20(S)- Protopanaxadiol suppresses hepatic stellate cell activation via WIF1 demethylation-mediated inactivation of the Wnt/β-catenin pathway

Chunxue Li; Yating Zhan; Rongrong Zhang; Qiqi Tao; Zhichao Lang; Jianjian Zheng

Journal of Ginseng Research (Jul 2023)

20(S)- Protopanaxadiol suppresses hepatic stellate cell activation via WIF1 demethylation-mediated inactivation of the Wnt/β-catenin pathway

Chunxue Li,
Yating Zhan,
Rongrong Zhang,
Qiqi Tao,
Zhichao Lang,
Jianjian Zheng

Affiliations

Chunxue Li: Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Yating Zhan: Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Rongrong Zhang: Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Qiqi Tao: Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Zhichao Lang: Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Jianjian Zheng: Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Corresponding author. Key Laboratory of Clinical Laboratory Diagnosis and Translational Research of Zhejiang Province, Key Laboratory of Surgery, The First Affiliated Hospital of Wenzhou Medical University, No.2 fuxue lane, Wenzhou, Zhejiang, PR China.

Journal volume & issue: Vol. 47, no. 4
pp. 515 – 523

Abstract

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Background: 20(S)-protopanaxadiol (PPD), one of the main components of ginseng, has anti-inflammatory, anti-estrogenic, and anti-tumor activities. It is known that activated hepatic stellate cells (HSCs) are the primary producers of extracellular matrix (ECM) in the liver, and the Wnt/β-catenin pathway participates in the activation of HSCs. We aimed to explore whether PPD inhibits liver fibrosis is associated with the Wnt/β-catenin pathway inactivation. Methods: The anti-fibrotic roles of PPD were examined both in vitro and in vivo. We also examined the levels of Wnt inhibitory factor 1 (WIF1), DNA methyltransferase 1 (DNMT1) and WIF1 methylation. Results: PPD obviously ameliorated liver fibrosis in carbon tetrachloride (CCl4)-treated mice and reduced collagen deposition. PPD also suppressed the activation and proliferation of primary HSCs. Notably, PPD inhibited the Wnt/β-catenin pathway, reduced TCF activity, and increased P-β-catenin and GSK-3β levels. Interestingly, WIF1 was found to mediate the inactivation of the Wnt/β-catenin pathway in PPD-treated HSCs. WIF1 silencing suppressed the inhibitory effects of PPD on HSC activation and also restored α-SMA and type I collagen levels. The downregulation of WIF1 expression was associated with the methylation of its promoter. PPD induced WIF1 demethylation and restored WIF1 expression. Further experiments confirmed that DNMT1 overexpression blocked the effects of PPD on WIF1 expression and demethylation and enhanced HSC activation. Conclusion: PPD up-regulates WIF1 levels and impairs Wnt/β-catenin pathway activation via the down-regulation of DNMT1-mediated WIF1 methylation, leading to HSC inactivation. Therefore, PPD may be a promising therapeutic drug for patients with liver fibrosis.

Published in Journal of Ginseng Research

ISSN: 1226-8453 (Print)
Publisher: Elsevier
Country of publisher: Korea, Republic of
LCC subjects: Science: Botany
Website: http://www.journals.elsevier.com/journal-of-ginseng-research/

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