Molecular targets of PXR-dependent ethanol-induced hepatotoxicity in female mice
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View abstract on PubMed
Summary
This summary is machine-generated.Pregnane X receptor (PXR) signaling exacerbates ethanol-induced liver injury in female mice. Female Pxr-null mice showed resistance to chronic ethanol toxicity, revealing PXR-dependent and independent protective mechanisms.
Area Of Science
- Hepatology
- Pharmacology
- Toxicology
Background
- The pregnane X receptor (PXR) is a xenobiotic sensor that influences drug metabolism and toxicity.
- PXR signaling potentiates ethanol (EtOH)-induced liver injury in male mice, but its role in females is unknown.
Purpose Of The Study
- To investigate the role of PXR signaling in EtOH-induced hepatotoxicity in female mice.
- To identify PXR-dependent and independent mechanisms of EtOH-induced liver injury.
Main Methods
- Wild type (WT) and Pxr-null female mice were fed ethanol-containing diets for 8 weeks.
- Assessed liver injury, EtOH elimination, histology, gene/protein expression, oxidative stress, and endoplasmic stress.
- Microarray and bioinformatic analyses identified PXR targets.
Main Results
- WT females showed increased liver injury markers, oxidative stress, and endoplasmic stress upon EtOH consumption.
- Female Pxr-null mice exhibited enhanced EtOH elimination and were protected from EtOH-induced hepatotoxicity and oxidative stress.
- EtOH upregulated genes in retinol and steroid hormone biosynthesis, chemical carcinogenesis, and arachidonic acid metabolism in a PXR-dependent manner.
Conclusions
- Female Pxr-null mice are resistant to chronic EtOH-induced hepatotoxicity.
- PXR signaling exacerbates EtOH-induced liver injury in females.
- Identified both PXR-dependent and independent mechanisms contributing to EtOH hepatotoxicity.
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