Time-dependent modulation of FXR and Nrf2 signaling in rat models of BDL-induced cholestasis.

OBJECTIVES: Farnesoid X receptor (FXR) and nuclear factor erythroid 2-related factor 2 (Nrf2) 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/Nrf2 signaling and their downstream mediators remain unclear. To investigate time-dependent changes in hepatic FXR, Nrf2, 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 1 to 6 post-surgery. Biochemical assays, histopathology, and molecular analyses were performed to assess dynamic changes in FXR, Nrf2, 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 1 to week 6, significantly declining in BDL rats compared to sham-operated ones. Nrf2 notably decreased at week 4 post-BDL (P-value<0.05). TNF-α exhibited an increasing trend, peaking at week 6 (P<0.001). FXR prominently decreased in weeks 1 and 5 (P<0.001), and SOD notably decreased in week 5 (P<0.05). α-GST and GCLM also markedly decreased, especially during BDL-W3 and BDL-W4 (P<0.001). CONCLUSION: Temporal suppression of FXR/Nrf2 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.