GATA3 promotes the autophagy and activation of hepatic stellate cell in hepatic fibrosis via regulating miR-370/HMGB1 pathway
GASTROENTEROLOGIA Y HEPATOLOGIA(2024)
摘要
Background: Hepatic fibrosis (HF) is a common result of the repair process of various chronic liver diseases. Hepatic stellate cells (HSCs) activation is the central link in the occurrence of HF. Methods: ELISA and histological analysis were performed to detect the pathological changes of liver tissues. In vitro, HSCs were treated with TGF-01 as HF cell model. Combination of GATA-binding protein 3 (GATA3) and miR-370 gene promoter was ensured by ChIP and luciferase reporter assay. Autophagy was monitored by observing the GFP-LC3 puncta formation. The interaction between miR-370 and high mobility group box 1 protein (HMGB1) was verified by luciferase reporter assay. Results: CCl4-induced HF mice exhibited an increase of ALT and AST, and severe damage and fibrosis of liver tissues. GATA3 and HMGB1 were up-regulated, and miR-370 was down-regulated in CCl4-induced HF mice and activated HSCs. GATA3 enhanced expression of the autophagyrelated proteins and activation markers in the activated HSCs. Inhibition of autophagy partly reversed GATA3-induced activation of HSCs and the promotion of GATA3 to hepatic fibrosis. Moreover, GATA3 suppressed miR-370 expression via binding with its promotor, and enhanced HMGB1 expression in HSCs. Increasing of miR-370 inhibited HMGB1 expression by directly targeting its mRNA 3'-UTR. The promotion of GATA3 to TGF-01-induced HSCs autophagy and activation was abrogated by miR-370 up-regulation or HMGB1 knockdown. Conclusions: This work demonstrates that GATA3 promotes autophagy and activation of HSCs by regulating miR-370/HMGB1 signaling pathway, which contributes to accelerate HF. Thus, this work suggests that GATA3 may be a potential target for prevention and treatment of HF. (c) 2023 Elsevier Espan similar to a, S.L.U. All rights reserved.
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关键词
Hepatic fibrosis,GATA3,HMGB1,Hepatic stellate cell,Autophagy
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