Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet β-Cell Endoplasmic Reticulum Stress and Proliferation

J Biol Chem. 2016 Jun 3;291(23):12029-38. doi: 10.1074/jbc.M116.728170. Epub 2016 Apr 8.

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.

Keywords: beta cell; diabetes; endoplasmic reticulum stress (ER stress); lysophospholipid; pancreatic islet; sphingosine-1-phosphate (S1P).

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Cell Proliferation / genetics*
  • Diet, High-Fat
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress / genetics*
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Enzymologic
  • HEK293 Cells
  • Heat-Shock Proteins
  • Humans
  • Immunohistochemistry
  • Insulin-Secreting Cells / metabolism*
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sphingolipids / metabolism
  • Streptozocin / pharmacology

Substances

  • Endoplasmic Reticulum Chaperone BiP
  • Heat-Shock Proteins
  • Isoenzymes
  • Membrane Proteins
  • Sphingolipids
  • Streptozocin
  • sphingosine-1-phosphate phosphatase
  • Phosphoric Monoester Hydrolases
  • Sgpp2 protein, mouse