Antiatherogenic activity of fungal beauveriolides, inhibitors of lipid droplet accumulation in macrophages.

Beauveriolides I and Ill, 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 Ill strongly inhibited the cholesteryl ester (CE) synthesis with IC[sub50] 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 Ill with lC[sub50] 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 Ill 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. Beauveniolides I and Ill are the first microbial cyclodepsipeptides having an in viva antiatherosclerotic effect and show promise as potential lead compounds for antiatherosclerotic agents. [ABSTRACT FROM AUTHOR]