Caveolae are membrane structures enriched in glycosphingolipids and cholesterol, and caveolin-1 (Cav-1) has been recognized to be pivotal in ischemic tolerance. Sphingosine-1-phosphate (S1P), one of the sphingolipid metabolites, is well known for its anti-apoptotic properties, counteracting ischemia and reperfusion (IR) injury. Here, we investigated the cytoprotective mechanism of Cav-1 against IR injury. Male C57BL/6 mice underwent 70% hepatic ischemia for 60 min, followed by reperfusion. Mice were pre-treated with methyl-beta-cyclodextrin (M beta CD, 10, 25 and 50 mg/kg, i.p.), a caveolae disruptor, or saline 48 and 24 h before ischemia. Serum and liver tissues were collected at the end of ischemia, at 0, 1, 4 and 24 h of reperfusion. Decreases in the expression of Cav-1 protein and in the number of caveolae of the liver ultrastructure were observed during IR, which were augmented by pretreatment with M beta CD. M beta CD also augmented the IR-induced increases in serum alanine aminotransferase and tumor necrosis factor-alpha levels. IR decreased the levels of sphingosine kinase 2 (SK2) and S1P receptor 2 (S1P(2)) mRNA expressions, while M beta CD also augmented these decreases. Moreover, IR resulted in increases of mitochondrial cytochrome c release, caspase 3, 8 activities and Bax/Bcl-xL ratio, and M beta CD augmented all of these apoptotic parameters. M beta CD also increased p38 MAPK and JNK phosphorylation, but did not affect ERK and PI3K/Akt. Our findings demonstrate that downregulation of Cav-1 mediates IR-induced liver damage by inhibiting SK2/S1P(2) signaling and enhancing the apoptotic pathway. (C) 2014 Elsevier Inc. All rights reserved.