Effects of dietary flavonoids on reverse cholesterol transport, HDL metabolism, and HDL function

Advances in Nutrition

Volumn 8, Issue 2, 2017, Pages 226-239

  Millar, Courtney L ^a   Duclos, Quinn ^a   Blesso, Christopher N ^a  

^a UNIVERSITY OF CONNECTICUT   (United States)

Author keywords

Anthocyanins; Atherosclerosis; Flavonoids; HDL; Polyphenols

Indexed keywords

ANTIINFLAMMATORY AGENT; ANTIOXIDANT; FLAVONOID; HIGH DENSITY LIPOPROTEIN CHOLESTEROL;

ANIMAL; ANIMAL MODEL; APOPTOSIS; BLOOD; DIET; DRUG EFFECTS; HUMAN; METABOLISM; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; ANTI-INFLAMMATORY AGENTS; ANTIOXIDANTS; APOPTOSIS; BIOLOGICAL TRANSPORT; CHOLESTEROL, HDL; DIET; FLAVONOIDS; HUMANS; MODELS, ANIMAL;

EID: 85020229213     PISSN: 21618313     EISSN: 21565376     Source Type: Journal    
DOI: 10.3945/an.116.014050     Document Type: Review

References (141)

1. Xu J, Murphy SL, Kochanek KD, Bastian BA. Deaths: final data for 2013. Natl Vital Stat Rep 2016;64:1-119.
2. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-95.
3. Barter P, Gotto AM, LaRosa JC, Maroni J, Szarek M, Grundy SM, Kastelein JJ, Bittner V, Fruchart JC. HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events. N Engl J Med 2007;357:1301-10.
4. Badimon JJ, Badimon L, Fuster V. Regression of atherosclerotic lesions by high density lipoprotein plasma fraction in the cholesterol-fed rabbit. J Clin Invest 1990;85:1234-41.
5. Miyazaki A, Sakuma S, Morikawa W, Takiue T, Miake F, Terano T, Sakai M, Hakamata H, Sakamoto Y, Natio M, et al. Intravenous injection of rabbit apolipoprotein A-I inhibits the progression of atherosclerosis in cholesterol-fed rabbits. Arterioscler Thromb Vasc Biol 1995;15:1882-8.
6. Shah PK, Yano J, Reyes O, Chyu KY, Kaul S, Bisgaier CL, Drake S, Cercek B. High-dose recombinant apolipoprotein A-I(milano) mobilizes tissue cholesterol and rapidly reduces plaque lipid and macrophage content in apolipoprotein e-deficient mice. Potential implications for acute plaque stabilization. Circulation 2001;103:3047-50.
7. Nissen SE, Tsunoda T, Tuzcu EM, Schoenhagen P, Cooper CJ, Yasin M, Eaton GM, Lauer MA, Sheldon WS, Grines CL, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-300.
8. Shaw JA, Bobik A, Murphy A, Kanellakis P, Blombery P, Mukhamedova N, Woollard K, Lyon S, Sviridov D, Dart AM. Infusion of reconstituted high-density lipoprotein leads to acute changes in human atherosclerotic plaque. Circ Res 2008;103:1084-91.
9. Tardy C, Goffinet M, Boubekeur N, Ackermann R, Sy G, Bluteau A, Cholez G, Keyserling C, Lalwani N, Paolini JF, et al. CER-001, a HDL- mimetic, stimulates the reverse lipid transport and atherosclerosis regression in high cholesterol diet-fed LDL-receptor deficient mice. Atherosclerosis 2014;232:110-8.
10. Castelli WP, Doyle JT, Gordon T, Hames CG, Hjortland MC, Hulley SB, Kagan A, Zukel WJ. HDL cholesterol and other lipids in coronary heart disease. The cooperative lipoprotein phenotyping study. Circulation 1977;55:767-72.
11. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med 1977;62:707-14.
12. Gordon DJ, Probstfield JL, Garrison RJ, Neaton JD, Castelli WP, Knoke JD, Jacobs DR Jr., Bangdiwala S, Tyroler HA. High-density lipoprotein cholesterol and cardiovascular disease. Four prospective American studies. Circulation 1989;79:8-15.
13. Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov 2005;4:193-205.
14. Chapman MJ, Assmann G, Fruchart JC, Shepherd J, Sirtori C. Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid-a position paper developed by the European Consensus Panel on HDL-C. Curr Med Res Opin 2004;20: 1253-68.
15. Rubins HB, Robins SJ, Collins D, Fye CL, Anderson JW, Elam MB, Faas FH, Linares E, Schaefer EJ, Schectman G, et al. Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High- Density Lipoprotein Cholesterol Intervention Trial Study Group. N Engl J Med 1999;341:410-8.
16. Kastelein JJ, van Leuven SI, Burgess L, Evans GW, Kuivenhoven JA, Barter PJ, Revkin JH, Grobbee DE, Riley WA, Shear CL, et al. Effect of torcetrapib on carotid atherosclerosis in familial hypercholesterolemia. N Engl J Med 2007;356:1620-30.
17. Barter PJ, Caulfield M, Eriksson M, Grundy SM, Kastelein JJ, Komajda M, Lopez-Sendon J, Mosca L, Tardif JC, Waters DD, et al. Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med 2007;357:2109-22.
18. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, Hindy G, Holm H, Ding EL, Johnson T, et al. Plasma HDL cholesterol and risk of myocardial infarction: a Men- delian randomisation study. Lancet 2012;380:572-80.
19. Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.
20. Van Eck M, Twisk J, Hoekstra M, Van Rij BT, Van der Lans CA, Bos IS, Kruijt JK, Kuipers F, Van Berkel TJ. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. J Biol Chem 2003;278:23699-705.
21. Pollard RD, Blesso CN, Zabalawi M, Fulp B, Gerelus M, Zhu X, Lyons EW, Nuradin N, Francone OL, Li XA, et al. Procollagen C-endopeptidase enhancer protein 2 (PCPE2) reduces atherosclerosis in mice by enhancing scavenger receptor class B1 (SR-BI)-mediated high-density lipoprotein (HDL)-cholesteryl ester uptake. J Biol Chem 2015;290:15496-511.
22. Rosenson RS, Brewer HB Jr., Davidson WS, Fayad ZA, Fuster V, Goldstein J, Hellerstein M, Jiang XC, Phillips MC, Rader DJ, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation 2012;125:1905-19.
23. Fielding CJ, Fielding PE. Molecular physiology of reverse cholesterol transport. J Lipid Res 1995;36:211-28.
24. Cavelier C, Lorenzi I, Rohrer L, von Eckardstein A. Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1. Biochim Biophys Acta 2006;1761:655-66.
25. Adorni MP, Zimetti F, Billheimer JT, Wang N, Rader DJ, Phillips MC, Rothblat GH. The roles of different pathways in the release of cholesterol from macrophages. J Lipid Res 2007;48:2453-62.
26. Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, Tall AR, Rader DJ. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest 2007;117:2216-24.
27. Mulya A, Lee JY, Gebre AK, Thomas MJ, Colvin PL, Parks JS. Minimal lipidation of pre-beta HDL by ABCA1 results in reduced ability to interact with ABCA1. Arterioscler Thromb Vasc Biol 2007;27:1828-36.
28. Czarnecka H, Yokoyama S. Regulation of cellular cholesterol efflux by lecithin:cholesterol acyltransferase reaction through nonspecific lipid exchange. J Biol Chem 1996;271:2023-8.
29. Gelissen IC, Harris M, Rye KA, Quinn C, Brown AJ, Kockx M, Cartland S, Packianathan M, Kritharides L, Jessup W. ABCA1 and ABCG1 synergize to mediate cholesterol export to apoA-I. Arterioscler Thromb Vasc Biol 2006;26:534-40.
30. Collet X, Tall AR, Serajuddin H, Guendouzi K, Royer L, Oliveira H, Barbaras R, Jiang XC, Francone OL. Remodeling of HDL by CETP in vivo and by CETP and hepatic lipase in vitro results in enhanced uptake of HDL CE by cells expressing scavenger receptor B-I. J Lipid Res 1999;40:1185-93.
31. Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 1996;271:518-20.
32. Rohrl C, Stangl H. HDL endocytosis and resecretion. Biochim Bio- phys Acta 2013;1831:1626-33.
33. Silver DL, Tall AR. The cellular biology of scavenger receptor class B type I. Curr Opin Lipidol 2001;12:497-504.
34. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res 2004;45:1594-607.
35. Tanigawa H, Billheimer JT, Tohyama J, Zhang Y, Rothblat G, Rader DJ. Expression of cholesteryl ester transfer protein in mice promotes macrophage reverse cholesterol transport. Circulation 2007;116:1267-73.
36. Guyard-Dangremont V, Desrumaux C, Gambert P, Lallemant C, Lagrost L. Phospholipid and cholesteryl ester transfer activities in plasma from 14 vertebrate species. Relation to atherogenesis susceptibility. Comp Biochem Physiol B Biochem Mol Biol 1998;120:517-25.
37. Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res 2009;50 Suppl:S189-94.
38. Boden WE, Probstfield JL, Anderson T, Chaitman BR, Desvignes- Nickens P, Koprowicz K, McBride R, Teo K, Weintraub W. Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med 2011;365:2255-67.
39. Shih DM, Gu L, Xia YR, Navab M, Li WF, Hama S, Castellani LW, Furlong CE, Costa LG, Fogelman AM, et al. Mice lacking serum paraoxonase are susceptible to organophosphate toxicity and atherosclerosis. Nature 1998;394:284-7.
40. Puranik R, Bao S, Nobecourt E, Nicholls SJ, Dusting GJ, Barter PJ, Celermajer DS, Rye KA. Low dose apolipoprotein A-I rescues carotid arteries from inflammation in vivo. Atherosclerosis 2008;196:240-7.
41. Nofer JR, Levkau B, Wolinska I, Junker R, Fobker M, von Eckardstein A, Seedorf U, Assmann G. Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids. J Biol Chem 2001;276:34480-5.
42. Nofer JR, Walter M, Kehrel B, Wierwille S, Tepel M, Seedorf U, Assmann G. HDL3-mediated inhibition of thrombin-induced platelet aggregation and fibrinogen binding occurs via decreased production of phosphoinositide-derived second messengers 1, 2-diacylglycerol and inositol 1, 4, 5-tris-phosphate. Arterioscler Thromb Vasc Biol 1998;18:861-9.
43. Nofer JR, van der Giet M, Tolle M, Wolinska I, von Wnuck Lipinski K, Baba HA, Tietge UJ, Godecke A, Ishii I, Kleuser B, et al. HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3. J Clin Invest 2004;113:569-81.
44. Vaisar T, Pennathur S, Green PS, Gharib SA, Hoofnagle AN, Cheung MC, Byun J, Vuletic S, Kassim S, Singh P, et al. Shotgun pro- teomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL. J Clin Invest 2007;117:746-56.
45. Mackness M, Mackness B. Human paraoxonase-1 (PON1): gene structure and expression, promiscuous activities and multiple physiological roles. Gene 2015;567:12-21.
46. Shih DM, Xia YR, Wang XP, Miller E, Castellani LW, Subbanagounder G, Cheroutre H, Faull KF, Berliner JA, Witztum JL, et al. Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis. J Biol Chem 2000;275:17527-35.
47. Navab M, Reddy ST, Van Lenten BJ, Anantharamaiah GM, Fogelman AM. The role of dysfunctional HDL in atherosclerosis. J Lipid Res 2009;50 Suppl:S145-9.
48. Mackness B, Davies GK, Turkie W, Lee E, Roberts DH, Hill E, Roberts C, Durrington PN, Mackness MI. Paraoxonase status in coronary heart disease: are activity and concentration more important than genotype? Arterioscler Thromb Vasc Biol 2001;21:1451-7.
49. Besler C, Heinrich K, Rohrer L, Doerries C, Riwanto M, Shih DM, Chroni A, Yonekawa K, Stein S, Schaefer N, et al. Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease. J Clin Invest 2011;121:2693-708.
50. Ferretti G, Bacchetti T, Masciangelo S, Bicchiega V. HDL-paraoxonase and membrane lipid peroxidation: a comparison between healthy and obese subjects. Obesity (Silver Spring) 2010;18:1079-84.
51. Yang RZ, Lee MJ, Hu H, Pollin TI, Ryan AS, Nicklas BJ, Snitker S, Horenstein RB, Hull K, Goldberg NH, et al. Acute-phase serum amyloid A: an inflammatory adipokine and potential link between obesity and its metabolic complications. PLoS Med 2006;3:e287.
52. Senti M, Tomas M, Fito M, Weinbrenner T, Covas MI, Sala J, Masia R, Marrugat J. Antioxidant paraoxonase 1 activity in the metabolic syndrome. J Clin Endocrinol Metab 2003;88:5422-6.
53. Kappelle PJ, Bijzet J, Hazenberg BP, Dullaart RP. Lower serum paraoxonase-1 activity is related to higher serum amyloid a levels in metabolic syndrome. Arch Med Res 2011;42:219-25.
54. Han CY, Chiba T, Campbell JS, Fausto N, Chaisson M, Orasanu G, Plutzky J, Chait A. Reciprocal and coordinate regulation of serum amyloid A versus apolipoprotein A-I and paraoxonase-1 by inflammation in murine hepatocytes. Arterioscler Thromb Vasc Biol 2006;26:1806-13.
55. Van Eck M, Hoekstra M, Hildebrand RB, Yaong Y, Stengel D, Kruijt JK, Sattler W, Tietge UJ, Ninio E, Van Berkel TJ, et al. Increased oxidative stress in scavenger receptor BI knockout mice with dysfunctional HDL. Arterioscler Thromb Vasc Biol 2007;27:2413-9.
56. Hafiane A, Genest J. High density lipoproteins: measurement techniques and potential biomarkers of cardiovascular risk. BBA Clin 2015;3:175-88.
57. Mackness B, Durrington P, McElduff P, Yarnell J, Azam N, Watt M, Mackness M. Low paraoxonase activity predicts coronary events in the Caerphilly Prospective Study. Circulation 2003;107:2775-9.
58. de la Llera-Moya M, Drazul-Schrader D, Asztalos BF, Cuchel M, Rader DJ, Rothblat GH. The ability to promote efflux via ABCA1 determines the capacity of serum specimens with similar high-density lipoprotein cholesterol to remove cholesterol from macrophages. Arterioscler Thromb Vasc Biol 2010;30:796-801.
59. Vergeer M, Boekholdt SM, Sandhu MS, Ricketts SL, Wareham NJ, Brown MJ, de Faire U, Leander K, Gigante B, Kavousi M, et al. Genetic variation at the phospholipid transfer protein locus affects its activity and high-density lipoprotein size and is a novel marker of cardiovascular disease susceptibility. Circulation 2010;122:470-7.
60. Rimm EB, Williams P, Fosher K, Criqui M, Stampfer MJ. Moderate alcohol intake and lower risk of coronary heart disease: meta-analysis of effects on lipids and haemostatic factors. BMJ 1999;319:1523-8.
61. Mensink RP, Zock PL, Kester AD, Katan MB. Effects of dietary fatty acids and carbohydrates on the ratio of serum total to HDL cholesterol and on serum lipids and apolipoproteins: a meta-analysis of 60 controlled trials. Am J Clin Nutr 2003;77:1146-55.
62. Howell WH, McNamara DJ, Tosca MA, Smith BT, Gaines JA. Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a metaanalysis. Am J Clin Nutr 1997;65:1747-64.
63. Scalbert A, Manach C, Morand C, Remesy C, Jimenez L. Dietary polyphenols and the prevention of diseases. Crit Rev Food Sci Nutr 2005;45:287-306.
64. Ross JA, Kasum CM. Dietary flavonoids: bioavailability, metabolic effects, and safety. Annu Rev Nutr 2002;22:19-34.
65. Hertog MG, Hollman PC, Katan MB, Kromhout D. Intake of potentially anticarcinogenic flavonoids and their determinants in adults in the Netherlands. Nutr Cancer 1993;20:21-9.
66. Kuhnau J. The flavonoids. A class of semi-essential food components: their role in human nutrition. World Rev Nutr Diet 1976;24:117-91.
67. Chun OK, Chung SJ, Song WO. Estimated dietary flavonoid intake and major food sources of U.S. adults. J Nutr 2007;137:1244-52.
68. Middleton E Jr., Kandaswami C, Theoharides TC. The effects of plant flavonoids on mammalian cells: implications for inflammation, heart disease, and cancer. Pharmacol Rev 2000;52:673-751.
69. Myhrstad MC, Carlsen H, Nordstrom O, Blomhoff R, Moskaug JO. Flavonoids increase the intracellular glutathione level by transactivation of the gamma-glutamylcysteine synthetase catalytical subunit promoter. Free Radic Biol Med 2002;32:386-93.
70. Sun GY, Chen Z, Jasmer KJ, Chuang DY, Gu Z, Hannink M, Simonyi A. Quercetin attenuates inflammatory responses in BV-2 microglial cells: role of MAPKs on the Nrf2 pathway and induction of heme oxygenase-1. PLoS One 2015;10:e0141509.
71. Karlsen A, Retterstol L, Laake P, Paur I, Bohn SK, Sandvik L, Blomhoff R. Anthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adults. J Nutr 2007;137:1951-4.
72. Hertog MG, Feskens EJ, Hollman PC, Katan MB, Kromhout D. Dietary antioxidant flavonoids and risk of coronary heart disease: the Zutphen Elderly Study. Lancet 1993;342:1007-11.
73. Mursu J, Nurmi T, Tuomainen TP, Ruusunen A, Salonen JT, Voutilainen S. The intake of flavonoids and carotid atherosclerosis: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br J Nutr 2007;98:814-8.
74. Cassidy A, Mukamal KJ, Liu L, Franz M, Eliassen AH, Rimm EB. High anthocyanin intake is associated with a reduced risk of myocardial infarction in young and middle-aged women. Circulation 2013;127: 188-96.
75. McCullough ML, Peterson JJ, Patel R, Jacques PF, Shah R, Dwyer JT. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am J Clin Nutr 2012;95:454-64.
76. Wang X, Ouyang YY, Liu J, Zhao G. Flavonoid intake and risk of CVD: a systematic review and meta-analysis of prospective cohort studies. Br J Nutr 2014;111:1-11.
77. Freedman LS, Schatzkin A, Midthune D, Kipnis V. Dealing with dietary measurement error in nutritional cohort studies. J Natl Cancer Inst 2011;103:1086-92.
78. He J, Giusti MM. Anthocyanins: natural colorants with health- promoting properties. Annu Rev Food Sci Technol 2010;1:163-87.
79. Perez-Jimenez J, Neveu V, Vos F, Scalbert A. Systematic analysis of the content of 502 polyphenols in 452 foods and beverages: an application of the phenol-explorer database. J Agric Food Chem 2010;58:4959-69.
80. Wang D, Xia M, Yan X, Li D, Wang L, Xu Y, Jin T, Ling W. Gut microbiota metabolism of anthocyanin promotes reverse cholesterol transport in mice via repressing miRNA-10b. Circ Res 2012;111:967-81.
81. Wang Y, Zhang Y, Wang X, Liu Y, Xia M. Cyanidin-3-O-beta- glucoside induces oxysterol efflux from endothelial cells: role of liver X receptor alpha. Atherosclerosis 2012;223:299-305.
82. Jia Y, Hoang MH, Jun HJ, Lee JH, Lee SJ. Cyanidin, a natural flavo- noid, is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes. Bioorg Med Chem Lett 2013;23:4185-90.
83. Jia Y, Kim JY, Jun HJ, Kim SJ, Lee JH, Hoang MH, Kim HS, Chang HI, Hwang KY, Um SJ, et al. Cyanidin is an agonistic ligand for peroxisome proliferator-activated receptor-alpha reducing hepatic lipid. Bio- chim Biophys Acta 2013;1831:698-708.
84. Du C, Shi Y, Ren Y, Wu H, Yao F, Wei J, Wu M, Hou Y, Duan H. Anthocyanins inhibit high-glucose-induced cholesterol accumulation and inflammation by activating LXRalpha pathway in HK-2 cells. Drug Des Devel Ther 2015;9:5099-113.
85. Xia M, Hou M, Zhu H, Ma J, Tang Z, Wang Q, Li Y, Chi D, Yu X, Zhao T, et al. Anthocyanins induce cholesterol efflux from mouse peritoneal macrophages: the role of the peroxisome proliferator- activated receptor (gamma)-liver X receptor (alpha)-ABCA1 pathway. J Biol Chem 2005;280:36792-801.
86. Farrell N, Norris G, Lee SG, Chun OK, Blesso CN. Anthocyanin-rich black elderberry extract improves markers of HDL function and reduces aortic cholesterol in hyperlipidemic mice. Food Funct 2015;6:1278-87.
87. Kim B, Ku CS, Pham TX, Park Y, Martin DA, Xie L, Taheri R, Lee J, Bolling BW. Aronia melanocarpa (chokeberry) polyphenol-rich extract improves antioxidant function and reduces total plasma cholesterol in apolipoprotein E knockout mice. Nutr Res 2013;33:406-13.
88. Zhu Y, Huang X, Zhang Y, Wang Y, Liu Y, Sun R, Xia M. Anthocyanin supplementation improves HDL-associated paraoxonase 1 activity and enhances cholesterol efflux capacity in subjects with hypercholesterolemia. J Clin Endocrinol Metab 2014;99:561-9.
89. Zhu Y, Xia M, Yang Y, Liu F, Li Z, Hao Y, Mi M, Jin T, Ling W. Purified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individuals. Clin Chem 2011;57:1524-33.
90. Zhu Y, Ling W, Guo H, Song F, Ye Q, Zou T, Li D, Zhang Y, Li G, Xiao Y, et al. Anti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: a randomized controlled trial. Nutrition, metabolism, and cardiovascular diseases. Nutr Metab Car- diovasc Dis 2013;23:843-9.
91. Qin Y, Xia M, Ma J, Hao Y, Liu J, Mou H, Cao L, Ling W. Anthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjects. Am J Clin Nutr 2009;90:485-92.
92. Li D, Zhang Y, Liu Y, Sun R, Xia M. Purified anthocyanin supplementation reduces dyslipidemia, enhances antioxidant capacity, and prevents insulin resistance in diabetic patients. J Nutr 2015;145:742-8.
93. Neveu V, Perez-Jimenez J, Vos F, Crespy V, du Chaffaut L, Mennen L, Knox C, Eisner R, Cruz J, Wishart D, et al. Phenol-Explorer: an online comprehensive database on polyphenol contents in foods. Database (Oxford) 2010;2010:bap024.
94. Hassellund SS, Flaa A, Kjeldsen SE, Seljeflot I, Karlsen A, Erlund I, Rostrup M. Effects of anthocyanins on cardiovascular risk factors and inflammation in pre-hypertensive men: a double-blind randomized placebo-controlled crossover study. J Hum Hypertens 2013;27:100-6.
95. Schroeter H, Heiss C, Spencer JP, Keen CL, Lupton JR, Schmitz HH. Recommending flavanols and procyanidins for cardiovascular health: current knowledge and future needs. Mol Aspects Med 2010;31:546-57.
96. Tas S, Sarandol E, Ziyanok S, Dirican M. Effects of green tea on serum paraoxonase/arylesterase activities in streptozotocin-induced diabetic rats. Nutr Res 2005;25:1061-74.
97. Rosenblat M, Volkova N, Coleman R, Almagor Y, Aviram M. Anti- atherogenicity of extra virgin olive oil and its enrichment with green tea polyphenols in the atherosclerotic apolipoprotein-E-deficient mice: enhanced macrophage cholesterol efflux. J Nutr Biochem 2008;19:514-23.
98. Hsu SP, Wu MS, Yang CC, Huang KC, Liou SY, Hsu SM, Chien CT. Chronic green tea extract supplementation reduces hemodialysis-enhanced production of hydrogen peroxide and hypochlorous acid, atherosclerotic factors, and proinflammatory cytokines. Am J Clin Nutr 2007;86:1539-47.
99. Baba S, Osakabe N, Kato Y, Natsume M, Yasuda A, Kido T, Fukuda K, Muto Y, Kondo K. Continuous intake of polyphenolic compounds containing cocoa powder reduces LDL oxidative susceptibility and has beneficial effects on plasma HDL-cholesterol concentrations in humans. Am J Clin Nutr 2007;85:709-17.
100. Martinez-Lopez S, Sarria B, Sierra-Cinos JL, Goya L, Mateos R, Bravo L. Realistic intake of a flavanol-rich soluble cocoa product increases HDL-cholesterol without inducing anthropometric changes in healthy and moderately hypercholesterolemic subjects. Food Funct 2014;5:364-74.
101. Curtis PJ, Sampson M, Potter J, Dhatariya K, Kroon PA, Cassidy A. Chronic ingestion of flavan-3-ols and isoflavones improves insulin sensitivity and lipoprotein status and attenuates estimated 10-year CVD risk in medicated postmenopausal women with type 2 diabetes: a 1-year, double-blind, randomized, controlled trial. Diabetes Care 2012;35:226-32.
102. Khan MK, Huma ZE, Dangles O. A comprehensive review on flava- nones, the major citrus polyphenols. J Food Compos Anal 2014;33: 85-104.
103. Mulvihill EE, Burke AC, Huff MW. Citrus flavonoids as regulators of lipoprotein metabolism and atherosclerosis. Annu Rev Nutr 2016;36: 275-99.
104. Jayachitra J, Nalini N. Effect of naringenin (citrus flavanone) on lipid profile in ethanol-induced toxicity in rats. J Food Biochem 2011;36: 502-11.
105. Jeon SM, Kim HK, Kim HJ, Do GM, Jeong TS, Park YB, Choi MS. Hypocholesterolemic and antioxidative effects of naringenin and its two metabolites in high-cholesterol fed rats. Transl Res 2007;149:15-21.
106. Kim HJ, Jeon SM, Lee MK, Cho YY, Kwon EY, Lee JH, Choi MS. Comparison of hesperetin and its metabolites for cholesterol-lowering and antioxidative efficacy in hypercholesterolemic hamsters. J Med Food 2010;13:808-14.
107. Haidari F, Rashidi MR, Mohammad-Shahi M. Effects of orange juice and hesperetin on serum paraoxonase activity and lipid profile in hyperuricemic rats. Bioimpacts 2012;2:39-45.
108. Iio A, Ohguchi K, Iinuma M, Nozawa Y, Ito M. Hesperetin upregu- lates ABCA1 expression and promotes cholesterol efflux from THP-1 macrophages. J Nat Prod 2012;75:563-6.
109. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, Piche LA, Serratore P HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am J Clin Nutr 2000;72: 1095-100.
110. Mollace V, Sacco I, Janda E, Malara C, Ventrice D, Colica C, Visalli V, Muscoli S, Ragusa S, Muscoli C, et al. Hypolipemic and hypo- glycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia 2011;82:309-16.
111. Jung UJ, Kim HJ, Lee JS, Lee MK, Kim HO, Park EJ, Kim HK, Jeong TS, Choi MS. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hyper- cholesterolemic subjects. Clin Nutr 2003;22:561-8.
112. Demonty I, Lin Y, Zebregs YE, Vermeer MA, van der Knaap HC, Jakel M, Trautwein EA. The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and women. J Nutr 2010;140:1615-20.
113. Xiao J, Kai G. A review of dietary polyphenol-plasma protein interactions: characterization, influence on the bioactivity, and structure- affinity relationship. Crit Rev Food Sci Nutr 2012;52:85-101.
114. Graf BA, Milbury PE, Blumberg JB. Flavonols, flavones, flavanones, and human health: epidemiological evidence. J Med Food 2005;8: 281-90.
115. Francisco V, Figueirinha A, Costa G, Liberal J, Ferreira I, Lopes MC, Garcia-Rodriguez C, Cruz MT, Batista MT. The flavone luteolin inhibits liver X receptor activation. J Nat Prod 2016;79:1423-8.
116. Li F, Wong TY, Lin SM, Chow S, Cheung WH, Chan FL, Chen S, Leung LK. Coadministrating luteolin minimizes the side effects of the aromatase inhibitor letrozole. J Pharmacol Exp Ther 2014;351:270-7.
117. Wang GG, Lu XH, Li W, Zhao X, Zhang C. Protective effects of luteolin on diabetic nephropathy in STZ-induced diabetic rats. Evid Based Complement Alternat Med 2011;2011:323171.
118. Wang S, Zhang X, Liu M, Luan H, Ji Y, Guo P, Wu C. Chrysin inhibits foam cell formation through promoting cholesterol efflux from RAW264.7 macrophages. Pharm Biol 2015;53:1481-7.
119. Chen CY, Shyue SK, Ching LC, Su KH, Wu YL, Kou YR, Chiang AN, Pan CC, Lee TS. Wogonin promotes cholesterol efflux by increasing protein phosphatase 2B-dependent dephosphorylation at ATP-binding cassette transporter-A1 in macrophages. J Nutr Biochem 2011;22:1015-21.
120. Aherne SA, O'Brien NM. Dietary flavonols: chemistry, food content, and metabolism. Nutrition 2002;18:75-81.
121. Boesch-Saadatmandi C, Niering J, Minihane AM, Wiswedel I, Gardeman A, Wolffram S, Rimbach G. Impact of apolipoprotein E genotype and dietary quercetin on paraoxonase 1 status in apoE3 and apoE4 transgenic mice. Atherosclerosis 2010;211:110-3.
122. Boesch-Saadatmandi C, Egert S, Schrader C, Coumoul X, Barouki R, Muller MJ, Wolffram S, Rimbach G. Effect of quercetin on para- oxonase 1 activity-studies in cultured cells, mice and humans. J Physiol Pharmacol 2010;61(1):99-105.
123. Leckey LC, Garige M, Varatharajalu R, Gong M, Nagata T, Spurney CF, Lakshman RM. Quercetin and ethanol attenuate the progression of atherosclerotic plaques with concomitant up regulation of paraoxonase1 (PON1) gene expression and PON1 activity in LDLR-/- mice. Alcohol Clin Exp Res 2010;34:1535-42.
124. Gong M, Garige M, Varatharajalu R, Marmillot P, Gottipatti C, Leckey LC, Lakshman RM. Quercetin up-regulates paraoxonase 1 gene expression with concomitant protection against LDL oxidation. Bio- chem Biophys Res Commun 2009;379:1001-4.
125. Center for Drug Evaluation and Research. Guidance for industry: estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers. Rockville (MD): US Department of Health and Human Services; 2005.
126. Garige M, Gong M, Varatharajalu R, Lakshman MR. Quercetin up- regulates paraoxonase 1 gene expression via sterol regulatory element binding protein 2 that translocates from the endoplasmic reticulum to the nucleus where it specifically interacts with sterol responsive element-like sequence in paraoxonase 1 promoter in HuH7 liver cells. Metabolism 2010;59:1372-8.
127. Lee SM, Moon J, Cho Y, Chung JH, Shin MJ. Quercetin up-regulates expressions of peroxisome proliferator-activated receptor gamma, liver X receptor alpha, and ATP binding cassette transporter A1 genes and increases cholesterol efflux in human macrophage cell line. Nutr Res 2013;33:136-43.
128. Rosenblat M, Volkova N, Khatib S, Mahmood S, Vaya J, Aviram M. Reduced glutathione increases quercetin stimulatory effects on HDL- or apoA1-mediated cholesterol efflux from J774A.1 macrophages. Free Radic Res 2014;48:1462-72.
129. Chang YC, Lee TS, Chiang AN. Quercetin enhances ABCA1 expression and cholesterol efflux through a p38-dependent pathway in macrophages. J Lipid Res 2012;53:1840-50.
130. Li XY, Kong LX, Li J, He HX, Zhou YD. Kaempferol suppresses lipid accumulation in macrophages through the downregulation of cluster of differentiation 36 and the upregulation of scavenger receptor class B type I and ATP-binding cassette transporters A1 and G1. Int J Mol Med 2013;31:331-8.
131. Setchell KD, Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J Nutr 1999;129:758S-67S.
132. Ahmad S, Scott JE. Estradiol enhances cell-associated paraoxonase 1 (PON1) activity in vitro without altering PON1 expression. Bio- chem Biophys Res Commun 2010;397:441-6.
133. Agacayak E, Basaranoglu S, Tunc SY, Icen MS, Findik FM, Kaplan I, Evliyaoglu O, Gul T. Oxidant/antioxidant status, paraoxonase activity, and lipid profile in plasma of ovariectomized rats under the influence of estrogen, estrogen combined with progesterone, and genistein. Drug Des Devel Ther 2015;9:2975-82.
134. Mohammadshahi M, Haidari F, Saei AA, Rashidi B, Mahboob S, Rashidi MR. Soy protein, genistein, and daidzein improve serum paraoxonase activity and lipid profiles in rheumatoid arthritis in rats. J Med Food 2013;16:147-54.
135. Ustundag B, Bahcecioglu IH, Sahin K, Duzgun S, Koca S, Gulcu F, Ozercan IH. Protective effect of soy isoflavones and activity levels of plasma paraoxonase and arylesterase in the experimental nonalcoholic steatohepatitis model. Dig Dis Sci 2007;52:2006-14.
136. Weggemans RM, Trautwein EA. Relation between soy-associated iso- flavones and LDL and HDL cholesterol concentrations in humans: a meta-analysis. Eur J Clin Nutr 2003;57:940-6.
137. Zhan S, Ho SC. Meta-analysis of the effects of soy protein containing isoflavones on the lipid profile. Am J Clin Nutr 2005;81: 397-408.
138. Taku K, Umegaki K, Sato Y, Taki Y, Endoh K, Watanabe S. Soy isoflavones lower serum total and LDL cholesterol in humans: a meta-analysis of 11 randomized controlled trials. Am J Clin Nutr 2007;85:1148-56.
139. Hall WL, Vafeiadou K, Hallund J, Bugel S, Reimann M, Koebnick C, Zunft HJ, Ferrari M, Branca F, Dadd T, et al. Soy-isoflavone-enriched foods and markers of lipid and glucose metabolism in postmenopausal women: interactions with genotype and equol production. Am J Clin Nutr 2006;83:592-600.
140. Tormala RM, Nikander E, Tiitinen A, Vaisanen-Tommiska M, Ylikorkala O, Mikkola TS. Serum cholesterol efflux potential in postmenopausal women treated with isolated isoflavones. Menopause 2006;13:96-101.
141. Badeau R, Jauhiainen M, Metso J, Nikander E, Tikkanen MJ, Ylikorkala O, Mikkola TS. Effect of isolated isoflavone supplementation on ABCA1-dependent cholesterol efflux potential in postmenopausal women. Menopause 2007;14:293-9.