TABLE 1.
Summary of preclinical studies examining the effects of flavonoids on RCT, HDL metabolism, and HDL function1
| Studies and flavonoids |
| Anthocyanidins |
| ApoE−/− mice |
| C3G (50 mg/kg), PCA (5 mg/kg), or the 2 in combination for 14 d |
| ↑ In vivo RCT (80) |
| Black elderberry extract (200 mg anthocyanins/kg) for 6 wk |
| ↑ Serum PON1 activity, ↑ hepatic LCAT and PON1 mRNA, ↑ intestinal apoA-I mRNA, ↓ hepatic SAA1 mRNA (86) |
| Macrophages |
| C3G or peonidin-3-glucoside (1–100 μM) |
| Mouse peritoneal: ↑ cholesterol efflux, ↑ ABCA1, ↑ binding of apoA-I to ABCA1 (85) |
| PCA (0.25–1 μM) |
| Mouse peritoneal and THP-1: ↑ cholesterol efflux and ABCA1 and ABCG1 (80) |
| Human aortic endothelial cells |
| C3G (0.5–50 μM) |
| ↑ Cholesterol efflux, ↑ ABCG1 via LXRα (81) |
| HK-2 kidney cells |
| C3G or cyanidin (50 μM) |
| ↑ Cholesterol efflux via PPARα-LXRα-ABCA1 pathway (84) |
| HepG2 cells |
| C3G (10–100 μM) |
| ↓ CETP activity in cell media (91) |
| Flavanols |
| ApoE−/− mice |
| Green tea polyphenol–enriched extra virgin olive oil [7 μL/(mouse ⋅ d)] for 2 mo |
| ↔ PON1 activity (97) |
| ↑ Ex vivo cholesterol efflux from peritoneal macrophages (97) |
| Sprague-Dawley rats |
| Green tea (2% wt:vol) in drinking water for 6 wk in diabetic rats |
| ↓ HDL cholesterol, but ↑ PON-1 activity (96) |
| Flavanones |
| Rats |
| Sprague-Dawley: High cholesterol diet with naringenin (0.02%) or its metabolites, PHPP (0.012%), and PHB (0.012%), for 5 wk |
| ↑ HDL cholesterol (105) |
| Wistar: High cholesterol diet with flavanone-rich bergamot polyphenol extract (10 and 20 mg/kg) for 30 d |
| ↔ HDL cholesterol (110) |
| Wistar: Naringenin (50 mg/kg) with or without ethanol (6 g/kg) for 60 d |
| ↑ HDL cholesterol, LCAT, and LPL activities (104) |
| Hyperuricemic Wistar: Orange juice (5 mL/kg) or hesperetin (5 mg/kg) for 2 wk |
| Orange juice, ↑ HDL cholesterol; hesperetin, ↑ serum PON1 paraoxonase and arylesterase activities (107) |
| Golden Syrian hamsters |
| Atherogenic diets for 12 wk with or without hesperetin (0.02%) or ferulic acid (0.013%) |
| Ferulic acid, ↑ serum PON1 paraoxonase activity; no effects of hesperetin (106) |
| THP-1 macrophages |
| Hesperetin (5–15 μM) |
| ↑ Cholesterol efflux, ↑ ABCA1 mRNA and protein, ↑ LXR enhancer activity and ABCA1 promoter activity (108) |
| Flavones |
| Diabetic Sprague-Dawley rats |
| Luteolin (200 mg/kg) for 8 wk |
| ↑ HDL cholesterol (117) |
| Ovariectomized mice |
| Luteolin (50 mg/kg) for 84 d |
| ↑ HDL cholesterol (116) |
| Macrophages |
| Wogonin (20–40 μM) |
| J774A.1: ↑ cholesterol efflux and ABCA1 stability (119) |
| Chrysin (10 μM) |
| RAW264.7: ↑ cholesterol efflux, ABCA1 and ABCG1 mRNA (possibly through PPARγ-LXR pathway) (118) |
| Luteolin (10–50 μM) and LXR agonist for 3 h |
| RAW264.7: LXRα/β activation and ABCA1 induction by LXR agonist was fully ↓ with 50 μM luteolin; other doses partially ↓ LXR activation (115) |
| Flavonols |
| Rats |
| Wistar: Pair-fed Lieber-Decarli liquid diet or quercetin (10 mg/L) liquid diet for 4 wk |
| ↑ Hepatic PON1 expression and serum PON1 paraoxonase activity (124) |
| Mice |
| Ldlr−/−: On atherogenic diet, given quercetin (0–25 mg/dL) in drinking water for 8 wk |
| Quercetin (12.5 and 25 mg/dL), ↑ hepatic PON1 expression and serum PON1 paraoxonase activity (123) |
| ApoE3/ApoE4 transgenic: Control diet or quercetin-added (2 mg/g) diet, both containing 21% butter fat |
| ↑ Hepatic PON1 mRNA in ApoE3 transgenic mice (121) |
| C57BL/6: Quercetin (0.05–2 mg/g of diet) for 6 wk |
| Quercetin (≥0.1 mg/g of diet), ↑ PON1 expression (122) |
| Huh7 hepatoma cells |
| Quercetin (20 μM) |
| ↑ PON1 paraoxonase activity, protein, and gene expression, possibly via SREBP2 activation (126) |
| Quercetin (25 μM) and transfected with PON1 gene |
| ↑ PON1 promoter activity (122) |
| Macrophages |
| Quercetin (0.3–30 μM) |
| THP-1: ↑ cholesterol efflux to apoA-I and HDL via PPARγ-LXRα-ABCA1 pathway (127) |
| Quercetin (20 μM) alone, or with glutathione (200 μM), or PON1 (10 μg/mL) |
| J774A.1: ↑ cholesterol efflux alone and with glutathione, ↑ ABCA1 and PPARα expressions, was not via PKA or JAK2 pathways (128) |
| Quercetin (100–200 μM) |
| RAW264.7: ↑ cholesterol efflux and ↑ ABCA1 gene/protein expression via p38-dependent binding of Sp1 and LXR to ABCA1 promoter (129) |
| Kaempferol (35 μM) |
| THP-1: ↑ cholesterol efflux, ↓ CD36, ↑ ABCA1, ↑ ABCG1, ↑ SR-BI mRNA expression/protein (130) |
| Isoflavones |
| Rats |
| Arthritic Sprague-Dawley: Genistein or daidzein (20 mg/kg) for 50 d |
| ↑ Serum PON1 paraoxonase and arylesterase activities (134) |
| Ovariectomized Sprague-Dawley: Genistein (10 mg/kg) for 8 wk |
| ↔ HDL cholesterol or PON1 activity (133) |
| 100 mg/kg Isoflavones (genistein, daidzein, glycitin), with or without MCD diet for 8 wk |
| ↑ HDL cholesterol, PON1 paraoxonase, and arylesterase activities (135) |
1
ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; CD36, cluster of differentiation 36; CETP, cholesteryl ester transfer protein; C3G, cyanidin-3-glucoside; C57BL/6, C57 black 6; JAK2, Janus kinase 2; LCAT, lecithin-cholesterol acyltransferase; LPL, lipoprotein lipase; LXR, liver X receptor; MCD, methionine choline–deficient; PCA, protocatechuic acid; PHB, ρ-hydroxybenzoic acid; PHPP, ρ-hyproxyphenylpropionic acid; PKA, protein kinase A; PON1, paraoxonase 1; RCT, reverse cholesterol transport; SAA1, serum amyloid A-1; Sp1, Sp1 transcription factor; SR-BI, scavenger receptor class B type I; SREBP2, sterol regulatory element binding protein 2; ↑, increase; ↓ decrease; ↔, no change.