Time-dependent modulation of FXR and Nrf۲ signaling in rat models of BDL-induced cholestasis

Objective(s): Farnesoid X receptor (FXR) and nuclear factor erythroid ۲-related factor ۲ (Nrf۲) protect the liver against cholestatic injury by regulating antioxidant and anti-inflammatory pathways. Bile duct ligation (BDL) is a standard model for studying cholestatic liver disease, yet the temporal dynamics of FXR/Nrf۲ signaling and their downstream mediators remain unclear. To investigate time-dependent changes in hepatic FXR, Nrf۲, and downstream effectors over six weeks following BDL in rats, to identify potential preventive and therapeutic targets.Materials and Methods: Forty-nine male Wistar rats were divided into one sham-operated group and six BDL groups, sacrificed sequentially from weeks ۱ to ۶ post-surgery. Biochemical assays, histopathology, and molecular analyses were performed to assess dynamic changes in FXR, Nrf۲, and related oxidative stress and inflammatory markers.Results: The most severe histological distortions were observed mainly at week six. Expression reductions in FXR, Superoxide Dismutase (SOD), Alpha-Glutathione S-Transferase (α-GST), and Glutamate-Cysteine Ligase Modifier Subunit (GCLM) were notable from week ۱ to week ۶, significantly declining in BDL rats compared to sham-operated ones. Nrf۲ notably decreased at week ۴ post-BDL (P-value<۰.۰۵). TNF-α exhibited an increasing trend, peaking at week ۶ (P<۰.۰۰۱). FXR prominently decreased in weeks ۱ and ۵ (P<۰.۰۰۱), and SOD notably decreased in week ۵ (P<۰.۰۵). α-GST and GCLM also markedly decreased, especially during BDL-W۳ and BDL-W۴ (P<۰.۰۰۱).Conclusion: Temporal suppression of FXR/Nrf۲ signaling and antioxidant defenses likely contribute to BDL-induced cholestatic injury, with a biphasic pattern across acute and sub-acute phases. These pathways may serve as therapeutic targets during disease progression.

کلیدواژه ها:

Bile duct ligation (BDL) ، cholestasis ، Cholestatic liver injury ، Farnesoid X receptor ، Nuclear factor erythroid ۲-related factor ۲