Regulation of taurocholate excretion by a hypo-osmolarity-activated signal transduction pathway in rat liver

Background & Aims: Hypo-osmotic cell swelling increases the capacity of taurocholate excretion into bile in the perfused rat liver. The aim of this study was to clarify the mechanisms linking cell swelling to bile acid secretion. Methods, The influence of hypo-osmotic cell swelling on intracellular signal transduction and bile acid secretion was studied in isolated rat hepatocytes and the perfused rat liver. Results: In rat livers perfused with hypo-osmotic buffer (225 mOsm/L), the maximum velocity of taurocholate excretion into bile is increased by 135% within 10-20 minutes. To unravel signaling events mediating this effect, the activities of the mitogen-activated protein kinases, extracellular signal-regulated kinase (Erk)-1 and Erk-2, were measured after hypo-osmotic treatment in cultured rat hepatocytes. A rapid parallel activation 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 minutes. The hypo-osmolarity-induced Erk activation and the increase in bile flow after hypo-osmotic liver perfusion were completely abolished by inhibitors of signal transduction at the level of G proteins and tyrosine kinases but remained unaffected by the inhibition of the protein 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 liver cell hydration changes.