Zhang Yue, Zeng Miao, Zhang Xiaolu, Yu Qun, Wang Luming, Zeng Wenyun, Wang Yijing, Suo Yanrong, Jiang Xijuan
School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China.
School of Preclinical Medicine, Zunyi Medical University, Guizhou, China.
J Ethnopharmacol. 2024 Apr 24;324:117814. doi: 10.1016/j.jep.2024.117814. Epub 2024 Jan 28.
Tiaogan Daozhuo Formula (TGDZF) is a common formulation against atherosclerosis, however, there is limited understanding of its therapeutic mechanism.
To examine the effectiveness of TGDZF in the treatment of atherosclerosis and to explore its mechanisms.
In ApoE mice, atherosclerosis was induced by a high-fat diet for 12 weeks and treated with TGDZF at different doses. The efficacy of TGDZF in alleviating atherosclerosis was evaluated by small animal ultrasound and histological methods. Lipid levels were measured by biochemical methods. The capacity of cholesterol efflux was tested with a cholesterol efflux assay in peritoneal macrophage, and the expression of AMPKα1, PPARγ, LXRα, and ABCA1 was examined at mRNA and protein levels. Meanwhile, RAW264.7-derived macrophages were induced into foam cells by ox-LDL, and different doses of TGDZF-conducting serum were administered. Similarly, we examined differences in intracellular lipid accumulation, cholesterol efflux rate, and AMPKα1, PPARγ, LXRα, and ABCA1 levels following drug intervention. Finally, changes in the downstream molecules were evaluated following the inhibition of AMPK by compound C or PPARγ silencing by small interfering RNA.
TGDZF administration reduced aortic plaque area and lipid accumulation in aortic plaque and hepatocytes, and improved the serum lipid profiles of ApoE mice. Further study revealed that its efficacy was accompanied by an increase in cholesterol efflux rate and the expression of PPARγ, LXRα, and ABCA1 mRNA and protein, as well as the promotion of AMPKα1 phosphorylation. Moreover, similar results were caused by the intervention of TGDZF-containing serum in vitro experiments. Inhibition of AMPK and PPARγ partially blocked the regulatory effect of TGDZF, respectively.
TGDZF alleviated atherosclerosis and promoted cholesterol efflux from macrophages by activating the AMPK-PPARγ-LXRα-ABCA1 pathway.
调肝导浊方（TGDZF）是一种常用的抗动脉粥样硬化方剂，然而，对其治疗机制的了解有限。
研究调肝导浊方治疗动脉粥样硬化的有效性并探讨其机制。
在载脂蛋白E（ApoE）小鼠中，通过高脂饮食诱导动脉粥样硬化12周，并用不同剂量的调肝导浊方进行治疗。通过小动物超声和组织学方法评估调肝导浊方减轻动脉粥样硬化的疗效。采用生化方法测量血脂水平。用胆固醇流出试验检测腹腔巨噬细胞的胆固醇流出能力，并在mRNA和蛋白质水平检测AMPKα1、PPARγ、LXRα和ABCA1的表达。同时，用氧化型低密度脂蛋白（ox-LDL）将RAW264.7来源的巨噬细胞诱导为泡沫细胞，并给予不同剂量的含调肝导浊方血清。同样，我们检测了药物干预后细胞内脂质蓄积、胆固醇流出率以及AMPKα1、PPARγ、LXRα和ABCA1水平的差异。最后，在用化合物C抑制AMPK或用小干扰RNA沉默PPARγ后，评估下游分子的变化。
给予调肝导浊方减少了ApoE小鼠的主动脉斑块面积和主动脉斑块及肝细胞中的脂质蓄积，并改善了其血脂谱。进一步研究表明，其疗效伴随着胆固醇流出率增加以及PPARγ、LXRα和ABCA1 mRNA和蛋白质表达增加，以及AMPKα1磷酸化的促进。此外，含调肝导浊方血清干预体外实验也产生了类似结果。抑制AMPK和PPARγ分别部分阻断了调肝导浊方的调节作用。
调肝导浊方通过激活AMPK-PPARγ-LXRα-ABCA1途径减轻动脉粥样硬化并促进巨噬细胞胆固醇流出。
