title: Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation.
abstract: Sphingosine-1-phosphate (S1P) is a sphingolipid metabolite that regulates basic cell functions through metabolic and signaling pathways. Intracellular metabolism of S1P is controlled, in part, by two homologous S1P phosphatases (SPPases), 1 and 2, which are encoded by the Sgpp1 and Sgpp2 genes, respectively. SPPase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. SPPase 1 is important for skin homeostasis, but little is known about the functional role of SPPase 2. To identify the functions of SPPase 2 in vivo, we studied mice with the Sgpp2 gene deleted. In contrast to Sgpp1(-/-) mice, Sgpp2(-/-) mice had normal skin and were viable into adulthood. Unexpectedly, WT mice expressed Sgpp2 mRNA at high levels in pancreatic islets when compared with other tissues. Sgpp2(-/-) mice had normal pancreatic islet size; however, they exhibited defective adaptive β-cell proliferation that was demonstrated after treatment with either a high-fat diet or the β-cell-specific toxin, streptozotocin. Importantly, β-cells from untreated Sgpp2(-/-) mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with β-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes β-cell endoplasmic reticulum stress, which is a known cause of β-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes.
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Taguchi
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Allende
authors.affiliation: the Department of Pathology and Molecular Medicine, Hirosaki University Graduate School of Medicine, Hirosaki, Aomori 036-8562, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizukami
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Emily K
authors.initials: EK
authors.lastname: Cook
authors.affiliation: Mouse Metabolism Core Laboratory, and.
authors.forename: Oksana
authors.initials: O
authors.lastname: Gavrilova
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Galina
authors.initials: G
authors.lastname: Tuymetova
authors.affiliation: From the Genetics of Development and Disease Branch.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Clarke
authors.affiliation: Genomics Core, NIDDK, and.
authors.forename: Weiping
authors.initials: W
authors.lastname: Chen
authors.affiliation: the Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892 and.
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
authors.affiliation: From the Genetics of Development and Disease Branch, proia@nih.gov.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000235:genetics*; D059305:Diet, High-Fat; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015971:Gene Expression Regulation, Enzymologic; D057809:HEK293 Cells; D006360:Heat-Shock Proteins; D006801:Humans; D007150:Immunohistochemistry; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D007515:Islets of Langerhans / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013107:Sphingolipids / Q000378:metabolism; D013311:Streptozocin / Q000494:pharmacology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D013107:Sphingolipids; D013311:Streptozocin; C401298:sphingosine-1-phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; C000612430:Sgpp2 protein, mouse
keywords: beta cell; diabetes; endoplasmic reticulum stress (ER stress); lysophospholipid; pancreatic islet; sphingosine-1-phosphate (S1P)