Discovery of Anti-Hypercholesterolemia Agents Targeting LXRα from Marine Microorganism-Derived Natural Products.
Yuwei FangJianglian SheXi ZhangTanwei GuDanni XieXiao-Wei LuoXiangxi YiChenghai GaoYong-Hong LiuCui-Xian ZhangLan TangXue-Feng ZhouPublished in: Journal of natural products (2024)
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.
Keyphrases
- molecular docking
- wild type
- high throughput
- low density lipoprotein
- binding protein
- single cell
- small molecule
- cardiovascular events
- cell therapy
- cancer therapy
- physical activity
- cardiovascular disease
- stem cells
- type diabetes
- coronary artery disease
- weight loss
- skeletal muscle
- metabolic syndrome
- adipose tissue
- risk assessment
- drug delivery
- optical coherence tomography
- mesenchymal stem cells
- atomic force microscopy
- weight gain
- bone marrow
- single molecule