The Citrus Flavonoid Nobiletin Downregulates Angiopoietin-like Protein 3 (ANGPTL3) Expression and Exhibits Lipid-Modulating Effects in Hepatic Cells and Adult Zebrafish Models

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Title:	The Citrus Flavonoid Nobiletin Downregulates Angiopoietin-like Protein 3 (ANGPTL3) Expression and Exhibits Lipid-Modulating Effects in Hepatic Cells and Adult Zebrafish Models
Authors:	Lin, Ching-Yen Chen, Pei-Yi Hsu, Hao-Jen Gao, Wan-Yun Wu, Ming-Jiuan Yen, Jui-Hung
Contributors:	Tzu Chi University Buddhist Tzu Chi General Hospital Tzu Chi University Tzu Chi University Department of Biotechnology, Chia Nan University of Pharmacy & Science
Keywords:	high-density-lipoprotein cardiovascular-disease selective uptake metabolism cholesterol lipase gene triglycerides suppresses kinase
Date:	2022
Issue Date:	2023-12-11 14:00:06 (UTC+8)
Publisher:	MDPI
Abstract:	Nobiletin, a dietary citrus flavonoid, exerts biological activities against hyperlipidemia, obesity, and atherosclerotic cardiovascular diseases (ASCVDs). The aim of this study was to explore the lipid-lowering effects of nobiletin and the underlying molecular mechanisms in vitro in hepatic cells and in vivo in zebrafish models. Transcriptome and gene ontology (GO) analyses of differentially expressed genes (DEGs) by gene set enrichment analysis (GSEA) showed that a set of twenty-eight core enrichment DEGs associated with GO BP regulation of lipid metabolic process (GO: 0019216) were significantly downregulated in nobiletin-treated cells. Among these genes, angiopoietin-like 3 (ANGPTL3), an inhibitor of lipoprotein lipase (LPL) activity that regulates TG-rich lipoprotein (TGRL) metabolism in circulation, was the protein most markedly downregulated by nobiletin. Nobiletin (20 and 40 mu M) significantly reduced the levels of ANGPTL3 mRNA and intracellular and secreted ANGPTL3 proteins in hepatic cell lines. Furthermore, alleviation of secreted ANGPTL3 production by nobiletin was found to reinstate LPL catalytic activity. Nobiletin significantly inhibited ANGPTL3 promoter activity and attenuated the transcription factor liver X receptor-alpha (LXR alpha)-mediated ANGPTL3 transcription. Molecular docking analysis predicted that nobiletin could bind to the ligand-binding domain of LXR alpha, thereby counteracting LXR alpha activation. In animal studies, orally administered nobiletin significantly alleviated the levels of plasma triglycerides (TGs) and cholesterol in zebrafish fed a high-fat diet. Moreover, nobiletin significantly reduced the amounts of hepatic ANGPTL3 protein in zebrafish. Our findings suggest that nobiletin may regulate the LXR alpha-ANGPTL3-LPL axis and exhibit lipid-modulating effects in vitro and in vivo. Thus, nobiletin is a potential ANGPTL3 inhibitor for the regulation of lipid metabolism to ameliorate dyslipidemia and ASCVDs.
Relation:	INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.23, n.20, 12485
Appears in Collections:	[Dept. of Biotechnology (including master's program)] Periodical Articles

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