Mitogen-activated protein kinases mediate the stimulation of bile acid secretion by tauroursodeoxycholate in rat liver

Abstract

Background and Aims: Tauroursodeoxycholate (TUDCA) is widely used in the treatment of cholestatic liver disease. The purpose of this study was to elucidate molecular mechanisms underlying its beneficial effect. Methods. TUDCA-induced signaling towards bile acid excretion was studied in 24-hour- cultured rat hepatocytes and perfused rat liver. Results: In rat hepatocytes. TUDCA (>100 μmol/L) led within 10 minutes to an activation of the mitogen- activated protein (MAP)kinases extracellular signal-regulated kinase (Erk)-1 and ERR-2. Erk activation by TUDCA was insensitive to inhibition of protein kinase C, tyrosine kinases, and G-protein function. TUPCA-induced Erk activation, however, was abolished in the presence of PD098059, a MAP kinase kinase (MAP-kinase/Erk-kinase [MEK]) inhibitor and after elevation of intracellular adenosine 3'.5'-cyclic monophosphate. Thus, TUDCA signaling towards MAP kinases is different from hypo-osmotic MAP-kinase activation, which is sensitive to inhibitors of tyrosine kinases and G-protein function. Addition of dibutyryl adenosine 3',5'-cyclic monophosphate or PD098059 also abolished the stimulatory effect of TUDCA (20 μmol/L) on taurocholate excretion in perfused rat liver, whereas tyrosine kinase inhibition was ineffective. Conclusions: TUDCA signaling towards bile acid secretion is mediated by an Raf/MEK-dependent activation of MAP kinases. Although both TUDCA and hypo-osmotic hepatocyte swelling lead to MAP-kinase activation and a stimulation of bile acid secretion, different upstream signaling events are involved.