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.