Urolithin A attenuated ox-LDL-induced cholesterol accumulation in macrophages partly through regulating miR-33a and ERK/AMPK/SREBP1 signaling pathways

Promoting cholesterol efflux from foam cells represents one of the therapeutic strategies for ameliorating atherosclerosis. Urolithin A (UA) has been shown before to attenuate ox-LDL induced endothelial dysfunction in endothelial cells with its anti-inflammatory properties. The aim of this study was to investigate whether UA could promote cholesterol effluxviamodulating related microRNA (miR) and signaling pathways. RAW264.7 cells were treated with 50 mu g mL(-1)ox-LDL to induce foam cell formation. After treatment with UA at different concentrations, intercellular and extracellular cholesterol levels were determined. Expression of Erk1/2, AMPK alpha and their phosphorylation forms, and SREBP1, was analyzed by western-blotting. The effect of UA on miR-33a expression and the involvement of miR-33a in cholesterol efflux regulation were also investigated. UA reduced ox-LDL induced cholesterol accumulation in macrophage cells and promoted cholesterol efflux from cells. Compared with ox-LDL treated cells, UA treatment reduced the level of phosphorylated ERK1/2, increased the expression of phosphorylated AMPK alpha and decreased the SREBP1 expression. Moreover, UA decreased the miR-33a expression at the transcriptional level but increased the transcriptional expression of ATP-binding cassette transporter A1 (ABCA1) and ABCG1, two genes contributing to reverse cholesterol transport. Furthermore, pre-miR-33a attenuated cholesterol efflux induced by UA. Collectively, UA promoted the reverse cholesterol transport in macrophage-derived foam cells and interfered with cholesterol metabolism possibly through regulating the miRNA-33 expression and interaction with the ERK/AMPK alpha/SREBP1 signaling pathway.