Department of Endocrinology and Metabolism, Fudan Institute for Metabolic Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou, China; and.
FASEB J. 2019 Mar;33(3):3636-3646. doi: 10.1096/fj.201801496R. Epub 2018 Nov 19.
Loss of functional β-cell mass caused by lipotoxicity is a key pathogenic factor in the development of type 2 diabetes mellitus (T2DM). We have previously reported that sphingosine kinase (SK)1 is an endogenous protector of β-cells against lipotoxicity. The current study reports that SK2, another isoform of SK, is a crucial mediator of lipotoxicity in β-cells. Exposure of β-cells to palmitatic acid (PA), a saturated free fatty acid, resulted in a nearly 2-fold increase in SK2 expression, which paralleled the induction of cell death in a similar dose- and time-dependent fashion. Silencing SK2 expression by its specific small interfering RNAs significantly inhibited PA-induced cell death and caspase-3 activation, whereas overexpression of SK2 promoted lipotoxicity in β-cells. Mechanistically, upon exposure to PA, endogenous SK2 was shuttled from the nucleus to the cytoplasm, where it interacted with B-cell lymphoma-extra-large (Bcl-xL), leading to mitochondrial apoptotic pathway activation and cell death. By blocking SK2 translocation and its interaction with Bcl-xL, either the nuclear export signal mutant (L423A/L425A) or the BH3 domain mutant (L219A) of SK2 significantly attenuated β-cell lipotoxicity. Furthermore, SK2 deficiency in mice significantly prevented the loss of β-cell mass, preserved insulin production, and ameliorated the diabetic phenotype in an established T2DM model induced by feeding a high-fat diet accompanied by administration of streptozotocin. These findings provide the first evidence, in vitro and in vivo, of a critical role for SK2 in mediating β-cell lipotoxicity and the progression of diabetes.-Song, Z., Wang, W., Li, N., Yan, S., Rong, K., Lan, T., Xia, P. Sphingosine kinase 2 promotes lipotoxicity in pancreatic β-cells and the progression of diabetes.
脂毒性引起的功能性β细胞数量减少是 2 型糖尿病（T2DM）发病的关键致病因素。我们之前的研究报道，鞘氨醇激酶（SK）1 是β细胞抵抗脂毒性的内源性保护剂。本研究报道，SK2 是 SK 的另一种同工酶，是β细胞脂毒性的关键介质。β细胞暴露于棕榈酸（PA），一种饱和游离脂肪酸，导致 SK2 表达增加近 2 倍，细胞死亡的诱导也呈相似的剂量和时间依赖性。其特异性小干扰 RNA 沉默 SK2 表达可显著抑制 PA 诱导的细胞死亡和半胱天冬酶-3 的激活，而过表达 SK2 则促进β细胞的脂毒性。机制上，PA 暴露后，内源性 SK2 从核内易位到细胞质，与 B 细胞淋巴瘤-extra-large（Bcl-xL）相互作用，导致线粒体凋亡途径的激活和细胞死亡。通过阻断 SK2 易位及其与 Bcl-xL 的相互作用，SK2 的核输出信号突变体（L423A/L425A）或 BH3 结构域突变体（L219A）显著减弱了β细胞的脂毒性。此外，SK2 敲除小鼠可显著防止β细胞数量减少，维持胰岛素的产生，并改善高脂饮食喂养联合链脲佐菌素给药建立的 T2DM 模型中的糖尿病表型。这些发现为 SK2 在介导β细胞脂毒性和糖尿病进展中的关键作用提供了体外和体内的首个证据。
