title: Comparative metabolomics reveals endogenous ligands of DAF-12, a nuclear hormone receptor, regulating C. elegans development and lifespan.
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.
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Parag
authors.initials: P
authors.lastname: Mahanti
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Neelanjan
authors.initials: N
authors.lastname: Bose
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Axel
authors.initials: A
authors.lastname: Bethke
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Joshua C
authors.initials: JC
authors.lastname: Judkins
authors.affiliation: Max Planck Institute for Biology of Ageing, Joseph Stelzmann Strasse 9b, 50931 Cologne, Germany.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wollam
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Kathleen J
authors.initials: KJ
authors.lastname: Dumas
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Zimmerman
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA.
authors.forename: Sydney L
authors.initials: SL
authors.lastname: Campbell
authors.affiliation: 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.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Hu
authors.affiliation: 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.
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
authors.affiliation: Boyce Thompson Institute and Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY 14853, USA. Electronic address: schroeder@cornell.edu.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Schroeder
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000254:growth & development* / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002782:Cholestenes / Q000737:chemistry / Q000378:metabolism; D008401:Gas Chromatography-Mass Spectrometry; D008024:Ligands; D008136:Longevity / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy; D055432:Metabolomics; D009154:Mutation / Q000235:genetics; D009928:Organ Specificity; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D015398:Signal Transduction; D013256:Steroids / Q000378:metabolism
chemical_list: D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; C410905:DAF-12 protein, C elegans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D013256:Steroids; C533799:delta4-dafachronic acid; C533798:delta7-dafachronic acid