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

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, 1 and 2, which are encoded by Sgpp1 and Sgpp2, respectively. S1P phosphatase activity is needed for efficient recycling of sphingosine into the sphingolipid synthesis pathway. S1P phosphatase 1 is important for skin homeostasis, but little is known about the functional role of S1P phosphatase 2. To identify the functions of S1P phosphatase 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 blood insulin levels and pancreatic islet size; however, Sgpp2-/- mice treated with a high-fat diet (HFD) had significantly lower blood insulin levels and smaller pancreatic islets compared with WT mice. The smaller islets in the HFD-treated Sgpp2-/- mice had a significantly lower adaptive -cell proliferation rate in response to the diet compared with HFD-treated WT mice. Importantly, -cells from Sgpp2-/- mice fed a normal diet showed significantly increased expression of proteins characteristic of the endoplasmic reticulum (ER) stress response compared with -cells from WT mice. Our results suggest that Sgpp2 deletion causes -cell ER stress, which is a known cause of -cell dysfunction, and reveal a novel juncture in the sphingolipid recycling pathway that could impact the development of diabetes.

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Taguchi Y, Allende ML, Mizukami H, Cook EK, Gavrilova O, Tuymetova G, Clarke BA, Chen W, Olivera A, Proia RL