Sphingosine kinase-1 inhibition protects primary rat hepatocytes against bile salt-induced apoptosis

Schematic drawing summarizing the proposed mechanisms for glycochenodeoxycholic acid (GCDCA)-induced apoptosis in rat hepatocyte involving sphingosine kinase-1 (SphK1), sphingosine-1 phosphate (S1P) and sphingosine-1 phosphate receptors (S1PR1 and S1PR2). GCDCA induces the activation of SphK1 and increases the generation of endogenous S1P. Activation of SphK1 mediates GCDCA-induced [Ca2 +] oscillations in hepatocytes via generation of endogenous S1P and thereby induces apoptosis in hepatocytes. Exogenous S1P protects hepatocytes against GCDCA-induced apoptosis via S1PR2-dependent signaling. S1PR1-dependent signaling plays a minor role in GCDCA-induced apoptosis in rat hepatocytes. ASMase: acidic sphingomyelinase, Cdase: ceramidase, Ntcp: sodium-taurocholate cotransporting polypeptide, Ski II: SphK1 inhibitor, N: nucleus.85