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...
Guardado en:
| Autores principales: | , , , , , , , , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
Nature Portfolio
2017
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/3d50e6bc0e2648bebc05dad65df544e8 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:3d50e6bc0e2648bebc05dad65df544e8 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:3d50e6bc0e2648bebc05dad65df544e82021-12-02T12:32:28ZSrc-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis10.1038/s41598-017-01572-z2045-2322https://doaj.org/article/3d50e6bc0e2648bebc05dad65df544e82017-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-01572-zhttps://doaj.org/toc/2045-2322Abstract 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.Tung-Hung SuChung-Wai ShiauPing JaoNian-Jie YangWei-Tien TaiChun-Jen LiuTai-Chung TsengHung-Chih YangChen-Hua LiuKai-Wen HuangTing-Chen HuYu-Jen HuangYao-Ming WuLi-Ju ChenPei-Jer ChenDing-Shinn ChenKuen-Feng ChenJia-Horng KaoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-11 (2017) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Medicine R Science Q |
| spellingShingle |
Medicine R Science Q 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 |
| 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. |
| format |
article |
| 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 |
| 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 Portfolio |
| publishDate |
2017 |
| url |
https://doaj.org/article/3d50e6bc0e2648bebc05dad65df544e8 |
| work_keys_str_mv |
AT tunghungsu srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT chungwaishiau srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT pingjao srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT nianjieyang srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT weitientai srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT chunjenliu srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT taichungtseng srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT hungchihyang srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT chenhualiu srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT kaiwenhuang srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT tingchenhu srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT yujenhuang srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT yaomingwu srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT lijuchen srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT peijerchen srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT dingshinnchen srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT kuenfengchen srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis AT jiahorngkao srchomologyproteintyrosinephosphatase1agonistsc43reducesliverfibrosis |
| _version_ |
1718394032259858432 |