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

Abstract

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-microns diam) were separated from large IBDU (> or = 15-microns 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 microns. 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. Secretion 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 (> or = 15-microns diam) but not small (< 15-microns diam) intrahepatic ducts.

Acute Carbon Tetrachloride Feeding Selectively Damages Large, But Not Small, Cholangiocytes From Normal Rat Liver

“…The comparability of the RNA used was determined by hybridization with GAPDH, the housekeeping gene. 5,[7][8][9]14 …”

“…Cholangiocytes play a key role in the modification of bile of canalicular origin by a series of spontaneous and hormoneregulated processes. 2,[5][6][7][8][9][10][11] For example, secretin enhances ductal secretory activity by interaction with specific receptors on cholangiocytes, 12 resulting in an increase in intracellular adenosine 3Ј,5Ј-monophosphate (cAMP) levels. [5][6][7]9,13,14 Increased cAMP levels induce the opening of Cl Ϫ channels and activation of the Cl Ϫ /HCO 3 Ϫ exchanger activity, which results in the secretin-induced bicarbonate-rich choleresis in vivo.…”

“…8,9,14,16,17 These functions are expressed in large cholangiocytes and large IBDU (Ͼ15 µm in diameter) and absent in small cholangiocytes and small IBDU (Ͻ15 µm), leading to the conclusion that the hormone-responsive segments of the intrahepatic biliary tree involved in electrolyte and water transport are bile ducts larger than 15 µm in diameter. 8 The precise role of the small cholangiocytes lining small intrahepatic bile ducts is undefined.…”

Physiology of Cholangiocytes

“…As with bile ducts, cholangiocytes themselves differ in size-from 6 to 15 m in diameteras well as in morphology, being flattened or cuboidal in small bile ducts, columnar in large bile ducts (7,11,35,126,136,232,235). Cholangiocyte size generally follows ductal size, that is, large cholangiocytes are found in large ducts (24).…”

“…In rodents, the intrahepatic biliary tree is categorized only into small bile ducts (lumen diameter < 15 m) and large bile ducts (lumen diameter > 15 m) (7,11,35,108,167). As in humans, the lumen of small bile ducts is formed by 4 to 5 cholangiocytes circumferentially, but large bile ducts are encircled by only 8 to 15 cholangiocytes (11,35,108,136).…”