Bile acid interactions with cholangiocytes

Abstract

Cholangiocytes are exposed to high concentrations of bile acids at their apical membrane. A selective transporter for bile acids, the Apical Sodium Bile Acid Cotransporter (ASBT) (also referred to as Ibat; gene name Slc10a2) is localized on the cholangiocyte apical membrane. On the basolateral membrane, four transport systems have been identified (t-ASBT, multidrug resistance (MDR)3, an unidentified anion exchanger system and organic solute transporter (Ost) heteromeric transporter, Ostalpha-Ostbeta. Together, these transporters unidirectionally move bile acids from ductal bile to the circulation. Bile acids absorbed by cholangiocytes recycle via the peribiliary plexus back to hepatocytes for re-secretion into bile. This recycling of bile acids between hepatocytes and cholangiocytes is referred to as the cholehepatic shunt pathway. Recent studies suggest that the cholehepatic shunt pathway may contribute in overall hepatobiliary transport of bile acids and to the adaptation to chronic cholestasis due to extrahepatic obstruction. ASBT is acutely regulated by an adenosine 3', 5'-monophosphate (cAMP)-dependent translocation to the apical membrane and by phosphorylation-dependent ubiquitination and proteasome degradation. ASBT is chronically regulated by changes in gene expression in response to biliary bile acid concentration and inflammatory cytokines. Another potential function of cholangiocyte ASBT is to allow cholangiocytes to sample biliary bile acids in order to activate intracellular signaling pathways. Bile acids trigger changes in intracellular calcium, protein kinase C (PKC), phosphoinositide 3-kinase (PI3K), mitogen-activated protein (MAP) kinase and extracellular signal-regulated protein kinase (ERK) intracellular signals. Bile acids significantly alter cholangiocyte secretion, proliferation and survival. Different bile acids have differential effects on cholangiocyte intracellular signals, and in some instances trigger opposing effects on cholangiocyte secretion, proliferation and survival. Based upon these concepts and observations, the cholangiocyte has been proposed to be the principle target cell for bile acids in the liver.

Figure 1

Classic cholehepatic shunt pathway (B) compared to direct biliary bile acid secretion (A). Bile acids that are poor substrates for coenzyme A (CoA) synthetase and inefficiently conjugated by hepatocytes are passively absorbed by biliary epithelium. After canalicular secretion, the unconjugated bile acid is absorbed by cholangiocytes because of the high lipophilicity of the protonated acid. The absorbed bile acid is returned to the hepatocyte mass via the periductular plexus. The osmotic effect of multiple passages of the unconjugated bile acid anions into canalicular bile results in hypercholeresis. The presence of ASBT on the apical membrane of cholangiocytes provides a potential mechanism for absorption of conjugated bile acids that then follows the same shunt pathway as described above.

Figure 2

Membrane recycling of ASBT. Increased cAMP enhances bile acid uptake in cholangiocytes. Under basal conditions, intracellular ASBT resides in an inactive position within the cytoplasm of cholangiocytes as well as on the apical membrane. Increased cAMP results in translocation of ASBT to the apical membrane where it inserts by exocytosis. Once on the apical membrane, ASBT becomes active and mediates absorption of bile acids from bile. Membrane recycling of ASBT is completed by removal of ASBT from the apical membrane by endocytosis.