Repression of Farnesoid X Receptor Contributes to Biliary Injuries of Liver Grafts Through Disturbing Cholangiocyte Bile Acid Transport

Biliary epithelial damage is the critical point in the development of nonanastomotic strictures, a serious biliary complication after liver transplantation (LT). Current study focuses on the roles and mechanisms of unbalanced bile acid (BA) transporting of cholangiocytes in biliary epithelial damages following LT. Using rat LT models, we observed that biliary transit time (BTT) of BA was prolonged, and the degree and duration of BTT prolongation were related to the cold ischemia time of donor liver. Moreover, prolonged BTT was correlated with bile duct injury severity. The expression of Farnesoid X receptor (FXR) underwent a dramatic decrease after transplantation, and the decrease in FXR was related to cold ischemic time of donor liver. Negative correlation was observed between FXR expression and BTT. With in vitro cultured human biliary epithelial cells, it was observed that FXR expressions and DNA binding activities were repressed under hypoxic conditions. FXR repression by hypoxia mediated unparallel expressions of BA transporters and intracellular accumulation of BAs, which induced higher cell apoptosis rates and enhanced profibrotic factor expression in cholangiocytes. These findings indicated that FXR repression under ischemic/hypoxic conditions contributed to biliary epithelial damages by disturbing BA transporting of cholangiocytes after LT.