Objective To investigate the mechanism by which Osmanthus fragrans and its active component salidroside improve hyperlipidemia. Methods An oleic acid-induced lipid deposition model was established in HepG2 cells. Lipid-regulating activities of O. fragrans ethanol extract and its components (acteoside, salidroside, isoacteoside, echinacoside) were evaluated using MTT assay and intracellular triglyceride (TG) level, supplemented by oil red O staining to visualize lipid droplet formation. A hyperlipidemic rat model was established via high-fat diet feeding. Control group, model group, O. fragrans ethanol extract group (810 mg/kg), salidroside low-, high-dose (40, 80 mg/kg) groups and simvastatin (2.1 mg/kg) group were set up, with eight rats per group, drugs were continuously administration for five weeks. Serum lipid levels, hepatic index, hepatic total cholesterol (TC) and TG levels in rats of each group were measured. Oil red O staining was used to observe hepatic lipid deposition in each group. Hematoxylin-eosin (HE) staining was used to examine the pathological morphology of epididymal adipose tissue. Transcriptome sequencing of liver tissue was performed to analyze the potential molecular mechanisms by which O. fragrans ethanol extract ameliorates hyperlipidemia. Molecular docking technology was employed to predict the affinity of salidroside, the primary active component, with pyroptosis-related proteins NOD like receptor family pyrin domain containing 3 (NLRP3), cystein-asparate protease-1 (Caspase-1), N-terminal fragment of gasdermin D (GSDMD-N), interleukin-1β (IL-1β), IL-18 and IL-6. Western blotting was used to further validate the effect of salidroside on expressions of pyroptosis-related proteins in liver tissue. Results O. fragrans ethanol extract and salidroside significantly reduced TG levels (P < 0.05, 0.01, 0.001), and diminished lipid droplet accumulation in oleic acid-induced HepG2 cells. Concurrently, they markedly lowered TC, TG and low density lipoprotein cholesterol (LDL-C) levels in serum (P < 0.01, 0.001), increased high density lipoprotein cholesterol (HDL-C) level (P < 0.001), reduced hepatic TC and TG levels (P < 0.01, 0.001), alleviated liver lipid deposition, and improved adipose tissue pathology in model rats. Transcriptomic gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses suggested that the lipid-regulating mechanism of O. fragrans ethanol extract may be related to regulating lipid metabolism and inflammatory responses. Molecular docking results indicated that salidroside exhibits high affinity for proteins involved in regulating inflammatory responses, such as NLRP3, Caspase-1 and IL-1β. Western blotting results showed that compared with model group, except for the cleaved Caspase-1 in liver tissues of salidroside low-dose group, the expression levels of pyroptosis-related proteins were significantly reduced in all other treatment groups (P < 0.05, 0.01, 0.001). Conclusion Salidroside may be one of the primary active components in O. fragrans for improving hyperlipidemia, and its lipid-regulating mechanism is associated with inhibiting NLRP3/Caspase-1/IL-1β signaling pathway to counteract hepatic pyroptosis.

hyperlipidemia  /  Osmanthus fragrans (Thunb.) Lour.  /  cell pyroptosis  /  NLRP3/Caspase-1/IL-1β signaling pathway  /  verbascoside  /  salidroside  /  isoacteoside  /  echinacoside