Compared to the understanding of the effects of bile acids on rodent cholangiocytes, very little is known regarding bile acid signaling of cholangiocyte function in health and disease in humans. Previous studies of biliary bicarbonate secretion in humans, by employing PET scanning, show that biliary bicarbonate secretion is reduced in primary biliary cirrhosis, the prototypic disease of bile duct damage in humans. After treatment with ursodeoxycholate, biliary bicarbonate secretion in primary biliary cirrhosis patients is increased compared to the pretreatment values. It is not clear why ursodeoxycholic acid inhibits cholangiocyte secretion in bile duct ligated rats but increases cholangiocyte secretion in primary biliary cirrhosis in humans. It is likely that the pathophysiology of these two forms of biliary injury is different.
Cystic fibrosis also targets biliary epithelium in the liver. Clinical studies have shown that ursodeoxycholate may improve liver tests in cystic fibrosis patients. It has been proposed that the mechanism for action of ursodeoxycholate in cystic fibrosis is increased ductal bile flow [as demonstrated by the opening of chloride channels by Shimokura et al] that reduces the bile plugs and obstruction due to thick biliary secretions. Ursodeoxycholate has been found to have measurable clinical effects in other diseases that target biliary epithelium (graft versus host disease involving the liver, liver allograft rejection and bile-duct paucity syndromes). Finally, ursodeoxycholate has been used in other chronic cholestatic liver disorders where biliary epithelium is not the primary target (intrahepatic cholestasis of pregnancy, progressive familial intrahepatic cholestasis, non alcoholic steatohepatitis, alcoholic liver disease, autoimmune hepatitis). The potential therapeutic effect of ursodeoxycholate in human liver diseases is reviewed elsewhere.
In summary, bile acids interact with cholangiocytes in numerous ways. A specific bile acid transporter (ASBT) is localized on the apical membrane, posed to absorb biliary bile acids[5,17]. On the basolateral membrane, four transport systems have been identified (t-ASBT, MDR3, an anion exchanger system and the Osta-Ostb heteromeric transporter)[6,28,29]. Studies in cultured cholangiocytes show that cholangiocytes transport bile acids from the apical to the basolateral membrane. Indirect evidence for a cholehepatic shunt pathway initiated by bile acid absorption from bile by ASBT that leads to bile acids return via the peribiliary plexus to hepatocytes for secretion into bile[7,34,36-38,41]. The contribution of the cholehepatic shunt pathway in overall hepatobiliary transport of bile acids and the role of the cholehepatic shunt pathway in the adaptation to chronic cholestasis due to extrahepatic obstruction remains to be determined. ASBT is both acutely regulated by a cAMP-dependent translocation to the apical membrane and chronically regulated by changes in gene expression in response to biliary bile acid concentration and ubiquitination-dependent proteasome disposal. Biliary bile acid concentration and composition may regulate cholangiocyte functions. After uptake by ASBT, bile acids signal calcium, PKC, PI3K, MEK and ERK intracellular signals in cholangiocytes with resultant changes in cholangiocyte secretion, proliferation and survival[59,61,66,96-98]. Different bile acids have differential effects on cholangiocyte intracellular signals, resulting in opposite effects on cholangiocyte secretion, proliferation and survival[12,96,99].
In future studies, the mechanisms explaining how bile acids with different structures can differentially regulate different intracellular signals will be determined. To address the question of how chronic cholestatic liver disease may adapt by changes in cholehepatic shunting, new experimental paradigms to directly quantify bile acid absorption in bile ducts in experimental animals will be developed. Since multiple transporters with varying substrate specificity are present in the sinusoidal and canalicular membrane of hepatocytes, additional bile acid transporters may be found in cholangiocytes. When the mechanisms for bile acid cytoprotective effects in cholangiocytes are defined, a new therapeutic window in human biliary disorders may open that operates through modulation of biliary bile acid concentration and composition. Finally, the role of cholangiocyte bile acid transport in the promotion or adaptation to human liver disease needs to be determined.