Molecular target of decursins in the inhibition of lipid droplet accumulation in macrophages
Molecular target of decursins in the inhibition of lipid droplet accumulation in macrophages
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DOI：
10.1248/bpb.29.981
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发表时间：
2006-05-01
影响因子：
2
通讯作者：
Tomoda, Hiroshi
中科院分区：
文献类型：
--
作者：
Ohshiro, Taichi;Namatame, Ichiji;Tomoda, Hiroshi
在筛选小鼠腹膜巨噬细胞脂滴积聚抑制剂的过程中，从当归根中分离出两种香豆素，鉴定为前尿素和前尿醇天使酸酯。研究了这些抑制剂在巨噬细胞中的细胞分子靶点。槲皮素和槲皮醇天使酸酯抑制胆固醇酯（CE）合成的IC50值分别为9.7和10.1 μ m，而促进甘油三酯（TG）合成。这些化合物抑制了溶酶体对CE的胆固醇代谢，表明该抑制位点是溶酶体排出胆固醇和内质网合成CE之间的一个步骤。因此，我们研究了小鼠巨噬细胞制备的微粒体组分中酰基辅酶a：胆固醇酰基转移酶（ACAT）的活性，结果表明，前尿素和天使化前尿素对该活性的抑制作用IC50值分别为43和22 μ m。由此可见，化合物抑制巨噬细胞ACAT活性降低CE合成，导致巨噬细胞脂滴减少。
During screening for inhibitors of lipid droplet accumulation in mouse peritoneal macrophages, two coumarins identified as decursin and decursinol angelate were isolated from the roots of Angelicae gigands. The cellular molecular target of these inhibitors in macrophages was studied. Decursin and decursinol angelate inhibited cholesteryl ester (CE) synthesis with IC50 values of 9.7 and 10.1 mu m, respectively, whereas they enhanced triacylglycerol (TG) synthesis. Lysosomal metabolism of cholesterol to CE was inhibited by the compounds, indicating that the site of inhibition is one of the steps between the exiting of cholesterol from the lysosomes and CE synthesis in the endoplasmic reticulum. Therefore, acyl-CoA:cholesterol acyltransferase (ACAT) activity in the microsomal fractions prepared from mouse macrophages was studied, and the results showed inhibition of this activity by decursin and decursinol angelate with IC50 values of 43 and 22 mu m, respectively. Thus, it was concluded that the compounds inhibit macrophage ACAT activity to decrease CE synthesis, leading to a reduction of lipid droplets in macrophages.