chapter  Chapter 14
10 Pages

Regulation of Secretion in Human Gallbladder Epithelial Cells

WithNicolas Chignard, Laura Fouassier, Annick Paul, Chantal Housset

The gallbladder stores and concentrates bile between meals. Fluid secretion prevents the stagnation of bile salts after feeding, while mucins secreted in the gallbladder ensure cytoprotection. Mucin secretion in human gallbladder is stimulated predominantly by Ca2+-dependent pathways that are activated by extracellular ATP and bile salts. Fluid transport across the gallbladder epithelium is reversed from absorption to secretion in response to gastrointestinal peptides such as secretin and VIP released after feeding. These gastrointestinal peptides stimulate adenylyl cyclase activities via G protein coupled receptors. The subsequent increase in cAMP in the epithelial cells causes concomitant inhibition of the Na+/H+ exchanger NHE3 activity and activation of the chloride channel CFTR. NHE3 inhibition results in the arrest of fluid absorption, while chloride extrusion through CFTR acts as a driving force for fluid secretion and bicarbonate output via the Cl/HCO3 exchanger AE2. Adenylyl cyclase activities in human gallbladder epithelial cells may be reduced by autocrine factors, such as endothelin-1, or amplified by luminal factors such as bile salts. The apical Na+-dependent bile acid transporter (ASBT) is expressed in human gallbladder epithelial cells and mediates stimulating effects of taurochenodeoxycholate (TCDC) and of tauroursodeoxycholate (TUDC) on chloride and mucin secretion in these cells. As compared with TCDC, TUDC induces significantly lower mucin secretion. By contrast, inductions of chloride secretion by TUDC and by TCDC are not significantly different, and both bile acids show similar potency in amplifying cAMP-dependent chloride secretion via PKC activation. Impairment of gallbladder epithelial functions may lead to the formation of gallstones and to reactive changes in the gallbladder mucosa as illustrated in cystic fibrosis. Ursodeoxycholic acid may provide benefit in modifying secretion in a direction that will increase fluidity.