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Selonsertib Inhibits Liver Fibrosis via Downregulation of ASK1/ MAPK Pathway of Hepatic Stellate Cells

Biomolecules & Therapeutics 2020년 28권 6호 p.527 ~ 536
윤영찬, Fang Zhenghuan, 이지은, 박정희, 류지간, 정경희, 홍순선,
소속 상세정보
윤영찬 ( Yoon Young-Chan ) - Inha University College of Medicine Department of Biomedical Sciences
 ( Fang Zhenghuan ) - Inha University College of Medicine Department of Biomedical Sciences
이지은 ( Lee Ji-Eun ) - Inha University College of Medicine Department of Biomedical Sciences
박정희 ( Park Jung-Hee ) - Inha University College of Medicine Department of Biomedical Sciences
류지간 ( Ryu Ji-Kan ) - Inha University College of Medicine Department of Urology
정경희 ( Jung Kyung-Hee ) - Inha University College of Medicine Department of Biomedical Sciences
홍순선 ( Hong Soon-Sun ) - Inha University College of Medicine Department of Biomedical Sciences

Abstract


Liver fibrosis constitutes a significant health problem worldwide due to its rapidly increasing prevalence and the absence of specific and effective treatments. Growing evidence suggests that apoptosis-signal regulating kinase 1 (ASK1) is activated in oxidative stress, which causes hepatic inflammation and apoptosis, leading to liver fibrogenesis through a mitogen-activated protein kinase (MAPK) downstream signals. In this study, we investigated whether selonsertib, a selective inhibitor of ASK1, shows therapeutic efficacy for liver fibrosis, and elucidated its mechanism of action in vivo and in vitro. As a result, selonsertib strongly suppressed the growth and proliferation of hepatic stellate cells (HSCs) and induced apoptosis by increasing Annexin V and TUNEL-positive cells. We also observed that selonsertib inhibited the ASK1/MAPK pathway, including p38 and c-Jun N-terminal kinase (JNK) in HSCs. Interestingly, dimethylnitrosamine (DMN)-induced liver fibrosis was significantly alleviated by selonsertib treatment in rats. Furthermore, selonsertib reduced collagen deposition and the expression of extracellular components such as α-smooth muscle actin (α-SMA), fibronectin, and collagen type I in vitro and in vivo. Taken together, selonsertib suppressed fibrotic response such as HSC proliferation and extracellular matrix components by blocking the ASK1/MAPK pathway. Therefore, we suggest that selonsertib may be an effective therapeutic drug for ameliorating liver fibrosis.

키워드

Liver fibrosis; ASK1; Selonsertib; MAPK

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