TGF-beta 1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM
文献类型：期刊论文
| 作者 | Wang, Kuifeng4,8; Fang, Shanhua5,6; Liu, Qian2,5; Gao, Jing5; Wang, Xiaoning3,6; Zhu, Hongwen5; Zhu, Zhenyun5; Ji, Feihong4,8; Wu, Jiasheng3; Ma, Yueming3 |
| 刊名 | EBIOMEDICINE
 |
| 出版日期 | 2019-04-01 |
| 卷号 | 42页码:458-469 |
| ISSN号 | 2352-3964 |
| 关键词 | Liver fibrosis TGF-beta 1 MAT2A p65 SAM |
| DOI | 10.1016/j.ebiom.2019.03.058 |
| 通讯作者 | Zhu, Jiansheng(zhujs@enzemed.com) ; Liu, Ping(liuliver@vip.sina.com) ; Zhou, Hu(zhouhu@simm.ac.cn) |
| 英文摘要 | Background: Hepatic stellate cell (HSC) activation induced by transforming growth factor beta 1 (TGF-beta 1) plays a pivotal role in fibrogenesis, while the complex downstream mediators of TGF-beta 1 in such process are largely unknown. Methods: We performed pharmacoproteomic profiling of the mice liver tissues from control, carbon tetrachloride (CCl4)-induced fibrosis and NPLC0393 administrated groups. The target gene MAT2A was overexpressed or knocked down in vivo by tail vein injection of AAV vectors. We examined NF-kappa B transcriptional activity on MAT2A promoter via luciferase assay. Intracellular SAM contents were analyzed by LC-MS method. Findings: We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice, and application of NPLC0393, a known small molecule inhibitor of TGF-beta 1 signaling pathway, inhibits the upregulation of MAT2A. Mechanistically, TGF-beta 1 induces phosphorylation of p65, i.e., activation of NF-kappa B, thereby promoting mRNA transcription and protein expression of MAT2A and reduces S-adenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4-and TGF-beta 1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393. Interpretation: This study identifies TGF-beta 1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis. (C) 2019 The Authors. Published by Elsevier B.V. |
| WOS关键词 | METHIONINE ADENOSYLTRANSFERASE 2A ; NF-KAPPA-B ; GROWTH-FACTOR-BETA ; STELLATE CELL ACTIVATION ; ADENOSYL-L-METHIONINE ; S-ADENOSYLMETHIONINE ; CARBON-TETRACHLORIDE ; TGF-BETA ; DIFFERENTIAL EXPRESSION ; MOLECULAR-MECHANISMS |
| 资助项目 | National Natural Science Foundation of China[81500469] ; National Natural Science Foundation of China[81573873] ; National Natural Science Foundation of China[81774196] ; National Natural Science Foundation of China[31800693] ; Zhejiang Provincial Natural Science Foundation of China[Y15H030004] ; National Key Research and Development Program from the Ministry of Science and Technology of China[2017YFC1700200] ; Key Program of National Natural Science Foundation of China[8153000502] |
| WOS研究方向 | General & Internal Medicine ; Research & Experimental Medicine |
| 语种 | 英语 |
| 出版者 | ELSEVIER SCIENCE BV |
| WOS记录号 | WOS:000466175100058 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/289947]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Zhu, Jiansheng; Liu, Ping; Zhou, Hu |
| 作者单位 | 1.Chinese Acad Sci, Innovat Ctr Cell Signaling Network, Shanghai Inst Biochem & Cell Biol, CAS Key Lab Syst Biol,CAS Ctr Excellence Mol Cell, 320 Yueyang Rd, Shanghai 200031, Peoples R China 2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 3.Shanghai Univ Tradit Chinese Med, Dept Pharmacol, Key Lab Liver & Kidney Dis, Minist Educ,Inst Liver Dis,Shuguang Hosp, 528 Zhangheng Rd, Shanghai 201203, Peoples R China 4.Wenzhou Med Univ, Affiliated Taizhou Hosp, Dept Infect Dis, 150 Ximen Rd Linhai City, Taizhou 317000, Peoples R China 5.Chinese Acad Sci, Shanghai Inst Mat Med, Dept Analyt Chem, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 6.Shanghai Univ Tradit Chinese Med, E Inst Shanghai Municipal Educ Comm, 1200 Cailun Rd, Shanghai 201203, Peoples R China 7.Nanjing Univ Chinese Med, Sch Med & Life Sci, State Key Lab Cultivat Base TCM Qual & Efficacy, 138 Xianlin Rd, Nanjing 210023, Jiangsu, Peoples R China 8.Suzhou GenHouse Pharmaceut Co Ltd, 388 Ruoshui Rd, Suzhou 215123, Jiangsu, Peoples R China |
| 推荐引用方式 GB/T 7714 | Wang, Kuifeng,Fang, Shanhua,Liu, Qian,et al. TGF-beta 1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM[J]. EBIOMEDICINE,2019,42:458-469. |
| APA | Wang, Kuifeng.,Fang, Shanhua.,Liu, Qian.,Gao, Jing.,Wang, Xiaoning.,...&Zhou, Hu.(2019).TGF-beta 1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM.EBIOMEDICINE,42,458-469. |
| MLA | Wang, Kuifeng,et al."TGF-beta 1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM".EBIOMEDICINE 42(2019):458-469. |
入库方式： OAI收割
来源：上海药物研究所
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