Abstract
Aberrant deposition of fat including free fatty acids 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. This 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 enhanced significantly 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 protected hepatocytes from lipotoxicity. Mechanistically, the protective effect of SphK1 is attributable to suppression of ER stress-mediated pro-apoptotic pathways, as reflected in the inhibition of IRE1α activation, XBP1 splicing, JNK phosphorylation, and CHOP induction. 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. Therefore, this study provides new insights into the role of SphK1 in hepatocyte survival and uncovers a novel mechanism for protection against ER stress-mediated cell death.