The NHR-8 Nuclear Receptor Regulates Cholesterol and Bile Acid Homeostasis in C. elegans

•nhr-8 loss results in misregulated cholesterol, bile acid, and fat metabolism•Production of dafachronic acid, a ligand for DAF-12, is reduced in nhr-8 mutants•nhr-8 interacts with daf-16/FOXO to regulate cholesterol balance•Cholesterol feeding rescues defects of development, reproduction, and life span

SummaryHormone-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.