REGULATION OF TAUROCHOLATE EXCRETION BY A HYPO-OSMOLARITY-ACTIVATED SIGNAL-TRANSDUCTION PATHWAY IN RAT-LIVER

Background & Aims: Hypo-osmotic cell swelling increases the capacity o f taurocholate excretion into bile in the perfused rat liver. The aim of this study was to clarify the mechanisms linking cell swelling to b ile acid secretion. Methods, The influence of hypo-osmotic cell swelli ng on intracellular signal transduction and bile acid secretion was st udied in isolated rat hepatocytes and the perfused rat liver. Results: In rat livers perfused with hypo-osmotic buffer (225 mOsm/L), the max imum velocity of taurocholate excretion into bile is increased by 135% within 10-20 minutes. To unravel signaling events mediating this effe ct, the activities of the mitogen-activated protein kinases, extracell ular signal-regulated kinase (Erk)-1 and Erk-2, were measured after hy po-osmotic treatment in cultured rat hepatocytes. A rapid parallel act ivation of Erk-1 and Erk-2 was observed within 1 minute, which became maximal after 10 minutes and returned to the basal level within 60 min utes. The hypo-osmolarity-induced Erk activation and the increase in b ile flow after hypo-osmotic liver perfusion were completely abolished by inhibitors of signal transduction at the level of G proteins and ty rosine kinases but remained unaffected by the inhibition of the protei n kinase C. Conclusions: A G protein-and tyrosine kinase-dependent but protein kinase C-independent activation of mitogen-activated protein kinases is involved in the regulation of taurocholate excretion by liv er cell hydration changes.