Gut microbiota derived metabolites 3-idoleacetic acid promotes IL-35+B cell production
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE166316 | GEO | 2021/02/08
REPOSITORIES: GEO
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Project description:The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital (PB) on gene transcription. To investigate the relative role of CAR and PXR in the induction response, cDNA arrays were generated containing 120 genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PB for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments unexpectedly revealed that if CAR and PXR are deleted, PB increases the expression of several other nuclear receptors and genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 100mg/kg phenobarbital or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the phenobarbital treated ones and hybridized to Sterolgene V1 arrays.
2008-08-23 | E-GEOD-12489 | biostudies-arrayexpress
Project description:The nuclear receptor PXR (Pregnane X rreceptor) mediates the effects of pregnenolone-16alpha-carbonitrile (PCN) on gene transcription. The relative role of PXR and also CAR to the induction response by PCN was studied on cDNA arrays containing 320 (Steroltalk V2) genes (genes involved in cyrcadian rhythm, drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PCN for gene expression within the European Framework V program âSteroltalkâ (www.steroltalk.net). Results from these experiments show the complex role of PXR receptor in the expression of genes involved in cyrcadian rhythm, drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 40mg/kg PCN or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the PCN treated ones and hybridized to Steroltalk V2 arrays.
2010-05-16 | E-GEOD-12537 | biostudies-arrayexpress
Project description:The nuclear receptor CAR (constitutive androstane receptor) mediates the effects of 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) on gene transcription. To investigate the relative role of CAR and also PXR in the induction response, cDNA arrays were generated containing 120 (Sterolgene V1) genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with TCPOBOP for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments show the complex role of CAR receptor in the expression of genes involved in drug metabolism and cholesterol biosynthesis. Animals were injected i.p. 10mg/kg TCPOBOP or vehicle (5% DMSO in corn oil). After 12h they were sacrificed and total RNA was isolated from the livers. Pools of untreated samples were mixed in each genetic variant group (wild type and CAR-/-, PXR-/- or CAR/PXR-/-) with the TCPOBOP treated ones and hybridized to Sterolgene V1 arrays.
2008-08-23 | E-GEOD-12509 | biostudies-arrayexpress
Project description:Liver tumors in rodents are frequently induced by non-genotoxic carcinogens. These hepatocarcinogens generally activate hepatic nuclear receptors (e.g., CAR and PXR), resulting in a cascade of signals causing modifications in the expression of genes responsible for several processes involved in carcinogenesis. Evaluation of the carcinogenic potential of chemicals is a regulatory requirement but is time-consuming and expensive. Consequently, several short-term in vivo and in vitro approaches, using molecular tools, have been proposed as predictive models for non-genotoxic hepatocarcinogens. The objective of our study was to discriminate between chemicals that are either non-genotoxic hepatocarcinogens or merely hepatotoxicants and also between CAR and PXR modulators on the basis of their gene expression profiles. Thus, we treated rats for seven days with the hepatoxicants, diclofenac and diazepam, or with several CAR and PXR modulators, which were mainly hepatocarcinogens. Different hepatic gene expression profiles were obtained not only between the hepatotoxicants and the non-genotoxic hepatocarcinogens but also between the CAR activators phenobarbital, phenytoin and 1,1-bis-(4-chlorophenyl)-2,2-dichloroethene which were grouped together, and the two PXR activators pregnenolone 16α-carbonitrile and clotrimazole. Diethylstilbestrol had an expression profile that was quite distinct from the other PXR activators, suggesting that this compound is certainly not a classic PXR modulator. Moreover, some differences were observed between phenytoin (not considered as a hepatocarcinogen), and the other two CAR activators. Our data therefore indicate that discrimination is possible between hepatocarcinogens and hepatotoxicants, between CAR and PXR modulators and also between compounds within the same class of modulators using a short-term transcriptomic approach. CAR or PXR inducers were administered in suspension to rats (7 weeks old at start of treatment) by oral gavage at a daily dose for 7 consecutive days. Treatment-related changes in gene expression were determined in the liver using whole genome oligonucleotide microarrays.
2013-07-31 | E-GEOD-39350 | biostudies-arrayexpress
Project description:The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcino- genesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARKO -PXRKO ), double humanized CAR and PXR (CARh - PXRh), and wild-type C57BL/6 mice. Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar tran- scriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were ob- served with peak expression occurring between 1 and 7 days PB ex- posure. All these transcriptional responses were absent in CARKO- PXRKO mouse livers and largely reversible in wild-type and CARh - PXRh mouse livers following 91 days of PB exposure and a subse- quent 4-week recovery period. Furthermore, PB-mediated upregu- lation of the noncoding RNA Meg3, which has recently been associ- ated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARh-PXRh mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB. 13-week oral (drinking water) investigative phenobarbital study in male C57BL/6 wild type, CAR/PXR knockout and humanized CAR/PXR mice with a 4 week recovery period
2014-08-24 | E-GEOD-60684 | biostudies-arrayexpress
Project description:The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) are closely related nuclear receptors involved in drug metabolism and play important roles in the mechanism of phenobarbital (PB)-induced rodent nongenotoxic hepatocarcino- genesis. Here, we have used a humanized CAR/PXR mouse model to examine potential species differences in receptor-dependent mechanisms underlying liver tissue molecular responses to PB. Early and late transcriptomic responses to sustained PB exposure were investigated in liver tissue from double knock-out CAR and PXR (CARKO -PXRKO ), double humanized CAR and PXR (CARh - PXRh), and wild-type C57BL/6 mice. Wild-type and CARh-PXRh mouse livers exhibited temporally and quantitatively similar tran- scriptional responses during 91 days of PB exposure including the sustained induction of the xenobiotic response gene Cyp2b10, the Wnt signaling inhibitor Wisp1, and noncoding RNA biomarkers from the Dlk1-Dio3 locus. Transient induction of DNA replication (Hells, Mcm6, and Esco2) and mitotic genes (Ccnb2, Cdc20, and Cdk1) and the proliferation-related nuclear antigen Mki67 were ob- served with peak expression occurring between 1 and 7 days PB ex- posure. All these transcriptional responses were absent in CARKO- PXRKO mouse livers and largely reversible in wild-type and CARh - PXRh mouse livers following 91 days of PB exposure and a subse- quent 4-week recovery period. Furthermore, PB-mediated upregu- lation of the noncoding RNA Meg3, which has recently been associ- ated with cellular pluripotency, exhibited a similar dose response and perivenous hepatocyte-specific localization in both wild-type and CARh-PXRh mice. Thus, mouse livers coexpressing human CAR and PXR support both the xenobiotic metabolizing and the proliferative transcriptional responses following exposure to PB. 13-week oral (drinking water) investigative phenobarbital study in male C57BL/6 wild type, CAR/PXR knockout and humanized CAR/PXR mice with a 4 week recovery period
2014-08-24 | E-GEOD-60688 | biostudies-arrayexpress
Project description:This SuperSeries is composed of the following subset Series: GSE12489: Effect of phenobarbital on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis GSE12509: Effect of TCPOBOP on CAR and PXR regulated genes involved in drug metabolism and cholesterol homeostasis Refer to individual Series
2008-08-23 | E-GEOD-12529 | biostudies-arrayexpress
Project description:The nuclear receptors CAR (constitutive androstane receptor) and PXR (pregnane X receptor) mediate the effects of phenobarbital (PB) on gene transcription. To investigate the relative role of CAR and PXR in the induction response, cDNA arrays were generated containing 120 genes which are known to be regulated with these or related nuclear receptors (genes involved in drug metabolism, cholesterol biosynthesis, sterol synthesis/transport, heme synthesis). Samples from livers of wild type and CAR-/-, PXR-/- or CAR/PXR-/- knockout mice were tested after treatment with PB for gene expression within the European Framework V program “Steroltalk” (www.steroltalk.net). Results from these experiments unexpectedly revealed that if CAR and PXR are deleted, PB increases the expression of several other nuclear receptors and genes involved in drug metabolism and cholesterol biosynthesis.
2008-08-23 | GSE12489 | GEO
Project description:The constitutive androstane receptor (CAR, NR1I3) modulates the transcription of numerous genes involving drug metabolism, energy homeostasis, and cell proliferation. Most functions of CAR however were defined from animal studies. Given the known species difference of CAR and the significant cross-talk between CAR and the pregnane X receptor (PXR), it is extremely difficult to decipher the exact role of human CAR (hCAR) in gene regulation, relying predominantly on pharmacological manipulations. Here, utilizing a newly generated hCAR-knockout (KO) HepaRG cell line, we carried out RNA-seq analysis of the global transcriptomes in wild-type (WT) and hCAR-KO HepaRG cells treated with CITCO, a selective hCAR agonist, phenobarbital (PB), a dual activator of hCAR and hPXR, or vehicle control. Real-time PCR assays in separate experiments were used to validate RNA-seq findings. Our results indicate that genes encoding drug-metabolizing enzymes are among the main clusters altered by both CITCO and PB. Specifically, CITCO significantly changed the expression of 135 genes in an hCAR-dependent manner, while PB altered the expression of 227 genes in WT cells of which 94 were simultaneously modulated in both cell lines reflecting the dual effects of PB on hCAR/PXR. Notably, we found that many genes promoting cell proliferation and tumorigenesis were up-regulated in hCAR-KO cells, suggesting that hCAR may play an important role in cell growth that differs from mouse CAR. Together, our results reveal both novel and known targets of hCAR and support the role of hCAR in maintaining the homeostasis of metabolism and cell proliferation in the liver.
2015-09-30 | GSE71446 | GEO
Project description:Pregnane X receptor (PXR) is generally considered the most important sensor of natural and anthropogenic xenobiotics in vertebrates. In Xenopus, however, PXR plays a role in neural development and it is irresponsive to xenobiotics. We report a first broad-spectrum amphibian xenobiotic receptor, which is an ortholog of the mammalian constitutive androstane receptor (CAR). The low basal activity and pronounced responsiveness to activators such as drugs and steroids displayed by the Xenopus CAR resemble PXR, which both trace back to a common ancestor early in the divergence of land vertebrates. The constitutive activity of CAR emerged first in Sauropsida (reptiles and birds) and it is common to all fully terrestrial land vertebrates (Amniota). This activity can be mimicked by humanizing just two amino acids of the Xenopus CAR. These results demonstrate a remarkable plasticity of CAR which enabled its employment as Xenopus xenosensors. They open way to toxicogenomic and bioaugmentation studies in amphibians, a critically endangered taxon of land vertebrates. Taken together, we provide evidence for a much earlier origin of CAR, for its conservation in tetrapods which exceeds that of PXR, and for its remarkable functional plasticity which enabled its role as a PXR-like xenosensor in Amphibia. We used microarrays to detect global transcriptional changes in Xenopus laevis livers following pregnenolone and artemisinin treatment in order to identify target genes of xlCAR. Arteminisin or pregnenolone were injected intraperitoneally into three frogs on two consecutive days. The control group received in parallel two DMSO injections. All frogs were sacrificed 24 h after the second injection by decapitation, and livers were immediately frozen in liquid nitrogen. After RNA isolation, specimens within the same experimental group were pooled.
2011-10-10 | E-GEOD-28510 | biostudies-arrayexpress