The Drosophila DHR96 nuclear receptor binds cholesterol and regulates cholesterol homeostasis

Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
Genes & development (Impact Factor: 10.8). 12/2009; 23(23):2711-6. DOI: 10.1101/gad.1833609
Source: PubMed


Cholesterol homeostasis is required to maintain normal cellular function and avoid the deleterious effects of hypercholesterolemia. Here we show that the Drosophila DHR96 nuclear receptor binds cholesterol and is required for the coordinate transcriptional response of genes that are regulated by cholesterol and involved in cholesterol uptake, trafficking, and storage. DHR96 mutants die when grown on low levels of cholesterol and accumulate excess cholesterol when maintained on a high-cholesterol diet. The cholesterol accumulation phenotype can be attributed to misregulation of npc1b, an ortholog of the mammalian Niemann-Pick C1-like 1 gene NPC1L1, which is essential for dietary cholesterol uptake. These studies define DHR96 as a central regulator of cholesterol homeostasis.

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Available from: Keith Pardee, Mar 14, 2014
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    • "The other NR1 clade includes NR1IJLAB members. NRs in this group include those activated by ecdysteroids and responsible for molting and development (EcR) (Fahrbach et al., 2012), the newly discovered HR97 group, RAR-and THR-like receptors (RARL_10, THRL_11), and HR96, a receptor involved in cholesterol and triacylglycerol homeostasis that is also promiscuous and involved in xenobiotic stress responses (King-Jones et al., 2006; Horner et al., 2009; Karimullina et al., 2012; Sieber and Thummel, 2012; Li et al., 2014). Many NR1 subfamily members are involved in resource allocation or energy metabolism, including LXR/FXR (NR1H) (Schultz et al., 2000; Zhang et al., 2012), CAR/PXR/VDR/HR96 (NR1I/J) (Dong et al., 2009; Gao and Xie, 2010; Karimullina et al., 2012; Sieber and Thummel, 2012), "
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    • "All C. gigas NR1J representatives contained the group-unique residues ESCKAFFR in their DBD sequence [68]. Characterised NR1J receptors include DHR96, which is believed to play a role in xenobiotic stress response [69] and is able to bind cholesterol to regulate cholesterol homeostasis [70]. Xenobiotic defence in C. elegans is thought to be managed by the NHR-8 [71]. "
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    • "LXR binds to oxysterols, including 24(S),25-epoxy- cholesterol and 22(R)-, 24(S)-, and 27-hydroxycholesterol, but these molecules did not activate NHR-8 in cell culture. The related Drosophila HR96 ortholog binds cholesterol (Horner et al., 2009), but this molecule also does not appear to directly regulate NHR-8 transcriptional activity (D.B.M. and A.A., unpublished data). A future challenge will be to identify ligands and direct target genes of NHR-8 and to further elucidate the transcriptional networks for cholesterol, lipid, and bile acid homeostasis. "
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