Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells
Abstract The excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In thi...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2020-12-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-020-03271-6 |
| _version_ | 1818726356839563264 |
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| author | Zhemin Shi Kun Zhang Ting Chen Yu Zhang Xiaoxiao Du Yanmian Zhao Shuai Shao Lina Zheng Tao Han Wei Hong |
| author_facet | Zhemin Shi Kun Zhang Ting Chen Yu Zhang Xiaoxiao Du Yanmian Zhao Shuai Shao Lina Zheng Tao Han Wei Hong |
| author_sort | Zhemin Shi |
| collection | DOAJ |
| description | Abstract The excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In this study, we reported that activating transcription factor 3 (ATF3) was over-expressed in mice and human fibrotic livers, in activated HSCs and injured hepatocytes (HCs). Both in vivo and in vitro study have revealed that silencing ATF3 reduced the expression of pro-fibrotic genes and inhibited the activation of HSCs, thus alleviating the extent of liver fibrosis, indicating a potential protective role of ATF3 knockdown. However, ATF3 was not involved in either the apoptosis or proliferation of HCs. In addition, our data illustrated that increased nuclear localization of ATF3 promoted the transcription of fibrogenic genes and lnc-SCARNA10, which functioned as a novel positive regulator of TGF-β signaling in liver fibrogenesis by recruiting SMAD3 to the promoter of these genes. Interestingly, further study also demonstrated that lnc-SCARNA10 promoted the expression of ATF3 in a TGF-β/SMAD3-dependent manner, revealing a TGF-β/ATF3/lnc-SCARNA10 axis that contributed to liver fibrosis by activating HSCs. Taken together, our data provide a molecular mechanism implicating induced ATF3 in liver fibrosis, suggesting that ATF3 may represent a useful target in the development of therapeutic strategies for liver fibrosis. |
| first_indexed | 2024-12-17T21:56:55Z |
| format | Article |
| id | doaj.art-35c5684d48e947018bb4ffdf01a44f6b |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-17T21:56:55Z |
| publishDate | 2020-12-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-35c5684d48e947018bb4ffdf01a44f6b2022-12-21T21:31:05ZengNature Publishing GroupCell Death and Disease2041-48892020-12-01111211610.1038/s41419-020-03271-6Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cellsZhemin Shi0Kun Zhang1Ting Chen2Yu Zhang3Xiaoxiao Du4Yanmian Zhao5Shuai Shao6Lina Zheng7Tao Han8Wei Hong9Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical UniversityDepartment of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Hepatology and Gastroenterology, Tianjin Third Central Hospital Affiliated to Nankai UniversityDepartment of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityDepartment of Hepatology and Gastroenterology, The Third Central Clinical College of Tianjin Medical UniversityDepartment of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical UniversityAbstract The excessive accumulation of extracellular matrix (ECM) is a key feature of liver fibrosis and the activated hepatic stellate cells (HSCs) are the major producer of ECM proteins. However, the precise mechanisms and target molecules that are involved in liver fibrosis remain unclear. In this study, we reported that activating transcription factor 3 (ATF3) was over-expressed in mice and human fibrotic livers, in activated HSCs and injured hepatocytes (HCs). Both in vivo and in vitro study have revealed that silencing ATF3 reduced the expression of pro-fibrotic genes and inhibited the activation of HSCs, thus alleviating the extent of liver fibrosis, indicating a potential protective role of ATF3 knockdown. However, ATF3 was not involved in either the apoptosis or proliferation of HCs. In addition, our data illustrated that increased nuclear localization of ATF3 promoted the transcription of fibrogenic genes and lnc-SCARNA10, which functioned as a novel positive regulator of TGF-β signaling in liver fibrogenesis by recruiting SMAD3 to the promoter of these genes. Interestingly, further study also demonstrated that lnc-SCARNA10 promoted the expression of ATF3 in a TGF-β/SMAD3-dependent manner, revealing a TGF-β/ATF3/lnc-SCARNA10 axis that contributed to liver fibrosis by activating HSCs. Taken together, our data provide a molecular mechanism implicating induced ATF3 in liver fibrosis, suggesting that ATF3 may represent a useful target in the development of therapeutic strategies for liver fibrosis.https://doi.org/10.1038/s41419-020-03271-6 |
| spellingShingle | Zhemin Shi Kun Zhang Ting Chen Yu Zhang Xiaoxiao Du Yanmian Zhao Shuai Shao Lina Zheng Tao Han Wei Hong Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells Cell Death and Disease |
| title | Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells |
| title_full | Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells |
| title_fullStr | Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells |
| title_full_unstemmed | Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells |
| title_short | Transcriptional factor ATF3 promotes liver fibrosis via activating hepatic stellate cells |
| title_sort | transcriptional factor atf3 promotes liver fibrosis via activating hepatic stellate cells |
| url | https://doi.org/10.1038/s41419-020-03271-6 |
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