Berberine attenuates cholestatic liver and bile duct injury in Mdr2 −/− mice by maintaining bile acid homeostasis

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Background Cholestatic liver injury is an important clinical problem with a limited understanding of disease pathologies. Modulation of the enterohepatic circulation of bile acids (BAs) may protect against BA‐mediated cholestatic liver injury. Berberine (BBR), a bioactive isoquinoline alkaloid found in a variety of herbs, has been used to treat many diseases, including liver diseases, over hundreds of years. Our previous studies have shown that BBR inhibits high fat‐diet‐induced steatosis and inflammation in rodent models of nonalcoholic fatty liver diseases. However, it remains unknown if BBR has any effect on cholestatic liver injury. The aim of this study is to examine the therapeutic effects and potential mechanisms of berberine on cholestatic liver disease in Mdr2 −/− mice, the best‐characterized mouse model of primary sclerosing cholangitis (PSC). Methods Mdr2 −/− mice with FVB background (100 days old, both male and female) were randomly divided into the control group and BBR group. Mice were treated with BBR (50 mg/kg) or vehicle (0.5% carmellose sodium solution) by intragastric administration once‐daily for eight weeks. Mice were kept in a temperature‐controlled room with 12/12‐hour light/dark cycles and fed ad libitum normal chow diet. At the end of the treatment, the mice were sacrificed. Blood was collected for measuring serum lipids and liver functional enzymes using the Alfa Wassermann Vet ACE Axcel® System. Liver tissues were processed for H&E and Masson’s trichrome staining, immunohistochemistry (IHC), and isolation of total RNA. The mRNA levels of the key genes involved in bile duct proliferation, inflammation, fibrotic injury, and bile acid metabolism were measured by real‐time RT PCR. Results BBR treatment significantly improved cholestatic liver injury as indicated by significant reduction of serum levels of ALT, AST, ALP, and BAs, as well as liver to body weight ratios. H&E and Masson's trichrome staining showed a significant reduction of liver fibrosis by BBR treatment. IHC staining of CK‐19 further showered that BBR treatment markedly reduced biliary proliferation and ductular reaction. In addition, BBR treatment reduced hepatic macrophage infiltration. Real‐time PCR results further showed that BBR treatment significantly reduced the mRNA levels of MCP‐1, IL‐1β, α‐SMA, CK‐19 and increased mRNA levels of FXR and SHP in the liver. Conclusion BBR significantly reduced cholestatic liver injury and has the potential to be used for the treatment of PSC and other cholestatic liver diseases. Support or Funding Information This work was supported by VA Merit Award I01BX004033 and 1I01BX001390, VA Career Scientist Award IK6BX004477 and National Institutes of Health Grant R01 DK104893 and R01DK‐057543

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