Diverse Effects of Cilostazol on Proprotein Convertase Subtilisin/Kexin Type 9 between Obesity and Non-Obesity

Po Wei Chen, Shih Ya Tseng, Hsien Yuan Chang, Cheng Han Lee, Ting Hsing Chao

研究成果: Article同行評審

1 引文 斯高帕斯(Scopus)

摘要

Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a key role in cholesterol homeostasis. Cilostazol exerts favorable cellular and metabolic effects; however, the effect of cilostazol on the expression of PCSK9 has not been previously reported. Our study aimed to investigate the potential mechanisms of action of cilostazol on the expression of PCSK9 and lipid homeostasis. We evaluated the effects of cilostazol on the expression of PCSK9 in HepG2 cells and evaluated potential molecular mechanisms by measuring signaling molecules in the liver and serum lipid profiles in high-fat diet-induced obese mice and normal chow-fed mice. Cilostazol treatment significantly induced the messenger RNA and protein expression of PCSK9 in HepG2 cells and enhanced PCSK9 promoter activity. Chromatin immunoprecipitation assays confirmed that cilostazol treatment enhanced PCSK9 transcription by binding to peroxisome proliferator-activated receptor-γ (PPARγ) via the PPARγ DNA response element. PPARγ knockdown attenuated the stimulatory effect of cilostazol on PCSK9. In vitro, cilostazol treatment increased PCSK9 expression in vehicle-treated HepG2 cells but decreased PCSK9 expression in palmitic acid-treated HepG2 cells. In vivo, cilostazol treatment increased the serum levels of PCSK9 in normal mice but significantly reduced PCSK9 levels in obese mice. The expressions of PCSK9-relevant microRNAs also showed similar results. Clinical data showed that cilostazol treatment significantly reduced serum PCSK9 levels in patients with obesity. The obesity-dependent effects of cilostazol on PCSK9 expression observed from bench to bedside demonstrates the therapeutic potential of cilostazol in clinical settings.

原文English
文章編號9768
期刊International journal of molecular sciences
23
發行號17
DOIs
出版狀態Published - 2022 9月

All Science Journal Classification (ASJC) codes

  • 催化
  • 分子生物學
  • 光譜
  • 電腦科學應用
  • 物理與理論化學
  • 有機化學
  • 無機化學

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