The DHR96 nuclear receptor regulates xenobiotic responses in Drosophila

Howard Hughes Medical Institute, Department of Human Genetics, University of Utah School of Medicine, 15 N 2030 E 5100, Salt Lake City, Utah 84112, USA.
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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    • "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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    ABSTRACT: In Drosophila larvae, growth and developmental timing are regulated by nutrition in a tightly coordinated fashion. The networks that couple these processes are far from understood. Here, we show that the intestine responds to nutrient availability by regulating production of a circulating lipoprotein-associated form of the signaling protein Hedgehog (Hh). Levels of circulating Hh tune the rates of growth and developmental timing in a coordinated fashion. Circulating Hh signals to the fat body to control larval growth. It regulates developmental timing by controlling ecdysteroid production in the prothoracic gland. Circulating Hh is especially important during starvation, when it is also required for mobilization of fat body triacylglycerol (TAG) stores. Thus, we demonstrate that Hh, previously known only for its local morphogenetic functions, also acts as a lipoprotein-associated endocrine hormone, coordinating the response of multiple tissues to nutrient availability. © 2014 Rodenfels et al.; Published by Cold Spring Harbor Laboratory Press.
    Genes & Development 12/2014; 28(23):2636-51. DOI:10.1101/gad.249763.114 · 10.80 Impact Factor
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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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    ABSTRACT: Most nuclear receptors (NRs) are ligand-dependent transcription factors crucial in homeostatic physiological responses or environmental responses. We annotated the Daphniamagna NRs and compared them to Daphniapulex and other species, primarily through phylogenetic analysis. Daphnia species contain 26 NRs spanning all seven gene subfamilies. Thirteen of the 26 receptors found in Daphnia species phylogenetically segregate into the NR1 subfamily, primarily involved in energy metabolism and resource allocation. Some of the Daphnia NRs, such as RXR, HR96, and E75 show strong conservation between D. magna and D. pulex. Other receptors, such as EcRb, THRL-11 and RARL-10 have diverged considerably and therefore may show different functions in the two species. Curiously, there is an inverse association between the number of NR splice variants and conservation of the LBD. Overall, D. pulex and D. magna possess the same NRs; however not all of the NRs demonstrate high conservation indicating the potential for a divergence of function.
    Gene 09/2014; 552(1). DOI:10.1016/j.gene.2014.09.024 · 2.14 Impact Factor
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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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    ABSTRACT: As social insects, termites live in densely populated colonies with specialized castes under conditions conducive to microbial growth and transmission. Furthermore, termites are exposed to xenobiotics in soil and their lignocellulose diet. Therefore, termites are valuable models for studying gene expression involved in response to septic injury, immunity and detoxification in relation to caste membership. In this study, workers and soldiers of the Formosan subterranean termite, Coptotermes formosanus, were challenged by bacterial injection or by no-choice feeding with a sublethal concentration (0.5%) of phenobarbital. Constitutive and induced expression of six putative immune response genes (two encoding for lectin-like proteins, one for a ficolin-precursor, one for the Down syndrome cell adhesion molecule, one for a chitin binding protein, and one for the gram-negative binding protein 2) and four putative detoxification genes (two encoding for cytochrome P450s, one for glutathione S-transferase, and one for the multi antimicrobial extrusion protein), were measured via quantitative real time polymerase chain reaction and compared within and among 1) colonies, 2) treatment types and 3) castes via ANOVA. Eight genes were inducible by septic injury, feeding with phenobarbital or both. Colony origin had no effect on inducibility or differential gene expression. However, treatment type showed significant effects on the expression of the eight inducible genes. Caste effects on expression levels were significant in five of the eight inducible genes with constitutive and induced expression of most target genes being higher in workers than in soldiers.
    PLoS ONE 08/2014; 9(8):e105582. DOI:10.1371/journal.pone.0105582 · 3.23 Impact Factor
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