nhr-80 Research Notes

Gene Overview

nhr-80 (H10E21.3) encodes a nuclear hormone receptor in C. elegans, homologous to mammalian HNF4 (hepatocyte nuclear factor 4). It functions as a transcription factor regulating delta-9 fatty acid desaturase expression and as a direct nuclear receptor for oleoylethanolamide (OEA) in the lysosome-to-nucleus longevity signaling pathway.

Core Pathway: LIPL-4 → LBP-8 → NHR-80

NHR-80 is the downstream nuclear receptor in the lysosome-to-nucleus retrograde lipid signaling pathway PMID:25554789.

OEA Receptor Function

• OEA directly binds NHR-80 (Kd ~7.8 µM) measured by intrinsic fluorescence PMID:25554789
• Confirmed by differential protease-sensitivity assay PMID:25554789
• NHR-49 does NOT bind OEA directly; NHR-49 acts as a co-factor of NHR-80 PMID:25554789

Delta-9 Desaturase Regulation

• NHR-80 regulates expression of all three delta-9 desaturases: fat-5, fat-6, fat-7 PMID:16839188
• fat-7 expression almost completely eliminated in nhr-80 mutants PMID:16839188
• fat-5 reduced ~66%, fat-6 reduced ~22% PMID:16839188
• nhr-80 mutants accumulate 18:0 (stearic acid) and have reduced 18:1Δ9 (oleic acid) PMID:16839188
• NHR-80 is required for compensatory upregulation of fat-7 in fat-6 mutants PMID:16839188
• fat-6;nhr-80 double mutants are synthetically lethal PMID:16839188

Interaction with NHR-49

• NHR-49 and NHR-80 physically interact directly PMID:22511885
• NHR-49/NHR-80 partnership specifically regulates desaturation pathway PMID:22511885
• Both derived from same ancestral gene (progenitor of mammalian HNF4) PMID:16839188
• However, distinct functions: NHR-49 also regulates beta-oxidation and sphingolipid genes PMID:22511885

Germline-Mediated Longevity

• NHR-80 specifically required for germline-mediated longevity PMID:21423649
• nhr-80(tm1011) completely suppresses glp-1 longevity but does NOT affect wild-type lifespan PMID:21423649
• nhr-80 OE extends glp-1 lifespan by 80% but NOT wild-type lifespan PMID:21423649
• NOT required for: daf-2/insulin longevity, dietary restriction, mitochondrial longevity PMID:21423649
• Functions DAF-16/FOXO independently but requires DAF-12/VDR PMID:21423649
• nhr-80 mRNA induced 5.6-fold in germline-less animals PMID:21423649
• NHR-80 induction is in intestinal cells specifically PMID:21423649

Target Gene Regulation

• fat-6 is a key NHR-80 target in germline-less context (fat-6 induction abolished in nhr-80 mutants) PMID:21423649
• acs-2 (acyl-CoA synthetase for beta-oxidation) is activated >15-fold by LIPL-4 Tg, dependent on NHR-49/NHR-80 PMID:25554789
• dgat-2 (acyltransferase) regulated by NHR-80 PMID:35021096
• NHR-80 does NOT regulate ech-1 or acs-2 independently of NHR-49 context PMID:16839188

Subcellular Localization

• Constitutively nuclear in intestine and neurons PMID:21423649
• Expressed in intestine, some head and tail neurons, ventral nerve cord PMID:21423649

Additional Functions

• Role in citrate-induced mtUPR: NHR-80 mediates lipid metabolic rewiring downstream of DVE-1 PMID:35021096
• Transgenerational lipid accumulation: required in F1 offspring for lipid accumulation from parental high-fat diet PMID:35140229
• nhr-80 mutants have slightly shorter lifespan (~10% reduction) but not dramatic like nhr-49 (~41% reduction) PMID:16839188
• No increase in fat storage in nhr-80 mutants (unlike nhr-49) PMID:16839188