S1P synthesis and signaling affects ER stress and apoptosis in insulin-producing β-cells
(English)Manuscript (preprint) (Other academic)
Palmitate has been proposed to exert its negative effects on apoptosis via modulation of the sphingolipid pool, specifically by changing the dynamic balance between pro-apoptotic ceramide and anti-apoptotic sphingosine-1-phosphate (S1P). S1P is produced by two sphingosine kinases (SphKs), and can activate both targets inside the cell and receptors (S1PRs) on the plasma membrane. In β-cells, the cytotoxic response to cytokines is believed to be partly mediated via SphK2, and signaling through the S1PRs has been shown to protect the β-cell from this assault. In the present study, we investigated the role of SphKs as well as S1P receptors in the modulation of palmitate-induced apoptosis. MIN6 cells with reduced levels of SphK1 and 2 were established by siRNA mediated knockdown. Reduction of SphK1 attenuated secretion of S1P while reduction of SphK2 had no effect. Knockdown of SphK1, the isoform associated with production of S1P capable of signaling through S1PRs, reduced Akt signaling after palmitate exposure and augmented apoptosis. In contrast, knockdown of SphK2 completely blocked short term (<60 min) palmitate-induced phosphorylation of JNK. Reducing the levels of SphK2 also attenuated phosphorylation of eIF2α and CHOP expression, and blocked apoptosis after 48 hours exposure to palmitate. Interestingly, when S1P1/3 or S1P2 was inhibited, palmitate-induced ER stress was attenuated but apoptosis unaffected. The addition of external S1P attenuated apoptosis in the presence of S1PR inhibition but did not affect ER stress. In conclusion, SphK2 is involved in mediating palmitate-induced ER stress and apoptosis. Furthermore, activation of S1PRs may protect the β-cell from palmitate-induced apoptosis independently of ER stress.
Sphingosine-1-phosphate, sphingosine-1-phosphate receptor, sphingosine kinase, palmitate, ER stress, apoptosis
Cell and Molecular Biology
Research subject Medical Cell Biology
IdentifiersURN: urn:nbn:se:uu:diva-129572OAI: oai:DiVA.org:uu-129572DiVA: diva2:344341