Activation of Sphingosine Kinase 1/Sphingosine-1-Phosphate Pathway Protects Nonalcoholic Fatty Liver from Ischemia/Reperfusion Injury by Alleviating Oxidative Stress in Hepatocytes

Background: Nonalcoholic fatty liver (NAFL) is emerging as a leading risk factor of hepatic ischemia/reperfusion (I/R) injury lacking of effective therapy. Lipid dyshomeostasis has been implicated in the hepatopathy of NAFL. Herein, we investigate the bioactive lipids that critically regulate I/R injury in NAFL. Methods: Lipidomics were performed to identify dysregulated lipids in mouse and human NAFL with I/R injury. The alteration of corresponding lipid-metabolizing genes was examined. The effects of the dysregulated lipid metabolism on I/R injury in NAFL were evaluated in mice and human cultured hepatocytes. Findings: Sphingolipid metabolic pathways responsible for the generation of sphingosine-1-phosphate (S1P) were uncovered to be substantially activated by I/R in mouse NAFL. Sphingosine kinase 1 (Sphk1) was found to be essential for hepatic S1P generation in response to I/R in mouse NAFL. Sphk1 knockdown inhibited the hepatic S1P rise while accumulating ceramides, leading to aggressive hepatic I/R injury with increased oxidative stress in NAFL mice. In contrast, administration of exogenous S1P protected NAFL mice from hepatic I/R injury. Clinical study revealed a significant activation of SPHK1/S1P pathway by I/R in liver specimens of NAFL patients. In vitro studies on cultured human hepatocytes consolidated that inhibiting the SPHK1/S1P pathway exaggerated I/R-induced damage and oxidative stress in human hepatocytes of NAFL. Interpretations: Activation of SPHK1/S1P pathway is important for protecting NAFL from I/R injury, which may serve as therapeutic targets for hepatic I/R injury in NAFL. Funding Statement: This work was supported by Dean Foundation of Nanfang Hospital, Southern Medical University (2018C029) to JPQ, Guangdong Province Science and Technology Program (2014A020212174) to CJL, Guangdong Province Science and Technology Program (2017A030313684) to JZ, National Natural Science Foundation of China (81803063) to YYL, National Natural Science Foundation of China (81600462) and the Outstanding Youth Development Scheme of Nanfang Hospital, Southern Medical University (2016006) to KW. Declaration of Interests: The authors declare no competing of interest. Ethics Approval Statement: All experiments using human samples were carried out following the protocols approved by the Medical Ethics Committee of Nanfang Hospital Southern Medical University (NFEC-2019-029).