Large but not small intrahepatic bile ducts are involved in secretin-regulated ductal bile secretion

We have shown that agonist-regulated ductal secretion is limited to large cholangiocytes. To directly study cholangiocyte heterogeneity along the length of the normal biliary tree, we defined the genetic and functional expression of agonist-induced ductal secretion in intrahepatic bile duct units (IBDU) of different sizes. Small IBDU (<15-mu m diam) were separated from large IBDU (greater than or equal to 15-mu m diam), and then ducts of different sizes were characterized by morphometric analysis, gene expression, secretin-induced adenosine 3',5'-cyclic monophosphate (cAMP) synthesis, and secretion by change in luminal size in response to agonists. IBDU diameters ranged from 11 to 65 mu m Secretin increased ductal secretion solely in large IBDU. Forskolin induced a modest increase in ductal secretion in small IBDU but markedly increased ductal secretion in large IBDU. Secretin increased Cl-/HCO3- exchanger activity and cAMP levels in large but not small IBDU. Secretin receptor and Cl-/HCO3- exchanger mRNAs were detected only in large IBDU. We propose that agonist-induced ductal secretion occurs in large (greater than or equal to 15-mu m diam) but not small (<15-mu m diam) intrahepatic ducts.