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Updated: May 6, 2026
Cell Type-specific Gene Expression Profiling in the Mouse Liver
Published on: September 17, 2019
A trend over time study of hepatic Farnesoid-X-activated receptor and its downstream targets modulation by valproic
Amir Saamaan Fattahi1, Azadeh Khalili2,3, Seyed Ali Hashemi4
1Department of Pharmacology and Toxicology, Faculty of Pharmacy, Pharmaceutical Sciences Branch, Islamic Azad University, Tehran, Iran.
Abstract:
Valproic acid (VA) is a broad-spectrum anticonvulsant agent that acts through several molecular mechanisms to control different types of seizures. The main concern of the drug is its liver toxicity. Considering the regulatory roles of the Farnesoid nuclear receptors and the nuclear transcription factor Nrf2 in modifying and neutralizing the harmful effects of oxidative damage, the present study was designed to evaluate the role of FXR-Nrf2 and some downstream target gene alterations in hepatotoxicity induced by VA. Thirty-five eight-week-old male albino mice were randomly divided into five groups, including a control group, and four groups were assigned to receive VA (300 mg/kg/day; oral) for 3, 7, 10, and 14 days. Serum levels of ALT, AST, ALP, and total and direct bilirubin (TB, DB) were measured. Liver histology and the expression of FXR, Nrf2, α-GST, SOD, and TNF-α were assessed using H&E staining and real-time RT-PCR techniques. Maximum extent of biochemical and histopathological damage was observed on the 14th day, but changes in the expression of FXR, Nrf2, α-GST, and SOD were seen at three points: a significant upregulation on the 3rd day, a remarkable downregulation on the 10th day, and a second-time upregulation on the 14th day. In conclusion, considering the observed dysregulation in FXR-Nrf2 cascade expression during VA administration, it seems that downregulation in this pathway and consequently its downstream detoxification and antioxidant genes may play a role in liver toxicity.
Insights
Valproic acid (VA) can cause liver damage, potentially by disrupting the FXR-Nrf2 pathway. This pathway
Area of Science:
- Hepatotoxicity and molecular mechanisms
- Drug-induced liver injury
- Oxidative stress and detoxification pathways
Background:
- Valproic acid (VA) is an anticonvulsant with known liver toxicity.
- Farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor 2 (Nrf2) regulate oxidative damage responses.
- Understanding VA's impact on FXR-Nrf2 is crucial for mitigating hepatotoxicity.
Purpose of the Study:
- To investigate the role of the FXR-Nrf2 pathway in VA-induced liver toxicity.
- To assess alterations in downstream target genes of FXR-Nrf2.
- To correlate molecular changes with biochemical and histological damage.
Main Methods:
- Male albino mice received daily oral doses of VA (300 mg/kg) for 3, 7, 10, and 14 days.
- Serum liver enzymes (ALT, AST, ALP) and bilirubin levels were measured.
- Liver histology (H&E staining) and gene expression (FXR, Nrf2, α-GST, SOD, TNF-α) via RT-PCR were analyzed.
Main Results:
- Maximal biochemical and histopathological liver damage occurred by day 14.
- FXR, Nrf2, α-GST, and SOD expression showed dynamic changes: upregulation on day 3, downregulation on day 10, and re-upregulation on day 14.
- TNF-α expression patterns were also observed.
Conclusions:
- Dysregulation of the FXR-Nrf2 cascade is evident during VA administration.
- Downregulation of the FXR-Nrf2 pathway and its target genes may contribute to VA-induced hepatotoxicity.
- This study highlights the potential involvement of oxidative stress and detoxification pathways in VA's liver side effects.
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