Cholangiocyte anion exchange and biliary bicarbonate excretion

Abstract

Primary canalicular bile undergoes a process of fluidization and alkalinization along the biliary tract that is influenced by several factors including hormones, innervation/neuropeptides, and biliary constituents. The excretion of bicarbonate at both the canaliculi and the bile ducts is an important contributor to the generation of the so-called bile-salt independent flow. Bicarbonate is secreted from hepatocytes and cholangiocytes through parallel mechanisms which involve chloride efflux through activation of Cl- channels, and further bicarbonate secretion via AE2/SLC4A2-mediated Cl-/HCO3- exchange. Glucagon and secretin are two relevant hormones which seem to act very similarly in their target cells (hepatocytes for the former and cholangiocytes for the latter). These hormones interact with their specific G protein-coupled receptors, causing increases in intracellular levels of cAMP and activation of cAMP-dependent Cl- and HCO3- secretory mechanisms. Both hepatocytes and cholangiocytes appear to have cAMP-responsive intracellular vesicles in which AE2/SLC4A2 colocalizes with cell specific Cl- channels (CFTR in cholangiocytes and not yet determined in hepatocytes) and aquaporins (AQP8 in hepatocytes and AQP1 in cholangiocytes). cAMP-induced coordinated trafficking of these vesicles to either canalicular or cholangiocyte lumenal membranes and further exocytosis results in increased osmotic forces and passive movement of water with net bicarbonate-rich hydrocholeresis.

Figure 1

The major ion carriers implicated in pH_i regulation and secretion of bicarbonate to bile from liver cells. A: Hepatocytes; B: Cholangiocytes.

Figure 2

Hormonal stimulation of bicarbonate excretion from hepatocytes and cholangiocytes. A: In hepatocytes, glucagon may induce an exocytic trafficking of vesicles with the anion exchanger AE2/SLC4A2 and the water channel AQP8, which can results in canalicular bicarbonate-rich hydrocholeresis. MRP2/ABCC2, while being a carrier for organic anions like glutathione rather than an inorganic ion transporter, is hereby depicted because of its possible colocalization with the other two flux proteins; B: In cholangiocytes, secretin induces trafficking of vesicles with the chloride channel CFTR, the anion exchanger AE2/SLC4A2, and the water channel AQP1, and further exocytosis to the lumenal membrane of these cells, which results in ductal bicarbonate-rich hydrocholeresis.