Cell swelling-induced translocation of rat liver Na+/taurocholate cotransport polypeptide is mediated via the phosphoinositide 3-kinase signaling pathway

Cell swelling stimulates phosphoinositide 3-kinase (PI3K) and mitogen-activ ated protein kinase (MAPK) in hepatocytes, and the PI3K signaling pathway i s involved in cAMP-mediated translocation of sinusoidal Na+/taurocholate (T C) cotransporter (Ntcp) to the plasma membrane. We determined whether cell swelling also stimulates TC uptake and Ntcp translocation via the PI3K and/ or MAPK signaling pathway. All studies were conducted in isolated rat hepat ocytes, Hepatocyte swelling induced by hypotonic media resulted in: 1) time - and medium osmolarity-dependent increases in TC uptake, 2) an increase in the V-max of Na+/TC cotransport, and 3) wortmannin-sensitive increases in TC uptake and plasma membrane Ntcp mass. Hepatocyte swelling also induced w ortmannin-sensitive activation of PI3K, protein kinase B, and p70(S6K). Rap amycin, an inhibitor of p70(S6K), inhibited cell swelling-induced activatio n of p70(S6K) but failed to inhibit cell swelling-induced stimulation of TC uptake. Because PD98095, an inhibitor of MAPK, did not inhibit cell swelli ng-induced increases in TC uptake, it is unlikely that the effect of cell s welling on TC uptake is mediated via the MAPK signaling pathway. Taken toge ther, these results indicate that 1) cell swelling stimulates TC uptake by translocating Ntcp to the plasma membrane, 2) this effect is mediated via t he PI3K, but not MAPK, signaling pathway, and 3) protein kinase B, but not p70(S6K), is a likely downstream effector of PI3K.