质谱分析指出这些饱和的二萜酸，其在4和64 μ M之间的浓度下诱导RXR依赖性活性。 虽然比植烷酸有效200倍，但在等量的提取物中无法检测到9 cRA，并且不能以可以解释活性的浓度存在。合成了另一种植醇代谢产物植烯酸，并以类似于植烷酸的效力和功效刺激RXR。 这些代谢物特异性地从RXR中置换[3 H]-9cRA，Ki值为4 μ M，表明它们的转录效应是由直接受体相互作用介导的。 植醇代谢物是生理效应物的引人注目的候选者，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。 通过比较缺乏植烷酸的饮食饲养的小鼠和大鼠与补充植烷酸的饮食饲养的动物组的生长情况，对这一假设进行了检验。 总之，这些发现使我们提出，植醇代谢物可能是营养信号，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。