The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila

University of Utah, Salt Lake City, Utah, United States
Cell Metabolism (Impact Factor: 17.57). 08/2006; 4(1):37-48. DOI: 10.1016/j.cmet.2006.06.006
Source: PubMed


Exposure to xenobiotics such as plant toxins, pollutants, or prescription drugs triggers a defense response, inducing genes that encode key detoxification enzymes. Although xenobiotic responses have been studied in vertebrates, little effort has been made to exploit a simple genetic system for characterizing the molecular basis of this coordinated transcriptional response. We show here that approximately 1000 transcripts are significantly affected by phenobarbital treatment in Drosophila. We also demonstrate that the Drosophila ortholog of the human SXR and CAR xenobiotic receptors, DHR96, plays a role in this response. A DHR96 null mutant displays increased sensitivity to the sedative effects of phenobarbital and the pesticide DDT as well as defects in the expression of many phenobarbital-regulated genes. Metabolic and stress-response genes are also controlled by DHR96, implicating its role in coordinating multiple response pathways. This work establishes a new model system for defining the genetic control of xenobiotic stress responses.

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Available from: Michael A Horner
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    • "Interestingly, work by others shows that hh transcription is increased by bacterial infection in the gut and also by loss of DHR96 (Bujold et al. 2010; Chakrabarti et al. 2012). This nuclear hormone receptor mediates the response to xenobiotics and regulates TAG metabolism (King-Jones et al. 2006; Sieber and Thummel 2009). Thus, it would be interesting to test whether circulating Hh might regulate growth and development in response to other physiological stresses. "
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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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    • "The majority of antiepileptic drugs such as PB show immunosuppressive effects in humans; however, under certain conditions, they can also stimulate the immune system [71]. Microarray analysis of gene expression revealed that Drosophila flies execute massive transcriptional response to PB treatment [72]. Not only were the detoxificication genes upregulated, but also genes involved in several metabolic and stress response pathways were affected. "
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