Nuclear Receptor DHR96 Acts as a Sentinel for Low Cholesterol Concentrations in Drosophila melanogaster

Abstract

All eukaryotic cells have to maintain cholesterol concentrations within defined margins in order to function normally. Perturbing cholesterol homeostasis can result in a wide range of cellular and systemic defects, including cardiovascular diseases, as well as Niemann-Pick and Tangier diseases. Here, we show that DHR96 is indispensable for mediating the transcriptional response to dietary cholesterol and that it acts as a key regulator of the Niemann-Pick type C gene family, as well as of other genes involved in cholesterol uptake, metabolism, and transport. DHR96 mutants are viable and phenotypically normal on a standard medium but fail to survive on diets that are low in cholesterol. DHR96 mutants have aberrant cholesterol levels, demonstrating a defect in maintaining cholesterol homeostasis. Remarkably, we found that a high-cholesterol diet phenocopied the genomic profile of the DHR96 mutation, indicating that DHR96 resides at the top of a genetic hierarchy controlling cholesterol homeostasis in insects. We propose a model whereby DHR96 is activated when cellular cholesterol concentrations drop below a critical threshold in order to protect cells from severe cholesterol deprivation.

The HR97 (NR1L) group of nuclear receptors: A new group of nuclear receptors discovered in Daphnia species

“…D. magna and D. pulex both express three distinct HR97 receptors of which HR97a and HR97b are found in tandem duplicate in the genome. Here we confirm that they are a novel group; separate but related to the invertebrate HR96 receptors that are involved in lipid metabolism and chemical detoxification (Bujold et al, 2010; Karimullina et al, 2012; King-Jones et al, 2006; Sieber and Thummel, 2009). …”

“…However, unlike their NR relative HR96/CAR/PXR, the HR97 receptors do not appear to be promiscuous. Similar to many other NR1 family members (Bujold et al, 2010; Dong et al, 2009; Finn et al, 2009; Horner et al, 2009; Sieber and Thummel, 2009), the HR97 receptors appear to respond to dietary cues, specifically the dietary fatty acid, AA or its metabolites. Last, the expression patterns of the HR97 receptors suggest a role in reproduction and because AA is one of two unsaturated fatty acids specifically retained by crustaceans and concentrated in the ovaries (Chansela et al, 2012).…”

The Digestive Tract of Drosophila melanogaster

“…An NPC1b mutation causes early larval lethality, possibly because of a defect in ecdysone synthesis that results from a sterol deficit (129,189). Interestingly, NPC genes are targets of the transcription factor DHR96, the activity of which is enhanced upon cholesterol scarcity, providing a homeostatic link between dietary cholesterol and its transport machinery (25,129).…”

Mechanisms of stable lipid loss in a social insect

“…For instance, genes related to amino acid metabolism (58 genes) were upregulated with the rich diet, but this process was not enriched among behaviorally responsive genes. Notably, a number of genes with conserved roles in nutritional regulation, including the insulin-related transcription factor FoxO (Accili and Arden, 2004), the cholesterol sensor Hr96 (Bujold et al, 2010) and the cGMP-dependent protein kinase foraging (Kaun and Sokolowski, 2009), were differentially expressed in the fat bodies in response to diet quality but not during maturation. These results suggest that maturation is not simply a result of nutritional differences between nurses and foragers.…”