title: A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity.
abstract: Endogenous small molecule metabolites that regulate animal longevity are emerging as a novel means to influence health and life span. In C. elegans, bile acid-like steroids called the dafachronic acids (DAs) regulate developmental timing and longevity through the conserved nuclear hormone receptor DAF-12, a homolog of mammalian sterol-regulated receptors LXR and FXR. Using metabolic genetics, mass spectrometry, and biochemical approaches, we identify new activities in DA biosynthesis and characterize an evolutionarily conserved short chain dehydrogenase, DHS-16, as a novel 3-hydroxysteroid dehydrogenase. Through regulation of DA production, DHS-16 controls DAF-12 activity governing longevity in response to signals from the gonad. Our elucidation of C. elegans bile acid biosynthetic pathways reveals the possibility of novel ligands as well as striking biochemical conservation to other animals, which could illuminate new targets for manipulating longevity in metazoans.
authors.affiliation: Department of Molecular and Cellular Biology, Huffington Center on Aging, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Joshua
authors.initials: J
authors.lastname: Wollam
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Magner
authors.forename: Lilia
authors.initials: L
authors.lastname: Magomedova
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Rass
authors.forename: Yidong
authors.initials: Y
authors.lastname: Shen
authors.forename: Veerle
authors.initials: V
authors.lastname: Rottiers
authors.forename: Bianca
authors.initials: B
authors.lastname: Habermann
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Cummins
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
mesh_terms: D015096:3-Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism / Q000502:physiology; D053898:Biosynthetic Pathways; D017173:Caenorhabditis elegans / Q000201:enzymology* / Q000235:genetics / Q000254:growth & development*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002782:Cholestenes / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism / Q000502:physiology; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics / Q000378:metabolism; D004843:Epistasis, Genetic; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D006706:Homeostasis; D007328:Insulin / Q000502:physiology; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D007664:Ketosteroids / Q000378:metabolism; D008136:Longevity; D009928:Organ Specificity; D010641:Phenotype; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D012098:Reproduction; D015398:Signal Transduction
chemical_list: D001647:Bile Acids and Salts; D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; C410905:DAF-12 protein, C elegans; D007328:Insulin; D007664:Ketosteroids; D018160:Receptors, Cytoplasmic and Nuclear; C533800:dafachronic acid; D007334:Insulin-Like Growth Factor I; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; C486228:DAF-9 protein, C elegans; D015096:3-Hydroxysteroid Dehydrogenases; C574084:DHS-16 protein, C elegans