Current treatment approaches for hyperlipidemia rely mainly on reducing the cholesterol level by inhibiting 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), which is involved in the presqualene pathway of cholesterol biosynthesis. Finding a compound that instead targets the postsqualene pathway could aid in the treatment of hyperlipidemia and synergistically reduce the cholesterol level when used in conjunction with HMGCR inhibitors. Ergosterol is a fungal sterol that is converted to brassicasterol by 7-dehydrocholesterol reductase (DHCR7). DHCR7 is also a cholesterol biosynthesis enzyme, and thus ergosterol may cause the accumulation of 7-dehydrocholesterol, a precursor of cholesterol and vitamin D₃, by a competitive effect. In this study, we examined the effect of ergosterol on the postsqualene pathway by quantifying cholesterol precursors and related sterols using gas chromatography–mass spectrometry and by conducting quantitative RT-PCR and western blot analysis for human HepG2 hepatoma cells. We found that ergosterol is converted into brassicasterol by the action of DHCR7 from HepG2 cells and that it induced the accumulation of cholesterol precursors (lathosterol, 7-dehydrocholesterol, and desmosterol) and decreased the cholesterol level by altering the mRNA and protein levels of cholesterol biosynthesis enzymes (increase of sterol 8,7-isomerase [EBP] and decrease of DHCR7 and 24-dehydrocholesterol reductase [DHCR24]). These results demonstrate that ergosterol inhibits the postsqualene pathway and may be useful for the prevention of hyperlipidemia.

中文翻译：

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麦角甾醇增加 7-脱氢胆固醇（一种胆固醇前体）并降低人 He​​pG2 细胞中的胆固醇

目前治疗高脂血症的方法主要依赖于通过抑制参与胆固醇生物合成的前鲨烯途径的 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR) 来降低胆固醇水平。寻找一种靶向角鲨烯后途径的化合物可以帮助治疗高脂血症，并在与 HMGCR 抑制剂联合使用时协同降低胆固醇水平。麦角甾醇是一种真菌甾醇，可通过 7-脱氢胆固醇还原酶 (DHCR7) 转化为菜子甾醇。DHCR7 也是一种胆固醇生物合成酶，因此麦角固醇可能会导致 7-脱氢胆固醇（胆固醇和维生素 D _{3的前体）的积累}, 通过竞争效应。在这项研究中，我们通过使用气相色谱 - 质谱法量化胆固醇前体和相关甾醇以及通过对人 HepG2 肝癌细胞进行定量 RT-PCR 和蛋白质印迹分析来检查麦角甾醇对角鲨烯途径的影响。我们发现麦角甾醇通过来自 HepG2 细胞的 DHCR7 的作用转化为菜子甾醇，它诱导胆固醇前体（花甾醇、7-脱氢胆固醇和去氨甾醇）的积累，并通过改变胆固醇生物合成的 mRNA 和蛋白质水平来降低胆固醇水平酶（甾醇 8,7-异构酶 [EBP] 增加，DHCR7 和 24-脱氢胆固醇还原酶 [DHCR24] 减少）。