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

Abstract

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.

Disease chemopreventive effects and molecular mechanisms of hydroxylated polymethoxyflavones

“…Wu et al suggested that heptaMF, but not 5‐demethylheptaMF, potently reduces phorbol 12‐myristate 13‐acetate (PMA)‐induced SR‐A mRNA expression and ox‐LDL uptake in THP‐1 monocytes during differentiation. However, 5‐demethylheptaMF was found to be more effective than heptaMF on ox‐LDL‐mediated CD36 and SR‐A expression in THP‐1‐derived macrophages, indicating that different mechanisms are involved in their anti‐atherogenic effects . In this study, the author also compared the inhibitory effect of heptaMF and 5‐demethylheptaMF with previously reported, nobiletin, 5‐demethylnobiletin, and 3′,4′‐didemethylnobiletin in the inhibition of ox‐LDL uptake in THP‐1‐derived macrophages, which showed 3′,4′‐didemethylnobiletin to be strongest one followed by 5‐demethylnobiletin and 5‐demethylheptaMF while nobiletin and heptaMF were the least active.…”

“…In this study, the author also compared the inhibitory effect of heptaMF and 5‐demethylheptaMF with previously reported, nobiletin, 5‐demethylnobiletin, and 3′,4′‐didemethylnobiletin in the inhibition of ox‐LDL uptake in THP‐1‐derived macrophages, which showed 3′,4′‐didemethylnobiletin to be strongest one followed by 5‐demethylnobiletin and 5‐demethylheptaMF while nobiletin and heptaMF were the least active. They further concluded that the 5‐hydroxyl group of PMF may play a vital role in the down‐regulation of SR activity in THP‐1 macrophages, although 3′,4′‐didemethylnobiletin was the most effective .…”

Pharmacokinetics, tissue distribution, and excretion study of GL‐V9 and its glucuronide metabolite 5‐O‐glucuronide GL‐V9 in Sprague–Dawley rats

“…Considering both clinical and experimental considerations, we opted for single-dose intravenous administration, as well as singleand multiple-dose intragastric administration. Previous reports have indicated the presence of a 5-O-glucuronide metabolite of wogonin in SD rats, affirming the reactivity of the 5-OH group in flavonoids (Kou et al, 2013). Given that GL-V9 features a 5-OH group in its structure, the possibility of glucuronide conjugation, if it occurs, may involve this position.…”

Isoflavone supplementation in postmenopausal women does not affect leukocyte LDL receptor and scavenger receptor CD36 expression: A double‐blind, randomized, placebo‐controlled trial

“…Flavonoids from citrus did not affect CD36 mRNA expression in the monocyte‐like cell line THP‐1. Interestingly, one of these flavonoids reduced oxLDL uptake through a reduction in class A scavenger receptor SR‐A expression . Furthermore, the expression of class B scavenger receptor SRB1 in rat livers was indirectly reduced by an estrogen‐dependent increase in LDLR activity , which could be a mechanism for potential estrogenic IF effects on CD36.…”