Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products

作者：Yuwei Fang, Jianglian She, Xi Zhang, Tanwei Gu, Danni Xie, Xiaowei Luo, Xiangxi Yi, Chenghai Gao, Yonghong Liu, Cui‐Xian Zhang, Lan Tang, Xuefeng Zhou · 发表于：Journal of Natural Products · 年份：2024 · DOI：10.1021/acs.jnatprod.3c01029 · 被引用次数：6 · 研究领域：Cholesterol and Lipid Metabolism、Cancer, Lipids, and Metabolism、Drug Transport and Resistance Mechanisms

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, 12 R,13 S -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.