TY - JOUR
T1 - The lipid-modulating effect of tangeretin on the inhibition of angiopoietin-like 3 (Angptl3) gene expression through regulation of lxrα activation in hepatic cells
AU - Chen, Pei Yi
AU - Chao, Tzu Ya
AU - Hsu, Hao Jen
AU - Wang, Chih Yang
AU - Lin, Ching Yen
AU - Gao, Wan Yun
AU - Wu, Ming Jiuan
AU - Yen, Jui Hung
N1 - Funding Information:
Funding: This research was supported by grants MOST 108-2320-B-320-002-MY3 (to J.-H. Yen, funding approval date 1 August 2019) from the Ministry of Science and Technology; TCMF-SP 110-01 (to J.-H. Yen, funding approval date 1 January 2021) from Buddhist Tzu Chi Medical Foundation; and TCRD-110-52 (P.-Y. Chen, funding approval date 1 January 2021) from Hualien Tzu Chi Hospital, Taiwan.
Funding Information:
This research was supported by grants MOST 108-2320-B-320-002-MY3 (to J.-H. Yen, funding approval date 1 August 2019) from the Ministry of Science and Technology; TCMF-SP 110-01 (to J.-H. Yen, funding approval date 1 January 2021) from Buddhist Tzu Chi Medical Foundation; and TCRD-110-52 (P.-Y. Chen, funding approval date 1 January 2021) from Hualien Tzu Chi Hospital, Taiwan.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/9
Y1 - 2021/9
N2 - The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pen-tamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyper-lipidemia, 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 bio-informatics 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 lipo-protein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential in-hibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly down-regulated 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 tange-retin. 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.
AB - The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pen-tamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyper-lipidemia, 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 bio-informatics 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 lipo-protein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential in-hibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly down-regulated 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 tange-retin. 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.
KW - ANGPTL3
KW - Lipoprotein lipase
KW - LXRα
KW - Tangeretin
KW - TG-rich lipoproteins
UR - http://www.scopus.com/inward/record.url?scp=85114629041&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85114629041&partnerID=8YFLogxK
U2 - 10.3390/ijms22189853
DO - 10.3390/ijms22189853
M3 - Article
C2 - 34576019
AN - SCOPUS:85114629041
SN - 1661-6596
VL - 22
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 18
M1 - 9853
ER -