The NHR-8 nuclear receptor regulates cholesterol and bile acid homeostasis in C. elegans.
Hormone-gated nuclear receptors (NRs) are conserved transcriptional regulators of metabolism, reproduction, and homeostasis. Here we show that C. elegans NHR-8 NR, a homolog of vertebrate liver X and vitamin D receptors, regulates nematode cholesterol balance, fatty acid desaturation, apolipoprotein production, and bile acid metabolism. Loss of nhr-8 results in a deficiency in bile acid-like steroids, called the dafachronic acids, which regulate the related DAF-12/NR, thus controlling entry into the long-lived dauer stage through cholesterol availability. Cholesterol supplementation rescues various nhr-8 phenotypes, including developmental arrest, unsaturated fatty acid deficiency, reduced fertility, and shortened life span. Notably, nhr-8 also interacts with daf-16/FOXO to regulate steady-state cholesterol levels and is synthetically lethal in combination with insulin signaling mutants that promote unregulated growth. Our studies provide important insights into nuclear receptor control of cholesterol balance and metabolism and their impact on development, reproduction, and aging in the context of larger endocrine networks.
Max Planck Institute for Biology of Ageing, Joseph-Stelzmann-Strasse, Cologne, Germany.
Daniel B
DB
Magner
Joshua
J
Wollam
Yidong
Y
Shen
Caroline
C
Hoppe
Dongling
D
Li
Christian
C
Latza
Veerle
V
Rottiers
Harald
H
Hutter
Adam
A
Antebi
D000595:Amino Acid Sequence; D000818:Animals; D001053:Apolipoproteins / Q000096:biosynthesis; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport; D017173:Caenorhabditis elegans / Q000235:genetics / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000378:metabolism*; D002782:Cholestenes / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism; D005298:Fertility / Q000235:genetics; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation; D006706:Homeostasis; D050356:Lipid Metabolism / Q000235:genetics*; D008136:Longevity / Q000235:genetics; D008969:Molecular Sequence Data; D010105:Oxygenases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D016415:Sequence Alignment; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000378:metabolism
D001053:Apolipoproteins; D001647:Bile Acids and Salts; D029742:Caenorhabditis elegans Proteins; D002782:Cholestenes; D002784:Cholesterol; D005227:Fatty Acids; D051858:Forkhead Transcription Factors; D010105:Oxygenases; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; C410905:DAF-12 protein, C elegans; C108831:daf-16 protein, C elegans; C533800:dafachronic acid; C439299:nhr-8 protein, C elegans; C510186:DAF-36 protein, C elegans