Inhibitory Effect of Sestrin 2 on Hepatic Stellate Cell Activation and Liver Fibrosis.

Abstract

Aims: Hepatic fibrosis results from chronic liver injury and inflammatory responses. Sestrin 2 (Sesn2), an evolutionarily conserved antioxidant enzyme, reduces the severities of acute hepatitis and metabolic liver diseases. However, the role of Sesn2 in the pathogenesis of liver fibrosis remains obscure. Here, we used cultured hepatic stellate cells (HSCs) and chronic carbon tetrachloride (CCl4) and bile duct ligation (BDL) murine models to investigate the effects of Sesn2 on fibrogenesis. Results: Sesn2 protein and mRNA levels were upregulated in activated primary HSCs, and by increasing transcription, transforming growth factor-β (TGF-β) also increased Sesn2 expression in HSCs. Furthermore, Smad activation was primarily initiated by TGF-β signaling, and Smad3 activation increased Sesn2 luciferase activity. In silico analysis of the 5' upstream region of the Sesn2 gene revealed a putative Smad-binding element (SBE), and its deletion demonstrated that the SBE between -964 and -956 bp within human Sesn2 promoter was critically required for TGF-β-mediated response. Moreover, ectopic expression of Sesn2 reduced gene expressions associated with HSC activation, and this was accompanied by marked decreases in SBE luciferase activity and Smad phosphorylation. Infection of recombinant adenovirus Sesn2 reduced hepatic injury severity, as evidenced by reductions in CCl4- or BDL-induced alanine aminotransferase and aspartate aminotransferase, and inhibited collagen accumulation. Furthermore, HSC-specific lentiviral delivery of Sesn2 prevented CCl4-induced liver fibrosis. Finally, Sesn2 expression was downregulated in the livers of patients with liver cirrhosis and in mouse models of hepatic fibrosis. Innovation and Conclusion: Our findings suggest that Sesn2 has the potential to inhibit HSC activation and hepatic fibrosis.

• Authors: Ji Hye Yang, Kyu Min Kim, Sam Seok Cho, Sang Mi Shin, Sun O Ka, Chang-Su Na, Byung Hyun Park, Kyung Hwan Jegal, Jae Kwang Kim, Sae Kwang Ku, Hee-Jeong Lee, Sang-Gon Park, Il Je Cho, Sung Hwan Ki
• Journal: Antioxidants & redox signaling (Antioxid Redox Signal) Vol. 31 Issue 3 Pg. 243-259 (07 20 2019) ISSN: 1557-7716 [Electronic] United States
• PMID: 30909713 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nuclear Proteins
• SESN2 protein, human
• SMAD3 protein, human
• Smad3 Protein
• Transforming Growth Factor beta
• Carbon Tetrachloride

Topics

• Animals
• Binding Sites
• Carbon Tetrachloride (adverse effects)
• Cells, Cultured
• Disease Models, Animal
• Down-Regulation
• Hepatic Stellate Cells (cytology, drug effects, metabolism)
• Humans
• Liver Cirrhosis (genetics, metabolism)
• Male
• Mice
• Nuclear Proteins (chemistry, genetics, metabolism)
• Promoter Regions, Genetic
• Smad3 Protein (metabolism)
• Transforming Growth Factor beta (pharmacology)