Liver necrosis and neutrophil infiltration were assessed with H&E

Liver necrosis and neutrophil infiltration were assessed with H&E and immunohistochemical staining, respectively. Serum and

hepatic bile acid levels were measured as well. RESULTS: Compared with wild-type, NHERF-1-/mice had more than 50% reduction in hepatic radixin expression (P<0.001). NHERF-1-/- BDL mice showed significantly lower scores of hepatic necrosis (P<0.01) as well as reduced neutrophil accumulation in the liver compared to the wild-type BDL group. Western blotting demonstrated that ICAM-1was reduced to about 70% of the wild-type in both sham and BDL NHERF-1-/- mouse liver (P<0.05). No significant difference in hepatic bile acid levels was detected between WT and NHERF1-/- mice in both the sham and BDL groups, but serum bile acid levels tended to be decreased in NHERF-1-/- BDL mice. CONCLUSIONS: These findings indicate that NHERF-1 is an important determinant of the expression of hepatic radixin as well as ICAM-1, an essential HIF cancer molecule involved in liver injury associated

with neutrophil-dependent inflammation after BDL. While changes in the expression of these proteins can have protective effects in cholestatic liver injury, the protection seems independent of hepatic bile acid concentrations. This study indicates that adhesion molecules are potential therapeutic targets in cholestasis. Disclosures: The following people have nothing to disclose: Man Li, Albert Mennone, Carol J. Soroka, Kathy M. Harry, Edward J. Weinman, James L. Boyer Sustained cholestasis results in injury to the biliary epithelium with subsequent ductular reaction, pericholangitis, stellate cell activation, and Barasertib fibrogenesis. Such pathologies are commonly associated with diseases such as primary biliary cirrhosis and primary sclersoing cholangitis. The Wnt/p-catenin pathway has been shown to play an important role during bile duct development, but its role in adult bile duct injury and repair remains

undetermined. Mice lacking p-catenin in hepatocytes and biliary epithelial cells (Kし)and littermate wild-type (WT) control mice were subjected to bile duct ligation (BDL), a short-term model of acute intrahepatic cholestasis. learn more Intriguingly, while bilirubin levels were comparably enhanced, hepatocyte injury, intrahepatic cholestasis and fibrosis were notably decreased in the KO after BDL. Further analysis yielded a significant decrease in total hepatic bile acids (BA) in the KO, which was associated with suppression of BA synthesis and an increase in apical BA transporter expression. Further, expression of Shp-1 mRNA was dramatically increased in KO after BDL. Hep3B cells transfected with Shp-1 reporter demonstrated a significant increase in activity when treated with p-catenin siRNA in the presence of FXR agonist GW4064. Finally, coprecipitation studies demonstrate a physical association of p-catenin and FXR in the WT that increases after BDL, suggesting an inhibitory function for pcatenin in FXR activation.

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