Protein S-nitrosylation Restricts Xenobiotic Receptor PXR Hyperactivity and Ameliorates Acetaminophen-induced Liver Injury in Mice
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ABSTRACT:
PROVIDER: PRJNA1019373 | ENA |
REPOSITORIES: ENA
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Project description:Drug-induced liver injury (DILI), especially acetaminophen overdose, is the leading cause of acute liver failure. Pregnane X receptor (PXR) is a nuclear receptor and the master regulator of drug metabolism. Aberrant activation of PXR plays a pathogenic role in the acetaminophen hepatotoxicity. Here, we aimed to examine the PXR S-nitrosylation (SNO) in response to acetaminophen. We found that PXR was S-nitrosylated in hepatocytes and the mouse livers after exposure to acetaminophen or S-nitrosoglutathione (GSNO). Mass-spectrometry and site-directed mutagenesis identified the cysteine 307 as the primary residue for SNO-modification. In hepatocytes, SNO suppressed both agonist (rifampicin and SR12813)-induced and constitutively active PXR (VP-PXR) activations. Furthermore, in acetaminophen overdosed mouse livers, PXR protein was decreased at the centrilobular regions overlapping with increased SNO. In PXR-deficient (PXR-/-) mice, replenishing the livers with the SNO-deficient PXR significantly aggravated hepatic necrosis and apoptosis, increased HMGB1 release, and exacerbated liver injury and inflammation. Particularly, we demonstrated that S-nitrosoglutathione reductase (GSNOR) inhibitor N6022 promoted hepatoprotection by increasing the levels of PXR S-nitrosylation. In conclusion, PXR is post-translationally modified by S-nitrosylation in hepatocytes in response to acetaminophen. This modification mitigated the acetaminophen-induced PXR hyperactivity. It may serve as a new target for therapeutical intervention.
2024-03-06 | GSE243679 | GEO
Project description:Phenobarbital is a well studied xenobiotic compound. In this study, we describe the genomic responses in fruit flies and examine whether animals mutant for DHR96, an ortholog of xenobiotic nuclear receptors PXR and CAR, plays a role in mediating xenobiotic responses in Drosophila. Experiment Overall Design: Canton S is a commonly used wild type control strain for xenobiotic studies. Wild type or DHR96 mutant flies were starved overnight and then exposed to either sucrose alone or sucrose supplemented with 0.3% Phenobarbital.
2007-11-11 | E-GEOD-5096 | biostudies-arrayexpress
Project description:This study aimed to quantify and compare the mRNA abundance of major xenobiotic processing genes in liver following activation of PXR and CAR using RNA-Seq
2017-10-10 | GSE104734 | GEO
Project description:The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion in Pxr+/+ vs Pxr-/- C57Bl6/J mice revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis revealed that microbiota-PXR interaction controlled fatty-acid and xenobiotic metabolism. Antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in livers from Pxr+/+ but not Pxr-/- male mice. These findings identify PXR as a hepatic effector of sexually dimorphic responses to microbiota-derived signals and reveal a potential new mechanism for unexpected drug-drug or food-drug interactions.
2020-08-26 | GSE156837 | GEO
Project description:Genetic disruption of thioredoxin reductase 1 protects against acetaminophen (APAP) toxicity. To determine the role of the thioredoxin system on xenobiotic metabolism we challeneged wildtype and txnrd1liver-null mice with acetaminophen.
2013-06-08 | GSE37874 | GEO
Project description:Many environmentally-relevant chemicals and drugs activate the nuclear receptor pregnane X receptor (PXR). Activation of PXR can lead to increases in liver weight in part through hepatocyte replication similar to a large number of compounds that activate other nuclear receptors such as the peroxisome proliferator-activated receptor alpha and the constitutive activated receptor (CAR). PXR controls the expression of a large battery of genes involved in xenobiotic metabolism. Identification of genes that are accurate predictors of PXR activation would be useful in high-throughput screens to assess potential toxicity and drug-drug interactions. Here, we identified PXR-dependent genes in the mouse liver after exposure to pregnenolone 16alpha-carbinonitrile (PCN), a chemical that is often used as a model PXR agonist.
2014-09-30 | GSE55746 | GEO
Project description:Background: Cisplatin-induced acute kidney injury (CAKI) has been recognized as one of the most serious side effects of cisplatin. Pregnane X receptor (PXR) is a ligand-dependent nuclear receptor and serves as a master regulator of xenobiotic detoxification. Increasing evidence also suggests PXR has many nonxenobiotic functions including the regulation of cell proliferation, inflammatory response and glucose and lipid metabolism. Methods: In this study, we aimed to investigate the role of PXR in cisplatin-induced nephrotoxicity. CAKI model was performed in wild-type or PXR knockout mice. Pregnenolone 16α-carbonitrile (PCN), a mouse PXR specific agonist, was used for PXR activation. The renal function, biochemical, histopathological and molecular alterations were examined in mouse blood, urine or renal tissues. Whole transcriptome analysis was performed by RNA sequencing. Dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays were applied to determine the regulation of PXR on its target genes. Results: We found that PXR activation significantly attenuated CAKI as reflected by improved renal function, reduced renal tubular apoptosis, ameliorated oxidative and endoplasmic reticulum stress, and suppressed inflammatory factor expression. RNA sequencing analysis revealed that the renoprotective effect of PXR was associated with multiple crucial signaling pathways. In particular, PXR protected against cisplatin-induced AKI by the activation of PI3K/AKT pathway and the induction of multidrug and toxin extrusion 1 (MATE1), an important transporter mediating cellular excretion of cisplatin, in the kidney. Conclusions: Our results demonstrate that PXR activation can preserve renal function in cisplatin-induced AKI and suggest a possibility of PXR as a novel therapeutic target for cisplatin-induced nephrotoxicity.
2023-03-20 | GSE147256 | GEO
Project description:Alcohol-associated liver disease (ALD) results from excessive alcohol consumption and is more severe in females. The prenane X receptor (PXR), a xenobiotic nuclear receptor essential for toxin defense, has been implicated in ALD, but the underlying mechanisms remain unclear. Due to species differences in ligand specificty, humanized PXR (hPXR) mouse models are necessary to investigate its role in the sexual dimorphism of ALD in humans. Ethanol exposure caused the most severe hepatoxicity in female hPXR mice with microarray analysis identifying 442 genes uniquely regulated by ethanol in female hPXR mice, implicated with ethanol-induced liver damage.
2024-10-31 | GSE280478 | GEO
Project description:Pregnane X receptor (PXR), a xenobiotic receptor involved in drug metabolism, has been reported to regulate lipid and glucose metabolism. The intestine tract is the first inner barrier of the body, which dysfunction contributes to the development of metabolic disorders. However, the role of intestinal PXR in metabolic diseases remains largely unknown. In this study, we showed that activation of PXR by tributyl citrate (TBC), an intestinal-selective agonist of PXR, improved high fat diet (HFD)-induced obesity and insulin resistance. The metabolic benefit of intestinal PXR activation was associated with upregulation of β-1,3 galactosyltransferase 5 (B3galt5). Our results revealed that B3galt5 is mainly expressed in the intestine and is a direct transcriptional target of PXR. Whole-body and intestine-specific knockout of B3galt5 exacerbated HFD-induced obesity, insulin resistance and inflammation. Mechanistically, B3galt5 is essential to maintain the integrity of intestinal mucus barrier. Ablation of B3galt5 impaired the O-glycosylation of mucin2, destabilized the mucus layer, and increased the permeability of intestinal barrier. Furthermore, B3galt5 deficiency abolished the beneficial effect of intestinal PXR activation on metabolic disorders. Our results suggested the intestinal-selective activation of PXR regulated B3galt5 expression holds an important role in maintaining metabolic homeostasis, making it a potential therapeutic strategy in obesity.
2024-07-02 | GSE266942 | GEO