Nuclear receptors (NR) are transcription factors that respond to lipophilic ligands, which play a critical role in coupling metabolic signals to development, reproduction, and longevity. From genetic screens, we identified the C. elegans nuclear receptor
nhr-8 as an important modulator of sterol and lipid metabolism, dauer formation, gonadal maturation and longevity. NHR-8 is a homolog of vertebrate LXR/FXR/PXR nuclear receptors implicated in sterol, lipid, and xenobiotic metabolism in mammals. Previous work suggested that
nhr-8 plays a role in xenobiotic metabolism (Lindblom 2000). The closest relative in C. elegans is DAF-12, a NR that regulates dauer formation and life span in response to its ligands, bile acid-like steroids called the dafachronic acids (DA). We find that
nhr-8 mutants have phenotypes reminiscent of a reduction in DA production: they are Daf-c at elevated temperatures (27degC), and form a high proportion of dauers or have gonadal outgrowth defects (Mig) under cholesterol deprivation.
nhr-8 animals also have reduced cholesterol levels indicating a role in mediating cholesterol homeostasis. In addition,
nhr-8 mutants exhibit a novel phenotype in which they arrest early in larval development in response to cholesterol deprivation and thermal stress. To better understand
nhr-8 physiology, we performed expression profiling using microarrays, Q-PCR, and GFP reporter constructs. This analysis indicates that
nhr-8 regulates a variety of genes involved in lipid, fatty-acid, and sterol metabolism. In accord with a role in DA production, levels of the hormone biosynthetic gene
daf-36/Rieske oxygenase were modestly reduced. We also find that
nhr-8 influences expression of the fatty-acid desaturase
fat-7 in vivo, suggesting it works in a complex regulatory network with other NRs such as
nhr-49 and
nhr-80 to maintain fatty-acid homeostasis. Finally, transcriptional assays in cell culture indicate that NHR-8 and DAF-12 directly activate the promoter of a cytochrome P450 identified from microarrays, supporting the idea that these NRs could also comprise a transcriptional network. NHR-8 also shows remarkable interactions with respect to aging in the germ-line longevity pathway.
nhr-8 mutants are 50% shorter-lived relative to wild type. Surprisingly however,
nhr-8 dramatically enhances by 50% the longevity of germ-line deficient
glp-1 animals. Presumably, longevity signals from the germ-line are modulated by one or more transcriptional targets of NHR-8. Collectively, our data suggest that
nhr-8 works as part of a network of transcription factors that govern sterol and lipid homeostasis, which impact development, reproduction and aging in C. elegans.