Tauroursodeoxycholic acid stimulates hepatocellular exocytosis and mobilizes extracellular Ca++ mechanisms defective in cholestasis.

Abstract

IntroductionTo assess the effects of tauroursodeoxycholic acid (TUDCA) on bile excretory function, we examined whether TUDCA modulates vesicular exocytosis in the isolated perfused liver of normal rats in the presence of high (1.9 mM) or low (0.19 mM)

Tauroursodeoxycholic acid inserts the bile salt export pump into canalicular membranes of cholestatic rat liver

“…As the bile salt and conjugate export pumps, Bsep and Mrp2, are regarded as key contributors to bile formation, these findings further support the hypothesis that UDCA conjugates may improve impaired bile secretion of the cholestatic liver by stimulating insertion of carrier proteins into the canalicular hepatocyte membrane 25,41,42 The exact molecular mechanisms need to be further elucidated.…”

“…Therefore, stimulation of Bsep and Mrp2 insertion into canalicular membranes may contribute to the anticholestatic effect of UDCA amides in cholestasis. The exact molecular mechanism by which TUD-CA stimulates exocytotic fusion of vesicles at the apical membrane 7,25 and apical carrier insertion 7,12,13 remains elusive. Various signaling molecules including isoforms of PKC, 7,9,13 cytosolic-free calcium (Ca 2 þ ) i , 9,25 mitogen-activated protein (MAP) kinases p38 MAPK6,12,13 and p44/42 MAPK , 11,14 src kinase 6 as well as PI3K 8,[26][27][28] have been shown to be involved in bile acid-dependent hepatobiliary exocytosis and carrier insertion/retrieval in apical membranes under various experimental conditions.…”

A biliary HCO3−umbrella constitutes a protective mechanism against bile acid-induced injury in human cholangiocytes

“…7 Advances have been made in understanding the mechanisms and sites of action of ursodeoxycholic acid (UDCA) in the therapy of chronic cholangiopathies. 45,46 Our data might emphasize its putative beneficial action as a hepatocyte 47,48 and cholangiocyte 49,50 HCO À 3 secretagogue, particularly for small intrahepatic bile ductules affected in PBC. Our data may also explain, in part, the superiority of norUDCA above UDCA in the treatment of experimental cholangiopathy in Mdr2 À/À mice, a disease affecting also medium-and large-sized ducts, such as PSC 51 : Exogenous norUDCA has been shown to represent the strongest biliary HCO À earlier described for melanoma cells, 29 thus contributing to the biliary HCO À 3 umbrella to prohibit apolar hydrophobic bile acids from entering the cell.…”

Ursodeoxycholic acid in cholestatic liver disease: Mechanisms of action and therapeutic use revisited

“…Experimental evidence suggests that the taurine conjugate of UDCA (TUDCA), by a complex network of signals, stimulates hepatobiliary vesicular exocytosis and insertion of carrier proteins into the apical membrane of the hepatocyte. [15][16][17][24][25][26] As recently shown in cholestatic rat liver, TUDCA significantly enhances the density of the conjugate export pump, Mrp2, in canalicular membranes and thereby stimulates secretion of potentially toxic compounds. 17 Cytosolic free calcium [Ca 2ϩ ] i seems to be critical for TUDCA-induced exocytosis in the model of the perfused rat liver.…”