Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis
Abstract This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)–signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative...
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2017-05-01
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doaj-3d50e6bc0e2648bebc05dad65df544e82020-12-08T01:53:51ZengNature Publishing GroupScientific Reports2045-23222017-05-017111110.1038/s41598-017-01572-zSrc-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosisTung-Hung Su0Chung-Wai Shiau1Ping Jao2Nian-Jie Yang3Wei-Tien Tai4Chun-Jen Liu5Tai-Chung Tseng6Hung-Chih Yang7Chen-Hua Liu8Kai-Wen Huang9Ting-Chen Hu10Yu-Jen Huang11Yao-Ming Wu12Li-Ju Chen13Pei-Jer Chen14Ding-Shinn Chen15Kuen-Feng Chen16Jia-Horng Kao17Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalInstitute of Biopharmaceutical Sciences, National Yang-Ming UniversityDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalNational Center of Excellence for Clinical Trial and Research, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalDepartment of Internal Medicine, National Taiwan University Hospital Jinshan BranchDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalHepatitis Research Center, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalDepartment of Surgery, National Taiwan University HospitalDepartment of Surgery, National Taiwan University HospitalNational Center of Excellence for Clinical Trial and Research, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalNational Center of Excellence for Clinical Trial and Research, National Taiwan University HospitalDivision of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University HospitalAbstract This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)–signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1–STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery.https://doi.org/10.1038/s41598-017-01572-z |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tung-Hung Su Chung-Wai Shiau Ping Jao Nian-Jie Yang Wei-Tien Tai Chun-Jen Liu Tai-Chung Tseng Hung-Chih Yang Chen-Hua Liu Kai-Wen Huang Ting-Chen Hu Yu-Jen Huang Yao-Ming Wu Li-Ju Chen Pei-Jer Chen Ding-Shinn Chen Kuen-Feng Chen Jia-Horng Kao |
spellingShingle |
Tung-Hung Su Chung-Wai Shiau Ping Jao Nian-Jie Yang Wei-Tien Tai Chun-Jen Liu Tai-Chung Tseng Hung-Chih Yang Chen-Hua Liu Kai-Wen Huang Ting-Chen Hu Yu-Jen Huang Yao-Ming Wu Li-Ju Chen Pei-Jer Chen Ding-Shinn Chen Kuen-Feng Chen Jia-Horng Kao Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis Scientific Reports |
author_facet |
Tung-Hung Su Chung-Wai Shiau Ping Jao Nian-Jie Yang Wei-Tien Tai Chun-Jen Liu Tai-Chung Tseng Hung-Chih Yang Chen-Hua Liu Kai-Wen Huang Ting-Chen Hu Yu-Jen Huang Yao-Ming Wu Li-Ju Chen Pei-Jer Chen Ding-Shinn Chen Kuen-Feng Chen Jia-Horng Kao |
author_sort |
Tung-Hung Su |
title |
Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis |
title_short |
Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis |
title_full |
Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis |
title_fullStr |
Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis |
title_full_unstemmed |
Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis |
title_sort |
src-homology protein tyrosine phosphatase-1 agonist, sc-43, reduces liver fibrosis |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2017-05-01 |
description |
Abstract This study aimed to investigate the role of src-homology protein tyrosine phosphatase-1 (SHP-1)–signal transducer and activator of transcription 3 (STAT3) pathway in liver fibrogenesis and the anti-fibrotic effect of SHP-1 agonist. The antifibrotic activity of SC-43, a sorafenib derivative with an enhanced SHP-1 activity, was evaluated in two fibrosis mouse models by carbon tetrachloride induction and bile duct ligation. Rat, human, and primary mouse hepatic stellate cells (HSCs) were used for mechanistic investigations. The results showed that SHP-1 protein primarily localized in fibrotic areas of human and mouse livers. SC-43 treatment reduced the activated HSCs and thus effectively prevented and regressed liver fibrosis in both fibrosis mouse models and improved mouse survival. In vitro studies revealed that SC-43 promoted HSC apoptosis, increased the SHP-1 activity and inhibited phospho-STAT3. The enhanced SHP-1 activity in HSCs significantly inhibited HSC proliferation, whereas SHP-1 inhibition rescued SC-43-induced HSC apoptosis. Furthermore, SC-43 interacted with the N-SH2 domain of SHP-1 to enhance the activity of SHP-1 as its antifibrotic mechanism. In conclusion, the SHP-1–STAT3 pathway is crucial in fibrogenesis. SC-43 significantly ameliorates liver fibrosis through SHP-1 upregulation. A SHP-1-targeted antifibrotic therapy may represent a druggable strategy for antifibrotic drug discovery. |
url |
https://doi.org/10.1038/s41598-017-01572-z |
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