PAL inhibits foam cell formation by regulating the PPAR-γ signaling pathway in oxidized low-density lipoprotein-induced THP-1 macrophages

Abstract Atherosclerotic cardiovascular disease continues to pose a major threat to human health. It has been shown that Chinese herbal medicines rich in palmatine(PAL) exert significant beneficial effects on atherosclerosis(AS). However, the specific biological functions and mechanisms of PAL in AS remain unclear. In this study, we investigated the effects of PAL on the core pathological changes in macrophage foam cell formation, a key process in the development of AS. The results demonstrated that PAL significantly reduced the formation of lipid droplets and accumulation of cholesterol ester in oxidized low-density lipoprotein (OX-LDL)-induced macrophage foam cells. RNA-sequencing was used to comprehensively analyze the effect of PAL. The findings revealed that the peroxisome proliferator-activated receptor-γ (PPAR-γ) pathway is the primary target of PAL in suppressing foam cell formation. Real-time fluorescence quantitative polymerase chain reaction and western blotting results confirmed that PAL substantially upregulated the transcription and expression levels of lipid metabolism-related proteins, such as PPAR-γ and liver X receptor-α (LXR-α), whereas it inhibited the transcription of inflammatory factors TNF-α, interleukin-1β (IL-1β), and IL-6. These biological changes were reversed by treatment with the PPAR-γ inhibitor T0070907. Molecular docking analysis showed that the binding sites of PAL with PPAR-γ (325THR) is close to the reported PPAR-γ agonist rosiglitazone（323HIS）, suggesting that PAL may act as a PPAR-γ partial agonist to improve atherosclerosis. Collectively, the results of this study suggest that PAL promotes cholesterol efflux and inhibits inflammatory responses mainly by regulating the PPAR-γ signaling pathway, thus ameliorating macrophage foam cell formation. Our findings may provide a foundation for further research on the pharmacological activity and potential value of PAL in the treatment of AS.