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Pregnane X receptor promotes ehtanol-induced hepatosteatosis in female mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE239714 | GEO | 2023/08/09

REPOSITORIES: GEO

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Human PXR signaling enhances ethanol-induced liver injury in females

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.

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Pregnane X Receptor (PXR) protects against cisplatin-induced acute kidney injury

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.

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Pregnane X receptor promotes ehtanol-induced hepatosteatosis in female mice

Project description:Pregnane X receptor promotes ehtanol-induced hepatosteatosis in female mice

| PRJNA1000615 | ENA

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