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

Ursodeoxycholic acid exerts anticholestatic effects in chronic cholestatic liver disease in humans as well as in experimental animal models of cholestasis. Its taurine conjugate, TUDCA, was recently shown to stimulate insertion of the apical conjugate export pump, Mrp2 (ABCC2), into canalicular membranes of rat hepatocytes made cholestatic by exposure to taurolithocholic acid (TLCA). The aim of this immunoelectronmicroscopic study was to test whether TLCA and TUDCA modulate the canalicular density of the other key apical transporter, the bile salt export pump, Bsep (ABCB11), in a similar way. Immunoelectronmicroscopic analysis of Bsep density on canalicular membranes, microvilli, and pericanalicular area of hepatocytes was performed in rat liver tissue prepared after liver perfusion with bile acids or carrier medium only. TLCA ( 10 mu mol/l for 50 min) decreased Bsep density in canalicular membranes to 31% of controls (P < 0.05) when bile flow was reduced to 35% of controls (P < 0.05). Concomitantly, Bsep density in a 1 mu m pericanalicular zone increased to 202% ( P < 0.05) indicating effective retrieval of Bsep from the canalicular membrane induced by TLCA. Coadministration of TUDCA (25 mu mol/l) led to a 3.2-fold increase of Bsep density in canalicular membranes equal to control liver (P < 0.05 vs TLCA) in association with a 3.8- fold increase of bile flow (P < 0.05 vs TLCA). Stimulation of apical membrane insertion of key transporters like the bile salt export pump, Bsep, and-as previously shown the conjugate export pump, Mrp2, may contribute to the anticholestatic action of UDCA amides in cholestatic conditions.