nhr-49 (K10C3.6) encodes a nuclear hormone receptor in C. elegans (UniProt: O45666), classified as an orphan receptor belonging to the HNF4 (hepatocyte nuclear factor 4) family PMID:15719061. NHR-49 is a central regulator of lipid metabolism, functioning analogously to mammalian PPARalpha in controlling fatty acid beta-oxidation and desaturation PMID:15719061. The protein contains a C4-type zinc finger DNA-binding domain (aa 8-83), a nuclear receptor ligand-binding domain (aa 157-422), and a 9aaTAD transactivation motif (aa 413-421). Four isoforms (a-d) are produced by alternative splicing. NHR-49 acts as a hub nuclear receptor that partners with distinct co-factors (NHR-80, NHR-66, NHR-13) to regulate separate branches of lipid metabolism PMID:22511885.
NHR-49 is a critical downstream component of the lysosome-to-nucleus retrograde lipid signaling pathway that promotes longevity. In this pathway, the lysosomal acid lipase LIPL-4 generates lipid signals including oleoylethanolamide (OEA), which are transported to the nucleus by the lipid chaperone LBP-8, where they activate the NHR-49/NHR-80 nuclear receptor heterodimer PMID:25554789.
Key details of NHR-49's role in this pathway:
- Both NHR-49 and NHR-80 are required for LIPL-4- and LBP-8-mediated longevity PMID:25554789
- NHR-49 does NOT directly bind OEA; rather, OEA binds NHR-80 directly (Kd ~7.8 uM) and NHR-49 functions as a co-factor PMID:25554789
- The NHR-49/NHR-80 heterodimer activates transcription of target genes including acs-2 (>15-fold increase in lipl-4 Tg animals) and lbp-8 itself, forming a positive feedback loop PMID:25554789
- The pathway is independent of dietary restriction PMID:25554789
NHR-49 forms a homodimer and physically interacts with distinct partner NHRs to regulate separate metabolic programs PMID:22511885.
NHR-49 regulates two distinct branches of fatty acid metabolism:
NHR-49 impacts lifespan through multiple mechanisms:
NHR-49 plays a critical role in adaptation to low oxygen environments, acting in parallel with HIF-1 [PMID:35285794, Doering et al. 2022]:
- nhr-49 mutants show severe hypoxia sensitivity: only 25% of embryos develop to L4 stage in 0.5% O2 vs. 86% in wild-type (UniProt, PMID:35285794)
- In a hif-1 mutant background, nhr-49 loss is nearly lethal under hypoxia (<2% survival to L4) (UniProt, PMID:35285794)
- NHR-49 activates expression of acs-2, autophagy-related genes, and autophagosome formation during hypoxia, independent of HIF-1 (UniProt, PMID:35285794)
- NHR-49 activates the detoxification gene fmo-2 (flavin mono-oxygenase), acting in parallel with HIF-1 during hypoxia (UniProt, PMID:35285794)
- NHR-49 acts in multiple somatic tissues, probably cell non-autonomously, in regulating hypoxia response (UniProt, PMID:35285794)
- nhr-49 mutants are unaffected by hydrogen sulfide (UniProt, PMID:35285794)
- Hypoxia exposure (0.5% oxygen) triggers nhr-49-dependent responses (UniProt, PMID:35285794)
MDT-15, a subunit of the C. elegans Mediator complex, acts as a transcriptional coactivator for NHR-49 PMID:16651656:
- MDT-15 is required for fasting-induced expression of NHR-49 target genes in vivo PMID:16651656
- MDT-15 is also required for fasting-independent expression of NHR-49 targets including fat-5 and fat-7 PMID:16651656
- MDT-15 additionally regulates NHR-49-independent targets, such as fat-6, suggesting it integrates multiple regulatory inputs PMID:16651656
- mdt-15 knockdown causes dramatically decreased unsaturated fatty acids and pleiotropic phenotypes (short lifespan, sterility, uncoordinated locomotion, morphological defects) PMID:16651656
- Physical interaction between NHR-49 and MDT-15 confirmed (IntAct, UniProt)
During short-term fasting, NHR-49 acts in the intestine to regulate lysosomal lipid accumulation in coordination with EGL-4/PKG signaling from sensory neurons PMID:24854345:
- NHR-49 inhibits lysosomal lipid accumulation during fasting via activation of IPLA-2 (intracellular phospholipase A2) in the cytoplasm and hydrolases in lysosomes PMID:24854345
- This fasting-induced lysosomal lipid accumulation is independent of autophagy and RAB-7-mediated endocytosis PMID:24854345
NHR-49 is required for transgenerational inheritance of high-fat-diet (HFD)-induced lipid accumulation PMID:35140229:
- NHR-49, NHR-80, SBP-1/SREBP, and DAF-16/FOXO are all required for transgenerational epigenetic inheritance of obesogenic lipid accumulation PMID:35140229
- NHR-49 and NHR-80 function as executors (effectors), not transmitters, of heritable lipid metabolic memory PMID:35140229
- The transgenerational signal is mediated by histone H3K4me3 modification PMID:35140229
- Delta-9 desaturases (fat-5, fat-6, fat-7) are also required for the transgenerational lipid phenotype PMID:35140229
nhr-49(nr2041) mutants (893 bp deletion) exhibit:
- Elevated fat storage: Increased Nile Red staining; high-fat phenotype due to reduced beta-oxidation gene expression PMID:15719061
- Shortened lifespan: ~41% reduction compared to wild-type; lifespan of 9.52+/-0.23 days vs. 17.35+/-0.34 at 20C [PMID:15719061, PMID:22511885]
- Altered fatty acid composition: Increased ratio of stearic acid to oleic acid (C18:0/C18:1n9 ratio of 3.74+/-0.33 vs. 0.98+/-0.06 in wild-type) [PMID:15719061, PMID:22511885]
- Vacuole formation and germline necrosis: Widespread vacuoles in intestine and gonadal collapse PMID:15719061
- Abnormal mitochondrial morphology: ~25% of intestinal mitochondria show irregular shape with more turns; reduced oxygen consumption (5.22 vs. 9.625 pmoles/min/worm in wild-type); reduced beta-oxidation PMID:22511885
- Hypoxia sensitivity: Only 25% embryo survival to L4 under 0.5% O2; L1 larvae survival reduced to 19% vs. 95% in wild-type (UniProt, PMID:35285794)
- Mild developmental delay: Slower larval growth (UniProt, PMID:35285794)
- Suppressed glp-1 longevity: Completely abolishes the lifespan extension of germline-less animals PMID:25474470
NHR-49 is important for maintaining mitochondrial morphology and function PMID:22511885:
- nhr-49 mutants have reduced basal oxygen consumption rates (5.22 pmoles/min/worm vs. 9.625 in wild-type) PMID:22511885
- Reduced beta-oxidation measured by radiolabeled palmitate assay (0.56 vs. 1.29 pmole/min/ug protein in wild-type) PMID:22511885
- NHR-49 maintains mitochondrial morphology via multiple pathways including NHR-66 and NHR-80 dependent regulation PMID:22511885