1. Sphingosine kinase 1 promotes liver fibrosis by preventing miR‐19b‐3p‐mediated inhibition of CCR2
- Author
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Yue Sun, Jiao Guo, Lihang Zhuang, Changzheng Li, Hui Li, Tian Lan, Genshu Wang, Yitao Ou, Guizhi Yang, David A. Brenner, and Tatiana Kisseleva
- Subjects
0301 basic medicine ,Liver Cirrhosis ,CCR2 ,Sphingosine kinase ,Medical Biochemistry and Metabolomics ,Inbred C57BL ,Chronic liver disease ,Oral and gastrointestinal ,Mice ,Fibrosis ,Receptors ,2.1 Biological and endogenous factors ,Aetiology ,Chemokine CCL2 ,Bone Marrow Transplantation ,Liver injury ,Mice, Knockout ,biology ,Chemistry ,Liver Disease ,hemic and immune systems ,Phosphotransferases (Alcohol Group Acceptor) ,Sphingosine kinase 1 ,Original Article ,Kupffer Cells ,Receptors, CCR2 ,Knockout ,Chronic Liver Disease and Cirrhosis ,Clinical Sciences ,Immunology ,03 medical and health sciences ,Rare Diseases ,Downregulation and upregulation ,medicine ,Hepatic Stellate Cells ,Animals ,Humans ,Gastroenterology & Hepatology ,Hepatology ,Original Articles ,Liver Failure/Cirrhosis/Portal Hypertension ,medicine.disease ,Mice, Inbred C57BL ,MicroRNAs ,Good Health and Well Being ,030104 developmental biology ,Hepatic stellate cell ,Cancer research ,biology.protein ,Digestive Diseases - Abstract
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).
- Published
- 2018