Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic β-cell death in diet-induced obese mice
Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic β-cell death in diet-induced obese mice
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DOI：
10.1096/fj.13-230052
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发表时间：
2013-10-01
期刊：
影响因子：
4.8
通讯作者：
Xia, Pu
中科院分区：
文献类型：
--
作者：
Qi, Yanfei;Chen, Jinbiao;Xia, Pu
脂毒性应激诱导的细胞死亡（脂毒性）被认为是2型糖尿病（T2 DM）发展的关键因素。目前的研究报道了鞘氨醇激酶1（SphK 1）在脂毒性条件下的细胞存活中的关键作用。为了研究SphK 1在体内脂毒性中的作用，我们用高脂饮食（HFD）或正常食物饮食喂养SphK 1（-/-）和野生型（WT）小鼠。值得注意的是，虽然HFD喂养的WT小鼠出现葡萄糖耐受不良和代偿性高胰岛素血症，但所有HFD喂养的Sphk 1（-/-）小鼠均表现出明显的糖尿病，并伴有胰岛素水平较WT小鼠降低近3倍。与普通饲料对照组相比，HFD喂养的WT小鼠的胰腺细胞质量增加了140%，但HFD喂养的Sphk 1（-/-）小鼠的胰腺细胞质量降低至50%。因此，通过阻断酶活性，SphK 1的显性负性形式的表达显著促进了MIN 6和INS-1 -细胞系中棕榈酸诱导的细胞死亡。此外，从Sphk 1（-/-）小鼠分离的原代胰岛表现出比WT对照更高的脂毒性易感性。值得注意的是，1-磷酸鞘氨醇（S1 P）深刻地消除了细胞或缺乏SphK 1活性的细胞和SphK 1（-/-）胰岛中的脂毒性，突出了S1 P在脂毒性条件下细胞存活中的关键作用。这些发现可能提示了一种新的治疗策略，用于预防β细胞死亡，从而预防T2 DM的发作。陈杰，Lay，A.，Don，A.，Vadas，M.，鞘氨醇激酶1的丧失通过促进饮食诱导的肥胖小鼠中的胰腺细胞死亡而易患糖尿病。
Lipotoxic stress-induced -cell death (lipotoxicity) is recognized as a key contributor to the development of type 2 diabetes mellitus (T2DM). The current study reports a critical role of sphingosine kinase 1 (SphK1) in -cell survival under lipotoxic conditions. In an attempt to investigate the role of SphK1 in lipotoxicity in vivo, we fed Sphk1(-/-) and wild-type (WT) mice with a high-fat diet (HFD) or normal chow diet. Remarkably, while HFD-fed WT mice developed glucose intolerance and compensatory hyperinsulinemia, all HFD-fed Sphk1(-/-) mice manifested evident diabetes, accompanied by a nearly 3-fold reduction in insulin levels compared with the WT mice. Pancreatic -cell mass was increased by 140% in HFD-fed WT mice but decreased to 50% in HFD-fed Sphk1(-/-) mice, in comparison with the chow diet control groups, respectively. Accordingly, by blocking the enzyme activity, expression of a dominant negative form of SphK1 markedly promoted palmitate-induced cell death in MIN6 and INS-1 -cell lines. Moreover, primary islets isolated from Sphk1(-/-) mice exhibited higher susceptibility to lipotoxicity than WT controls. Of note, sphingosine 1-phosphate (S1P) profoundly abrogated lipotoxicity in cells or the cells lacking SphK1 activity and Sphk1(-/-) islets, highlighting a pivotal role of S1P in -cell survival under lipotoxic conditions. These findings could suggest a new therapeutic strategy for preventing -cell death and thus the onset of T2DM.Qi, Y., Chen, J., Lay, A., Don, A., Vadas, M., Xia, P. Loss of sphingosine kinase 1 predisposes to the onset of diabetes via promoting pancreatic -cell death in diet-induced obese mice.