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

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.

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.

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).

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.