2. Academic Validation
  3. Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis

Src-homology protein tyrosine phosphatase-1 agonist, SC-43, reduces liver fibrosis

  • Sci Rep. 2017 May 11;7(1):1728. doi: 10.1038/s41598-017-01572-z.
Tung-Hung Su 1 2 3,  Chung-Wai Shiau 4,  Ping Jao 1,  Nian-Jie Yang 1,  Wei-Tien Tai 5,  Chun-Jen Liu 1 2 3,  Tai-Chung Tseng 6,  Hung-Chih Yang 1,  Chen-Hua Liu 1 2,  Kai-Wen Huang 2 7,  Ting-Chen Hu 1,  Yu-Jen Huang 7,  Yao-Ming Wu 7,  Li-Ju Chen 5 8,  Pei-Jer Chen 1 2 3,  Ding-Shinn Chen 1 2 3 9,  Kuen-Feng Chen 10 11,  Jia-Horng Kao 12 13 14 15
Affiliations

Affiliations

  • 1 Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10002, Taiwan.
  • 2 Hepatitis Research Center, National Taiwan University Hospital, Taipei, 10002, Taiwan.
  • 3 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 10002, Taiwan.
  • 4 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, 11221, Taiwan.
  • 5 National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, 10002, Taiwan.
  • 6 Department of Internal Medicine, National Taiwan University Hospital Jinshan Branch, New Taipei City, 20844, Taiwan.
  • 7 Department of Surgery, National Taiwan University Hospital, Taipei, 10002, Taiwan.
  • 8 Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, Taiwan.
  • 9 Genomics Research Center, Academia Sinica, Taipei, Nankang, 11529, Taiwan.
  • 10 National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, 10002, Taiwan. kfchen1970@ntu.edu.tw.
  • 11 Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, Taiwan. kfchen1970@ntu.edu.tw.
  • 12 Division of Gastroenterology and Hepatology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 10002, Taiwan. kaojh@ntu.edu.tw.
  • 13 Hepatitis Research Center, National Taiwan University Hospital, Taipei, 10002, Taiwan. kaojh@ntu.edu.tw.
  • 14 Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine, Taipei, 10002, Taiwan. kaojh@ntu.edu.tw.
  • 15 Department of Medical Research, National Taiwan University Hospital, Taipei, 10002, Taiwan. kaojh@ntu.edu.tw.
PMID: 28496142 DOI: 10.1038/s41598-017-01572-z
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z