posted on 2022-03-14, 22:46authored byAnne-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 Poitout
Fatty-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.
This study was supported by the National Institutes of Health (R01-DK58096 to V.P., DK115824, DK116888, and DK116450 to SAS; DK108833 and DK112826 to WLH) the Canadian Institutes of Health Research (grant MOP 77686 to V.P.), the Juvenile Diabetes Research Foundation (JDRF 3-SRA-2019-768-A-B to SAS), the American Diabetes Association (to SAS), the American Heart Association (to SAS), and the Margolis Foundation (to SAS). It benefited from the support of the Canadian Foundation for Innovation and the Montreal Heart Institute (MHI) Foundation for the MHI Metabolomic Platform (CFI grant 20415 and 36283 to C.D.R. co-PI). A.L.C was supported by the Association pour la Recherche sur le Diabète, the Société Française d’Endocrinologie et Diabétologie Pédiatriques and the Société Francophone du Diabète. V. S. M. was supported by a Postdoctoral Fellowship from the CRCHUM. M.R is a FRQS Junior 1 Scholar.