A novel role of glutathione S-transferase A3 in inhibiting hepatic stellate cell activation and rat hepatic fibrosis

Abstract

Background and aims Glutathione S -transferase A3 (GSTA3) is known as an antioxidative protease, however, the crucial role of GSTA3 in liver fibrosis remains unclear. As a recently we developed water-soluble pyridone agent with antifibrotic features, fluorofenidone (AKF-PD) can attenuate liver fibrosis, present studies were designed to explore the role of GSTA3 in liver fibrosis and its modulation by AKF-PD in vivo and in vitro. Methods Rats liver fibrosis models were induced by dimethylnitrosamine (DMN) or carbon tetrachloride (CCl4). The two activated hepatic stellate cells (HSCs) lines, rat CFSC-2G and human LX2 were treated with AKF-PD respectively. The lipid peroxidation byproduct malondialdehyde (MDA) in rat serum was determined by ELISA. The accumulation of reactive oxygen species (ROS) was measured by dichlorodihydrofluorescein fluorescence analysis. The expression of α-smooth muscle actin (α-SMA), fibronectin (FN), and phosphorylation of extracellular signal-regulated kinase1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK) and glycogen synthase kinase 3 beta (GSK-3β) were detected by western blotting (WB). Results GSTA3 was substantially reduced in the experimental fibrotic livers and transdifferentiated HSCs. AKF-PD alleviated rat hepatic fibrosis and potently inhibited HSCs activation correlated with restoring GSTA3. Moreover, GSTA3 overexpression prevented HSCs activation and fibrogenesis, while GSTA3 knockdown enhanced HSCs activation and fibrogenesis resulted from increasing accumulation of ROS and subsequent amplified MAPK signaling and GSK-3β phosphorylation. Conclusions We demonstrated firstly that GSTA3 inhibited HSCs activation and liver fibrosis through suppression of the MAPK and GSK-3β signaling pathways. GSTA3 may represent a promising target for potential therapeutic intervention in liver fibrotic diseases.

A model of twenty-three metabolic-related genes predicting overall survival for lung adenocarcinoma

“…In our twenty-three gene prognosis model, several metabolic genes, including GSTA3, ENTPD2, HK3, CHPT1, CTPS2, and ADCY9, were confirmed for the first time to be correlated with the prognosis of LUAD. GSTA3 is recognized as an antioxidative protease (Chen et al, 2019a). Studies of genetic analysis models and the mechanism of GSTA3 found that it was associated with tumour prognosis (Bruzzoni-Giovanelli et al, 2015).…”

“…For example, GSTA3 was identified and regarded as a prognostic biomarker for nasopharyngeal carcinoma and gastric cancer ( Duan et al, 2018 ; Zhang, Wu & Cheng, 2019 ). GSTA3 inhibits HSC activation and liver fibrosis by inhibiting MAPK and GSK-3 β signalling pathways, suggesting that GSTA3 could be a feasible target for therapeutic interventions for liver fibrosis ( Chen et al, 2019a ). GSTA3 overexpression in breast cancer cells stimulates proliferation and inhibits apoptosis, which leads to chemotherapy resistance and radiation resistance in tumour cells ( Thewes et al, 2010 ).…”

Peer Review #1 of "A model of twenty-three metabolic-related genes predicting overall survival for lung adenocarcinoma (v0.1)"

“…Manuscript to be reviewed In our twenty-three gene prognosis model, several metabolic genes, including GSTA3, ENTPD2, HK3, CHPT1, CTPS2, and ADCY9, were confirmed for the first time to be correlated with the prognosis of LUAD. GSTA3 is recognized as an antioxidative protease (Chen et al,2019a). Studies of genetic analysis models and the mechanism of GSTA3 found that it was associated with tumour prognosis (Bruzzoni-Giovanelli et al,2015).…”

“…For example, GSTA3 was identified and regarded as a prognostic biomarker for nasopharyngeal carcinoma and gastric cancer (Duan et al,2018;Zhang Wu & Cheng,2019). GSTA3 inhibits HSC activation and liver fibrosis by inhibiting MAPK and GSK-3β signalling pathways, suggesting that GSTA3 could be a feasible target for therapeutic interventions for liver fibrosis (Chen et al,2019a). GSTA3 overexpression in breast cancer cells stimulates proliferation and inhibits apoptosis, which leads to chemotherapy resistance and radiation resistance in tumour cells (Thewes et al,2010).…”

Glycogen synthase kinase-3β: a promising candidate in the fight against fibrosis

“…Acetaldehyde stimulates GSK-3β phosphorylation at Ser9 and promotes ROS accumulation, which exacerbates the fibrogenic pathway in human HSC 77 . Glutathione S-transferase A3 (GSTA3) is regarded as an anti-oxidative protease, Chen et al 78 discovered that GSTA3 suppresses intracellular ROS accumulation and further mitigates CCl 4 -induced fibrotic livers in rat models by activating GSK-3β, which results in potently blocked the expression of the α-SMA and FN. Besides, HG stimulates ROS production, leading to the inhibition of GSK-3β and the promotion of EMT process.…”