Tauroursodesoxycholate-induced choleresis involves p38MAPK activation and translocation of the bile salt export pump in rats

Background & Aims: Canalicular secretion of bile acids is stimulated by tauroursodesoxycholate (TUDC). This study investigates the underlying mechanisms. Methods. TUDC effects on mitogen-activated protein (MAP) kinases, taurocholate (TC) excretion, proteolysis, and the localization of the bile salt export pump (Bsep) were studied in rat hepatocytes and perfused liver. Results: TUDC induced a transient and concentration-dependent activation of p38(MAPK) and of extracellular signal-regulated kinase 2 (Erk-2), but not of c-Jun-N-terminal kinase (JNK). In perfused liver, TUDC concentrations of 20 mu mol/L was sufficient to elicit the MAP kinase responses and TC choleresis. SIB 202190, a specific inhibitor of p38(MAPK), had no effect on TUDC-induced Erk activation but abolished the stimulatory effect of TUDC on TC excretion in perfused liver, indicating the requirement of p38(MAPK) in addition to the reported Erk dependence for the choleretic response. TUDC-induced stimulation of TC excretion was accompanied by a p38(MAPK)-dependent insertion of subcanalicular immunoreactive Bsep into the canalicular membrane. In addition TUDC induced a P38(MAPK)-sensitive inhibition of proteolysis. Conclusions: TUDC-induced stimulation of canalicular TC excretion involves a MAP kinase-dependent translocation of subcanalicular Bsep to the canalicular membrane. Dual activation of Erks and p38(MAPK) is required for the choleretic effect of both TUDC and hypo-osmotic cell swelling.