栝楼皮注射液通过抑制小鼠KLF6/ABCC5通路改善非酒精性脂肪性肝病。
Trichosanthis Pericarpium injection ameliorates non-alcoholic fatty liver disease via inhibiting the KLF6/ABCC5 pathway in mice.
作者信息
Yu Dongsheng, Li Jiye, Wei Qianyi, Zhu Chunsheng, Zhang Xiaodan, Li Xiaoping, Guo Danfeng
机构信息
Department of Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
Department of Emergency, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, China.
出版信息
Phytomedicine. 2025 Sep;145:156998. doi: 10.1016/j.phymed.2025.156998. Epub 2025 Jun 16.
BACKGROUND
Trichosanthis Pericarpium injection (TPI) exhibits notable therapeutic effects on cardiovascular disease caused by phlegm-turbidity (tan zhuo), yet its impact on non-alcoholic fatty liver disease (NAFLD) which has similarly resulted by phlegm-turbidity remains largely unexplored. This study investigates the ameliorative effects of TPI on NAFLD and elucidates its underlying mechanisms.
METHODS
This study was conducted both in vivo and in vitro using a mouse model of NAFLD and oleic acid (OA)-stimulated AML-12 cells, respectively. The chemical constituents of TPI were analyzed using UPLC-MS. Non-targeted metabolomics, transcriptome sequencing, molecular docking and surface plasmon resonance (SPR) were employed to identify gene and pathway alterations linked to lipid metabolism in the NAFLD model, and assess TPI's molecular and functional protective effects.
RESULTS
A total of 628 compounds were identified from TPI. TPI significantly ameliorated metabolic dysregulation and hepatic fat deposition in high-fat diet (HFD) mice. Similar protective effects were observed in OA-treated AML-12 cells. Metabolomic analysis identified significant changes in metabolites, with the ABC transporter pathway being the most affected. RT-qPCR and immunoblotting analysis revealed a substantial upregulation of ABCC5 in HFD mice, which was effectively suppressed by TPI. Transcriptomic analysis further confirmed the increased expression of KLF6 and ABCC5 in HFD group. Luciferase assays verified that KLF6 binds directly to the ABCC5 promoter, influencing lipid metabolism and contributing to NAFLD progression, while TPI inhibited KLF6's impact on ABCC5 transcriptional activity. Molecular docking and SPR showed that the active components of TPI-rutin, apigenin, and luteolin-form hydrogen bonds with specific amino acid residues of KLF6. Further mechanistic studies showed ABCC5 promoted cellular lipid deposition by suppressing glucagon-like peptide-1 (GLP-1) synthesis and secretion, whereas TPI enhanced their production and release.
CONCLUSIONS
In summary, TPI ameliorates NAFLD by mitigating hepatic lipid accumulation both in vivo and in vitro, through inhibition of the KLF6/ABCC5 pathway.
背景
瓜蒌皮注射液（TPI）对痰浊所致心血管疾病具有显著治疗作用，但其对同样由痰浊引起的非酒精性脂肪性肝病（NAFLD）的影响尚不清楚。本研究探讨TPI对NAFLD的改善作用并阐明其潜在机制。
方法
本研究分别在体内和体外进行，体内采用NAFLD小鼠模型，体外采用油酸（OA）刺激的AML-12细胞。采用超高效液相色谱-质谱联用（UPLC-MS）分析TPI的化学成分。运用非靶向代谢组学、转录组测序、分子对接和表面等离子体共振（SPR）技术，鉴定NAFLD模型中与脂质代谢相关的基因和通路变化，并评估TPI的分子和功能保护作用。
结果
从TPI中鉴定出628种化合物。TPI显著改善高脂饮食（HFD）小鼠的代谢失调和肝脏脂肪沉积。在OA处理的AML-12细胞中也观察到类似的保护作用。代谢组学分析确定代谢物有显著变化，其中ABC转运蛋白途径受影响最大。RT-qPCR和免疫印迹分析显示HFD小鼠中ABCC5显著上调，而TPI可有效抑制其上调。转录组分析进一步证实HFD组中KLF6和ABCC5表达增加。荧光素酶报告基因检测证实KLF6直接结合ABCC5启动子，影响脂质代谢并促进NAFLD进展，而TPI抑制KLF6对ABCC5转录活性的影响。分子对接和SPR显示TPI的活性成分——芦丁、芹菜素和木犀草素——与KLF6的特定氨基酸残基形成氢键。进一步的机制研究表明，ABCC5通过抑制胰高血糖素样肽-1（GLP-1）的合成和分泌促进细胞脂质沉积，而TPI增强其产生和释放。
结论
总之，TPI通过抑制KLF6/ABCC5途径，在体内和体外减轻肝脏脂质积累，从而改善NAFLD。
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