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Cell Metab. 2010 Oct 6;12(4):398-410. doi: 10.1016/j.cmet.2010.08.013.

Regulation of C. elegans fat uptake and storage by acyl-CoA synthase-3 is dependent on NR5A family nuclear hormone receptor nhr-25.

Author information

1
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.
2
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Anatomy, University of California, San Francisco, San Francisco, CA 94158, USA.
4
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.
5
Department of Biochemistry and Molecular Biology, University of Southern Denmark, 5230 Odense M, Denmark.
6
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
7
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.

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.

PMID:
20889131
PMCID:
PMC2992884
DOI:
10.1016/j.cmet.2010.08.013
[Indexed for MEDLINE]
Free PMC Article

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