Xanthohumol, a prenylated chalcone, regulates lipid metabolism by modulating the LXRα/RXR-ANGPTL3-LPL axis in hepatic cell lines and high-fat diet-fed zebrafish models

Wan-Yun Gao; Pei-Yi Chen; Hao-Jen Hsu; Je-Wen Liou; Chia-Ling Wu; Ming-Jiuan Wu; Jui-Hung Yen

Biomedicine & Pharmacotherapy (May 2024)

Xanthohumol, a prenylated chalcone, regulates lipid metabolism by modulating the LXRα/RXR-ANGPTL3-LPL axis in hepatic cell lines and high-fat diet-fed zebrafish models

Wan-Yun Gao,
Pei-Yi Chen,
Hao-Jen Hsu,
Je-Wen Liou,
Chia-Ling Wu,
Ming-Jiuan Wu,
Jui-Hung Yen

Affiliations

Wan-Yun Gao: Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan
Pei-Yi Chen: Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan
Hao-Jen Hsu: Department of Biomedical Science and Engineering, Tzu Chi University, Hualien 970374, Taiwan
Je-Wen Liou: Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 970374, Taiwan
Chia-Ling Wu: Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan
Ming-Jiuan Wu: Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717301, Taiwan
Jui-Hung Yen: Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan; Correspondence to: Department of Molecular Biology and Human Genetics; and Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan.

Journal volume & issue: Vol. 174
p. 116598

Abstract

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Angiopoietin-like 3 (ANGPTL3) acts as an inhibitor of lipoprotein lipase (LPL), impeding the breakdown of triglyceride-rich lipoproteins (TGRLs) in circulation. Targeting ANGPTL3 is considered a novel strategy for improving dyslipidemia and atherosclerotic cardiovascular diseases (ASCVD). Hops (Humulus lupulus L.) contain several bioactive prenylflavonoids, including xanthohumol (Xan), isoxanthohumol (Isoxan), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN), with the potential to manage lipid metabolism. The aim of this study was to investigate the lipid-lowering effects of Xan, the effective prenylated chalcone in attenuating ANGPTL3 transcriptional activity, both in vitro using hepatic cells and in vivo using zebrafish models, along with exploring the underlying mechanisms. Xan (10 and 20 μM) significantly reduced ANGPTL3 mRNA and protein expression in HepG2 and Huh7 cells, leading to a marked decrease in secreted ANGPTL3 proteins via hepatic cells. In animal studies, orally administered Xan significantly alleviated plasma triglyceride (TG) and cholesterol levels in zebrafish fed a high-fat diet. Furthermore, it reduced hepatic ANGPTL3 protein levels and increased LPL activity in zebrafish models, indicating its potential to modulate lipid profiles in circulation. Furthermore, molecular docking results predicted that Xan exhibits a higher binding affinity to interact with liver X receptor α (LXRα) and retinoic acid X receptor (RXR) than their respective agonists, T0901317 and 9-Cis-retinoic acid (9-Cis-RA). We observed that Xan suppressed hepatic ANGPTL3 expression by antagonizing the LXRα/RXR-mediated transcription. These findings suggest that Xan ameliorates dyslipidemia by modulating the LXRα/RXR-ANGPTL3-LPL axis. Xan represents a novel potential inhibitor of ANGPTL3 for the prevention or treatment of ASCVD.

Published in Biomedicine & Pharmacotherapy

ISSN: 0753-3322 (Print); 1950-6007 (Online)
Publisher: Elsevier
Country of publisher: France
LCC subjects: Medicine: Therapeutics. Pharmacology
Website: https://www.journals.elsevier.com/biomedicine-and-pharmacotherapy

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