State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China; Clinical Metabolomics Center, China Pharmaceutical University, Nanjing 210009, China.
Department of Pathology, The Affiliated Drum Tower Hospital, Nanjing University Medical School, Nanjing 210009, China.
Phytomedicine. 2024 Dec;135:156223. doi: 10.1016/j.phymed.2024.156223. Epub 2024 Nov 8.
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.
The aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation.
We established liver fibrosis models in mice using carbon tetrachloride (CCl) 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.
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.
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.
肝纤维化是一种动态过程，其特征是由于肝星状细胞（HSCs）激活而导致细胞外基质的积累。人参皂苷化合物 K（CK）是其母体人参皂苷的一种罕见衍生物，已知可显著改善代谢紊乱。
本研究旨在阐明 CK 对肝纤维化的保护作用，重点是代谢调节。
我们使用四氯化碳（CCl）挑战、胆管结扎或蛋氨酸-胆碱缺乏饮食在小鼠中建立肝纤维化模型，并以特定剂量和间隔连续口服 CK。同时，我们检查了 CK 对培养的 HSCs 代谢调节的影响，并研究了相关机制。
CK 减轻了小鼠模型中的肝损伤和纤维化反应，并降低了升高的肝酶水平。体外代谢组学分析强调了丙酮酸和谷氨酰胺代谢在代谢重塑中的关键作用。免疫组织化学染色表明，肝硬化患者的乳酸脱氢酶 A（LDHA）（p=0.014）和谷氨酰胺酶 1（GLS1）（p=0.024）表达显著升高。在模型小鼠的肝脏和培养的 HSCs 中也观察到类似的变化。分子对接和生物层干涉实验表明，CK 与 LDHA 和 GLS1 相互作用并抑制其活性。正如预期的那样，CK 减弱了糖酵解和谷氨酰胺分解作用，使 HSC 的生长依赖于乳酸和α-酮戊二酸（α-KG）。在 HSC 激活后，代谢会被重新编程，Myc 作为关键调节因子，转录控制 LDHA、GLS1 和谷氨酰胺转运蛋白 SLC1A5 和 SLC38A5。CK 抑制 Myc 的诱导，整合糖酵解和谷氨酰胺分解调节，以对抗纤维化反应。
CK 抑制 LDHA 和 GLS1 的活性，从而抑制肝纤维化。这些发现为人参皂苷在肝脏保护中的作用提供了新的见解，特别是在代谢紊乱方面。
