Sphingosine kinase 2 promotes lipotoxicity in pancreatic β‐cells and the progression of diabetes

What is it about?

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 1 (SK1) is an endogenous protector of β-cells against lipotoxicity. The current study reports herein 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 siRNAs 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 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 with a high-fat diet accompanied by administration of streptozotocin. Thus, these findings provide the first evidence, both in vitro and in vivo, showing a critical role for SK2 in mediating β-cell lipotoxicity and the progression of diabetes.

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