Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2.
Sphingosine kinase 1 promotes liver fibrosis by preventing miR-19b-3p-mediated inhibition of CCR2.
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DOI：
10.1002/hep.29885
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发表时间：
2018-09
期刊：
影响因子：
--
通讯作者：
Guo J
中科院分区：
文献类型：
--
作者：
Lan T;Li C;Yang G;Sun Y;Zhuang L;Ou Y;Li H;Wang G;Kisseleva T;Brenner D;Guo J
由肝星状细胞(HSCs)和枯否细胞(KCs)激活介导的慢性肝病可导致肝纤维化。在这里，我们的目的是研究参与介导鞘氨酸激酶(SphK)1依赖的肝纤维化作用的分子机制和细胞类型。肝纤维化组织中SphK1的表达水平和活性均显著高于正常肝组织。在肝纤维化肝组织中，SphK1与结蛋白、α-平滑肌肌动蛋白(α-SMA)和F4/80等一系列肝干细胞/KC标志物共表达。缺乏SphK1(SphK1−/−)可显著改善CCl_4或胆管结扎小鼠肝损伤，包括转氨酶活性、组织学、胶原沉积、α-SMA和炎症反应。同样，使用SphK1的特异性抑制剂5C治疗也显著防止了CCl4或BDL诱导的小鼠肝损伤和纤维化。在细胞水平上，抑制SphK1显著阻断了HSCs和KCs的激活和迁移。此外，KCs中的SphK1基因敲除减少了CCL2的分泌，而HSCs中的SphK1基因敲除降低了HSC中C-C基序趋化因子受体2([CCR2]CCL2受体)的表达。与野生型(WT)小鼠相比，SphK1−/−小鼠的CCL2较低，而microRNA-19b-3p较SphK1−/−小鼠高。此外，microRNA-19b-3p下调了HSCs中CCR2的表达。采用骨髓移植(BMT)方法的动物实验结果进一步加强了SphK1在HSC中对肝纤维化的功能作用。结论：SphK1在肝纤维化过程中对KCs和HSCs的激活具有明显的作用。在机制上，KCs中的SphK1介导CCL2的分泌，而HSCs中的SphK1通过下调miR-19b-3p上调CCR2。(2018年《肝病》)。
Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) leads to liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the sphingosine kinase (SphK)1‐dependent effect on liver fibrosis. The levels of expression and activity of SphK1 were significantly increased in fibrotic livers compared with the normal livers in human. SphK1 was coexpressed with a range of HSC/KC markers including desmin, α‐smooth muscle actin (α‐SMA) and F4/80 in fibrotic liver. Deficiency of SphK1 (SphK1−/−) resulted in a marked amelioration of hepatic injury, including transaminase activities, histology, collagen deposition, α‐SMA and inflammation, in CCl4 or bile duct ligation (BDL)‐induced mice. Likewise, treatment with a specific inhibitor of SphK1, 5C, also significantly prevented liver injury and fibrosis in mice induced by CCl4 or BDL. In cellular levels, inhibition of SphK1 significantly blocked the activation and migration of HSCs and KCs. Moreover, SphK1 knockout in KCs reduced the secretion of CCL2, and SphK1 knockout in HSCs reduced C‐C motif chemokine receptor 2 ([CCR2] CCL2 receptor) expression in HSCs. CCL2 in SphK1−/− mice was lower whereas microRNA‐19b‐3p in SphK1−/− mice was higher compared with wild‐type (WT) mice. Furthermore, microRNA‐19b‐3p downregulated CCR2 in HSCs. The functional effect of SphK1 in HSCs on liver fibrosis was further strengthened by the results of animal experiments using a bone marrow transplantation (BMT) method. Conclusion: SphK1 has distinct roles in the activation of KCs and HSCs in liver fibrosis. Mechanistically, SphK1 in KCs mediates CCL2 secretion, and SphK1 in HSCs upregulates CCR2 by downregulation of miR‐19b‐3p. (Hepatology 2018).
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DOI：
10.1042/cs20110515
发表时间：
2012-10
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Galastri S;Zamara E;Milani S;Novo E;Provenzano A;Delogu W;Vizzutti F;Sutti S;Locatelli I;Navari N;Vivoli E;Caligiuri A;Pinzani M;Albano E;Parola M;Marra F
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DOI：
10.1002/hep.23338
发表时间：
2009-11-01
期刊：
Hepatology (Baltimore, Md.)
影响因子：
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作者：
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影响因子：
25.7
作者：
Li, Changyong;Zheng, Sujun;Li, Liying
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