Resolvins (Rvs) are endogenous lipid mediators that promote resolution of inflammation and return to homeostasis. We previously reported that RvD1 both facilitates M2 macrophage polarization of Kupffer cells (KCs) and efferocytosis and modulates thioredoxin 2-mediated mitochondrial quality control in liver ischemia/reperfusion (IR) injury. However, the specific cellular or molecular targets of RvD1 remain poorly understood. Sphingosine-1-phosphate (SIP), the natural sphingolipid ligand for a family of G protein-coupled receptors (S1P(1) S1P(5)), regulates lymphocyte circulation and various immune responses.Here we investigated the role of RvD1 in IR-induced hepatocellular damage with a focus on SIP signaling. Male C57BL/6 mice were subjected to partial hepatic ischemia for 60 min, followed by reperfusion. Mice were pretreated with RvD1 (15 mu g/kg, i.p.) 1 h prior to ischemia and immediately before reperfusion. To deplete KCs, liposome clodronate was administered (100 mu L/mice, i.v.) 24 h prior to ischemia. Mice were pretreated with VPC23019 (100 mu g/kg, i.p.), an antagonist for S1P(1)/S1P(3) 10 min prior to initial RvD1 treatment. Exogenous RvD1 attenuated IR-induced hepatocellular damage as evidenced by serum HMGB1 release. RvD1 attenuated the decrease in hepatic SIP concentration induced by IR. KC depletion by liposome clodronate did not alter the effect of RvD1 on sphingosine kinases (SKs) and SIP receptors, suggesting independency of KCs. Moreover, in purified hepatocytes of mice exposed to IR, mRNA expression of SKI, SK2, S1131, and SIP3 decreased significantly, and this was attenuated by RvEll. Finally, VPC23019 pretreatment abolished the hepatoprotective effects of RvD1 in serum HMGB1 release. Our findings suggest that RvD1 protects the liver against IR injury by activating SIP signaling. (C) 2019 Published by Elsevier Inc.