https://scholars.lib.ntu.edu.tw/handle/123456789/629216
標題: | Di-(2-ethylhexyl) Phthalate Limits the Lipid-Lowering Effects of Simvastatin by Promoting Protein Degradation of Low-Density Lipoprotein Receptor: Role of PPARγ-PCSK9 and LXRα-IDOL Signaling Pathways | 作者: | Guo, Bei-Chia Kuo, Ko-Lin JENQ-WEN HUANG Chen, Chia-Hui Tarng, Der-Cherng TZONG-SHYUAN LEE |
關鍵字: | di-(2-ethylhexyl) phthalate; inducible degrader of the low-density lipoprotein receptor; liver X receptor α; low-density lipoprotein receptor; peroxisome proliferator-activated receptor γ; proprotein convertase subtilisin/kexin type 9; reactive oxygen species; statin; transient receptor potential ankyrin 1 | 公開日期: | 14-二月-2023 | 出版社: | MDPI | 卷: | 12 | 期: | 2 | 來源出版物: | Antioxidants (Basel, Switzerland) | 摘要: | Dialysis prevents death from uremia in patients with end-stage renal disease (ESRD). Nevertheless, during hemodialysis, circulating levels of di-(2-ethylhexyl) phthalate (DEHP) are increased due to phthalates leaching from medical tubes. Statins are an effective therapy for reducing the risks associated with cardiovascular diseases in patients with chronic kidney disease; however, the mechanism by which statins fail to reduce cardiovascular events in hemodialysis ESRD patients remains unclear. In this study, we investigated whether DEHP and its metabolites interfere with the lipid-lowering effect of statins in hepatocytes. In Huh7 cells, treatment with DEHP and its metabolites abolished the simvastatin-conferred lipid-lowering effect. Mechanistically, DEHP down-regulated the expression of low-density lipoprotein receptor (LDLR) and led to a decrease in LDL binding, which was mediated by the activation of the PPARγ-PCSK9 and LXRα-IDOL signaling pathways. Additionally, the NOX-ROS-TRPA1 pathway is involved in the DEHP-mediated inhibition of LDLR expression and LDL binding activity. Blockage of this pathway abrogated the DEHP-mediated inhibition in the LDLR expression and LDL binding of simvastatin. Collectively, DEHP induces the activation of the NOX-ROS-TRPA1 pathway, which in turn activates PPARγ-PCSK9- and LXRα-IDOL-dependent signaling, and, ultimately, diminishes the statin-mediated lipid-lowering effect in hepatocytes. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/629216 | ISSN: | 2076-3921 | DOI: | 10.3390/antiox12020477 |
顯示於: | 醫學系 |
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