Sestrin 2 Attenuates Rat Hepatic Stellate Cell (HSC) Activation and Liver Fibrosis via an mTOR/AMPK-Dependent Mechanism

Abstract

Background/Aims: Sestrin 2 is associated with the pathophysiology of several diseases. The aim of this study was to investigate the effects and potential mechanisms of Sestrin 2 in rat hepatic stellate cells (HSCs) during liver fibrogenesis. Methods: In this study, Sestrin 2 protein expression was detected in rat HSC-T6 cells challenged with transforming growth factor-β (TGF-β) and in mice treated with carbon tetrachloride (CCl₄), a well-known model of hepatic fibrosis. Next, HSC-T6 cells and fibrotic mice were transfected with lentivirus. The mRNA expression levels of markers of liver fibrosis [alpha-smooth muscle actin (α-SMA) and collagen 1A1 (Col1A1)] were analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR). Cell death and proliferation were evaluated by the MTT assay, and biochemical markers of liver damage in serum [alanine transaminase (ALT) and aspartate transaminase (AST)] were also measured using a biochemical analyzer. Histopathological examination was used to evaluate the degree of liver fibrosis, and protein expression [phospho-adenosine monophosphate-activated protein kinase (p-AMPK), AMPK, phospho-mammalian target of rapamycin (p-mTOR), and mTOR] was determined by western blotting. Results: We found that Sestrin 2 was elevated in both the HSC-T6 cell and hepatic fibrosis models. In vitro, overexpression of Sestrin 2 attenuated the mRNA levels of α-SMA and Col1A1, suppressed α-SMA protein expression, and modulated HSC-T6 cell proliferation. In vivo, overexpression of Sestrin 2 reduced the ALT and AST levels as well as the α-SMA and Col1A1 protein expression in the CCl₄ model of liver fibrosis. Moreover, the degree of liver fibrosis was ameliorated. Interestingly, overexpression of Sestrin 2 increased p-AMPK but decreased p-mTOR protein expression. Conclusion: Our findings indicate that Sestrin 2 may attenuate the activation of HSCs and ameliorate liver fibrosis, most likely via upregulation of AMPK phosphorylation and suppression of the mTOR signaling pathway.

Correlation between sestrin2 expression and airway remodeling in COPD

“…Sestrin2, a critical antioxidant protein, plays a protective role in antioxidant defense and functions to reduce intracellular reactive oxygen species (ROS) [32][33][34][35]. Emerging evidence have shown that ses-trin2 plays a vital role in the formation and development of fibrosis in many organs, including the heart, liver and kidney [8,[36][37][38]. To further explore whether sestrin2 is related to airway remodeling in COPD, immunohistochemical staining in the airway was done and showed that there was a significantly higher expression of ses-trin2 in the airway in the COPD group compared with the control group, especially in the bronchial epithelial cells, which are replete with MMP9.…”

Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

“…20 SIRT7 locates in nucleus and participated in the ribosomal RNA transcription, cell metabolism, cell stress and DNA damage repair. 21 AMPK has been proved involved in the pathophysiology of liver fibrosis, 22 and up-regulation of AMPK phosphorylation facilitated to the attenuation of liver fibrosis. 23 Interestingly, SIRT3 has been reported as a downstream effector of AMPK in several disease models, and activation of AMPK-SIRT3 signalling contributes to the improvement of mitochondrial function, thus alleviating the progress of diseases.…”

Sestrin2 Was Involved in Airway Remodeling in COPD: A Multi-level Research

“…Emerging evidence have shown that sestrin2 plays a vital role in the formation and development of brosis in many organs, including heart, liver and renal (8,(29)(30)(31). Consistent with previous reports (19,24,32), the serum concentration of MMP9 was signi cantly increased in the COPD group in our study.…”