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

Abstract

SUMMARY 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 lifespan. 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.

Sex Differences: A Resultant of an Evolutionary Pressure?

“…the intestine in nematodes, the fat body in insects, the hepatopancreas in arthropods) (Della Torre et al, 2014;Geminard et al, 2009;Magner et al, 2013). The main activity of this organ is in fact the drainage of nutrients from circulation, their transformation in molecules for energy storage and the transport of lipids to the whole organism after.…”

The mysterious relationship between reproduction and longevity

“…The nuclear hormone receptor DAF-12, which mediates steroid signaling in developing wildtype animals 22 (and in germline-less animals 19 ), is not implicated in DR-induced lifespan extension. Rather, the closely related homolog NHR-8, involved in cholesterol homeostasis, 24 is required. However, dafachronic acids do not directly transactivate NHR-8 in vitro 23 .…”

WITHDRAWN: Caenorhabditis elegans nuclear hormone receptor NHR-14, cooperates with p53/cep-1 to regulate DNA damage-induced apoptosis

“…There are 284 predicted www.impactjournals.com/oncotarget/ Oncotarget, Advance Publications 2017 www.impactjournals.com/oncotarget NHR genes in C.elegans [2]. Nuclear hormone receptors have been shown to regulate important developmental process [3][4][5][6]. However, the role of NHR in programmed cell death has not been documented.…”