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探讨化合物E23869体外对脂代谢的作用及其机制。本研究利用前期已建立的人ATP结合盒转运体A1(ATP-binding cassette transporter A1,ABCA1)和清道夫受体B型I(scavenger receptor class B type I,SR-BI/CLA-1)表达上调剂筛选模型,对20 000个化合物进行筛选,获得能上调ABCA1和CLA-1表达的化合物E23869,其上调活性分别为196%和198%,EC50值分别为0.25和0.66μmol·L-1;Western blotting实验结果表明,在RAW264.7和L02细胞中,活性化合物E23869均能显著上调ABCA1、SR-BI/CLA-1及ATP结合盒转运体G1(ATP-binding cassette transporter G1,ABCG1)的蛋白水平;体外功能实验证实,E23869能有效地抑制巨噬细胞泡沫化和促进细胞内胆固醇外排。进一步研究表明,化合物E23869能通过部分激活PPARα和PPARγ从而上调ABCA1、SR-BI/CLA-1和ABCG1的表达,并且对前脂肪细胞3T3-L1诱导分化的作用较弱。总之,化合物E23869能够上调ABCA1和SR-BI/CLA-1活性,并且具有较好的体外调节脂代谢的作用,为新型调血脂药物的先导化合物。
To investigate the effect of compound E23869 on lipid metabolism in vitro and its mechanism. In this study, the expression of human ATP-binding cassette transporter A1 (ABCA1) and scavenger receptor class B type I (SR-BI / CLA-1) 20 000 compounds were screened to obtain the compound E23869 which up-regulates the expression of ABCA1 and CLA-1 with the up-regulation activity of 196% and 198%, respectively, and the EC50 values of 0.25 and 0.66 μmol·L-1, respectively The results of blotting showed that the active compound E23869 significantly up-regulated the protein levels of ABCA1, SR-BI / CLA-1 and ATP-binding cassette transporter G1 (ABCG1) in RAW264.7 and L02 cells In vitro functional experiments confirmed that E23869 can effectively inhibit the foaming of macrophages and promote intracellular cholesterol efflux. Further studies showed that E23869 could upregulate the expression of ABCA1, SR-BI / CLA-1 and ABCG1 by partial activation of PPARα and PPARγ, and had a weaker effect on 3T3-L1 preadipocyte differentiation. In conclusion, E23869 could up-regulate the activity of ABCA1 and SR-BI / CLA-1 and has a good in vitro regulation of lipid metabolism as a lead compound for a novel lipid-lowering drug.