The role of sphingosine 1-phosphate (S1P) and its sphingosine-1-phosphate receptors (S1PRs) in non-alcoholic steatohepatitis (NASH) is unclear. We aimed to analyze the role of S1P/S1PRs in a Melanocortin-4 receptor (Mc4r)-deficient NASH murine model using FTY720, the functional antagonist of S1PR1, S1PR3, S1PR4, and S1PR5, and JTE-013, the antagonist of S1PR2. We observed that, compared to that in the control, the mRNA of S1pr1 tended to decrease, whereas those of S1pr2 and S1pr3 significantly increased in Mc4r-knockout (KO) mice subjected to a Western diet (WD). While the fat area did not differ, fibrosis progression differed significantly between control mice and mice in which liver S1PRs were blocked. Lipidomic and metabolomic analysis of liver tissues showed that JTE-013-administered mice showed elevation of S-adenosyl-l-methionine level, which can induce aberrant methylation due to reduction in glycine N-methyltransferase (GNMT) and elevation in diacylglycerol (DG) and triacylglycerol (TG) levels, leading to increased susceptibility to hepatocellular carcinoma (HCC). These phenotypes are similar to those of Gnmt-KO mice, suggesting that blocking the S1P/S1PR2 axis triggers aberrant methylation, which may increase DG and TG, and hepatocarcinogenesis. Our observations that the S1P/S1PR2 axis averts HCC occurrence may assist in HCC prevention in NASH.

尚不清楚1-磷酸鞘氨醇（S1P）及其鞘氨醇-1-磷酸受体（S1PRs）在非酒精性脂肪性肝炎（NASH）中的作用。我们旨在使用功能性S1PR1，S1PR3，S1PR4和S1PR5的拮抗剂FTY720和S1PR2的拮抗剂JTE-013分析S1P / S1PRs在缺乏Melanocortin-4受体（Mc4r）的NASH鼠模型中的作用。我们观察到，相比于控制，mRNA的S1pr1呈下降趋势，而那些S1pr2和S1pr3在显著上升MC4R-敲除（KO）小鼠接受西方饮食（WD）。尽管脂肪面积没有变化，但对照组和肝S1PRs阻滞的小鼠之间的纤维化进程却有显着差异。肝组织的脂组学和代谢组学分析表明，施用JTE-013的小鼠显示S-腺苷-1-蛋氨酸水平升高，由于甘氨酸N-甲基转移酶（GNMT）降低和二酰基甘油（DG）升高，可诱导异常甲基化和三酰甘油（TG）的水平，导致对肝细胞癌（HCC）的敏感性增加。这些表型与Gnmt相似-KO小鼠，提示阻断S1P / S1PR2轴会触发异常甲基化，这可能会增加DG和TG以及肝癌的发生。我们关于S1P / S1PR2轴避免发生HCC的观察结果可能有助于NASH的HCC预防。