Recovery Kinetics and Persistent Hepatic Alterations in a Xenobiotic-induced Murine Model of Chronic Cholestatic Liver Disease

Introduction: Objective: Chronic cholestatic liver disease (CCLD) is characterized by impaired bile production and excretion due to its inflammatory nature and potential progression to biliary cirrhosis. Murine models mimic cholestatic-type human liver diseases, such as the 3,5-diethoxycarbonyl-1,4-dihydrocholidine (DDC) model. Nonetheless, the timeline for liver regeneration following cessation of the DDC diet remains unclear. This study aimed to evaluate the duration of hepatic alterations after cessation of the DDC diet. Methods: C57BL/6J male mice (16-17 weeks old) were randomly assigned to Control (standard diet) and CCLD (DDC-supplemented diet) groups. After six weeks of diet exposure, the DDC group transitioned to a standard diet. Liver parameters were evaluated at 3-, 18-, and 36-days post-diet cessation. Analysis included liver damage and weight, histopathology, and biochemical markers. Results and Discussion: Liver damage remained elevated until day 36, whereas liver weight remained elevated until day 18. Histological analysis confirmed that bile duct obstruction and fibrosis scores in the DDC group remained significantly higher than in controls up to 36 days after the DDC diet. Serum bile acid levels remained elevated for up to 18 days, while GGT levels did not differ across time points. AST levels were markedly increased at 3 days, whereas ALT levels remained elevated at 3 and 18 days. Conclusion: Total cholesterol and triglyceride levels increased until day 18, highlighting changes in lipid metabolism. Our study demonstrates hepatic effects in the DDC-induced CCLD model, with alterations persisting beyond cessation of hepatotoxin exposure. These findings show the temporal dynamics of CCLD after diet cessation through different liver parameters.