Abstract：
A strategy integrating in silico molecular docking with LXRα and phenotypic assays was adopted to discover anti-hypercholesterolemia agents in a small library containing 205 marine microorganism-derived natural products, collected by our group in recent years. Two fumitremorgin derivatives, 12R,13S-dihydroxyfumitremorgin C (1) and tryprostatin A (3), were identified as potential LXRα agonists, by real-time qPCR and Western blot (WB) analysis, together with a surface plasmon resonance (SPR) assay. The anti-hypercholesterolemic effects of 1 and 3, together with their mechanisms, were investigated in depth using different cell and mouse models, among which the study of LXRα is of crucial importance. Compound 1 or 3 exhibited the capacity to effectively reverse excessive lipid accumulation in a hepatic steatosis cell model and significantly reduce liver damage and blood cholesterol levels in high cholesterol diet (HCD)-fed wild-type mice, whereas those beneficial effects were completely nullified in HCD-fed LXRα-knockout mice. Furthermore, 1 and 3 outperformed common LXRα agonists by suppressing the expression of sterol regulatory element-binding protein 1 (SREBP1) in HCD-fed mice, mitigating lipotoxicity. Thus, this study highlights the discovery of two marine microorganism-derived anti-hypercholesterolemia agents targeting LXRα.
摘要：
采用了将LXRα和表型分析整合到计算机分子对接中的策略，以在包含205个海洋微生物来源的天然产物的小文库中发现抗高胆固醇血症药物。我们小组近年来收集的。两种Fumitremorgin衍生物，12R,13S-二羟基富马酸丙酯C(1)和曲前列素A(3)，被鉴定为潜在的LXRα激动剂，通过实时qPCR和蛋白质印迹（WB）分析，以及表面等离子体共振(SPR)测定。1和3的抗高胆固醇血症作用及其机制，使用不同的细胞和小鼠模型进行了深入研究，其中LXRα的研究至关重要。化合物1或3在肝脂肪变性细胞模型中表现出有效逆转过度脂质积累的能力，并显着降低高胆固醇饮食（HCD）喂养的野生型小鼠的肝损伤和血液胆固醇水平，而这些有益作用在HCD喂养的LXRα基因敲除小鼠中完全无效。此外，1和3通过抑制HCD喂养的小鼠中固醇调节元件结合蛋白1（SREBP1）的表达，优于常见的LXRα激动剂，减轻脂毒性。因此，这项研究强调了两种针对LXRα的海洋生物来源的抗高胆固醇血症药物的发现。
