Abstract
This study investigated the effects and mechanisms of 7-ketocholesterol in promoting macrophage foaming and inflammation. Single-cell RNA sequencing showed that dietary cholesterol oxidation products increased the inflammatory macrophage and Trem2high macrophage numbers in the atherosclerotic aorta of ApoE−/− mice. Enrichment analysis demonstrated activation of inflammation-related pathways (NF-κB pathway and NLRP3 inflammasome) in inflammatory macrophages and cholesterol metabolism-related pathways (LDLR and ABCG1) in Trem2high macrophages. An oxidized-LDL-treated macrophage model was employed to verify the effects and mechanisms of 7-KC on macrophage inflammation and foam cell formation. 7-KC promoted the inflammation and M1 polarization of macrophage in association with the activations of the NF-κB pathway and NLRP3 inflammasome. Furthermore, 7-KC-mediated excessive cholesterol accumulation was attributed to enhanced cholesterol uptake rather than inhibition of cholesterol efflux. Consequently, LDLR expression was up-regulated by 7-KC, while no significant effect on ABCG1 expression was observed.
Published Version
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