| First Author | Song Z | Year | 2019 |
| Journal | FASEB J | Volume | 33 |
| Issue | 3 | Pages | 3636-3646 |
| PubMed ID | 30452878 | Mgi Jnum | J:288002 |
| Mgi Id | MGI:6391301 | Doi | 10.1096/fj.201801496R |
| Citation | Song Z, et al. (2019) Sphingosine kinase 2 promotes lipotoxicity in pancreatic beta-cells and the progression of diabetes. FASEB J 33(3):3636-3646 |
| abstractText | Loss of functional beta-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 beta-cells against lipotoxicity. The current study reports that SK2, another isoform of SK, is a crucial mediator of lipotoxicity in beta-cells. Exposure of beta-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 beta-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 beta-cell lipotoxicity. Furthermore, SK2 deficiency in mice significantly prevented the loss of beta-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 beta-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 beta-cells and the progression of diabetes. |
