BDE-47 Inhibits Cholesterol Efflux in Macrophagesthrough Interfering with Endogenous Agonists of Liver X Receptors

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Abstract Brominated flame retardant BDE-47 is a widespread environmental contaminant and was shown to be pro-atherosclerotic. However, the molecular mechanisms underlying the BDE-47-triggered atherosclerotic effect are still elusive. Here, BDE-47 was uncovered to markedly decrease cholesterol efflux through repression of ATP-binding cassette (ABC) transporter A1 (ABCA1) and ABCG1 in human THP-1 macrophages, contributing to the generation of foam cells. Liver X receptors (LXRs) served as the most important regulator for the expression of ABCA1 and ABCG1. Interestingly, BDE-47 did not directly bind to LXRs-LBD or alter LXRα levels, but caused a significant reduction of endogenous LXRs agonists, desmosterol and 24(S),25-epoxycholesterol. Moreover, exogenous addition of desmosterol or 24(S),25-epoxycholesterol could well restore inhibition of cholesterol efflux triggered by BDE-47. Furthermore, sterol metabolic profiles pointed out that BDE-47 disturbed the activity of 7-dehydrocholesterol reductase (DHCR7), and docking analysis suggested that BDE-47 binds with DHCR7 at its catalytic domain. Concurrently, chronic, environment-relevant dose exposure (0.05, 5 mg/kg/day) of BDE-47 was confirmed to exacerbate atherosclerosis in ApoE–/– mice. Altogether, these results uncovered that BDE-47 disturbs macrophages’ cholesterol efflux via disrupting LXR endogenous agonist biosynthesis, providing novel insights into understanding the molecular mechanisms and cardiovascular toxicity of BDE-47, as well as highlighting a novel manner of environmental pollutants to interfere with LXRs’ activity.