RRC ID 46470
Author Wollam J, Magner DB, Magomedova L, Rass E, Shen Y, Rottiers V, Habermann B, Cummins CL, Antebi A.
Title A novel 3-hydroxysteroid dehydrogenase that regulates reproductive development and longevity.
Journal PLoS Biol.
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.
Volume 10(4)
Pages e1001305
Published 2012
DOI 10.1371/journal.pbio.1001305
PMID 22505847
PMC PMC3323522
MeSH 3-Hydroxysteroid Dehydrogenases / genetics 3-Hydroxysteroid Dehydrogenases / metabolism* Animals Bile Acids and Salts / metabolism Bile Acids and Salts / physiology Biosynthetic Pathways Caenorhabditis elegans / enzymology* Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development* Caenorhabditis elegans Proteins / genetics Caenorhabditis elegans Proteins / metabolism* Cholestenes / metabolism Cholesterol / metabolism Cholesterol / physiology Cytochrome P-450 Enzyme System / genetics Cytochrome P-450 Enzyme System / 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
IF 8.386
Times Cited 34
C.elegans tm1890