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Cell Metab. 2014 Jan 7;19(1):73-83. doi: 10.1016/j.cmet.2013.11.024.

Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan.

Author information

1
Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
2
Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, 50931 Cologne, Germany.
3
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
4
Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Departments of Internal Medicine and Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
5
Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, 50931 Cologne, Germany; Huffington Center on Aging, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
6
Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address: schroeder@cornell.edu.

Abstract

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.

PMID:
24411940
PMCID:
PMC3924769
DOI:
10.1016/j.cmet.2013.11.024
[Indexed for MEDLINE]
Free PMC Article

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