Rosiglitazone Inhibits Activation of Hepatic Stellate Cells via Up-Regulating Micro-RNA-124-3p to Alleviate Hepatic Fibrosis
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The activation of hepatic stellate cells (HSCs) is involved in hepatic fibrogenesis and is regulated by the decreased expression of peroxisome proliferator-activated receptor γ (PPARγ). Rosiglitazone (RGZ) is a highly potent agonist of PPARγ.
To clarify molecular regulatory mechanism of RGZ in the activation of HSCs in hepatic fibrosis.
A mouse model of hepatic fibrosis was established by carbon tetrachloride with or without RGZ intervention. A vector carrying pcDNA-HOTAIR was constructed and injected into a mouse model. HSCs were isolated from liver tissue and activated by transforming growth factor-β. The expression of miR-124-3p, HOTAIR, Col1A1, α-SMA, and PPARγ mRNAs was measured by quantitative real-time PCR. The level of PPARγ was measured by Western blotting. The interaction between HOTAIR and PPARγ was assessed by RNA immunoprecipitation (RIP) and RNA pull-down. The target gene of miR-124-3p was determined by luciferase reporter assay and RNA interference approaches.
The expression of Col1A1 and α-SMA was reduced after RGZ intervention. Different expressions of HOTAIR and miR-124-3p were observed in liver tissue and HSCs. The luciferase reporter assay and RNA interference approaches indicated that miR-124-3p negatively regulated HOTAIR expression. RIP and RNA pull-down results revealed that PPARγ was interacted by HOTAIR. The therapeutic effect of RGZ on hepatic fibrosis was reversed by overexpression of HOTAIR.
RGZ inhibits the activation of HSCs by up-regulating miR-124-3p. The silencing of HOTAIR by miR-124-3p in HSC activation provided the foundation to understand interactions of ncRNAs and potential treatment target in hepatic fibrosis.
KeywordsHepatic fibrosis HOTAIR MiR-124-3p PPARγ Rosiglitazone
This study was funded by Zhejiang Provincial Natural Science Foundation (Grant Number: LY16H030014) and Zhejiang Provincial Medical Technology Project (Grant Number: 2019KY104) and Zhejiang Provincial Science Technology Project (Grant Number: 2015C37101).
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This study was approved by the Institutional Ethics Committee of the First Affiliated Hospital of Wenzhou Medical University. All of these experiments in the current research were in compliance with the government policies and defined protocols.
Informed consent was obtained from all individual participants included in the study.
Availability of data and material
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
- 3.Hsu W-H, Lee BH, Hsu YW, Pan TM. Peroxisome proliferator-activated receptor-gamma activators monascin and rosiglitazone attenuate carboxymethyllysine-induced fibrosis in hepatic stellate cells through regulating the oxidative stress pathway but independent of the receptor for advanced glycation end products signaling. J Agric Food Chem. 2013;61:6873–6879.CrossRefGoogle Scholar
- 9.Asano T, Yamazaki H, Kasahara C, et al. Identification, synthesis, and biological evaluation of 6-[(6R)-2-(4-fluorophenyl)-6-(hydroxymethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyr imidin-3-yl]-2-(2-methylphenyl)pyridazin-3(2H)-one (AS1940477), a potent p38 MAP kinase inhibitor. J Med Chem. 2012;55:7772–7785.CrossRefGoogle Scholar
- 17.Wang Y, Hu M. Peroxisome proliferators activated receptor γ protects against acute lung injury alveolar macrophages inflammation by upregulating miR-124 expression. Chin J Lung Dis. 2015;8:160–165.Google Scholar
- 18.Carninci P, Kasukawa T, Katayama S, et al. The transcriptional landscape of the mammalian genome. SPJ. 2005;309:1559–1563.Google Scholar