Authors: Wollam J; Magner DB; Magomedova L; Rass E; Shen Y; Rottiers V; Habermann B; Cummins CL; Antebi A
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.
Keywords: 3-Hydroxysteroid Dehydrogenases/genetics/*metabolism; Animals; Bile Acids and Salts/metabolism/physiology; Biosynthetic Pathways; Caenorhabditis elegans/*enzymology/genetics/*growth & development; Caenorhabditis elegans Proteins/genetics/*metabolism; Cholestenes/metabolism; Cholesterol/metabolism/physiology; Cytochrome P-450 Enzyme System/genetics/metabolism; Epistasis, Genetic; Feedback, Physiological; Gene Expression Profiling; Homeostasis; Insulin/physiology; Insulin-Like Growth Factor I/physiology; Ketosteroids/metabolism; *Longevity; Organ Specificity; Phenotype; Receptors, Cytoplasmic and Nuclear/metabolism; Reproduction; Signal Transduction|
Journal: PLoS biology Volume: 10 Issue: 4 Pages: e1001305 Date: April 17, 2012 PMID: 22505847 |
Wollam J, Magner DB, Magomedova L, Rass E, Shen Y, Rottiers V, Habermann B, Cummins CL, Antebi A (2012) A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity. PLoS biology 10: e1001305.
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