Abstract

Mammalian nuclear receptors broadly influence metabolic fitness and serve as popular targets for developing drugs to treat cardiovascular disease, obesity, and diabetes. However, the molecular mechanisms and regulatory pathways that govern lipid metabolism remain poorly understood. We previously found that the Caenorhabditis elegans nuclear hormone receptor NHR-49 regulates multiple genes in the fatty acid beta-oxidation and desaturation pathways. Here, we identify additional NHR-49 targets that include sphingolipid processing and lipid remodeling genes. We show that NHR-49 regulates distinct subsets of its target genes by partnering with at least two other distinct nuclear receptors. Gene expression profiles suggest that NHR-49 partners with NHR-66 to regulate sphingolipid and lipid remodeling genes and with NHR-80 to regulate genes involved in fatty acid desaturation. In addition, although we did not detect a direct physical interaction between NHR-49 and NHR-13, we demonstrate that NHR-13 also regulates genes involved in the desaturase pathway. Consistent with this, gene knockouts of these receptors display a host of phenotypes that reflect their gene expression profile. Our data suggest that NHR-80 and NHR-13's modulation of NHR-49 regulated fatty acid desaturase genes contribute to the shortened lifespan phenotype of nhr-49 deletion mutant animals. In addition, we observed that nhr-49 animals had significantly altered mitochondrial morphology and function, and that distinct aspects of this phenotype can be ascribed to defects in NHR-66– and NHR-80–mediated activities. Identification of NHR-49's binding partners facilitates a fine-scale dissection of its myriad regulatory roles in C. elegans. Our findings also provide further insights into the functions of the mammalian lipid-sensing nuclear receptors HNF4α and PPARα.

Highlights

  • Modern day lifestyle and diet dramatically increase the threat of chronic diseases including obesity, diabetes and atherosclerosis

  • We identified NHR-49 co-factors NHR-66 and NHR-80 that regulate specific subsets of NHR-49 target genes and that contribute to distinct phenotypes of nhr-49 animals

  • We previously found that NHR-49 promotes two distinct aspects of lipid metabolism, fatty acid desaturation and fatty acid b-oxidation [16]

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Summary

Introduction

Modern day lifestyle and diet dramatically increase the threat of chronic diseases including obesity, diabetes and atherosclerosis. These metabolic disorders have been consistently linked to the imbalance between energy consumption and expenditure. The control of fat metabolism is often mediated by nuclear receptors (NR), which are ligand-regulated transcription factors that play a central role in the cell’s ability to sense, transduce and respond to lipophilic signals by modulating the appropriate target genes [2]. Ligand binding affects nuclear receptor activity by inducing structural changes within the LBD, which alters the receptor’s affinity to different co-factor proteins such as co-regulators and binding partner(s). Co-regulators include both co-activators and co-repressors, and are critical in mediating transcriptional responses. Binding of distinct co-factors determines how nuclear receptors influence different gene networks

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