Citrus flavonoids and the prevention of atherosclerosis

Cardiovascular and Hematological Disorders - Drug Targets

Volumn 12, Issue 2, 2012, Pages 84-91

  Mulvihill, Erin E ^a,b   Huff, Murray W ^a,b  

^a ROBARTS RESEARCH INSTITUTE   (Canada)

^b UNIVERSITY OF WESTERN ONTARIO   (Canada)

Author keywords

ApoB; Atherosclerosis; Cardiovascular disease; Flavonoids; Hesperitin; Insulin resistance; Naringenin; Nobiletin; Tangeretin

Indexed keywords

APOLIPOPROTEIN B; BIOFLAVONOID; CHOLESTEROL; ENDOTHELIAL NITRIC OXIDE SYNTHASE; GELATINASE B; HESPERIDIN; HIGH DENSITY LIPOPROTEIN CHOLESTEROL; INTERLEUKIN 6; LOW DENSITY LIPOPROTEIN CHOLESTEROL; MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN; NARINGENIN; NOBILETIN;

APPLE; ATHEROSCLEROSIS; BIOAVAILABILITY; BLUEBERRY; CARDIOMETABOLIC RISK; CARDIOVASCULAR RISK; DYSLIPIDEMIA; FRUIT JUICE; GENE EXPRESSION; GLUCOSE HOMEOSTASIS; GLUCOSE TRANSPORT; HUMAN; INFLAMMATION; INSULIN RESISTANCE; NONHUMAN; OXIDATION; OXIDATIVE STRESS; PEAR; REVIEW; SUPPLEMENTATION; UPREGULATION;

ANIMALS; CARDIOVASCULAR DISEASES; CITRUS; FLAVONOIDS; HUMANS; PLANT EXTRACTS;

EID: 84872874857     PISSN: 1871529X     EISSN: None     Source Type: Journal    
DOI: 10.2174/1871529X11202020084     Document Type: Review

References (73)

1. Lloyd-Jones, D.; Adams R.; Carnethon M.; De Simone G.; Ferguson T.B.; Flegal K.; Ford E.; Furie K.; Go A.; Greenlund K.; Haase N.; Hailpern S.; Ho M.; Howard V.; Kissela B.; Kittner S.; Lackland D.; Lisabeth L.; Marelli A.; McDermott M.; Meigs J.; Mozaffarian D.; Nichol G.; O'Donnell C.; Roger V.; Rosamond W.; Sacco R.; Sorlie P.; Stafford R.; Steinberger J.; Thom T.; Wasserthiel-Smoller S.; Wong N.; Wylie-Rosett J.; Hong Y. Heart disease and stroke statistics--2009 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation, 2009, 119, e21-181.
2. Ross, R. Atherosclerosis--an inflammatory disease. N. Engl. J. Med., 1999, 340,115-126.
3. Jain, K.S.; Kathiravan M.K.; Somani R.S.; Shishoo C.J. The biology and chemistry of hyperlipidemia. Bioorg Med. Chem., 2007, 15, 4674-4699.
4. Hackam, D.G.; Anand S.S. Emerging risk factors for atherosclerotic vascular disease: a critical review of the evidence. JAMA, 2003, 290, 932-940.
5. Nesto, R.W. Beyond low-density lipoprotein: addressing the atherogenic lipid triad in type 2 diabetes mellitus and the metabolic syndrome. Am. J. Cardiovasc. Drugs, 2005, 5, 379-387.
6. Tkac, I.; Kimball B.P.; Lewis G.; Uffelman K.; Steiner G. The severity of coronary atherosclerosis in type 2 diabetes mellitus is related to the number of circulating triglyceride-rich lipoprotein particles. Arterioscler. Thromb. Vasc. Biol., 1997, 17, 3633-3638.
7. de Graaf, J.; Couture P.; Sniderman A. A diagnostic algorithm for the atherogenic apolipoprotein B dyslipoproteinemias. Nat. Clin. Pract. Endocrinol. Metab., 2008, 4, 608-618.
8. Consigny, P.M. Pathogenesis of atherosclerosis. AJR Am. J. Roentgenol., 1995, 164, 553-558.
9. Stary, H.C.; Chandler A.B.; Glagov S.; Guyton J.R.; Insull W., Jr.; Rosenfeld M.E.; Schaffer S.A.; Schwartz C.J.; Wagner W.D.; Wissler R.W. A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Circulation, 1994, 89, 2462-2478.
10. Dansky, H.M.; Barlow C.B.; Lominska C.; Sikes J.L.; Kao C.; Weinsaft J.; Cybulsky M.I.; Smith J.D. Adhesion of monocytes to arterial endothelium and initiation of atherosclerosis are critically dependent on vascular cell adhesion molecule-1 gene dosage. Arterioscler. Thromb. Vasc. Biol., 2001, 21, 1662-1667.
11. Tall, A.R. Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins. J. Intern. Med., 2008, 263, 256-273.
12. Moore, K.J.; Freeman M.W. Scavenger receptors in atherosclerosis: beyond lipid uptake. Arterioscler. Thromb. Vasc. Biol., 2006, 26,1702-1711.
13. Bornfeldt, K.E.; Tabas I. Insulin resistance, hyperglycemia, and atherosclerosis. Cell Metab., 2011, 14, 575-585.
14. Ross, R.; Glomset J.A. Atherosclerosis and the arterial smooth muscle cell: Proliferation of smooth muscle is a key event in the genesis of the lesions of atherosclerosis. Science, 1973, 180, 1332-1339.
15. Hooper, L.; Kroon P.A.; Rimm E.B.; Cohn J.S.; Harvey I.; Le Cornu K.A.; Ryder J.J.; Hall W.L.; Cassidy A. Flavonoids, flavonoid-rich foods, and cardiovascular risk: a meta-analysis of randomized controlled trials. Am. J. Clin. Nutr., 2008, 88, 38-50.
16. Wedick, N.M.; Pan A.; Cassidy A.; Rimm E.B.; Sampson L.; Rosner B.; Willett W.; Hu F.B.; Sun Q.; van Dam R.M. Dietary flavonoid intakes and risk of type 2 diabetes in US men and women. Am. J. Clin. Nutr., 2012. Feb 22. [Epub ahead of print].
17. McCullough, M.L.; Peterson J.J.; Patel R.; Jacques P.F.; Shah R.; Dwyer J.T. Flavonoid intake and cardiovascular disease mortality in a prospective cohort of US adults. Am. J. Clin. Nutr., 2012, 95, 454-464.
18. Aherne, S.A.; O'Brien N.M. Mechanism of protection by the flavonoids, quercetin and rutin, against tert-butylhydroperoxideand menadione-induced DNA single strand breaks in Caco-2 cells. Free Radic. Biol. Med., 2000, 29, 507-514.
19. Huxley, R.R.; Neil H.A. The relation between dietary flavonol intake and coronary heart disease mortality: a meta-analysis of prospective cohort studies. Eur. J. Clin. Nutr., 2003, 57, 904-908.
20. Nijveldt, R.J.; van Nood E.; van Hoorn D.E.; Boelens P.G.; van Norren K.; van Leeuwen P.A. Flavonoids: a review of probable mechanisms of action and potential applications. Am. J. Clin. Nutr., 2001, 74, 418-425.
21. Robak, J.; Gryglewski R.J. Flavonoids are scavengers of superoxide anions. Biochem. Pharmacol., 1988, 37, 837-841.
22. Badimon, L.; Vilahur G.; Padro T. Nutraceuticals and atherosclerosis: human trials. Cardiovasc. Ther., 2010, 28, 202-215.
23. Bokkenheuser, V.D.; Shackleton C.H.; Winter J. Hydrolysis of dietary flavonoid glycosides by strains of intestinal Bacteroides from humans. Biochem. J., 1987, 248, 953-956.
24. Nielsen, I.L.; Chee W.S.; Poulsen L.; Offord-Cavin E.; Rasmussen S.E.; Frederiksen H.; Enslen M.; Barron D.; Horcajada M.N.; Williamson G. Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans: a randomized, doubleblind, crossover trial. J. Nutr., 2006, 136, 404-408.
25. Manach, C.; Williamson G.; Morand C.; Scalbert A.; Remesy C. Bioavailability and bioefficacy of polyphenols in humans. I. Review of 97 bioavailability studies. Am. J. Clin. Nutr., 2005, 81, 230S-242S.
26. Manthey, J.A.; Cesar T.B.; Jackson E.; Mertens-Talcott S. Pharmacokinetic study of nobiletin and tangeretin in rat serum by high-performance liquid chromatography-electrospray ionizationmass spectrometry. J. Agric. Food Chem., 2011, 59,145-151.
27. Gorinstein, S.; Caspi A.; Libman I.; Lerner H.T.; Huang D.; Leontowicz H.; Leontowicz M.; Tashma Z.; Katrich E.; Feng S.; Trakhtenberg S. Red grapefruit positively influences serum triglyceride level in patients suffering from coronary atherosclerosis: studies in vitro and in humans. J. Agric. Food Chem., 2006, 54, 1887-1892.
28. Kurowska, E.M.; Spence J.D.; Jordan J.; Wetmore S.; Freeman D.J.; Piche L.A.; Serratore P. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am J Clin Nutr, 2000, 72,1095-1100.
29. Miwa, Y.; Mitsuzumi H.; Sunayama T.; Yamada M.; Okada K.; Kubota M.; Chaen H.; Mishima Y.; Kibata M. Glucosyl hesperidin lowers serum triglyceride level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein metabolic abnormality. J. Nutr. Sci. Vitaminol. (Tokyo), 2005, 51, 460-470.
30. Miwa, Y.; Yamada M.; Sunayama T.; Mitsuzumi H.; Tsuzaki Y.; Chaen H.; Mishima Y.; Kibata M. Effects of glucosyl hesperidin on serum lipids in hyperlipidemic subjects: preferential reduction in elevated serum triglyceride level. J. Nutr. Sci. Vitaminol. (Tokyo), 2004, 50, 211-218.
31. Jung, U.J.; Kim H.J.; Lee J.S.; Lee M.K.; Kim H.O.; Park E.J.; Kim H.K.; Jeong T.S.; Choi, M.S. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin. Nutr., 2003, 22, 561-568.
32. Allister, E.M.; Borradaile N.M.; Edwards J.Y.; Huff M.W. Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogenactivated protein kinase pathway in hepatocytes. Diabetes, 2005, 54, 1676-1683.
33. Borradaile, N.M.; Carroll K.K.; Kurowska E.M. Regulation of HepG2 cell apolipoprotein B metabolism by the citrus flavanones hesperetin and naringenin. Lipids, 1999, 34, 591-598.
34. Borradaile, N.M.; de Dreu L.E.; Barrett P.H.; Behrsin C.D.; Huff M.W. Hepatocyte apoB-containing lipoprotein secretion is decreased by the grapefruit flavonoid, naringenin, via inhibition of MTPmediated microsomal triglyceride accumulation. Biochemistry, 2003, 42,1283-1291.
35. Borradaile, N.M.; de Dreu L.E.; Barrett P.H.; Huff M.W. Inhibition of hepatocyte apoB secretion by naringenin: enhanced rapid intracellular degradation independent of reduced microsomal cholesteryl esters. J. Lipid Res., 2002, 43, 1544-1554.
36. Borradaile, N.M.; de Dreu L.E.; Huff M.W. Inhibition of net HepG2 cell apolipoprotein B secretion by the citrus flavonoid naringenin involves activation of phosphatidylinositol 3-kinase, independent of insulin receptor substrate-1 phosphorylation. Diabetes, 2003, 52, 2554-2561.
37. Allister, E.M.; Mulvihill E.E.; Barrett P.H.; Edwards J.Y.; Carter L.P.; Huff M.W. Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor. J. Lipid Res., 2008, 49, 2218-2229.
38. Jeon, S.M.; Park Y.B.; Choi M.S. Antihypercholesterolemic property of naringin alters plasma and tissue lipids, cholesterolregulating enzymes, fecal sterol and tissue morphology in rabbits. Clin. Nutr., 2004, 23, 1025-1034.
39. Kim, H.J.; Oh G.T.; Park Y.B.; Lee M.K.; Seo H.J.; Choi M.S. Naringin alters the cholesterol biosynthesis and antioxidant enzyme activities in LDL receptor-knockout mice under cholesterol fed condition. Life Sci., 2004, 74,1621-1634.
40. Mulvihill, E.E.; Allister E.M.; Sutherland B.G.; Telford D.E.; Sawyez C.G.; Edwards J.Y.; Markle J.M.; Hegele R.A.; Huff M.W. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes, 2009, 58, 2198-2210.
41. Cho, K.W.; Kim Y.O.; Andrade J.E.; Burgess J.R.; Kim Y.C. Dietary naringenin increases hepatic peroxisome proliferatorsactivated receptor alpha protein expression and decreases plasma triglyceride and adiposity in rats. Eur. J. Nutr., 2011, 50, 81-88.
42. Goldwasser, J.; Cohen P.Y.; Yang E.; Balaguer P.; Yarmush M.L.; Nahmias Y. Transcriptional regulation of human and rat hepatic lipid metabolism by the grapefruit flavonoid naringenin: role of PPARalpha, PPARgamma and LXRalpha. PLoS One, 2010, 5, e12399.
43. Rizza, S.; Muniyappa R.; Iantorno M.; Kim J.A.; Chen H.; Pullikotil P.; Senese N.; Tesauro M.; Lauro D.; Cardillo C.; Quon M.J. Citrus polyphenol hesperidin stimulates production of nitric oxide in endothelial cells while improving endothelial function and reducing inflammatory markers in patients with metabolic syndrome. J. Clin. Endocrinol. Metab., 2011, 96, E782-792.
44. Liu, L.; Xu D.M.; Cheng Y.Y. Distinct effects of naringenin and hesperetin on nitric oxide production from endothelial cells. J. Agric. Food Chem., 2008, 56, 824-829.
45. Lee, E.J.; Kim D.I.; Kim W.J.; Moon S.K. Naringin inhibits matrix metalloproteinase-9 expression and AKT phosphorylation in tumor necrosis factor-alpha-induced vascular smooth muscle cells. Mol. Nutr. Food Res., 2009, 53,1582-1591.
46. Lee, J.J.; Yi H.; Kim I.S.; Kim Y.; Nhiem N.X.; Kim Y.H.; Myung C.S. (2S)-Naringenin from Typha angustata inhibits vascular smooth muscle cell proliferation via a G(0)/G(1) arrest. J. Ethnopharmacol., 2012, 139(3): 873-8.
47. Leray, V.; Freuchet B.; Le Bloc'h J.; Jeusette I.; Torre C.; Nguyen P. Effect of citrus polyphenol- and curcumin-supplemented diet on inflammatory state in obese cats. Br. J. Nutr., 2011, 106(1), S198-201.
48. Morand, C.; Dubray C.; Milenkovic D.; Lioger D.; Martin J.F.; Scalbert A.; Mazur A. Hesperidin contributes to the vascular protective effects of orange juice: a randomized crossover study in healthy volunteers. Am. J. Clin. Nutr., 2010, 93, 73-80.
49. Ghanim, H.; Sia C.L.; Upadhyay M.; Korzeniewski K.; Viswanathan P.; Abuaysheh S.; Mohanty P.; Dandona P. Orange juice neutralizes the proinflammatory effect of a high-fat, highcarbohydrate meal and prevents endotoxin increase and Toll-like receptor expression. Am. J. Clin. Nutr., 2010, 91, 940-949.
50. Choi, J.S.; Yokozawa T.; Oura H. Improvement of hyperglycemia and hyperlipemia in streptozotocin-diabetic rats by a methanolic extract of Prunus davidiana stems and its main component, prunin. Planta Med., 1991, 57, 208-211.
51. Zygmunt, K.; Faubert B.; Macneil J.; Tsiani E. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem. Biophys. Res. Commun., 2010, 398,178-183.
52. Xulu, S.; Oroma Owira, P.M. Naringin ameliorates atherogenic dyslipidemia but not hyperglycemia in rats with type 1 diabetes. J. Cardiovasc. Pharmacol., 2011, 59, 133-141.
53. Jung, U.J.; Lee M.K.; Park Y.B.; Kang M.A.; Choi M.S. Effect of citrus flavonoids on lipid metabolism and glucose-regulating enzyme mRNA levels in type-2 diabetic mice. Int J Biochem Cell Biol., 2006, 38,1134-1145.
54. Mulvihill, E.E.; Assini J.M.; Sutherland B.G.; DiMattia A.S.; Khami M.; Koppes J.B.; Sawyez C.G.; Whitman S.C.; Huff M.W. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice. Arterioscler. Thromb. Vasc. Biol., 2010, 30, 742-748.
55. Chanet, A.; Milenkovic D.; Deval C.; Potier M.; Constans J.; Mazur A.; Bennetau-Pelissero C.; Morand C.; Berard A.M. Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. J. Nutr. Biochem., 2012, 23(5): 469-77.
56. Lee, C.H.; Jeong T.S.; Choi Y.K.; Hyun B.H.; Oh G.T.; Kim E.H.; Kim J.R.; Han J.I.; Bok S.H. Anti-atherogenic effect of citrus flavonoids, naringin and naringenin, associated with hepatic ACAT and aortic VCAM-1 and MCP-1 in high cholesterol-fed rabbits. Biochem. Biophys. Res. Commun., 2001, 284, 681-688.
57. Lee, S.; Lee C.H.; Moon S.S.; Kim E.; Kim C.T.; Kim B.H.; Bok S.H.; Jeong T.S. Naringenin derivatives as anti-atherogenic agents. Bioorg. Med. Chem. Lett., 2003, 13, 3901-3903.
58. Mortensen, A.; Breinholt V.; Dalsgaard T.; Frandsen H.; Lauridsen S.T.; Laigaard J.; Ottesen B.; Larsen J.J. 17beta-Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation in WHHL rabbits. J. Lipid Res., 2001, 42, 834-843.
59. Demonty, I.; Lin Y.; Zebregs Y.E.; Vermeer M.A.; van der Knaap H.C.; Jakel M.; Trautwein E.A. The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and women. J. Nutr., 2010, 140, 1615-1620.
60. Kurowska, E.M.; Manthey J.A.; Casaschi A.; Theriault A.G. Modulation of HepG2 cell net apolipoprotein B secretion by the citrus polymethoxyflavone, tangeretin. Lipids, 2004, 39,143-151.
61. Mulvihill, E.E.; Assini J.M.; Lee J.K.; Allister E.M.; Sutherland B.G.; Koppes J.B.; Sawyez C.G.; Edwards J.Y.; Telford D.E.; Charbonneau A.; St-Pierre P.; Marette A.; Huff M.W. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes, 2011, 60,1446-1457.
62. Tsai, J.; Qiu W.; Kohen-Avramoglu R.; Adeli K. MEK-ERK inhibition corrects the defect in VLDL assembly in HepG2 cells: potential role of ERK in VLDL-ApoB100 particle assembly. Arterioscler. Thromb. Vasc. Biol., 2007, 27, 211-218.
63. Morin, B.; Nichols L.A.; Zalasky K.M.; Davis J.W.; Manthey J.A.; Holland L.J. The citrus flavonoids hesperetin and nobiletin differentially regulate low density lipoprotein receptor gene transcription in HepG2 liver cells. J. Nutr., 2008, 138, 1274-1281.
64. Yen, J.H.; Weng C.Y.; Li S.; Lo Y.H.; Pan M.H.; Fu S.H.; Ho C.T.; Wu M.J. Citrus flavonoid 5-demethylnobiletin suppresses scavenger receptor expression in THP-1 cells and alters lipid homeostasis in HepG2 liver cells. Mol. Nutr. Food Res., 2011, 55, 733-748.
65. Nichols, L.A.; Jackson D.E.; Manthey J.A.; Shukla S.D.; Holland L.J. Citrus flavonoids repress the mRNA for stearoyl-CoA desaturase, a key enzyme in lipid synthesis and obesity control, in rat primary hepatocytes. Lipids Health Dis., 2011, 10, 36.
66. Lee, Y.S.; Cha B.Y.; Saito K.; Yamakawa H.; Choi S.S.; Yamaguchi K.; Yonezawa T.; Teruya T.; Nagai K.; Woo J.T. Nobiletin improves hyperglycemia and insulin resistance in obese diabetic ob/ob mice. Biochem. Pharmacol., 2010, 79,1674-1683.
67. Li, R.W.; Theriault A.G.; Au K.; Douglas T.D.; Casaschi A.; Kurowska E.M.; Mukherjee R. Citrus polymethoxylated flavones improve lipid and glucose homeostasis and modulate adipocytokines in fructose-induced insulin resistant hamsters. Life Sci., 2006, 79, 365-373.
68. Whitman, S.C.; Kurowska E.M.; Manthey J.A.; Daugherty A. Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis, 2005, 178, 25-32.
69. Lo, Y.H.; Pan M.H.; Li S.; Yen J.H.; Kou M.C.; Ho C.T.; Wu M.J. Nobiletin metabolite, 3',4'-dihydroxy-5,6,7,8-tetramethoxyflavone, inhibits LDL oxidation and down-regulates scavenger receptor expression and activity in THP-1 cells. Biochim. Biophys. Acta, 2011, 1801,114-126.
70. Eguchi, A.; Murakami A.; Li S.; Ho C.T.; Ohigashi H. Suppressive effects of demethylated metabolites of nobiletin on phorbol esterinduced expression of scavenger receptor genes in THP-1 human monocytic cells. Biofactors, 2007, 31, 107-116.
71. Lin, N.; Sato T.; Takayama Y.; Mimaki Y.; Sashida Y.; Yano M.; Ito A. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem. Pharmacol., 2003, 65, 2065-2071.
72. Stossel, T.P. The discovery of statins. Cell, 2008, 134, 903-905.
73. Hadden, D.R. Goat's rue - French lilac - Italian fitch - Spanish sainfoin: gallega officinalis and metformin: the Edinburgh connection. JR Coll. Physicians. Edinb., 2005, 35, 258-260.