Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan.
Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan.
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DOI：
10.1016/j.cmet.2013.11.024
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发表时间：
2014-01-07
期刊：
影响因子：
29
通讯作者：
Schroeder FC
中科院分区：
文献类型：
--
作者：
Mahanti P;Bose N;Bethke A;Judkins JC;Wollam J;Dumas KJ;Zimmerman AM;Campbell SL;Hu PJ;Antebi A;Schroeder FC
核激素受体的小分子配体调控后生动物发育、细胞分化和代谢的转录调控。然而，由于缺乏强大的分析技术，许多nhr的生理配体仍然很差。利用比较代谢组学，我们发现了内源性类固醇，作为秀丽隐杆线虫NHR、DAF-12的配体，DAF-12是一种维生素d和肝x受体同源物，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，并且只包括先前报道的两种DAF-12配体中的一种，这需要对先前提出的配体生物合成途径进行修订。我们进一步发现，配体谱受一个复杂的酶网络调控，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。我们的研究结果证明了比较代谢组学相对于传统的基于候选物的方法的优势，并为其他秀丽隐杆线虫和哺乳动物nhr的配体鉴定提供了蓝图。
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.
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影响因子：
11.8
作者：
Gerisch, B;Weitzel, C;Antebi, A
通讯作者：
Antebi, A
影响因子：
9.9
作者：
通讯作者：
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影响因子：
11.8
作者：
Hannich, J. Thomas;Entchev, Eugeni V.;Kurzchalia, Teymuras V.
通讯作者：
Kurzchalia, Teymuras V.
影响因子：
64.8
作者：
Heery, DM;Kalkhoven, E;Parker, MG
通讯作者：
Parker, MG
DOI：
10.1073/pnas.0908131106
发表时间：
2009-11-03
影响因子：
11.1
作者：
Hammell, Christopher M.;Karp, Xantha;Ambros, Victor
通讯作者：
Ambros, Victor