2,2′,4,4′-Tetrabromodiphenyl Ether (PBDE 47) Selectively Stimulates Proatherogenic PPARγ Signatures in Human THP-1 Macrophages to Contribute to Foam Cell Formation

罗格列酮 CD36 下调和上调 过氧化物酶体增殖物激活受体 化学 泡沫电池 细胞生物学 芳香烃受体 THP1细胞系 转录组 兴奋剂 受体 细胞培养 生物化学 转录因子 生物 基因表达 胆固醇 基因 脂蛋白 遗传学
作者
Qidong Ren,X. C. Xie,Chuanfang Zhao,Qing Wen,Ruiying Pan,Yuguo Du
出处
期刊:Chemical Research in Toxicology [American Chemical Society]
卷期号:35 (6): 1023-1035 被引量:7
标识
DOI:10.1021/acs.chemrestox.2c00043
摘要

2,2′,4,4′-Tetrabromodiphenyl ether (PBDE 47) is one of the most prominent PBDE congeners detected in the human body, suggesting that the potential health risks of PBDE 47 should be thoroughly considered. However, the cardiovascular toxicity of PBDE 47 remains poorly understood. Here, toxic outcomes of PBDE 47 in human THP-1 macrophages concerning foam cell formation, which play crucial roles in the occurrence and development of atherosclerosis, were elucidated. First, our results indicated that PBDE 47 affected the PPARγ pathway most efficiently in THP-1 macrophages by transcriptomic analysis. Second, the PPARγ target genes CD36 and FABP4, responsible for lipid uptake and accumulation in macrophages, were consistently upregulated both at transcriptional and translational levels in THP-1 macrophages upon PBDE 47. Unexpectedly, PBDE 47 failed to activate the PPARγ target gene LXRα and PPARγ-LXRα-ABCA1/G1 cascade, which is activated by the PPARγ full agonist rosiglitazone and enables cholesterol efflux in macrophages. Thus, coincident with the selective upregulation of the PPARγ target genes CD36 and FABP4, PBDE 47, distinct from rosiglitazone, functionally resulted in more lipid accumulation and oxLDL uptake in THP-1 macrophages through high-content analysis (HCA). Moreover, these effects were markedly abrogated by the addition of the PPARγ antagonist T0070907. Mechanistically, the structural basis of selective activation of PPARγ by PBDE 47 was explored by molecular docking and dynamics simulation, which indicated that PBDE 47 interacted with the PPARγ ligand binding domain (PPARγ-LBD) distinctively from that of rosiglitazone. PBDE 47 was revealed to interact with helix 3 and helix 5 but not helix 12 in the PPARγ-LBD. Collectively, these results unraveled the potential cardiovascular toxicity of PBDE 47 by selective activation of PPARγ to facilitate foam cell formation for the first time.
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