Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages
Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages
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DOI：
10.1073/pnas.0307757100
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发表时间：
2004-01-20
影响因子：
11.1
通讯作者：
Omura, S
中科院分区：
文献类型：
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作者：
Namatame, I;Tomoda, H;Omura, S
从真菌Beauveria sp. FO-6979的培养液中分离的Beauveriolides I和III显示出有效的抑制小鼠腹腔巨噬细胞中脂滴积累的活性。在巨噬细胞中研究了这种抑制活性的细胞分子靶标。Beauveriolides I和III强烈抑制胆固醇酯（CE）的合成，IC 50值分别为0.78和0.41 μ M，而对三酰甘油和磷脂的合成没有显着影响。此外，化合物抑制巨噬细胞中溶酶体胆固醇代谢为CE，表明抑制位点位于胆固醇离开溶酶体和内质网中CE合成之间的步骤内。因此，酰基辅酶A：胆固醇酰基转移酶（ACAT）的活性在从小鼠巨噬细胞制备的膜组分进行了研究，导致剂量依赖性抑制beauveriolides I和III的IC 50值分别为6.0和5.5 μ M。因此，我们表明，白僵菌内酯特异性地抑制巨噬细胞ACAT活性，导致CE合成的阻断，导致巨噬细胞中脂滴的减少。从小鼠肝脏和Caco-2细胞制备的膜组分中的ACAT活性也受到抑制，表明白僵菌内酯阻断ACAT-1和-2。此外，白僵菌内酯I和III在低密度脂蛋白受体和载脂蛋白E基因敲除小鼠中发挥抗动脉粥样硬化活性，而没有任何副作用，如腹泻或对肾上腺组织的细胞毒性，如许多合成ACAT抑制剂所观察到的。Beauveriolides I和III是第一个具有体内抗动脉粥样硬化作用的微生物环缩肽，并显示出作为抗动脉粥样硬化剂的潜在先导化合物的前景。
Beauveriolides I and III, isolated from the culture broth of fungal Beauveria sp. FO-6979, showed potent inhibitory activity of lipid droplet accumulation in primary mouse peritoneal macrophages. The cellular molecular target of this inhibitory activity was studied in macrophages. Beauveriolides I and III strongly inhibited the cholesteryl ester (CE) synthesis with IC50 values of 0.78 and 0.41 muM, respectively, without showing significant effects on the triacylglycerol and phospholipid synthesis. Furthermore, lysosomal cholesterol metabolism to CE in macrophages was inhibited by the compounds, indicating that the inhibition site lies within steps between cholesterol departure from the lysosome and CE synthesis in the endoplasmic reticulum. Therefore, acyl-CoA:cholesterol acyltransferase (ACAT) activity in the membrane fractions prepared from mouse macrophages was studied, resulting in a dose-dependent inhibition by beauveriolides I and III with IC50 values of 6.0 and 5.5 muM, respectively. Thus, we showed that the beauveriolides inhibit macrophage ACAT activity specifically, resulting in blockage of the CE synthesis, leading to a reduction of lipid droplets in macrophages. ACAT activity in the membrane fractions prepared from mouse liver and Caco-2 cells was also inhibited, indicating that the beauveriolides block both ACAT-1 and -2. Moreover, beauveriolides I and III exert antiatherogenic activity in both low-density lipoprotein receptor- and apolipoprotein E-knockout mice without any side effects such as diarrhea or cytotoxicity to adrenal tissues as observed for many synthetic ACAT inhibitors. Beauveriolides I and III are the first microbial cyclodepsipeptides having an in vivo antiatherosclerotic effect and show promise as potential lead compounds for antiatherosclerotic agents.