Network pharmacology analysis and experimental validation to explore the mechanism of sea buckthorn flavonoids on hyperlipidemia

Ethnopharmacological relevance: Sea buckthorn is popularly used as a herbal medicine and food additive in the world. Sea buckthorn flavonoids (SF) is reported to have an ameliorative effect on obesity and hyperlipidemia (HLP). Aim: To identify the major bioactive compounds and the lipid-lowering mechanism of SF. Methods: We used network pharmacology analysis and in vitro experiments to identify the major bioactive compounds and the lipid-lowering mechanism of SF. Results: A total of 12 bioactive compounds, 60 targets related to SF and HLP were identified, and a componenttarget-disease network was constructed. The KEGG analysis revealed that SF regulated cholesterol metabolism, fat digestion and absorption, and PPAR signaling pathways in HLP. The experimental validation indicated that sea buckthorn flavonoids extract (SFE) and 4 bioactive compounds reduced lipid droplet accumulation, upregulated the mRNA expression of PPAR-gamma, PPAR-alpha, ABCA1 and CPT1A, etc, down-regulated SREBP-2 and its target gene LDLR, which are closely related to cholesterol conversion into bile acids, de novo synthesis and fatty acids oxidation. The major bioactive flavonoid isorhamnetin (ISOR) also increased the protein expression of PPAR-gamma, LXR alpha and CYP7A1. Conclusion: SF might promote cholesterol transformation into bile acids and cholesterol efflux, inhibit cholesterol de novo synthesis and accelerate fatty acids oxidation for ameliorating HLP.