The Lipid-Modulating Effect of Tangeretin on the Inhibition of Angiopoietin-like 3 (ANGPTL3) Gene Expression through Regulation of LXR alpha Activation in Hepatic Cells

doi:10.3390/ijms22189853

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Title:	The Lipid-Modulating Effect of Tangeretin on the Inhibition of Angiopoietin-like 3 (ANGPTL3) Gene Expression through Regulation of LXR alpha Activation in Hepatic Cells
Authors:	Chen, Pei-Yi Chao, Tzu-Ya Hsu, Hao-Jen Wang, Chih-Yang Lin, Ching-Yen Gao, Wan-Yun Wu, Ming-Jiuan Yen, Jui-Hung
Contributors:	Hualien Tzu Chi Hosp, Buddhist Tzu Chi Med Fdn, Ctr Med Genet Tzu Chi Univ, Dept Mol Biol & Human Genet Tzu Chi Univ, Dept Life Sci Taipei Med Univ, Program Canc Mol Biol & Drug Discovery Taipei Med Univ, Grad Inst Canc Biol & Drug Discovery Tzu Chi Univ, Inst Med Sci Chia Nan Univ Pharm & Sci, Dept Biotechnol
Keywords:	TG-rich lipoproteins tangeretin lipoprotein lipase ANGPTL3 LXR alpha
Date:	2021
Issue Date:	2023-11-11 11:47:39 (UTC+8)
Publisher:	MDPI
Abstract:	The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, 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 bioinformatics 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 lipoprotein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential inhibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly downregulated 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 tangeretin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor-alpha (LXR alpha) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXR alpha-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligandbinding domain of LXR alpha, which would result in suppression of LXR alpha activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXR alpha-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia.
Relation:	INT J MOL SCI, v.22, n.18, pp.9853
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

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