Cholangiocytes, bile duct lining cells, actively adjust the amount of 
cholesterol and bile acids in bile through expression of enzymes and channels 
involved in transportation and metabolism of the cholesterol and bile acids. 
Herein, we report molecular mechanisms regulating bile acid biosynthesis in 
cholangiocytes. Among the cytochrome p450 (Cyp) enzymes involved in bile acid 
biosynthesis, sterol 27-hydroxylase (Cyp27) that is the rate-limiting enzyme for 
the acidic pathway of bile acid biosynthesis expressed in cholangiocytes. 
Expression of other Cyp enzymes for the basic bile acid biosynthesis was hardly 
detected. The Cyp27 expression was negatively regulated by a hydrophobic bile 
acid through farnesoid X receptor (FXR), a nuclear receptor activated by bile 
acid ligands. Activated FXR exerted the negative effects by inducing an 
expression of fibroblast growth factor 15/19 (FGF15/19). Similar to its 
repressive function against cholesterol 7α-hydroxylase (Cyp7a1) expression in 
hepatocytes, secreted FGF15/19 triggered Cyp27 repression in cholangiocytes 
through interaction with its cognate receptor fibroblast growth factor receptor 
4 (FGFR4). The involvements of FXR and FGFR4 for the bile acid-induced Cyp27 
repression were confirmed in vivo using knockout mouse models. Different from 
the signaling in hepatocytes, wherein the FGF15/19-induced repression signaling 
is mediated by c-Jun N-terminal kinase (JNK), FGF15/19-induced Cyp27 repression 
in cholangiocytes was mediated by p38 kinase. Thus, the results collectively 
suggest that cholangiocytes may be able to actively regulate bile acid 
biosynthesis in cholangiocytes and even hepatocyte by secreting FGF15/19. We 
suggest the presence of cholangiocyte-mediated intrahepatic feedback loop in 
addition to the enterohepatic feedback loop against bile acid biosynthesis in 
the liver.