Sphingosine-1-phosphate Phosphatase 2 Regulates Pancreatic Islet beta-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 β-cell proliferation rate in response to the diet compared with HFD-treated WT mice. Importantly, β-cells from Sgpp2-/- mice fed a normal diet showed significantly increased expression of proteins characteristic of the endoplasmic reticulum (ER) stress response compared with beta-cells from WT mice. Our results suggest that Sgpp2 deletion causes beta-cell ER stress, which is a known cause of beta-cell dysfunction, and reveal a novel juncture in the sphingolipid recycling pathway that could impact the development of diabetes. Three replications of Mouse (WT vs KO) that were treated with with Normal and HFD foods.鞘氨醇-1-磷酸（Sphingosine-1-phosphate，S1P）是一种鞘脂代谢物，可通过代谢与信号通路调控细胞的基本生命活动。S1P的胞内代谢部分由两种同源的S1P磷酸酶（1型与2型）调控，二者分别由Sgpp1与Sgpp2基因编码。S1P磷酸酶活性对于鞘氨醇高效循环进入鞘脂合成通路不可或缺。1型S1P磷酸酶对皮肤稳态具有关键作用，但目前学界对2型S1P磷酸酶的功能机制尚所知甚少。为阐明2型S1P磷酸酶的体内功能，本研究对Sgpp2基因敲除小鼠展开了实验分析。与Sgpp1敲除（Sgpp1-/-）小鼠不同，Sgpp2敲除（Sgpp2-/-）小鼠皮肤表型正常，且可存活至成年阶段。出乎意料的是，与其他组织相比，野生型（Wild Type, WT）小鼠的胰岛中Sgpp2 mRNA的表达水平显著升高。Sgpp2-/-小鼠的血液胰岛素水平与胰岛体积均处于正常范围；然而，经高脂饮食（High-Fat Diet, HFD）干预的Sgpp2-/-小鼠，其血液胰岛素水平显著低于同处理组的野生型小鼠，胰岛体积也更小。进一步分析显示，经高脂饮食处理的Sgpp2-/-小鼠的小型胰岛，其β细胞针对饮食刺激的适应性增殖速率显著低于野生型小鼠。尤为关键的是，与野生型小鼠的β细胞相比，正常饮食喂养的Sgpp2-/-小鼠β细胞中，内质网（Endoplasmic Reticulum, ER）应激反应相关特征蛋白的表达水平显著升高。本研究结果表明，Sgpp2基因敲除会引发β细胞内质网应激——这是已知的β细胞功能异常的重要诱因——同时揭示了鞘脂循环通路中一个可影响糖尿病发生发展的全新调控节点。本数据集包含3组生物学重复，对应经正常饮食与高脂饮食处理的野生型与基因敲除（Knockout, KO）小鼠样本。