title: Regulation of C. elegans fat uptake and storage by acyl-CoA synthase-3 is dependent on NR5A family nuclear hormone receptor nhr-25.
abstract: Acyl-CoA synthases are important for lipid synthesis and breakdown, generation of signaling molecules, and lipid modification of proteins, highlighting the challenge of understanding metabolic pathways within intact organisms. From a C. elegans mutagenesis screen, we found that loss of ACS-3, a long-chain acyl-CoA synthase, causes enhanced intestinal lipid uptake, de novo fat synthesis, and accumulation of enlarged, neutral lipid-rich intestinal depots. Here, we show that ACS-3 functions in seam cells, epidermal cells anatomically distinct from sites of fat uptake and storage, and that acs-3 mutant phenotypes require the nuclear hormone receptor NHR-25, a key regulator of C. elegans molting. Our findings suggest that ACS-3-derived long-chain fatty acyl-CoAs, perhaps incorporated into complex ligands such as phosphoinositides, modulate NHR-25 function, which in turn regulates an endocrine program of lipid uptake and synthesis. These results reveal a link between acyl-CoA synthase function and an NR5A family nuclear receptor in C. elegans.
authors.affiliation: Graduate Program in Neuroscience, University of California, San Francisco, San Francisco, CA 94158, USA; Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Brendan C
authors.initials: BC
authors.lastname: Mullaney
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Raymond D
authors.initials: RD
authors.lastname: Blind
authors.affiliation: Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: George A
authors.initials: GA
authors.lastname: Lemieux
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Molecular and Cellular Biology Program, University of Washington, Seattle, WA 98195, USA.
authors.forename: Carissa L
authors.initials: CL
authors.lastname: Perez
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Ida C
authors.initials: IC
authors.lastname: Elle
authors.affiliation: Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
authors.forename: Nils J
authors.initials: NJ
authors.lastname: Faergeman
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
authors.forename: Marc R
authors.initials: MR
authors.lastname: Van Gilst
authors.affiliation: Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
authors.forename: Holly A
authors.initials: HA
authors.lastname: Ingraham
authors.affiliation: Department of Physiology, University of California, San Francisco, San Francisco, CA 94158, USA; UCSF Diabetes Center, University of California, San Francisco, San Francisco, CA 94158, USA. Electronic address: kaveh.ashrafi@ucsf.edu.
authors.forename: Kaveh
authors.initials: K
authors.lastname: Ashrafi
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000378:metabolism*; D003066:Coenzyme A Ligases / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D005223:Fats / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008055:Lipids / Q000096:biosynthesis; D016297:Mutagenesis, Site-Directed; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors / Q000502:physiology*; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D004268:DNA-Binding Proteins; D005223:Fats; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C486359:nuclear hormone receptor NHR-25, C elegans; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase