Coordinate Regulation of Lipid Metabolism by Novel Nuclear Receptor Partnerships

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.

NHR‐49/HNF4 integrates regulation of fatty acid metabolism with a protective transcriptional response to oxidative stress and fasting

“…Although NHR‐13, NHR‐66, and NHR‐80 heterodimerize with NHR‐49 (Pathare et al., 2012), these three NHRs were not required for tBOOH‐induced gene activation (Figure S2a). In the tBOOH and fasting response, NHR‐49 may instead homodimerize or partner with other NHRs.…”

“…NHR‐49 dimerizes with NHR‐13, NHR‐66, and NHR‐80 to regulate genes involved in lipid metabolism (Folick et al., 2015; Pathare et al., 2012). However, the tBOOH‐induced expression of fmo‐2 , K05B2.4, and icl‐1 was largely unchanged in nhr‐13 ( ok796 ), nhr‐66 ( ok940 ), and nhr‐80 ( tm1011 ) null mutants (Figure S2a).…”

“…We found that the nuclear hormone receptor (NHR)‐49, an HNF4/PPARα ortholog and established regulator of C. elegans lipid metabolism and longevity (Pathare, Lin, Bornfeldt, Taubert & Van Gilst, 2012; Ratnappan et al., 2014; Van Gilst, Hadjivassiliou, Jolly & Yamamoto, 2005; Van Gilst, Hadjivassiliou & Yamamoto, 2005), is also activated by and required for oxidative stress resistance. We show that NHR‐49 and MDT‐15 are both required for the increased expression of fmo‐2 as part of a stress response program activated by organic peroxide, fasting, and in long‐lived, germline‐less glp‐1 mutants.…”

Nuclear hormone receptors as mediators of metabolic adaptability following reproductive perturbations

“…Through these dimerizations, NHRs, including NHR-49/PPARa, control the transcription of different subsets of targets. [37][38][39] Since our screen identified multiple NHRs that were essential for germline-less longevity, we asked if NHR-49/PPARa exhibited similar heterodimeric interactions with the other NHRs too. Using yeast 2 hybrid (Y2H) assays, we tested the potential interactions of 6 NHRs (genes encoding 5 of these, nhr-60, nhr-71, nhr-81, nhr-212 and nhr-213, were identified in our screen 22 ) with NHR-49/PPARa, DAF-16/FOXO3A and two of five TCER1/TCERG1 transcripts, TCER1a and TCER-1d).…”

“…Interestingly, NHR-71/HNF4 and NHR-49/PPARa were reported to exhibit reciprocal interactions with each other in a previous report that characterized transcriptional networks in C. elegans. 39 To address the mechanistic relevance of this interaction in GSC-less animals, we asked if NHR-71/HNF4 is also required for any of the molecular events controlled by NHR-49/PPARa upon germline ablation, i.e., b¡oxidation, and desaturation. In temperature-sensitive glp-1 mutants, a widely used genetic surrogate for the longevity caused by GSC removal, 14 nhr-71 RNAi moderately impaired the expression of acs-2 ( Fig.…”