Zexie Tang targeting FKBP38/mTOR/SREBPs pathway improves hyperlipidemia
Zexie Tang targeting FKBP38/mTOR/SREBPs pathway improves hyperlipidemia
复制标题
DOI：
10.1016/j.jep.2022.115101
复制
发表时间：
2022-02-20
影响因子：
5.4
通讯作者：
Zhang, Zhenqiang
中科院分区：
文献类型：
--
作者：
Xie, Zhishen;Li, Er-wen;Zhang, Zhenqiang
民族药理学相关性：泽泻汤（ZXT）与《金匮匮略》中具有2000年历史的经典中药方泽泻（AR）和苍术（AM）仅存两种。近年来的临床观察发现ZXT具有优异的降脂效果。研究目的：探讨ZXT通过FKBP38/ mTOR/SREBPs通路改善高脂血症的可能机制。材料与方法：采用白藜芦醇诱导的高脂血症小鼠和油酸诱导的细胞脂质堆积模型研究其药效学。采用报告基因法检测ZXT对SREBPs转录活性的影响。在体内和体外检测mTOR/SREBPs通路的蛋白和下游基因。结合网络药理学和HPLC-Q-TOF/MS对其有效成分进行筛选鉴定。对接分析ZXT活性化合物与FKBP38蛋白之间的相互作用。结果：ZXT降低了wd致高脂血症小鼠模型血液中TC、TG和LDL-c水平，改善了体内胰岛素抵抗。ZXT还能降低细胞系TC、TG和脂质积累，抑制SREBPs荧光素酶活性、蛋白及其靶基因FASN、HMGCR等表达。同时，ZXT在体外和体内均抑制p-mTOR、p-S6K等蛋白的表达水平。结合网络药理学和HPLC-Q-TOF/MS，筛选鉴定了16种有效成分。对接结果表明ZXT活性化合物与FKBP38结合并形成氢键。结论：ZXT具有改善高脂血症的作用，其中FKBP/mTOR/SREBPs通路可能是其潜在的调控机制。
Ethnopharmacological relevance: Zexie Tang (ZXT), only two consists with Alismatis Rhizoma (AR) and Atractylodes macrocephala Rhizoma (AM), a classical Chinese medicine formula from Synopsis of the Golden Chamber with a history of 2000 years. Clinical observation in recent years has found that ZXT has excellent lipid-lowering effect.Aim of the study: To explore the potential mechanism of ZXT ameliorates hyperlipidemia based on FKBP38/ mTOR/SREBPs pathway.Materials and methods: WD-induced hyperlipidemia mice and oleic acid induced cell lipid accumulation model were used to investigate pharmacodynamic. The effect of ZXT on the transcriptional activity of SREBPs was detected by reporter gene assay. Proteins and downstream genes of mTOR/SREBPs pathway were detected in vivo and in vitro. Combined with network pharmacology and HPLC-Q-TOF/MS, the active ingredients were screened and identified. The interaction between active compounds of ZXT and FKBP38 protein were analyzed by docking analysis.Results: ZXT decreased TC, TG and LDL-c levels in blood of WD-induced hyperlipidemia mouse model, and improved insulin resistance in vivo. ZXT also reduced TC, TG and lipid accumulation in cells line, and inhibited SREBPs luciferase activity, protein and its target genes expression such as FASN, HMGCR, etc. Meanwhile, ZXT inhibited protein expression levels of p-mTOR, p-S6K, etc in vitro and in vivo. Combined with network pharmacology and HPLC-Q-TOF/MS, 16 active ingredients were screened and identified. Docking results showed that active compounds of ZXT binding to FKBP38 and formed hydrogen bond.Conclusion: Our findings highlighted that ZXT ameliorates hyperlipidemia, in which FKBP/mTOR/SREBPs pathway might be the potential regulatory mechanism.