{"title":"neuropilin-1与肝细胞生长因子/C-Met通路在肝细胞特异性NRP-1敲除小鼠肝纤维化进展中的相互作用","authors":"Han Ding, Huanran Lv, Minghao Sui, Xinyu Wang, Yanning Sun, Miaomiao Tian, Shujun Ma, Yuchan Xue, Miao Zhang, Xin Wang, Jianni Qi, Le Wang, Qiang Zhu","doi":"10.1007/s00535-025-02262-8","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Hepatocyte growth factor (HGF)/c-Met signaling critically influences liver fibrosis, but its interaction with neuropilin-1 (NRP-1) in hepatocytes remains unclear. We investigated the role of hepatocyte-specific NRP-1 deletion in liver fibrosis progression and its relationship with the HGF/c-Met pathway.</p><p><strong>Methods: </strong>Hepatocyte-specific NRP-1 knockout mice were generated using the Cre-lox system, and liver fibrosis was induced by carbon tetrachloride injections or a methionine- and choline-deficient diet. Fibrosis severity, hepatocyte injury, and cytokine secretion were evaluated via histology, biochemical assays, and molecular analyses in isolated hepatocytes. In vitro experiments were conducted in primary hepatocytes and Huh7 cells using lentiviral overexpression and knockdown of NRP-1. Chromatin immunoprecipitation and dual-luciferase reporter assays were performed to analyze transcription factor binding to the NRP-1 promoter.</p><p><strong>Results: </strong>Hepatocyte NRP-1 expression increased significantly during liver fibrosis and was positively correlated with HGF/c-Met expression and fibrosis severity. In vivo, NRP-1 inhibition reduced extracellular matrix accumulation and abnormal angiogenesis in Alb-Cre NRP-1<sup>f/f</sup> mice. In vitro, NRP-1 blockade inhibited c-Met activation and reduced transforming growth factor-beta and vascular endothelial growth factor secretion in hepatocytes. NRP-1 functioned as a co-receptor for HGF/c-Met, with HGF upregulating NRP-1 expression at transcript and protein levels. NRP-1 promoted fibrosis through the Met/extracellular signal-regulated kinase pathway. Furthermore, HGF increased retinoic acid receptor alpha expression, promoting NRP-1 transcription.</p><p><strong>Conclusions: </strong>HGF-induced upregulation of hepatocyte NRP-1, mediated by RARA binding to its promoter, drives liver fibrosis through c-Met pathway activation, highlighting NRP-1 as a potential therapeutic target for liver fibrosis.</p>","PeriodicalId":16059,"journal":{"name":"Journal of Gastroenterology","volume":" ","pages":""},"PeriodicalIF":6.9000,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Interaction of neuropilin-1 and hepatocyte growth factor/C-Met pathway in liver fibrosis progression in hepatocyte-specific NRP-1 knockout mice.\",\"authors\":\"Han Ding, Huanran Lv, Minghao Sui, Xinyu Wang, Yanning Sun, Miaomiao Tian, Shujun Ma, Yuchan Xue, Miao Zhang, Xin Wang, Jianni Qi, Le Wang, Qiang Zhu\",\"doi\":\"10.1007/s00535-025-02262-8\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>Hepatocyte growth factor (HGF)/c-Met signaling critically influences liver fibrosis, but its interaction with neuropilin-1 (NRP-1) in hepatocytes remains unclear. We investigated the role of hepatocyte-specific NRP-1 deletion in liver fibrosis progression and its relationship with the HGF/c-Met pathway.</p><p><strong>Methods: </strong>Hepatocyte-specific NRP-1 knockout mice were generated using the Cre-lox system, and liver fibrosis was induced by carbon tetrachloride injections or a methionine- and choline-deficient diet. Fibrosis severity, hepatocyte injury, and cytokine secretion were evaluated via histology, biochemical assays, and molecular analyses in isolated hepatocytes. In vitro experiments were conducted in primary hepatocytes and Huh7 cells using lentiviral overexpression and knockdown of NRP-1. Chromatin immunoprecipitation and dual-luciferase reporter assays were performed to analyze transcription factor binding to the NRP-1 promoter.</p><p><strong>Results: </strong>Hepatocyte NRP-1 expression increased significantly during liver fibrosis and was positively correlated with HGF/c-Met expression and fibrosis severity. In vivo, NRP-1 inhibition reduced extracellular matrix accumulation and abnormal angiogenesis in Alb-Cre NRP-1<sup>f/f</sup> mice. In vitro, NRP-1 blockade inhibited c-Met activation and reduced transforming growth factor-beta and vascular endothelial growth factor secretion in hepatocytes. NRP-1 functioned as a co-receptor for HGF/c-Met, with HGF upregulating NRP-1 expression at transcript and protein levels. NRP-1 promoted fibrosis through the Met/extracellular signal-regulated kinase pathway. Furthermore, HGF increased retinoic acid receptor alpha expression, promoting NRP-1 transcription.</p><p><strong>Conclusions: </strong>HGF-induced upregulation of hepatocyte NRP-1, mediated by RARA binding to its promoter, drives liver fibrosis through c-Met pathway activation, highlighting NRP-1 as a potential therapeutic target for liver fibrosis.</p>\",\"PeriodicalId\":16059,\"journal\":{\"name\":\"Journal of Gastroenterology\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":6.9000,\"publicationDate\":\"2025-05-26\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Gastroenterology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1007/s00535-025-02262-8\",\"RegionNum\":2,\"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":"Journal of Gastroenterology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s00535-025-02262-8","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
Interaction of neuropilin-1 and hepatocyte growth factor/C-Met pathway in liver fibrosis progression in hepatocyte-specific NRP-1 knockout mice.
Background: Hepatocyte growth factor (HGF)/c-Met signaling critically influences liver fibrosis, but its interaction with neuropilin-1 (NRP-1) in hepatocytes remains unclear. We investigated the role of hepatocyte-specific NRP-1 deletion in liver fibrosis progression and its relationship with the HGF/c-Met pathway.
Methods: Hepatocyte-specific NRP-1 knockout mice were generated using the Cre-lox system, and liver fibrosis was induced by carbon tetrachloride injections or a methionine- and choline-deficient diet. Fibrosis severity, hepatocyte injury, and cytokine secretion were evaluated via histology, biochemical assays, and molecular analyses in isolated hepatocytes. In vitro experiments were conducted in primary hepatocytes and Huh7 cells using lentiviral overexpression and knockdown of NRP-1. Chromatin immunoprecipitation and dual-luciferase reporter assays were performed to analyze transcription factor binding to the NRP-1 promoter.
Results: Hepatocyte NRP-1 expression increased significantly during liver fibrosis and was positively correlated with HGF/c-Met expression and fibrosis severity. In vivo, NRP-1 inhibition reduced extracellular matrix accumulation and abnormal angiogenesis in Alb-Cre NRP-1f/f mice. In vitro, NRP-1 blockade inhibited c-Met activation and reduced transforming growth factor-beta and vascular endothelial growth factor secretion in hepatocytes. NRP-1 functioned as a co-receptor for HGF/c-Met, with HGF upregulating NRP-1 expression at transcript and protein levels. NRP-1 promoted fibrosis through the Met/extracellular signal-regulated kinase pathway. Furthermore, HGF increased retinoic acid receptor alpha expression, promoting NRP-1 transcription.
Conclusions: HGF-induced upregulation of hepatocyte NRP-1, mediated by RARA binding to its promoter, drives liver fibrosis through c-Met pathway activation, highlighting NRP-1 as a potential therapeutic target for liver fibrosis.
期刊介绍：
The Journal of Gastroenterology, which is the official publication of the Japanese Society of Gastroenterology, publishes Original Articles (Alimentary Tract/Liver, Pancreas, and Biliary Tract), Review Articles, Letters to the Editors and other articles on all aspects of the field of gastroenterology. Significant contributions relating to basic research, theory, and practice are welcomed. These publications are designed to disseminate knowledge in this field to a worldwide audience, and accordingly, its editorial board has an international membership.
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
