F Schliess1, A K Kurz, S vom Dahl, D Häussinger. 1. Heinrich-Heine Universität, Klinik für Gastroenterologie, Hepatologie, und Infektiologie, Düsseldorf, Germany. freimut.schliess@uni-duesseldorf.de
Abstract
BACKGROUND & 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 mumol/L) led within 10 minutes to an activation of the mitogen-activated protein (MAP)-kinases extracellular signal-regulated kinase (Erk)-1 and Erk-2. Erk activation by TUDCA was insensitive to inhibition of protein kinase C, tyrosine kinases, and G-protein function. TUDCA-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 mumol/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.
BACKGROUND & 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 mumol/L) led within 10 minutes to an activation of the mitogen-activated protein (MAP)-kinases extracellular signal-regulated kinase (Erk)-1 and Erk-2. Erk activation by TUDCA was insensitive to inhibition of protein kinase C, tyrosine kinases, and G-protein function. TUDCA-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 mumol/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.
Authors: Jessica K Dyson; Gideon M Hirschfield; David H Adams; Ulrich Beuers; Derek A Mann; Keith D Lindor; David E J Jones Journal: Nat Rev Gastroenterol Hepatol Date: 2015-02-03 Impact factor: 46.802
Authors: L Qiao; E Studer; K Leach; R McKinstry; S Gupta; R Decker; R Kukreja; K Valerie; P Nagarkatti; W El Deiry; J Molkentin; R Schmidt-Ullrich; P B Fisher; S Grant; P B Hylemon; P Dent Journal: Mol Biol Cell Date: 2001-09 Impact factor: 4.138