Pregnane X receptor promotes ehtanol-induced hepatosteatosis in female mice
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1000615 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The pregane X receptor (PXR), a xenobiotioc-sensing nuclear receptor has been implicated in alcohol-associated liver disease (ALD). The role of PXR signaling in potentiating ethanol (EtOH)-induced hepatotoxicty in male wild-type (WT) mice was reported previously, however, how PXR signaling modulated EtOH-induced hepatotoxicty in female is still unknown. Several mRNAs that are involved in retinol and steroid hormone biosynthesis, chemical carcinogeneiss, and arachidonic acid metabolism were increased by EtOH in a PXR-dependent manner. Overall, female PXR-null mice are resistant against chronic EtOH-induced hepatotoxicity than their WT counterparts.
2023-08-09 | GSE239714 | GEO
Project description:The pregnane X receptor (PXR, NR1I2) is a xenobiotic-sensing nuclear receptor that modulates the metabolic response to drugs and toxic agents. Both PXR activation and deficiency promote hepatic triglyceride accumulation, a hallmark feature of alcoholic liver disease. However, the molecular mechanism of PXR-mediated activation of ethanol (EtOH)-induced steatosis is unclear. Here, using male wildtype (WT) and Pxr-null mice, we examined PXR-mediated regulation of chronic EtOH-induced hepatic lipid accumulation and hepatotoxicity. EtOH ingestion for 8 weeks significantly (1.8-fold) up-regulated Pxr mRNA levels in WT mice. The EtOH exposure also increased mRNAs encoding hepatic constitutive androstane receptor (3-fold) and its target, Cyp2b10 (220-fold), in a PXR-dependent manner. Furthermore, WT mice had higher serum EtOH levels and developed hepatic steatosis characterized by micro- and macrovesicular lipid accumulation. Consistent with the development of steatosis, lipogenic gene induction was significantly increased in WT mice, including sterol regulatory element-binding protein 1c target gene fatty-acid synthase (3.0-fold), early growth response-1 (3.2-fold), and TNF? (3.0-fold), whereas the expression of peroxisome proliferator-activated receptor ? target genes was suppressed. Of note, PXR deficiency suppressed these changes and steatosis. Protein levels, but not mRNAs levels, of EtOH-metabolizing enzymes, including alcohol dehydrogenase 1, aldehyde dehydrogenase 1A1, and catalase, as well as the microsomal triglyceride transfer protein, involved in regulating lipid output were higher in Pxr-null than in WT mice. These findings establish that PXR signaling contributes to ALD development and suggest that PXR antagonists may provide a new approach for ALD therapy.
| S-EPMC5766906 | biostudies-other
Project description:Pregnane X Receptor (PXR) protects against cisplatin-induced acute kidney injury
| PRJNA613607 | ENA
Project description:Steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and the intestine. They function as xenobiotic sensors by inducing genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our findings indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging.
2015-03-31 | GSE60401 | GEO
Project description:Post-treatment recurrence remains a major clinical challenge in colorectal cancer (CRC), and increasing evidence suggests that Cancer Stem Cells (CSCs) may mediate this process due to their enhanced resistance to conventional therapeutics. We hypothesized that the Pregnane-X receptor (PXR) may drive the chemoresistance of colorectal CSCs.. shRNA-mediated PXR down-regulation was used to analyze the role of PXR on self-renewal in the colorectal cancer cell Line LS174T. Expression and activity of PXR were quantified under conditions that promote Cancer Stem Cells (CSCs) enrichment. Conversely, CSC characterization was performed in cells enriched along their PXR activity level.
2016-08-01 | E-MTAB-3471 | biostudies-arrayexpress
Project description:Steroid and xenobiotic receptor (SXR) and its murine ortholog pregnane X receptor (PXR) are nuclear receptors that are expressed mainly in the liver and the intestine. They function as xenobiotic sensors by inducing genes involved in detoxification and drug excretion. Recent evidence showed that SXR and PXR are also expressed in bone tissue where they mediate bone metabolism. Here we report that systemic deletion of PXR results in aging-dependent wearing of articular cartilage of knee joints. Histomorphometrical analysis showed remarkable reduction of width and an enlarged gap between femoral and tibial articular cartilage in PXR knockout mice. We hypothesized that genes induced by SXR in chondrocytes have a protective effect on articular cartilage and identified Fam20a (family with sequence similarity 20a) as an SXR-dependent gene induced by the known SXR ligands, rifampicin and vitamin K2. Lastly, we demonstrated the biological significance of Fam20a expression in chondrocytes by evaluating osteoarthritis-related gene expression of primary articular chondrocytes. Consistent with epidemiological findings, our findings indicate that SXR/PXR protects against aging-dependent wearing of articular cartilage and that ligands for SXR/PXR have potential role in preventing osteoarthritis caused by aging. ADC5 cells were infected with adeno-SXR or adeno-DsRed and cultured in phenol red-free DMEM with charcoal/dextran-treated FCS (5%) containing rifampicin (10 μM), vitamin K2 (10 μM), or ethanol. Total RNA was extracted from the cells using the ToTALLY RNA Kit (Ambion, Austin, TX). Profiling of mRNA was performed on Affymetrix Mouse Gene 1.0 ST arrays (Affymetrix Inc., Santa Clara, USA) according to the Gene Chip labeling assay manual version 4.
2015-03-31 | E-GEOD-60401 | biostudies-arrayexpress
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:Estrogen Promotes Mandibular Condylar Fibrocartilage Chondrogenesis and Inhibits Degeneration Via Estrogen Receptor Alpha in Female Mice
| PRJNA433406 | ENA
Project description:Comparison of target genes from the pregnane X receptor (Pxr) in the liver vs the intestine
| PRJNA509890 | ENA
Project description:Kolodkin2013 - Nuclear receptor-mediated
cortisol signalling network
This model is described in the article:
Optimization of stress
response through the nuclear receptor-mediated cortisol
signalling network.
Kolodkin A, Sahin N, Phillips A,
Hood SR, Bruggeman FJ, Westerhoff HV, Plant N.
Nat Commun 2013; 4: 1792
Abstract:
It is an accepted paradigm that extended stress predisposes
an individual to pathophysiology. However, the biological
adaptations to minimize this risk are poorly understood. Using
a computational model based upon realistic kinetic parameters
we are able to reproduce the interaction of the stress hormone
cortisol with its two nuclear receptors, the high-affinity
glucocorticoid receptor and the low-affinity pregnane
X-receptor. We demonstrate that regulatory signals between
these two nuclear receptors are necessary to optimize the
body's response to stress episodes, attenuating both the
magnitude and duration of the biological response. In addition,
we predict that the activation of pregnane X-receptor by
multiple, low-affinity endobiotic ligands is necessary for the
significant pregnane X-receptor-mediated transcriptional
response observed following stress episodes. This integration
allows responses mediated through both the high and
low-affinity nuclear receptors, which we predict is an
important strategy to minimize the risk of disease from chronic
stress.
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2024-09-02 | BIOMD0000000576 | BioModels