Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 291, Issue 23, Pages 12029-12038Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M116.728170
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Funding
- Intramural Research Program of NIDDK, National Institutes of Health
- Intramural Research Program of NIAID, National Institutes of Health
- Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina [P30 CA138313]
- Lipidomics Core in the SC Lipidomics and Pathobiology COBRE [P20 RR017677]
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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 beta-cell proliferation that was demonstrated after treatment with either a high-fat diet or the beta-cell-specific toxin, streptozotocin. Importantly, beta-cells from untreated Sgpp2(-/)-mice showed significantly increased expression of proteins characteristic of the endoplasmic reticulum stress response compared with beta-cells from WT mice, indicating a basal islet defect. Our results show that Sgpp2 deletion causes beta-cell endoplasmic reticulum stress, which is a known cause of beta-cell dysfunction, and reveal a juncture in the sphingolipid recycling pathway that could impact the development of diabetes.
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