Purely arterial blood is supplied by the biliary plexus. Focal ischemia can have severe effects on the biliary epithelium and its secretory function. The detrimental effect of ischemia on cholangiocytes and formation of ischemia-induced portal casts28 could be explained by a collapse of the biliary HCO umbrella potentiating bile acid toxicity. Biliary HCO formation is under tight control of local

factors such as bile salts or purinergic agonists as well as of visceral neurohormonal factors including secretin, AZD1208 cholinergic and adrenergic agents, vasoactive intestinal peptide (VIP), glucagon, glucagon-like peptide-1, and somatostatin. We restrict our discussion to local factors Selleck GSI-IX contributing to formation of a stable HCO umbrella. For the role of visceral neurohormonal factors which, like secretin, also may depend on local factors to induce HCO formation,29 we refer to recent reviews on the neurohormonal control of the adaptive cholangiocyte response.30 The bile salt sensing receptor TGR5 (GPBAR-1) is localized on the tip of the cilia of apical mouse and human cholangiocyte membranes31, 32 reaching beyond the hypothetical HCO umbrella, thus sensing real bile composition. An obvious function of luminal bile salt sensing would be to modulate the

cellular defense strategies by varying HCO secretion through direct stimulation of secretory channels or proteins and/or insertion/retrieval of key carriers/channels such as AE2 and cystic fibrosis transmembrane conductance regulator (CFTR).33 Recent in vitro studies strongly support this view: stimulation of TGR5 was shown to increase Cl− secretion of human gallbladder mucosa by way of CFTR in a cAMP-dependent way.34 The reportedly low levels of the apical bile salt transporter expression in cholangiocytes would argue in favour of a sensor function rather than a high throughput transport function of apical bile salt transporter. Rates of HCO formation as the major oxyclozanide human biliary defense mechanism against bile acid

toxicity in the intrahepatic biliary tree would then be under tight control of at least two types of bile acid sensors. Extracellular adenosine triphosphate (ATP) is increasingly recognized as an important signaling molecule in the regulation of bile secretion and composition.35, 36 ATP and its metabolites adenosine diphosphate (ADP), adenosine monophosphate (AMP), and adenosine are present in human bile collected from the common bile duct.37 Cholangiocytes express purinergic receptors from the P2Y family on their membranes and cilia, and these receptors translate the signal of adenosine nucleotides in bile into intracellular cAMP levels as well as changes in cytosolic-free calcium [Ca++]I and activation of different conventional, novel, and atypical protein kinase C (PKC) isoforms.