Dingxin Recipe IV attenuates atherosclerosis by regulating lipid metabolism through LXR-α/SREBP1 pathway and modulating the gut microbiota in ApoE-/- mice fed with HFD
Dingxin Recipe IV attenuates atherosclerosis by regulating lipid metabolism through LXR-α/SREBP1 pathway and modulating the gut microbiota in ApoE-/- mice fed with HFD
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DOI：
10.1016/j.jep.2020.113436
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发表时间：
2021-02-10
影响因子：
5.4
通讯作者：
Zhou, Fenghua
中科院分区：
文献类型：
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作者：
Zhang, Yaxin;Gu, Yuyan;Zhou, Fenghua
民族药理学相关性：定心方是一种治疗心律失常、冠心病等心血管疾病安全有效的中药方剂。定心方Ⅳ号是在定心方的基础上进一步改进而成。本研究旨在探讨DXR IV是否通过调节动脉粥样硬化小鼠的脂质代谢和肠道菌群来改善动脉粥样硬化。材料和方法：40只雄性ApoE-/小鼠，以HFD喂养12周，然后分别给予DXR IV（1.8，0.9和0.45 g/kg/d）治疗12周。DXR IV制剂中含有四种中药：黄连干燥根茎。丹参（Salvia miltiorrhiza Bunge）根（28.30%）、酸枣仁（Ziziphus ereba Mill.）（37.74%）和灵芝子实体（Leyss. ex Fr.）喀斯特（18.87%）。8只雄性c57 BL/6小鼠作为对照组，正常饮食喂养。采用油红O染色和Masson三色染色对动脉粥样硬化斑块进行定量。收集小鼠粪便。通过16S rRNA基因测序检测肠道微生物群，并通过1H NMR光谱分析粪便代谢物。观察静注DXR对血脂（TG、TC、LDL-C、HDL-C）的影响。结果：DXR IV通过抑制主动脉胆固醇过度沉积，调节TG、TC、LDL-C和HDL-C水平，发挥抗动脉粥样硬化作用。肠道微生物群的组成发生了变化。有趣的是，在DXR IV给药后，Muribaculaceae和Ruminococcaceae的相对丰度增加，而丹毒丝菌科的丰度降低，这有利于脂质代谢。筛选出9种与脂肪酸代谢相关的代谢生物标志物，包括乙酸、丁酸、丙酸、丙氨酸、琥珀酸、戊酸、木糖、胆碱、谷氨酸。进一步通过RT-qPCR和Western blotting检测脂肪酸的途径。与模型组比较，DXR IV组LXR-α、SREBP 1水平明显降低，LXR-β、SREBP 2水平无统计学意义。结论：DXR IV具有潜在的抗动脉粥样硬化作用，其机制与脂质代谢和肠道菌群密切相关。这项研究可能为DXR IV治疗动脉粥样硬化的机制提供新的见解，并为有前途的临床应用提供依据。
Ethnopharmacological relevance: Dingxin Recipe (DXR) is a traditional Chinese medicine formula that has been reported to be effective and safe treatment for cardiovascular diseases, such as arrhythmias, coronary heart disease. Dingxin Recipe IV (DXR IV) was further improved from the DXR according to the traditional use. However, the mechanism of DXR IV in atherosclerosis is unclear.Aim of the study: This study aimed to illustrate whether DXR IV improve atherosclerosis through modulating the lipid metabolism and gut microbiota in atherosclerosis mice.Materials and methods: 40 male ApoE-/mice were fed on HFD for 12 weeks and were then treated with DXR IV (1.8, 0.9, or 0.45 g/kg/d) for another 12 weeks. The decroation of DXR IV contains four traditional Chinese medicines: the dried rhizome of Coptis chinensis Franch. (15.09%), the root of Salvia miltiorrhiza Bunge (28.30%), the seed of Ziziphus jujuba Mill. (37.74%) and the fruiting body of Ganoderma lucidum (Leyss.ex Fr.) Karst. (18.87%). 8 male c57BL/6 mice fed a normal diet served as control group. The atherosclerotic plaque was quantified by oil-red O staining and masson trichrome staining. Mice feces were collected. The gut micobiota were detected by 16S rRNA gene sequencing and fecal metabolites were analyzed by 1H NMR spectroscopy. The effect of DXR IV on blood lipids (TG, TC, LDL-C, HDL-C) was investigated. The lipid metabolism related genes were determined by RT-qPCR and western blotting respectively.Results: DXR IV exerted the anti-atherosclerosis effect by inhibiting the excessive cholesterol deposition in aorta and regulating the level of TG, TC, LDL-C and HDL-C. The composition of gut microbiota was changed. Interestingly, the relative abundance of Muribaculaceae and Ruminococcaceae increased after DXR IV administration, whereas the abundance of Erysipelotrichaceae decreased, which have been beneficial to lipid metabolism. Nine potential metabolic biomarkers, including acetate, butyrate, propionate, alanine, succinate, valerate, xylose, choline, glutamate, were identified, which were related to fatty acid metabolism. Further, the pathway of fatty acid was detected by the RT-qPCR and western blotting. Compared with model group, the level of LXR-alpha and SREBP1 decreased significantly in DXR IV group while LXR-beta, SREBP2 showed no statistical significance. It indicated that DXR IV modulated lipid metabolism by LXR-alpha/SREBP1 but not LXR beta and SREBP2.Conclusions: DXR IV exhibits potential anti-atherosclerosis effect, which is closely related to lipid metabolism and the gut microbiota. This study may provide novel insights into the mechanism of DXR IV on atherosclerosis and a basis for promising clinical usage.