Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet ?-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 ?-cell proliferation that was demonstrated after treatment with either a high-fat diet or the ?-cell-specific toxin, streptozotocin. Importantly, ?-cells from untreated Sgpp2(-/-) mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with ?-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes ?-cell endoplasmic reticulum stress, which is a known cause of ?-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes.

SUBMITTER: Taguchi Y 

PROVIDER: S-EPMC4933255 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature