Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH
Blocking sphingosine 1-phosphate receptor 2 accelerates hepatocellular carcinoma progression in a mouse model of NASH
复制标题
阻断 1-磷酸鞘氨醇受体 2 可加速 NASH 小鼠模型的肝细胞癌进展
DOI：
10.1016/j.bbrc.2020.07.099
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发表时间：
2020
期刊：
影响因子：
--
通讯作者：
Terai S.
中科院分区：
文献类型：
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作者：
Yoshida T;Tsuchiya A;Kumagai M;Takeuchi S;Nojiri S;Watanabe T;Ogawa M;Itoh M;Takamura M;Suganami T;Ogawa Y;Terai S.
1-磷酸鞘氨醇 (S1P) 及其 1-磷酸鞘氨醇受体 (S1PR) 在非酒精性脂肪性肝炎 (NASH) 中的作用尚不清楚。我们的目的是使用 S1PR1、S1PR3、S1PR4 和 S1PR5 的功能性拮抗剂 FTY720 和 S1PR2 的拮抗剂 JTE-013 分析 S1P/S1PR 在 Melanocortin-4 受体 (Mc4r) 缺陷的 NASH 小鼠模型中的作用。我们观察到，与对照组相比，在接受西方饮食（WD）的Mc4r敲除（KO）小鼠中，S1pr1的mRNA趋于减少，而S1pr2和S1pr3的mRNA显着增加。虽然脂肪面积没有差异，但对照小鼠和肝脏 S1PR 被阻断的小鼠之间的纤维化进展存在显着差异。肝组织的脂质组学和代谢组学分析显示，给予JTE-013的小鼠显示S-腺苷-L-甲硫氨酸水平升高，这可能由于甘氨酸N-甲基转移酶（GNMT）减少以及二酰基甘油（DG）和三酰基甘油（TG）水平升高而诱导异常甲基化，导致对肝细胞癌（HCC）的易感性增加。这些表型与 Gnmt-KO 小鼠的表型相似，表明阻断 S1P/S1PR2 轴会触发异常甲基化，从而可能增加 DG 和 TG 以及肝癌发生。我们观察到 S1P/S1PR2 轴可以避免 HCC 的发生，这可能有助于 NASH 中 HCC 的预防。
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 ofS1pr1tended to decrease, whereas those ofS1pr2andS1pr3significantly increased inMc4r-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 glycineN-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 ofGnmt-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.