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

FASEB J. 2019 Mar;33(3):3636-3646. doi: 10.1096/fj.201801496R. Epub 2018 Nov 19.

Abstract

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.

Keywords: apoptosis; sphingolipids; type 2 diabetes; β-cell biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / physiology
  • Caspase 3 / metabolism
  • Cell Death / physiology
  • Cells, Cultured
  • Cytoplasm / metabolism
  • Diabetes Mellitus, Type 2 / metabolism*
  • Diet, High-Fat
  • Disease Progression
  • Humans
  • Insulin / metabolism
  • Insulin-Secreting Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria / metabolism
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Signal Transduction / physiology
  • bcl-X Protein / metabolism

Substances

  • Insulin
  • bcl-X Protein
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase 2, human
  • Caspase 3