Regulation of C. elegans fat uptake and storage by acyl-CoA synthase-3 is dependent on NR5A family nuclear hormone receptor nhr-25.
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.
Mullaney
Brendan C
BC
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.
Blind
Raymond D
RD
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Lemieux
George A
GA
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
Perez
Carissa L
CL
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.
Elle
Ida C
IC
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Faergeman
Nils J
NJ
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
Van Gilst
Marc R
MR
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Ingraham
Holly A
HA
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
Ashrafi
Kaveh
K
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.
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
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