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Very Long-Chain Unsaturated Sphingolipids Mediate Oleate-Induced Rat β-Cell Proliferation
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posted on 2022-03-14, 22:46 authored by Anne-Laure Castell, Alexis Vivoli, Trevor S. Tippetts, Isabelle Robillard Frayne, Zuraya Elisa Angeles, Valentine S. Moullé, Scott A. Campbell, Matthieu Ruiz, Julien Ghislain, Christine Des Rosiers, William L. Holland, Scott A. Summers, Vincent PoitoutFatty-acid (FA) signaling contributes to β-cell mass expansion in response to nutrient
excess, but the underlying mechanisms are poorly understood. In the presence of elevated
glucose, FA metabolism is shifted towards synthesis of complex lipids,
including sphingolipids. Here
we tested the hypothesis that sphingolipids are involved in the β-cell proliferative
response to FA. Isolated rat islets were exposed to FA and 16.7 mM glucose for
48-72 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 knockdown of SphK, fatty-acid-elongase-1 (ELOVL1)
and acyl-CoA-binding protein (ACBP). Rats 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. Sphingolipids were analyzed by LC-MS/MS.
Amongst the FA tested, only oleate increased β-cell proliferation. Myriocin, SKI II, and SphK knockdown all
decreased oleate-induced b-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 C24:1 acyl-CoA pool mediate oleate-induced β-cell
proliferation in rats.