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A novel role of glutathione S-transferase A3 in inhibiting hepatic stellate cell activation and rat hepatic fibrosis.
- Source :
-
Journal of translational medicine [J Transl Med] 2019 Aug 23; Vol. 17 (1), pp. 280. Date of Electronic Publication: 2019 Aug 23. - Publication Year :
- 2019
-
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.<br />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).<br />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.<br />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.
- Subjects :
- Animals
Cell Line
Down-Regulation drug effects
Down-Regulation genetics
Glycogen Synthase Kinase 3 beta metabolism
Hepatic Stellate Cells drug effects
Liver drug effects
Liver metabolism
Liver pathology
Liver Cirrhosis pathology
Male
Mitogen-Activated Protein Kinases metabolism
Pyridones pharmacology
Rats, Wistar
Reactive Oxygen Species metabolism
Signal Transduction drug effects
Up-Regulation drug effects
Up-Regulation genetics
Glutathione Transferase metabolism
Hepatic Stellate Cells metabolism
Liver Cirrhosis enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 1479-5876
- Volume :
- 17
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Journal of translational medicine
- Publication Type :
- Academic Journal
- Accession number :
- 31443720
- Full Text :
- https://doi.org/10.1186/s12967-019-2027-8