Deletion of sphingosine kinase 1 ameliorates hepatic steatosis in diet-induced obese mice: Role of PPARγ

作者：Chen, Jinbiao; Wang, Wei; Qi, Yanfei; Kaczorowski, Dominik; McCaughan, Geoffrey W.; Gamble, Jennifer R.; Don, Anthony S.; Gao, Xin; Vadas, Mathew A.; Xia, Pu^*

来源：Biochimica et Biophysica Acta-Molecular and Cell Biology of Lipids, 2016, 1861(2): 138-147.

DOI：10.1016/j.bbalip.2015.11.006

• Sphingosine kinase 1
• Sphingolipids
• Hepatocytes
• Nonalcoholic fatty liver disease
• PPAR gamma

Sphingolipid metabolites have emerged playing important roles in the pathogenesis of nonalcoholic fatty liver disease, whereas the underlying mechanism remains largely unknown. In the present study, we provide both in vitro and in vivo evidence showing a pathogenic role of sphingosine kinase 1 (SphK1) in hepatocellular steatosis. We found that levels of SphK1 expression were significantly increased in steatotic hepatocytes. Enforced overexpression of SphK1 or treatment with sphingosine 1-phosphate (SIP) markedly enhanced hepatic lipid accumulation. In contrast, the siRNA-mediated knockdown of SphK1 or SW receptors, S1P(2) and S1P(3), profoundly inhibited lipid accumulation in hepatocytes. Moreover, Sphk1(-/-) mice exhibited a significant amelioration of hepatosteatosis under diet-induced obese (DIO) conditions, compared to wild-type littermates. In addition, DIO-induced up-regulation of PPAR gamma and its target genes were significantly reduced by SphK1 deficiency. Furthermore, treatment of hepatocytes with SW induces a dose-dependent increase in PPAR gamma expression at the transcriptional level. Blockage of SUP receptors and the Akt-mTOR signaling profoundly inhibited S1P-induced PPAR gamma expression. Notably, down-regulation of PPAR gamma by using its siRNA significantly diminished the pro-steatotic effect of SphK1/S1P. Thus, the study demonstrates a new pathway connecting SphK1 and PPAR gamma involved in the pathogenesis of hepatocellular steatosis.

• 出版日期2016-2
• 单位复旦大学