Abstract
Nuclear hormone receptors (NHRs) play vital roles in the regulation of metabolism, reproduction, and development. We found that inactivation of a C. elegans HNF4 homologue nhr-64 by RNA interference (RNAi) suppresses low fat stores in stearoyl-CoA desaturase-deficient fat-6;fat-7 double mutants and sterol regulatory element binding protein (SREBP) sbp-1 mutants. Furthermore, inactivation of nhr-64 improves the growth rate of the fat-6;fat-7and sbp-1 strains. While nhr-64RNAi subtly affects fatty acid composition and fat storage in wild-type C. elegans, its effects on lipid metabolism are most apparent in the background of stearoyl-CoA desaturase or SREBP deficiency. NHR-64 displays transcriptional activating activity when expressed in yeast, and inactivation of nhr-64 affects the expression of at least 14 metabolic genes. Wild-type worms treated with nhr-64 RNAi display increased expression of acetyl-CoA carboxylase as well as increased abundance of de novo synthesized monomethyl branched chain fatty acids, suggesting an increase in fat synthesis. However, reduced expression of the acetyl-CoA synthetase gene acs-2 and an acyl-CoA oxidase gene indicates that a key role of NHR-64 may be to promote fatty acid oxidation in mitochondria and peroxisomes. These studies reveal that NHR-64 is an important regulator of fat storage in C. elegans.
Highlights
Nuclear hormone receptors (NHRs) are transcription factors that respond to lipophilic molecules to regulate the expression of target genes involved in metabolism, reproduction, and development
Previous studies indicated that reduction of nhr-80 and nhr-49 would enhance fat-6;fat-7 growth defects, since these two NHRs are required for the induction of fat-5, which encodes a palmitic acid-specific D9 desaturase activity that partially compensates for fat-6 and fat-7 deficiency [10,11]
We suspected that some NHRs may regulate other lipid metabolism pathways that may compensate for the fat-6;fat-7 defects and improve the fat-6;fat-7 growth and fat storage defects
Summary
Nuclear hormone receptors (NHRs) are transcription factors that respond to lipophilic molecules to regulate the expression of target genes involved in metabolism, reproduction, and development. The genome of nematode Caenorhabditis elegans contains 284 NHRs, several of which have been implicated in lipid metabolism [2,3]. DAF-12, a homologue of the vertebrate vitamin D receptor, responds to its ligand, dafachronic acid, to regulate fat metabolism as well as development, dauer formation, and longevity [4,5,6]. Two C. elegans HNF4a orthologs, NHR-49 and NHR-80, regulate fatty acid desaturation [10,11]. NHR-49 regulates fatty acid oxidation and the response of nematodes to fasting [10,12]
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