ECM1 通过干扰潜伏 TGF-β1 激活的介质减轻肝纤维化

IF 23 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gut Pub Date : 2024-10-24 DOI:10.1136/gutjnl-2024-333213
Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe C Nwosu, Ye Yao, Shanshan Wang, Chenjun Huang, Roman Liebe, Seddik Hammad, Hui Liu, Chen Shao, Chunfang Gao, Bing Sun, Natalie J Török, Huiguo Ding, Matthias PA Ebert, Honglei Weng, Peter ten Dijke, Dirk Drasdo, Steven Dooley, Sai Wang
{"title":"ECM1 通过干扰潜伏 TGF-β1 激活的介质减轻肝纤维化","authors":"Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe C Nwosu, Ye Yao, Shanshan Wang, Chenjun Huang, Roman Liebe, Seddik Hammad, Hui Liu, Chen Shao, Chunfang Gao, Bing Sun, Natalie J Török, Huiguo Ding, Matthias PA Ebert, Honglei Weng, Peter ten Dijke, Dirk Drasdo, Steven Dooley, Sai Wang","doi":"10.1136/gutjnl-2024-333213","DOIUrl":null,"url":null,"abstract":"Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1 -KO and Fxr -KO mice, patient liver tissue and computer simulations. Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1 -KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation while KTFR treatment reversed Ecm1 -KO-mediated and Fxr -KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-β1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. Conclusion Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-β1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD. Data are available in a public, open access repository. Data are available on reasonable request.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"97 1","pages":""},"PeriodicalIF":23.0000,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation\",\"authors\":\"Frederik Link, Yujia Li, Jieling Zhao, Stefan Munker, Weiguo Fan, Zeribe C Nwosu, Ye Yao, Shanshan Wang, Chenjun Huang, Roman Liebe, Seddik Hammad, Hui Liu, Chen Shao, Chunfang Gao, Bing Sun, Natalie J Török, Huiguo Ding, Matthias PA Ebert, Honglei Weng, Peter ten Dijke, Dirk Drasdo, Steven Dooley, Sai Wang\",\"doi\":\"10.1136/gutjnl-2024-333213\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1 -KO and Fxr -KO mice, patient liver tissue and computer simulations. Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1 -KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation while KTFR treatment reversed Ecm1 -KO-mediated and Fxr -KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-β1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. Conclusion Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-β1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD. Data are available in a public, open access repository. Data are available on reasonable request.\",\"PeriodicalId\":12825,\"journal\":{\"name\":\"Gut\",\"volume\":\"97 1\",\"pages\":\"\"},\"PeriodicalIF\":23.0000,\"publicationDate\":\"2024-10-24\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Gut\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1136/gutjnl-2024-333213\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GASTROENTEROLOGY & HEPATOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gut","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/gutjnl-2024-333213","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

目的 细胞外基质蛋白 1(ECM1)通过维持转化生长因子-β1(TGF-β1)的潜伏状态,充当肝纤维化的守门员。ECM1 基因敲除(KO)会导致潜伏(L)的 TGF-β1 激活,导致肝纤维化并迅速死亡。在慢性肝病(CLD)中,ECM1 会随着慢性肝病严重程度的增加而减少。我们研究了 ECM1 在 TGF-β1 生物利用率中的调节作用及其对 CLD 进展的影响。设计 对肝脏基因表达进行 RNAseq 分析。使用肝星状细胞(HSCs)、Ecm1 -KO 和 Fxr -KO 小鼠、患者肝组织和计算机模拟进行功能测试。结果 在 Ecm1 -KO 小鼠的肝组织中,LTGF-β1 激活剂(包括血栓软骨素 (TSP)、ADAMTS 蛋白酶和基质金属蛋白酶 (MMP))的表达与组织坏死基因的表达同时增加。在造血干细胞中,ECM1 的过表达可阻止由 TSP-1、ADAMTS1 和 MMP-2/9 介导的 LTGF-β1 激活。体外相互作用试验表明,ECM1 通过各自固有的 KRFK 或 KTFR 氨基酸序列与 TSP-1 和 ADAMTS1 相互作用,并抑制 MMP-2/9 的蛋白水解活性,从而抑制 LTGF-β1 的活化。在小鼠体内,ECM1 的过表达可减轻 KRFK 诱导的 LTGF-β1 激活,而 KTFR 治疗可逆转 Ecm1 -KO 介导的肝损伤和 Fxr -KO 介导的肝损伤。在 CLD 患者中,ECM1 的表达与 TSP-1、ADAMTS1、MMP-2/9 的表达和 LTGF-β1 的激活成反比。此外,代表肝纤维化过程中细胞表型和预测相互作用的关键网络的计算分区模型对这些结果进行了补充。结论 我们的发现强调了 ECM1 的保肝作用,它能干扰 LTGF-β1 激活的介质,这表明 ECM1 或其代表肽是治疗慢性肝病的潜在抗纤维化疗法。数据可在公开、开放的资源库中获取。如有合理要求,可提供数据。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ECM1 attenuates hepatic fibrosis by interfering with mediators of latent TGF-β1 activation
Objective Extracellular matrix protein 1 (ECM1) serves as a gatekeeper of hepatic fibrosis by maintaining transforming growth factor-β1 (TGF-β1) in its latent form. ECM1 knockout (KO) causes latent (L) TGF-β1 activation, resulting in hepatic fibrosis with rapid mortality. In chronic liver disease (CLD), ECM1 decreases with increasing CLD severity. We investigate the regulatory role of ECM1 in TGF-β1 bioavailability and its impact on CLD progression. Design RNAseq was performed to analyse hepatic gene expression. Functional assays were performed using hepatic stellate cells (HSCs), Ecm1 -KO and Fxr -KO mice, patient liver tissue and computer simulations. Results Expression of LTGF-β1 activators, including thrombospondins (TSPs), ADAMTS proteases and matrix metalloproteinases (MMPs), increased along with profibrotic gene expression in liver tissue of Ecm1 -KO mice. In HSCs, overexpression of ECM1 prevented LTGF-β1 activation mediated by TSP-1, ADAMTS1, and MMP-2/9. In vitro interaction assays demonstrated that ECM1 inhibited LTGF-β1 activation by interacting with TSP-1 and ADAMTS1 via their respective, intrinsic KRFK or KTFR amino acid sequences and by suppressing MMP-2/9 proteolytic activity. In mice, ECM1 overexpression attenuated KRFK-induced LTGF-β1 activation while KTFR treatment reversed Ecm1 -KO-mediated and Fxr -KO-mediated liver injury. In patients with CLD, ECM1 expression was inversely correlated with TSP-1, ADAMTS1, MMP-2/9 expression and LTGF-β1 activation. And, these results were complemented by a computational compartment model representing the key network of cellular phenotypes and predicted interactions in liver fibrogenesis. Conclusion Our findings underscore the hepatoprotective effect of ECM1, which interferes with mediators of LTGF-β1 activation, suggesting ECM1 or its representative peptide as potential antifibrotic therapies in CLD. Data are available in a public, open access repository. Data are available on reasonable request.
求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Gut
Gut 医学-胃肠肝病学
CiteScore
45.70
自引率
2.40%
发文量
284
审稿时长
1.5 months
期刊介绍: Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts. As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信