Generation of sphingosine-1-phosphate by sphingosine kinase 1 protects nonalcoholic fatty liver from ischemia/reperfusion injury through alleviating reactive oxygen species production in hepatocytes
Generation of sphingosine-1-phosphate by sphingosine kinase 1 protects nonalcoholic fatty liver from ischemia/reperfusion injury through alleviating reactive oxygen species production in hepatocytes
复制标题
鞘氨醇激酶 1 生成 1-磷酸鞘氨醇，通过减少肝细胞中活性氧的产生，保护非酒精性脂肪肝免受缺血/再灌注损伤
DOI：
10.1016/j.freeradbiomed.2020.07.004
复制
发表时间：
2020-11-01
影响因子：
7.4
通讯作者：
Li, Chuanjiang
中科院分区：
文献类型：
--
作者：
Li, Qingping;Qian, Jianping;Li, Chuanjiang
背景资料：非酒精性脂肪肝（NAFL）是肝脏缺血/再灌注（I/R）损伤的主要危险因素，目前尚无有效的治疗方法。脂质稳态异常与NAFL的肝病有关。在此，我们调查的生物活性脂质，关键调节I/R损伤NAFL。方法：脂质组学进行识别失调的脂质在小鼠和人NAFL与I/R损伤。检测相应脂代谢基因的改变。结果：在小鼠NAFL中，I/R激活了负责产生鞘氨醇-1-磷酸（S1 P）的鞘脂代谢途径。发现鞘氨醇激酶1（Sphkl）对于NAFL小鼠肝细胞中响应I/R的肝SIP产生是必需的。Sphk 1敲低抑制肝脏SIP上升，同时在NAFL小鼠肝细胞中积累神经酰胺，导致侵袭性肝脏I/R损伤，氧化应激上调和活性氧（ROS）增加。与此相反，外源性S1 P的管理保护NAFL小鼠肝细胞的肝I/R损伤。临床研究表明，在NAFL患者的肝标本中，I/R显著激活了S1 P的产生。结论：SPHK 1抑制S1 P的产生对NAFL肝细胞I/R损伤具有重要的保护作用，可作为NAFL肝I/R损伤的治疗靶点。
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 primary hepatocytes.Results: Sphingolipid metabolic pathways responsible for the generation of sphingosine-l-phosphate (S1P) were uncovered to be substantially activated by I/R in mouse NAFL. Sphingosine kinase 1 (Sphkl) was found to be essential for hepatic SIP generation in response to I/R in hepatocytes of NAFL mice. Sphk1 knockdown inhibited the hepatic SIP rise while accumulating ceramides in hepatocytes of NAFL mice, leading to aggressive hepatic I/R injury with upregulation of oxidative stress and increase of reactive oxygen species (ROS). In contrast, administration of exogenous S1P protected hepatocytes of NAFL mice from hepatic I/R injury. Clinical study revealed a significant activation of S1P generation by I/R in liver specimens of NAFL patients. In vitro studies on the L02 human hepatocytes consolidated that inhibiting the generation of S1P by knocking down SPHK1 exaggerated I/R-induced damage and oxidative stress in human hepatocytes of NAFL.Conclusions: Generation of S1P by SPHK1 is important for protecting NAFL from I/R injury, which may serve as therapeutic targets for hepatic I/R injury in NAFL.