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首页> 外文期刊>Cell metabolism >Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan
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Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan

机译：比较代谢组学揭示了DAF-12（一种核激素受体）的内源性配体，可调节秀丽隐杆线虫的发育和寿命

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摘要

Small-molecule ligands of nuclear hormone receptors (NHRs) govern the transcriptional regulation of metazoan development, cell differentiation, and metabolism. However, the physiological ligands of many NHRs remain poorly characterized, primarily due to lack of robust analytical techniques. Using comparative metabolomics, we identified endogenous steroids that act as ligands of the C. elegans NHR, DAF-12, a vitamin D and liver X receptor homolog regulating larval development, fat metabolism, and lifespan. The identified molecules feature unexpected chemical modifications and include only one of two DAF-12 ligands reported earlier, necessitating a revision of previously proposed ligand biosynthetic pathways. We further show that ligand profiles are regulated by a complex enzymatic network, including the Rieske oxygenase DAF-36, the short-chain dehydrogenase DHS-16, and the hydroxysteroid dehydrogenase HSD-1. Our results demonstrate the advantages of comparative metabolomics over traditional candidate-based approaches and provide a blueprint for the identification of ligands for other C. elegans and mammalian NHRs.
机译：核激素受体（NHR）的小分子配体控制后生动物发育，细胞分化和代谢的转录调控。然而，许多NHR的生理配体仍然表征不佳，主要是由于缺乏可靠的分析技术。使用比较代谢组学，我们确定了内源性类固醇，可作为线虫NHR，DAF-12，维生素D和肝X受体同源物的配体，调节幼虫的发育，脂肪代谢和寿命。鉴定出的分子具有意想不到的化学修饰，仅包含较早报道的两种DAF-12配体之一，因此有必要对先前提出的配体生物合成途径进行修订。我们进一步显示，配体谱受复杂的酶网络调节，包括Rieske加氧酶DAF-36，短链脱氢酶DHS-16和羟基类固醇脱氢酶HSD-1。我们的结果证明了相对代谢组学优于传统的基于候选物的方法的优势，并为鉴定其他秀丽隐杆线虫和哺乳动物NHRs的配体提供了蓝图。

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