Very Long-Chain Unsaturated Sphingolipids Mediate Oleate-Induced Rat β-Cell Proliferation

ABSTRACT Fatty-acid (FA) signaling contributes to β-cell mass expansion in the face of nutrient excess, but the underlying mechanisms are poorly understood. Here we tested the hypothesis that sphingolipids, generated by the intracellular metabolism of FA, are implicated in the β-cell proliferative response to FA. Isolated rat islets were exposed to individual FA in the presence of 16.7 mM glucose for 48 h and the contribution of the de novo sphingolipid synthesis pathway was tested using the serine palmitoyltransferase inhibitor myriocin, the sphingosine kinase (SphK) inhibitor SKI II, or adenovirus-mediated knockdown of SphK, fatty-acid-elongase-1 (ELOVL1) and acyl-CoA-binding protein (ACBP). Wistar rat were infused with glucose and the lipid emulsion ClinOleic and received SKI II by gavage. B-cell proliferation was assessed by immunochemistry or flow cytometry. Sphingolipidomic analyses were performed by LC-MS/MS. Amongst the various FA tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all decreased oleate-induced β-cell proliferation. Oleate exposure did not increase the total amount of sphingolipids but led to a specific rise in 24:1 species. Knockdown of ACBP or ELOVL1 inhibited oleate-induced β-cell proliferation. We conclude that unsaturated very long-chain sphingolipids produced from the available pool of C24:1 acyl-CoA mediate oleate-induced β-cell proliferation in rats.