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Premium Sestrin2 Inhibited the Activation of Hepatic Stellate cells and Liver Fibrosis via Blocking Transforming Growth Factor‐β Signaling
Yang Ji Hye,
Ki Sung Hwan
Publication year2017
Publication title
the faseb journal
Resource typeJournals
PublisherThe Federation of American Societies for Experimental Biology
Hepatic fibrosis results from chronic liver injury and inflammatory responses. Sestrin2 (Sesn2), an evolutionally conserved antioxidant proteins, prevents acute hepatitis and metabolic liver diseases. However, the role of Sesn2 in the pathogenesis of hepatic fibrosis remains obscure. In the current study, we first investigated whether Sesn2 protects fibrogenesis in cultured hepatic stellate cells (HSC) or in chronic carbon tetrachloride (CCl 4 )‐treated or bile duct ligation (BDL)‐performed mice. Activated primary HSC up‐regulates the levels of Sesn2 protein and mRNA. Transforming growth factor‐β (TGF‐β) also increased Sesn2 expression in cultured HSC, which was due to increased transcription. TGF‐β signaling occurs primarily by activation of Smad proteins and overexpressed Smad3 increased Sesn2 luciferase activity. In silico analysis of the 5′ upstream region of Sesn2 gene identified a putative Smad binding element (SBE) sequence. Deletion of the putative SBE demonstrated in the human Sesn2 promoter was critical for the TGF‐β‐mediated response. Moreover, ectopic expression of Sesn2 reduces epithelial‐mesenchymal transition (EMT) markers, which is accompanied with a marked decrease in SBE luciferase activity and Smad phosporylation. A recombinant adenovirus Sens2 (Ad‐Sesn2) administration presents less severe hepatic injury as supported by decreases in CCl 4 ‐or BDL‐induced ALT/AST levels. Furthermore, Ad‐Sesn2 reduced liver injury and collagen accumulation. Finally, expression of Sesn2 is down‐regulated in the livers from patients with liver cirrhosis or CCl 4 ‐or BDL‐induced hepatic fibrosis mice. Taken together, our findings suggest that Sesn2 protects HSC activation and hepatic fibrosis via antagonizing TGF‐β signaling. Support or Funding Information This research was supported by the National Research Foundation of Korea (NRF) funded by the Ministry of science, ICT & Future Planning (No. R13‐2008‐010‐‐0)
SCImago Journal Rank1.709

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