Tiaogan daozhuo formula attenuates atherosclerosis via activating AMPK -PPARγ-LXRα pathway

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.