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

Mullaney BC, Blind RD, Lemieux GA, Perez CL, Elle IC, Faergeman NJ, Van Gilst MR, Ingraham HA, Ashrafi K
Cell Metab. 2010 12 (4): 398-410

PMID: 20889131 · PMCID: PMC2992884 · DOI:10.1016/j.cmet.2010.08.013

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.

Copyright © 2010 Elsevier Inc. All rights reserved.

MeSH Terms (10)

Animals Caenorhabditis elegans Coenzyme A Ligases DNA-Binding Proteins Fats Intestinal Mucosa Lipids Mutagenesis, Site-Directed Receptors, Cytoplasmic and Nuclear Transcription Factors

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