Effects of citrus flavonoids, 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone and 3,5,6,7,8,3',4'-heptamethoxyflavone, on the activities of macrophage scavenger receptors and the hepatic LDL receptor.
Epidemiological and animal studies point to a possible protective effect of citrus flavonoids against cardiovascular diseases. The aim of this study is to investigate the effects of citrus flavonoids, 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5-OH-HxMF) and 3,5,6,7,8,3',4'-heptamethoxyflavone (HpMF), on the activities and expressions of macrophage scavenger receptors and the hepatic LDL receptor. Treatment of HpMF (20 μM) during THP-1 differentiation successfully attenuated 12-myristate 13-acetate (PMA)-mediated DiI-labeled oxidized low-density lipoprotein (oxLDL) uptake as evidenced by flow cytometry, indicating that the functions of scavenger receptors were blocked. RT-Q-PCR analysis suggests that the decrease in oxLDL uptake was due to the down-regulation of PMA-induced SR-A mRNA expression. In terminally differentiated THP-1 macrophages, 5-OH-HxMF and HpMF could significantly reduce DiI-oxLDL uptake, with the former having a greater effect. 5-OH-HxMF attenuated oxLDL-mediated CD36 and SR-A expression; while HpMF only decreased CD36 expression. The effects of these two flavonoids on the activity and expression of the hepatic LDL receptor (LDLR) were further investigated in HepG2 cells. 5-OH-HxMF (10-20 μM) enhanced DiI-LDL uptake by 1.33-fold due to the enhanced LDLR expression. These results imply that HpMF is better at inhibiting PMA-induced oxLDL uptake during THP-1 differentiation, while 5-OH-HxMF is more powerful in attenuating oxLDL-induced scavenger receptor expression and activity in terminally differentiated THP-1 macrophages. Furthermore, 5-OH-HxMF may have hypolipidemic activity due to its up-regulating hepatic LDLR expression.
Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717, Taiwan.
Mei-Chun
MC
Kou
Shih-Hang
SH
Fu
Jui-Hung
JH
Yen
Ching-Yi
CY
Weng
Shiming
S
Li
Chi-Tang
CT
Ho
Ming-Jiuan
MJ
Wu
D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002957:Citrus / Q000737:chemistry*; D047309:Flavones / Q000494:pharmacology*; D005419:Flavonoids / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D010936:Plant Extracts / Q000494:pharmacology*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D051116:Receptors, Scavenger / Q000235:genetics / Q000378:metabolism*
D047309:Flavones; D005419:Flavonoids; D008077:Lipoproteins, LDL; D010936:Plant Extracts; D011973:Receptors, LDL; D051116:Receptors, Scavenger; C521815:5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone; C059294:3,3',4',5,6,7,8-heptamethoxyflavone