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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages
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Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages

机译：真菌性金紫苏内酯的抗动脉粥样硬化活性，巨噬细胞中的脂滴积累抑制剂

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摘要

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 IC_(50) values of 0.78 and 0.41 μM, respectively, without showing significant effects on the tri-acylglycerol 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 acyl-transferase (ACAT) activity in the membrane fractions prepared from mouse macrophages was studied, resulting in a dose-dependent inhibition by beauveriolides Ⅰ and Ⅲ with IC_(50) values of 6.0 and 5.5 μM, 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.
机译：从真菌白僵菌的培养液中分离出白僵菌内酯Ⅰ和Ⅲ。 FO-6979在原代小鼠腹膜巨噬细胞中显示出有效的脂滴积聚抑制作用。在巨噬细胞中研究了这种抑制活性的细胞分子靶标。白藜芦醇酯Ⅰ和Ⅲ强烈抑制胆固醇酯（CE）的合成，IC_（50）值分别为0.78和0.41μM，而对三酰基甘油和磷脂合成没有显着影响。此外，该化合物抑制了巨噬细胞中溶酶体胆固醇向CE的代谢，这表明该抑制位点位于胆固醇从溶酶体离开和内质网中CE合成之间的步骤内。因此，研究了由小鼠巨噬细胞制备的膜级分中的酰基辅酶A：胆固醇酰基转移酶（ACAT）活性，导致了甜菊酯Ⅰ和Ⅲ的剂量依赖性抑制作用，IC_（50）值分别为6.0和5.5μM。 。因此，我们表明，甜菜碱内酯特异性地抑制巨噬细胞ACAT活性，导致CE合成的阻断，导致巨噬细胞脂质滴的减少。从小鼠肝脏和Caco-2细胞制备的膜级分中的ACAT活性也被抑制，表明双金叶内酯同时阻断ACAT-1和-2。此外，在许多低密度脂蛋白受体敲除和载脂蛋白E敲除小鼠中，金紫苏内酯Ⅰ和Ⅲ均具有抗动脉粥样硬化活性，而对许多合成的ACAT抑制剂均未观察到腹泻或对肾上腺组织的细胞毒性等副作用。白藜芦醇酯Ⅰ和Ⅲ是最早的具有体内抗动脉粥样硬化作用的微生物环二肽，有望作为抗动脉粥样硬化剂的潜在先导化合物。

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