Bile acid feeding induces cholangiocyte proliferation and secretion: Evidence for bile acid-regulated ductal secretion

Background & Aims: We have shown that taurocholate (TC) and taurolithocholate (TLC) interact in vitro with normal cholangiocytes, increasing DNA synthesis, secretin receptor (SR) gene expression, and adenosine 3',5'-cyclic monophosphate (cAMP) synthesis. To further extend these in vitro studies, we tested the hypothesis that bile acids (BAs) directly stimulate cholangiocyte proliferation and secretion in vivo. Methods: After feeding with TC or TLC (1% for 1-4 weeks), we assessed the following in vivo: (1) ductal proliferation by both morphometry and immunohistochemistry for proliferating cell nuclear antigen (PCNA) and measurement of [H-3]thymidine incorporation; and (2) the effect of secretin on bile secretion and bicarbonate secretion in vivo. Genetic expression of H-3-histone and SR and intracellular cAMP levels were measured in isolated cholangiocytes. Results: After BA feeding, there was an increased number of PCNA-positive cholangiocytes and an increased number of ducts compared with control rats. [H-3]Thymidine incorporation, absent in control cholangiocytes, was increased in cholangiocytes from BA-fed rats. In BA-fed rats, there was increased SR gene expression (approximately 2.5-fold) and secretin-induced cAMP levels (approximately 3.0-fold) in cholangiocytes, which was associated with de novo secretin-stimulated bile flow and bicarbonate secretion. Conclusions: These data indicate that elevated BA levels stimulate ductal secretion and cholangiocyte proliferation.