Regulation of C. elegans Fat Uptake and Storage by Acyl-CoA Synthase-3 Is Dependent on NR5A Family Nuclear Hormone Receptor nhr-25

SummaryAcyl-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.

► Mutation of acs-3 disrupts C. elegans lipid storage
► acs-3 functions in a tissue distinct from major sites of fat storage
► Loss of fatty acyl-CoA-utilizing enzymes suppresses acs-3 phenotypes
► acs-3 regulates metabolism through the conserved nuclear hormone receptor nhr-25