Bile Acid Interactions with Cholangiocytes
Bile acids interact with cholangiocytes numerous ways. A specific bile acid transporter (ASBT) is localized on the apical membrane posed to absorb biliary bile acids. On the basolateral membrane three transport systems have been identified (t-ASBT, MDR3 and an anion exchanger system). Studies in cultured cholangiocytes show one-way transport bile acids from the apical to the basolateral membrane. Indirect evidence for a cholehepatic shunt pathway initiated by bile acid absorption by ASBT from bile that obligates bile acids to return via the peribiliary plexus to hepatocytes for resecretion into bile. 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 remain 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. Biliary bile acid concentration and composition may regulate cholangiocyte functions. After uptake by ASBT, bile acids signal intracellular calcium protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and extracellular signal-regulated protein kinase (ERK) intracellular signals in cholangiocytes with resultant changes in cholangiocyte secretion proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals resulting in opposite effects on cholangiocyte secretion, proliferation and survival.