Benzotriazole ultraviolet stabilizer UV-234 promotes foam cell formation in RAW264.7 macrophages

Benzotriazole ultraviolet stabilizers (BUVSs) have been reported to induce inflammatory responses which may promote cholesterol accumulation and to downregulate the expression of genes involved in cholesterol biosynthesis; hence, we speculated whether BUVSs promote foam cell formation, which plays a key role in all stages of atherosclerosis. Herein, we used high-content imaging to screen all available BUVSs; of all the 17 candidates, 6 of them could promote foam cell formation at 10 μM. Further analyses showed that one BUVS UV-234 markedly increased the foam cell staining intensity by 15.0%-55.9% in the 0.5-10 μM exposure groups in a dose-dependent manner. Cholesterol influx was markedly enhanced by 21.0%-24.5% in the 5-10 μM exposure groups and cholesterol efflux was downregulated by 21.2%-59.3% in the 0.5-10 μM exposure groups, indicating that cholesterol efflux may play a major role in foam formation considering cholesterol efflux was downregulated at a relatively low concentration. Gene expression of ABCA1 and ABCG1 which regulate the cholesterol efflux were also decreased at 0.5-10 μM. The degradation of hypoxia-inducible factor 1α (HIF1α) via the ubiquitin-proteasome system was observed at 0.5-10 μM, probably contributing to the downregulated expression of the genes encoding liver X receptors (LXR) α/β and their targets, ABCA1 and ABCG1. Thus, our study revealed that BUVSs frequently detected in the environment can promote foam cell formation in macrophages, contributing to the risk of atherosclerosis in humans.