Sphingosine Kinase 1 Protects Hepatocytes from Lipotoxicity via Down-regulation of IRE1{alpha} Expression [Signal Transduction]

August 3rd, 2015 by Qi, Y., Wang, W., Chen, J., Dai, L., Kaczorowski, D., Gao, X., Xia, P.

Aberrant deposition of fat including free fatty acids (FFA) in the liver often causes damage to hepatocytes, namely lipotoxicity, which is a key pathogenic event in the development and progression of fatty liver diseases. The present study demonstrates a pivotal role of sphingosine kinase 1 (SphK1) in protecting hepatocytes from lipotoxicity. Exposure of primary murine hepatocytes to palmitate resulted in dose-dependent cell death, which was significantly enhanced in Sphk1 deficient cells. In keeping with this, expression of dominant-negative mutant SphK1 also markedly promoted palmitate-induced cell death. In contrast, overexpression of wild-type SphK1 profoundly prevented hepatocytes from lipotoxicity. Mechanistically, SphK1 significantly suppresses ER stress-mediated pro-apoptotic pathways, as reflected in the inhibition of IRE1α activation, XBP1 splicing, JNK phosphorylation and CHOP induction, in hepatocytes underwent lipotoxic stress. Of note, SphK1 inhibited the IRE1α pathway by reducing IRE1α expression at the transcriptional level. Moreover, S1P mimicked the effect of SphK1, suppressing IRE1α expression in a receptor-dependent manner. Furthermore, enforced overexpression of IRE1α significantly blocked the protective effect of SphK1 against lipotoxicity. Thus, this study provides a new insight into the role of SphK1 in hepatocyte survival, and uncovers a novel mechanism for protection against ER stress-mediated cell death.