The lipid-modulating effect of tangeretin on the inhibition of angiopoietin-like 3 (Angptl3) gene expression through regulation of lxrα activation in hepatic cells

Pei Yi Chen, Tzu Ya Chao, Hao Jen Hsu, Chih Yang Wang, Ching Yen Lin, Wan Yun Gao, Ming Jiuan Wu, Jui Hung Yen

研究成果: 雜誌貢獻文章同行評審

5 引文 斯高帕斯(Scopus)

摘要

The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pen-tamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyper-lipidemia, diabetes, and obesity. The aim of this study was to investigate the lipid-modulating effects and the underlying mechanisms of tangeretin action in hepatic cells. Transcriptome and bio-informatics analyses with the Gene Ontology (GO) database showed that tangeretin significantly regulated a set of 13 differentially expressed genes (DEGs) associated with the regulation of lipo-protein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential in-hibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly down-regulated by tangeretin. We demonstrated that tangeretin significantly inhibited the mRNA expression of ANGPTL3 in HepG2 and Huh-7 cells. Tangeretin treatment of hepatic cells also reduced the levels of both intracellular and secreted ANGPTL3 proteins. Moreover, we found that inhibition of ANGPTL3 production by tangeretin augmented LPL activity. We further demonstrated that the transcriptional activity of the ANGPTL3 promoter was significantly attenuated by tangeretin, and we identified a DNA element located between the −250 and −121 positions that responded to tange-retin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor α (LXRα) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXRα-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligand-binding domain of LXRα, which would result in suppression of LXRα activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXRα-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia.
原文英語
文章編號9853
期刊International journal of molecular sciences
22
發行號18
DOIs
出版狀態已發佈 - 9月 2021

ASJC Scopus subject areas

  • 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

指紋

深入研究「The lipid-modulating effect of tangeretin on the inhibition of angiopoietin-like 3 (Angptl3) gene expression through regulation of lxrα activation in hepatic cells」主題。共同形成了獨特的指紋。

引用此