Hydroxytyrosol Reduces Foam Cell Formation and Endothelial Inflammation Regulating the PPARγ/LXRα/ABCA1 Pathway

Cholesterol accumulation in macrophages leads to the formation of foam cells and in‐ creases the risk of developing atherosclerosis. We have verified whether hydroxytyrosol (HT), a phenolic compound with anti‐inflammatory and antioxidant properties, can reduce the cholesterol build up in THP‐1 macrophage‐derived foam cells. We have also investigated the potential mecha‐ nisms. Oil Red O staining and high‐performance liquid chromatography (HPLC) assays were uti‐ lized to detect cellular lipid accumulation and cholesterol content, respectively, in THP‐1 macro‐ phages foam cells treated with HT. The impact of HT on cholesterol metabolism‐related molecules (SR‐A1, CD36, LOX‐1, ABCA1, ABCG1, PPARγ and LRX‐α) in foam cells was assessed using real‐ time PCR (RT‐qPCR) and Western blot analyses. Finally, the effect of HT on the adhesion of THP‐1 monocytes to human vascular endothelial cells (HUVEC) was analyzed to study endothelial activa‐ tion. We found that HT activates the PPARγ/LXRα pathway to upregulate ABCA1 expression, re‐ ducing cholesterol accumulation in foam cells. Moreover, HT significantly inhibited monocyte ad‐ hesion and reduced the levels of adhesion factors (ICAM‐1 and VCAM‐1) and pro‐inflammatory factors (IL‐6 and TNF‐α) in LPS‐induced endothelial cells. Taken together, our findings suggest that HT, with its ability to interfere with the import and export of cholesterol, could represent a new therapeutic strategy for the treatment of atherosclerotic disease.