These gene mutations are associated with the clinical entities of ABCB4 deficiency and cystic fibrosis–associated liver disease, respectively.1 Most recently, anion

exchanger 2 (AE2), a variant of the Cl−/HCO exchanger, has been shown to influence prognosis in patients with PBC under treatment with ursodeoxycholic acid (UDCA).4 This finding supports the view that impaired AE2 activity and thereby reduced biliary HCO secretion may play a key role in the pathogenesis of PBC.5-9 A variant of GPBAR1, selleck chemicals the gene coding for the G-protein–coupled bile acid receptor 1, also called TGR5, appeared as a likely disease gene in the first genome-wide association analysis of primary sclerosing cholangitis.10 TGR5 is expressed on apical cholangiocyte membranes and is putatively involved in cAMP-dependent modulation of cholangiocellular HCO secretion. Thus, functional modifications in proteins involved AUY-922 research buy in apical transport of pH modifying bile contents may contribute to development and progression of chronic forms of sclerosing/fibrosing cholangitis such as PBC, PSC, cystic fibrosis–associated liver disease, and ABCB4 deficiency. AE2, anion exchanger 2; ADP, adenosine diphosphate;

AMP, adenosine monophosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; CFTR, cystic fibrosis transmembrane conductance regulator; norUDCA, norursodeoxycholic acid; PBC, primary biliary cirrhosis; PKC, protein kinase C; PSC, primary sclerosing cholangitis; UDCA, ursodeoxycholic acid. The cholangiocyte is exposed to millimolar concentrations of hydrophobic bile salts,11, 12 which are toxic to other cells such as hepatocytes at moderate micromolar selleck kinase inhibitor levels.13 Resistance against these noxious compounds and their cytolytic potential is therefore essential. Which

strategies help cholangiocytes survive in the unfriendly environment of bile? One protective mechanism is the formation of mixed micelles of phospholipids and bile salts in bile.11 High millimolar amounts of bile salts are buffered by micelle formation with phospholipids. However, although this mechanism protects cells from bile salts in micelles, it has no effect on the toxicity of bile salt monomers that are always present at submicellar concentrations. Formation of mixed micelles is critically dependent on adequate biliary phospholipid secretion. Its impairment by mutations of ABCB4/MDR3 leads to progressive familial intrahepatic cholestasis (PFIC type 3) in children and in milder forms to sclerosing cholangitis, ductopenia, and occasionally biliary cirrhosis in adults.3 Thus, micelle formation in bile appears to be crucial for bile ductular integrity. A second protective mechanism known as dilution of bile or flushing of bile is more speculative. This mechanism involves secretion of an alkaline, HCO-rich, mainly cholangiocyte-derived fluid11, 14 that reduces the concentration of toxic compounds in bile.