Dehydrocostus lactone attenuates atherogenesis by promoting cholesterol efflux and inhibiting inflammation via TLR2/PPAR-γ/NF-κB signaling pathway.

BACKGROUND: Dehydrocostus lactone (DHL), a natural sesquiterpene lactone, has significant anti-inflammatory effects and has the potential to inhibit ox-LDL-induced atherosclerosis in laboratory settings. However, the in vivo anti-atherosclerotic effects of DHL and their molecular mechanisms remain unclear. This study explores the anti-atherosclerosis effects of DHL on apolipoprotein E-deficient (ApoE(−/−)) mice, and the potential mechanism on macrophage-derived foam cells. METHODS: Blood lipid and arterial plaque were assessed to evaluate the anti-atherosclerosis effect. The levels of inflammatory cytokines were quantified by ELISA assay. A serum metabolomics assay was performed to determine the changes in blood metabolites. A cholesterol efflux assay was used to measure the cholesterol efflux rate. Expression of genes or proteins were examined by qRT-PCR, western blot analysis, or immunofluorescence staining. RESULTS: Treatment with DHL greatly reduced blood lipid levels and decreased the formation of atherosclerotic plaques in the aorta in high-fat diet-fed ApoE(−/−) mice. DHL treatment enhanced cholesterol efflux from foam cells by increasing the expression of ATP-binding cassette (ABC) A1, ABCG1, and peroxisome proliferator-activated receptor gamma (PPAR-γ), both in vitro and in vivo. DHL treatment decreased the levels of IL-1β and TNF-α, elevated IL-10 levels, and promoted the formation of M2 macrophages by inhibiting myeloid differentiation factor 88 and nuclear factor kappa B (NF-κB). Inhibition of TLR2 in foam cells derived from macrophages significantly reduced the inflammatory response and enhanced cholesterol efflux. CONCLUSION: This study demonstrates that treatment with DHL alleviates atherosclerosis by promoting cholesterol efflux and inhibiting inflammation through the TLR2/PPAR-γ/NF-κB signaling pathway. GRAPHICAL ABSTRACT: [Image: see text]