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,Chih-Yang Wang,Wan-Yun Gao,Ming-Jiuan Wu,Hao-Jen Hsu,Jui-Hung Yen,Ching-Yen Lin

doi:10.3390/ijms22189853

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 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.

Highlights

Patients with dyslipidemia, a major risk factor for atherosclerotic cardiovascular diseases (ASCVDs) and myocardial infarction (MI), often have high levels of total cholesterol, triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) in the blood circulation [1]
Before the examination of molecule’s regulating effect, we need be that sureitthat it not have detrimental effects in tested cells; we examine the cytotoxic effect of tangedoes not have detrimental effects in tested cells; we examine the cytotoxic effect of retintangeretin (Figure 1a)(Figure on hepatic
The amounts of secreted angiopoietin-like 3 (ANGPTL3) proteins in the tangeretin-treated cells were anthe transcriptional level; we further investigated the effect of tangeretin on the tranalyzed by ELISA

Summary

Introduction

A major risk factor for atherosclerotic cardiovascular diseases (ASCVDs) and myocardial infarction (MI), often have high levels of total cholesterol, triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), and very low-density lipoprotein cholesterol (VLDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) in the blood circulation [1]. The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is known to accompany dyslipidemia and ASCVDs [2,3]. TGRL particles, including chylomicrons and VLDLs, can be degraded by lipoprotein lipase (LPL). Located on endothelial cells of capillary vessels, which may lead to decreased TG contents of lipoproteins and the release of free fatty acids in plasma. Released fatty acids can be absorbed and utilized by surrounding tissues such as the heart, muscle, and adipose tissue [4]. The modulation of LPL activity plays an essential role in regulating the amount of plasma TG and atherogenic lipoproteins and maintaining lipid homeostasis in circulation

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