Key genes and histopathological alterations in hepatic fibrogenesis after segmental cholestasis in weaned rats.

Abstract

BACKGROUND: The selective bile duct ligation (sBDL) model has been proposed to study fibrosis progression in segmental cholestasis, replicating histopathological features of biliary obstruction in both liver parenchyma with biliary obstruction (BO) and without biliary obstruction (WBO). However, the molecular mechanisms driving fibrogenesis in WBO parenchyma remain unclear. This study aimed to characterize gene expression and histological alterations in fibrogenesis using the sBDL model. METHODS: Liver samples were collected at 1, 4, and 8 weeks post-surgery from both BO and WBO parenchyma, undergoing histological, immunohistochemical, biochemical, and molecular analyses. RESULTS: Differentially expressed genes (DEGs) were associated to inflammatory response, extracellular matrix production, angiogenesis, and negative regulation of peptidase activity. Histologically, ductular proliferation, inflammatory infiltration, and collagen deposition were observed in both BO and WBO parenchyma, with more pronounced inflammation and hepatocellular degeneration in BO. BO parenchyma showed more pathways related to disease progression. In contrast, pathways related to cellular senescence and the PI3K-Akt signaling, suggesting suppression of apoptosis and cell proliferation. CONCLUSION: The sBDL model mirrors key aspects of human biliary fibrosis, offering novel molecular insights into fibrogenesis in segmental cholestasis and serving as a valuable tool for developing diagnostic and therapeutic strategies. IMPACT: This study demonstrates that hepatic fibrogenesis extends beyond regions directly affected by biliary obstruction, involving non-obstructed liver parenchyma. Using the selective bile duct ligation (sBDL) model, we identified key molecular pathways associated with fibrogenesis in segmental cholestasis. Our findings provides new insights into the mechanisms of cholestatic fibrosis and highlighting the sBDL model as a valuable preclinical tool. These results may inform the development of novel therapeutic strategies for treating biliary fibrosis.