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characterized activity profile of CAR and compared with hCAR and mCAR; related this to structural homology among the 3 orthologues; 5 alternative splice variants identified and sequenced each of which generated a truncated protein product
RNA-Seq performed from livers of adult male C57BL/6 mice treated with PXR or CAR agonists identified differentially expressed lncRNAs-protein-coding genes (PCGs) pairs that displayed a high coregulatory pattern by PXR and CAR activation. Study was among the first to demonstrate that lncRNAs are regulated by PXR and CAR activation and that they may be important regulators of PCGs involved in xenobiotic metabolism.
new findings in this report link an important role in CAR activation that is dependent upon oxidative stress.
he ChIP-exo analyses also identified distinct binding motifs for the respective mouse and human receptors. Together, the results provide new insights into the important roles that CAR contributes as a key modulator of numerous signaling pathways in mammalian organisms, presenting a genomic context that specifies species variation in biological processes under CAR's control, including liver cell proliferation
the CAR-Akt-Foxo1 signalling pathway has an essential role in controlling hepatocyte proliferation by repressing the cell cycle regulator Cdkn1a (p21)
Study uncovered a novel function of CAR in mediating the kidney-liver cross-talk in acute kidney injury (AKI). Renal IR downregulated the expression and activity of CAR and decreased the expression of microsomal triglyceride transfer protein (MTTP), which resulted in a decreased very-low-density lipoprotein triglyceride (VLDL-TG) secretion and lipid accumulation and liver injury.
The role of the CAR signaling pathways within testis was validated using specific CAR agonist (TCPOBOP) and inverse agonist (androstanol) that respectively inhibited or reproduced the phenotype observed in Fxralpha-/- males fed Bile acids (BAs)-diet. These data open interesting perspectives to better define how BA homeostasis contributes to physiological or pathophysiological conditions via the modulation of CAR activity.
data provide a comprehensive view of the CAR-regulated transcriptome and give insight into the mechanism of sex-biased susceptibility to CAR-dependent mouse liver tumorigenesis
FXR signaling is a bile acid nuclear receptor that regulates lipids and glucose homeostasis and lack of it causes hepatomegaly and liver dysfunction.
These results revealed the bilirubin transport regulatory mechanisms and highlighted the importance of CAR in modulating the bilirubin clearance pathway in the ALD mouse model.
Activation of constitutive androstane receptor results in maintained biliary excretion of bile acids despite a marked decrease of bile acids in liver.
CAR plays an important role in acifluorfen-induced liver injury and tumor development in mice.
Activation of the nuclear receptor constitutive androstane receptor (CAR) induced FNDC5 mRNA expression in the liver.
CAR is important for hepatic clearance of several widely prescribed drugs metabolized by P450 enzymes, however the fasting-induced alterations in P450-mediated drug clearance are largely independent of CAR.
A functional network among CAR targeted genes and the affected microRNAs was constructed to illustrate how CAR modulation of microRNA expression may potentially mediate its biological role in mouse hepatocyte proliferation.
The present study has revealed known and novel, as well as common and unique targets of PXR and CAR in mouse liver following pharmacological activation using their prototypical ligands.
Results show that circadian disruption activates CAR via sympathetic dysfunction and cholestasis. The nuclear receptor CAR drives NAFLD to NASH, fibrosis, and hepatocellular carcinoma progression
These data provide new insights into the regulation by CAR of glycolytic and lipogenic genes and on pathogenesis of steatosis
CAR plays an important role in maintaining the homeostasis of cholesterol, bile acids, and triglycerides levels.
CAR activation initiates a transcriptional program that facilitates the coordinated metabolic activities required for cell proliferation.
This study demonstrated that Lack of CAR impacts neuronal function and cerebrovascular integrity in mice.
specific association of NR1I3, C6 and TNN with low hip BMD risk
Expression of microRNA potentially regulated by AhR and CAR in malignant tumors of the endometrium has been reported.
Phosphomimetic substitution of Thr-38 with Asp increased co-immunoprecipitation of the CAR DNA Binding Domain with CAR Ligand Binding Domain in Huh-7 cells. The underlying molecular mechanism that regulates CAR activation is its homodimer-monomer-heterodimer conversion; the monomer and homodimer are phosphorylated at Thr-38 and inactive.
Results suggest that TRIM24 is a novel coactivator of the CAR that is involved in cell- and/or promoter- selective transactivation.
An overview of NR1I2 and NR1I3 pharmacogenetic studies in various therapeutic fields.
replication confirmed at genome-wide significance the association of loci at FOXE1 with hypothyroidism, and PDE8B, CAPZB and PDE10A with serum TSH. A total of 12 SNPs seemed to explain nearly 7% of the serum TSH variation
Dual ligands of CAR/PXR show distinct gene regulation patterns by regulating cross-talk between CAR and PXR.
Data suggest both PXR and CAR are expressed in testis/Sertoli cells; exposure of Sertoli cells (in vitro model of blood-testis barrier) to PXR or CAR ligands (including antiretroviral drugs) up-regulates expression of Pgp/ABCB1, BCRP, and MRP4. (PXR = pregnane X receptor; CAR = constitutive androstane receptor; Pgp/ABCB1 = P-glycoprotein ABCB1; BCRP = breast cancer resistance protein; MRP4 =multidrug resistance protein 4)
Genome-wide comparison of the inducible transcriptomes of nuclear receptors CAR, PXR and PPARalpha in primary human hepatocytes has been presented.
Integrative analysis of four RNA-Seq datasets and differential expression revealed for the first time, splicing alterations of SLC39A14 and NR1I3 in hepatocellular carcinoma.
These 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.
The homozygous variant genotype of MPJ6_1I3008 is associated with a significant reduced risk of neonatal hyperbilirubinemia in females.
Around 42.5% of the overall interindividual variability in warfarin dose requirements was explained : VKORC1 genotype accounted for 29.6%, CYP2C9 genotype for 4.3%, age for 3.6%, the CYP4F2 genotype for 3.3%, and CAR/HNF4alpha (rs2501873/rs3212198) for 1.7%
It is suggested that the functions of PXR, CAR and AhR may be closely implicated in the pathogeneses of metabolic vascular diseases, such as hyperlipidemia, atherogenesis, and hypertension.
Suggest that PXR and CAR double humanized mice are more sensitive rifampcin induction of cytochrome P450 and UDP-glucuronosyltransferases.
PRMT5 enhances transcriptional activity of constitutive androstane receptor.PRMT5 is a gene-selective co-activator for CAR.
The nuclear receptor constitutive androstane receptor/NR1I3 enhances the profibrotic effects of transforming growth factor beta and contributes to the development of experimental dermal fibrosis.
Donor CYP3A5, NR1I3 gene polymorphisms.
This gene encodes a member of the nuclear receptor superfamily, and is a key regulator of xenobiotic and endobiotic metabolism. The protein binds to DNA as a monomer or a heterodimer with the retinoid X receptor and regulates the transcription of target genes involved in drug metabolism and bilirubin clearance, such as cytochrome P450 family members. Unlike most nuclear receptors, this transcriptional regulator is constitutively active in the absence of ligand but is regulated by both agonists and inverse agonists. Ligand binding results in translocation of this protein to the nucleus, where it activates or represses target gene transcription. These ligands include bilirubin, a variety of foreign compounds, steroid hormones, and prescription drugs. Multiple transcript variants encoding different isoforms have been found for this gene.
constitutive androstane receptor
, constitutively transactivates RAREs
, nuclear receptor subfamily 1 group I member 3
, orphan nuclear receptor MB67
, constitutive androstane receptor NR1I3
, nuclear receptor constitutive active receptor
, strain Fischer nuclear receptor (CAR)
, constitutive activator of retinoid response
, constitutive active receptor
, constitutive active response
, constitutive androstane nuclear receptor variant 2
, constitutive androstane nuclear receptor variant 3
, constitutive androstane nuclear receptor variant 4
, constitutive androstane nuclear receptor variant 5
, orphan nuclear hormone receptor
, xenobiotic receptor