Xanthohumol Suppresses NPC1L1 Gene Expression through Downregulation of HNF-4 alpha( )and Inhibits Cholesterol Uptake in Caco-2 Cells

doi:10.1021/acs.jafc.9b05221

Chia Nan University of Pharmacy & Science Institutional Repository > 藥理學院 > 生物科技系(所) > 期刊論文 > Item 310902800/32669

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標題:	Xanthohumol Suppresses NPC1L1 Gene Expression through Downregulation of HNF-4 alpha( )and Inhibits Cholesterol Uptake in Caco-2 Cells
作者:	Thang, Sang Kim Chen, Pei-Yi Gao, Wan-Yun Wu, Ming-Jiuan Pan, Min-Hsiung Yen, Jui-Hung
貢獻者:	Tzu Chi Univ, Inst Med Sci Hualien Tzu Chi Hosp, Buddhist Tzu Chi Fdn, Ctr Med Genet Tzu Chi Univ, Dept Mol Biol & Human Genet Chia Nan Univ Pharm & Sci, Dept Biotechnol Natl Taiwan Univ, Inst Food Sci & Technol
關鍵字:	xanthohumol cholesterol absorption NPC1L1 HNF-4 alpha statin
日期:	2019
上傳時間:	2020-07-29 13:54:32 (UTC+8)
出版者:	AMER CHEMICAL SOC
摘要:	Xanthohumol (Xan) is a prenylated chalcone mainly found in hops; it has been demonstrated to function against hypercholesterolemia, hyperlipidemia, and atherosclerosis. In this study, we focused on the hypocholesterolemic effect of Xan on cholesterol uptake and the underlying molecular mechanisms of Xan in human intestinal Caco-2 cells. The microarray data showed that Niemann-Pick C1-like 1 (NPC1L1), an essential transporter for dietary cholesterol absorption, was significantly downregulated in Xan-treated Caco-2 cells. We demonstrated that Xan (10 and 20 mu M) suppressed the mRNA and protein expression of NPC1L1 by 0.65 +/- 0.12-fold and 0.54 +/- 0.15-fold and 0.72 +/- 0.04-fold and 0.44 +/- 0.12-fold, respectively, compared to that of the vehicle-treated Caco-2 cells. Moreover, Xan (10 and 20 mu M) significantly inhibited cholesterol uptake by approximately 12 and 32% in Caco-2 cells. NPC1L1 promoter activity was significantly suppressed by Xan, and a DNA element within the NPC1L1 promoter involved in Xan-mediated NPC1L1 reduction located between the -120 and -20 positions was identified. Moreover, Xan markedly decreased the mRNA and protein levels of hepatocyte nuclear factor 4 alpha (HNF-4 alpha), a critical activator of NPC1L1 transcription, and subsequently attenuated HNF-4 alpha/NPC1L1 promoter complex formation, resulting in the suppression of NPC1L1 gene expression. Finally, we demonstrated that Xan markedly abolished lovastatin-induced NPC1L1 overexpression in Caco-2 cells. These findings reveal that Xan suppresses NPC1L1 expression via downregulation of HNF-4 alpha and exerts inhibitory effects on cholesterol uptake in the intestinal Caco-2 cells. Our findings suggest Xan could serve as a potential cholesterol-lowering agent and supplement for statin therapy.
關聯:	Journal of Agricultural and Food Chemistry, v.67, n.40, pp.
显示于类别:	[生物科技系(所)] 期刊論文

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