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Phytomedicine

Phytomedicine

IF: 6.7
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Ginsenoside compound K restrains hepatic fibrotic response by dual-inhibition of GLS1 and LDHA

Published:8 November 2024 DOI: 10.1016/j.phymed.2024.156223 PMID: 39561660
Wen-hui Wu , Ya-Lan Yang , Ting Wang , Xiao-Meng Sun , Meng-Guang Wei , Xin-Yue Zhou , Li-Zeng Zhu , Gaoxiang Ma , Baolin Liu , Lian-Wen Qi , Qun Liu

Abstract

Background

Liver fibrosis is a dynamic process marked by the accumulation of extracellular matrix due to hepatic stellate cells (HSCs) activation. Ginsenoside compound K (CK), a rare derivative of its parent ginsenosides, is known to significantly ameliorate metabolic disorders.

Purpose

The aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation.

Methods

We established liver fibrosis models in mice using carbon tetrachloride (CCl4) challenge, bile duct ligation, or a methionine-choline deficient diet, with continuous oral administration of CK at specified doses and intervals. Simultaneously, we examined the impact of CK on metabolic regulation in cultured HSCs and investigated the associated mechanisms.

Results

CK was found to alleviate liver injury and curb fibrotic responses in mouse models, as well as decrease elevated levels of liver enzyme. Metabolomic analysis in vitro highlighted the crucial roles of pyruvate and glutamine metabolism in metabolic remodeling. Immunohistochemical staining indicated significantly elevated expressions of lactate dehydrogenase A (LDHA) (p = 0.014) and glutaminase 1 (GLS1) (p = 0.024) in liver cirrhosis patients. Comparable alterations were noted in the liver of model mice and in cultured HSCs. Molecular docking and bio-layer interferometry demonstrated that CK interacts with and inhibits the activities of LDHA and GLS1. As expected, CK attenuated glycolysis and glutaminolysis, reducing HSC growth dependently on lactate and α-ketoglutarate (α-KG). Upon HSC activation, metabolism is reprogrammed with Myc as a key regulator, transcriptionally controlling LDHA, GLS1, and glutamine transporters SLC1A5 and SLC38A5. CK inhibited Myc induction, integrating glycolysis and glutaminolysis regulation to counteract the fibrotic response.

Conclusion

CK inhibited LDHA and GLS1 activities, thereby inhibiting hepatic fibrosis. These findings offer new insights into the role of ginsenosides in liver protection, especially regarding metabolic disorders.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Dimethyl 2-oxoglutarate 13192-04-6 C7H10O5 206 suppliers $10.00-$1880.00
Dimethyl 2-oxoglutarate 13192-04-6 C7H10O5 206 suppliers $10.00-$1880.00
Dimethyl 2-oxoglutarate 13192-04-6 C7H10O5 206 suppliers $10.00-$1880.00
Dimethyl 2-oxoglutarate 13192-04-6 C7H10O5 206 suppliers $10.00-$1880.00

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