Department of Bio-Analytical Chemistry, Niigata University of Pharmacy and Applied Life Sciences, Niigata, Japan.
Department of Health Chemistry, Niigata University of Pharmacy and Applied Sciences, Niigata, Japan.
Lipids. 2022 Nov;57(6):303-311. doi: 10.1002/lipd.12357. Epub 2022 Sep 13.
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 D , 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.
目前治疗高脂血症的方法主要依赖于通过抑制 3-羟-3-甲基戊二酰辅酶 A 还原酶（HMGCR）来降低胆固醇水平，该酶参与胆固醇生物合成的前鲨烯途径。寻找一种替代后鲨烯途径的化合物可能有助于治疗高脂血症，并与 HMGCR 抑制剂联合使用时协同降低胆固醇水平。麦角固醇是一种真菌固醇，通过 7-脱氢胆固醇还原酶（DHCR7）转化为 brassicasterol。DHCR7 也是一种胆固醇生物合成酶，因此麦角固醇可能通过竞争性作用导致胆固醇和维生素 D 的前体 7-脱氢胆固醇的积累。在这项研究中，我们通过使用气相色谱-质谱法定量胆固醇前体和相关甾醇，并对人 HepG2 肝癌细胞进行定量 RT-PCR 和 Western blot 分析，研究了麦角固醇对后鲨烯途径的影响。我们发现麦角固醇在 HepG2 细胞中 DHCR7 的作用下转化为 brassicasterol，它通过改变胆固醇生物合成酶的 mRNA 和蛋白质水平（甾醇 8,7-异构酶[EBP]增加和 DHCR7 和 24-脱氢胆固醇还原酶[DHCR24]减少）诱导胆固醇前体（羊毛甾醇、7-脱氢胆固醇和 desmosterol）的积累，并降低胆固醇水平。这些结果表明麦角固醇抑制后鲨烯途径，可能有助于预防高脂血症。
