Citrus Flavonoids as Regulators of Lipoprotein Metabolism and Atherosclerosis

Annual Review of Nutrition

Volumn 36, Issue , 2016, Pages 275-299

  Mulvihill, Erin E ^a,c   Burke, Amy C ^a   Huff, Murray W ^a,b  

^a UNIVERSITY OF WESTERN ONTARIO   (Canada)

^b ROBARTS RESEARCH INSTITUTE   (Canada)

^c MOUNT SINAI HOSPITAL   (Canada)

Author keywords

Adipose tissue; Atherosclerosis; Citrus flavonoids; Glucose metabolism; Inflammation; Lipid metabolism

Indexed keywords

ANTIHYPERTENSIVE AGENT; ANTIINFLAMMATORY AGENT; ANTILIPEMIC AGENT; BIOFLAVONOID; FATTY ACID; GLUCOSE; HESPERETIN; INSULIN; INSULIN SENSITIZING AGENT; LIPOPROTEIN; NARINGENIN; NOBILETIN; TANGERETIN; ANTIOBESITY AGENT; ANTIOXIDANT; FLAVONOID; NONSTEROID ANTIINFLAMMATORY AGENT;

ADIPOSE TISSUE; ANTIHYPERTENSIVE ACTIVITY; ANTIINFLAMMATORY ACTIVITY; ATHEROGENESIS; ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CELL CULTURE; DIET SUPPLEMENTATION; DRUG BIOAVAILABILITY; DRUG MECHANISM; DRUG STRUCTURE; DYSLIPIDEMIA; FATTY ACID OXIDATION; FATTY ACID SYNTHESIS; FATTY LIVER; GLUCOSE METABOLISM; HUMAN; INFLAMMATION; INSULIN RESISTANCE; LIPOPROTEIN METABOLISM; METABOLIC PARAMETERS; METABOLIC REGULATION; METABOLIC SYNDROME X; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; WEIGHT REDUCTION; ANIMAL; BLOOD; CHEMISTRY; CITRUS; DIET THERAPY; DIETARY SUPPLEMENT; HYPERLIPIDEMIA; IMMUNOLOGY; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; OBESITY; RISK FACTOR;

ANIMALS; ANTI-INFLAMMATORY AGENTS, NON-STEROIDAL; ANTI-OBESITY AGENTS; ANTIOXIDANTS; ATHEROSCLEROSIS; CITRUS; DIABETES MELLITUS, TYPE 2; DIETARY SUPPLEMENTS; FLAVONOIDS; HUMANS; HYPERLIPIDEMIAS; HYPOLIPIDEMIC AGENTS; INSULIN RESISTANCE; LIPOPROTEINS; NON-ALCOHOLIC FATTY LIVER DISEASE; OVERWEIGHT; RISK FACTORS;

EID: 84979018808     PISSN: 01999885     EISSN: 15454312     Source Type: Book Series    
DOI: 10.1146/annurev-nutr-071715-050718     Document Type: Review

References (100)

1. Al Rifai M, Silverman MG, Nasir K, Budoff MJ, Blankstein R, et al. 2015. The association of nonalcoholic fatty liver disease, obesity, and metabolic syndrome, with systemic inflammation and subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 239:629-33
2. Ali MM, El Kader MA. 2004. The influence of naringin on the oxidative state of rats with streptozotocininduced acute hyperglycaemia. Z. Naturforsch. C 59:726-33
3. AllisterEM, BorradaileNM,Edwards JY, HuffMW.2005. Inhibition of microsomal triglyceride transfer protein expression and apolipoprotein B100 secretion by the citrus flavonoid naringenin and by insulin involves activation of the mitogen-activated protein kinase pathway in hepatocytes. Diabetes 54:1676-83
4. Allister EM, Mulvihill EE, Barrett PH, Edwards JY, Carter LP, Huff MW. 2008. Inhibition of apoB secretion from HepG2 cells by insulin is amplified by naringenin, independent of the insulin receptor. J. Lipid Res. 49:2218-29
5. Aptekmann NP, Cesar TB. 2013. Long-term orange juice consumption is associated with low LDLcholesterol and apolipoprotein B in normal and moderately hypercholesterolemic subjects. Lipids Health Dis. 12:119
6. Assini JM, Mulvihill EE, Burke AC, Sutherland BG, Telford DE, et al. 2015. Naringenin prevents obesity, hepatic steatosis, and glucose intolerance in male mice independent of fibroblast growth factor. Endocrinology 156:2087-102
7. Assini JM, Mulvihill EE, Sutherland BG, Telford DE, Sawyez CG, et al. 2013. Naringenin prevents cholesterol-induced systemic inflammation, metabolic dysregulation, and atherosclerosis in Ldlr-/-mice. J. Lipid Res. 54:711-24
8. Ballantyne CM, Neutel J, Cropp A, Duggan W, Wang EQ, et al. 2015. Results of bococizumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9, from a randomized, placebocontrolled, dose-ranging study in statin-treated subjects with hypercholesterolemia. Am. J. Cardiol. 115:1212-21
9. Bazzano LA, Li TY, Joshipura KJ, Hu FB. 2008. Intake of fruit, vegetables, and fruit juices and risk of diabetes in women. Diabetes Care 31:1311-17
10. Beecher GR. 2003. Overview of dietary flavonoids: nomenclature, occurrence and intake. J. Nutr. 133:3248-54S
11. Borradaile NM, de Dreu LE, Barrett PH, Behrsin CD, Huff MW. 2003. Hepatocyte apoB-containing lipoprotein secretion is decreased by the grapefruit flavonoid, naringenin, via inhibition of MTPmediated microsomal triglyceride accumulation. Biochemistry 42:1283-91
12. Borradaile NM, de Dreu LE, Barrett PH, Huff MW. 2002. Inhibition of hepatocyte apoB secretion by naringenin: enhanced rapid intracellular degradation independent of reduced microsomal cholesteryl esters. J. Lipid Res. 43:1544-54
13. Borradaile NM, de Dreu LE, Huff MW. 2003. 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 52:2554-61
14. Burke AC, Sutherland BG, Assini JM, Huff MW. 2015. Intervention with naringenin enhances weight loss, potentiates improvements in metabolic dysregulation and halts progression of atherosclerosis induced by a high-fat diet in Ldlr-/-mice. Arterioscler. Thromb. Vasc. Biol. 35:A686
15. Burke AC, Sutherland BG, Sawyez CG, Telford DE, Umoh J, et al. 2014. Intervention with citrus flavonoids reverses existing metabolic disorders and attenuates the progression of advanced atherosclerosis in high fat-fed Ldlr-/-mice. Arterioscler. Thromb. Vasc. Biol. 34:A67
16. Cassidy A, Rimm EB, O'Reilly EJ, Logroscino G, Kay C, et al. 2012. Dietary flavonoids and risk of stroke in women. Stroke 43:946-51
17. Chanet A, Milenkovic D, Deval C, Potier M, Constans J, et al. 2012. Naringin, the major grapefruit flavonoid, specifically affects atherosclerosis development in diet-induced hypercholesterolemia in mice. J. Nutr. Biochem. 23:469-77
18. Chen S, Ding Y, TaoW, Zhang W, Liang T, Liu C. 2012. Naringenin inhibits TNF-αinduced VSMC proliferation and migration via induction of HO-1. Food Chem. Toxicol. 50:3025-31
19. Cho KW, Kim YO, Andrade JE, Burgess JR, Kim YC. 2011. Dietary naringenin increases hepatic peroxisome proliferators-activated receptor αprotein expression and decreases plasma triglyceride and adiposity in rats. Eur. J. Nutr. 50:81-88
20. Choi JS,YokozawaT,OuraH. 1991. Improvement of hyperglycemia and hyperlipemia in streptozotocindiabetic rats by a methanolic extract of Prunus davidiana stems and its main component, prunin. Planta Med. 57:208-11
21. Chtourou Y, Fetoui H, JemaiR,Ben SlimaA,MakniM,GdouraR. 2015. Naringenin reduces cholesterolinduced hepatic inflammation in rats by modulating matrix metalloproteinases-2, 9 via inhibition of nuclear factor κB pathway. Eur. J. Pharmacol. 746:96-105
22. Chun OK, Chung SJ, Song WO. 2007. Estimated dietary flavonoid intake and major food sources of U.S. adults. J. Nutr. 137:1244-52
23. Croft KD. 1998. The chemistry and biological effects of flavonoids and phenolic acids. Ann. N. Y. Acad. Sci. 854:435-42
24. Dallas C, Gerbi A, Elbez Y, Caillard P, Zamaria N, Cloarec M. 2014. Clinical study to assess the efficacy and safety of a citrus polyphenolic extract of red orange, grapefruit, and orange (Sinetrol-XPur) on weight management and metabolic parameters in healthy overweight individuals. Phytother. Res. 28:212-18
25. Dallas C, Gerbi A, Tenca G, Juchaux F, Bernard FX. 2008. Lipolytic effect of a polyphenolic citrus dry extract of red orange, grapefruit, orange (SINETROL) in human body fat adipocytes. Mechanism of action by inhibition of cAMP-phosphodiesterase (PDE). Phytomedicine 15:783-92
26. Dauchet L, Amouyel P, Dallongeville J. 2009. Fruits, vegetables and coronary heart disease. Nat. Rev. Cardiol. 6:599-608
27. DeBoer MD, Gurka MJ,Woo JG, Morrison JA. 2015. Severity of the metabolic syndrome as a predictor of type 2 diabetes between childhood and adulthood: the Princeton Lipid Research Cohort Study. Diabetologia 58:2745-52
28. Demonty I, Lin Y, Zebregs YE, Vermeer MA, van der Knaap HC, et al. 2010. The citrus flavonoids hesperidin and naringin do not affect serum cholesterol in moderately hypercholesterolemic men and women. J. Nutr. 140:1615-20
29. Dow CA, Going SB, Chow HH, Patil BS, Thomson CA. 2012. The effects of daily consumption of grapefruit on body weight, lipids, and blood pressure in healthy, overweight adults. Metabolism 61:1026-35
30. Edmands WM, Ferrari P, Rothwell JA, Rinaldi S, Slimani N, et al. 2015. Polyphenol metabolome in human urine and its association with intake of polyphenol-rich foods across European countries. Am. J. Clin. Nutr. 102:905-13
31. Erlund I, Meririnne E, Alfthan G, Aro A. 2001. Plasma kinetics and urinary excretion of the flavanones naringenin and hesperetin in humans after ingestion of orange juice and grapefruit juice. J. Nutr. 131:235-41
32. FujiokaK,Greenway F, Sheard J, Ying Y. 2006. The effects of grapefruit on weight and insulin resistance: relationship to the metabolic syndrome. J. Med. Food 9:49-54
33. Fukuchi Y, Hiramitsu M, Okada M, Hayashi S, Nabeno Y, et al. 2008. Lemon polyphenols suppress diet-induced obesity by up-regulation of mRNA levels of the enzymes involved in beta-oxidation in mouse white adipose tissue. J. Clin. Biochem. Nutr. 43:201-9
34. Gonzalez-Gallego J, Garcia-Mediavilla MV, Sanchez-Campos S, Tunon MJ. 2010. Fruit polyphenols, immunity and inflammation. Br. J. Nutr. 104(Suppl. 3):S15-27
35. Heim KE, Tagliaferro AR, Bobilya DJ. 2002. Flavonoid antioxidants: chemistry, metabolism and structure-activity relationships. J. Nutr. Biochem. 13:572-84
36. Hirai S, Kim YI, Goto T, Kang MS, Yoshimura M, et al. 2007. Inhibitory effect of naringenin chalcone on inflammatory changes in the interaction between adipocytes and macrophages. Life Sci. 81:1272-79
37. Hollman PC, Cassidy A, Comte B, Heinonen M, Richelle M, et al. 2011. The biological relevance of direct antioxidant effects of polyphenols for cardiovascular health in humans is not established. J. Nutr. 141:989-1009S
38. Hovingh GK, Ray KK, Boekholdt SM. 2015. Is cholesteryl ester transfer protein inhibition an effective strategy to reduce cardiovascular risk? CETP as a target to lower CVD risk: suspension of disbelief? Circulation 132:433-40
39. Huong DT, Takahashi Y, Ide T. 2006. Activity and mRNA levels of enzymes involved in hepatic fatty acid oxidation in mice fed citrus flavonoids. Nutrition 22:546-52
40. Jeon SM, Park YB, Choi MS. 2004. Antihypercholesterolemic property of naringin alters plasma and tissue lipids, cholesterol-regulating enzymes, fecal sterol and tissue morphology in rabbits. Clin. Nutr. 23:1025-34
41. Joshipura KJ, Ascherio A, Manson JE, Stampfer MJ, Rimm EB, et al. 1999. Fruit and vegetable intake in relation to risk of ischemic stroke. JAMA 282:1233-39
42. Joshipura KJ, Hu FB,Manson JE, Stampfer MJ, Rimm EB, et al. 2001. The effect of fruit and vegetable intake on risk for coronary heart disease. Ann. Intern. Med. 134:1106-14
43. Jung UJ, Kim HJ, Lee JS, Lee MK, Kim HO, et al. 2003. Naringin supplementation lowers plasma lipids and enhances erythrocyte antioxidant enzyme activities in hypercholesterolemic subjects. Clin. Nutr. 22:561-68
44. Jung UJ, Lee MK, Jeong KS, Choi MS. 2004. The hypoglycemic effects of hesperidin and naringin are partly mediated by hepatic glucose-regulating enzymes in C57BL/KsJ-db/db mice. J. Nutr. 134:2499-503
45. Kanaze FI, Bounartzi MI, Georgarakis M, Niopas I. 2007. Pharmacokinetics of the citrus flavanone aglycones hesperetin and naringenin after single oral administration in human subjects. Eur. J. Clin. Nutr. 61:472-77
46. Kang SI, Shin HS, Kim HM,Hong YS, Yoon SA, et al. 2012. Immature Citrus sunki peel extract exhibits antiobesity effects by β-oxidation and lipolysis in high-fat diet-induced obese mice. Biol. Pharm. Bull. 35:223-30
47. Kannappan S, Anuradha CV. 2010. Naringenin enhances insulin-stimulated tyrosine phosphorylation and improves the cellular actions of insulin in a dietary model of metabolic syndrome. Eur. J. Nutr. 49:101-9
48. Katz R, Budoff MJ, O'Brien KD, Wong ND, Nasir K. 2015. The metabolic syndrome and diabetes mellitus as predictors of thoracic aortic calcification as detected by non-contrast computed tomography in the Multi-Ethnic Study of Atherosclerosis. Diabet. Med. doi: 10.1111/dme.12958
49. Ke JY, Cole RM,Hamad EM,Hsiao YH, Cotten BM, et al. 2015. Citrus flavonoid, naringenin, increases locomotor activity and reduces diacylglycerol accumulation in skeletal muscle of obese ovariectomized mice. Mol. Nutr. Food Res. doi: 10.1002/mnfr.201500379
50. Ke JY, Kliewer KL, Hamad EM, Cole RM, Powell KA, et al. 2015. The flavonoid, naringenin, decreases adipose tissue mass and attenuates ovariectomy-associated metabolic disturbances in mice. Nutr. Metab. (Lond.) 12:1
51. Kim GS, Park HJ, Woo JH, Kim MK, Koh PO, et al. 2012. Citrus aurantium flavonoids inhibit adipogenesis through the Akt signaling pathway in 3T3-L1 cells. BMC Complement. Altern. Med. 12:31
52. Kim HY, ParkM, Kim K, Lee YM, Rhyu MR. 2013. Hesperetin stimulates cholecystokinin secretion in enteroendocrine STC-1 cells. Biomol. Ther. (Seoul) 21:121-25
53. Kurowska EM, Spence JD, Jordan J, Wetmore S, Freeman DJ, et al. 2000. HDL-cholesterol-raising effect of orange juice in subjects with hypercholesterolemia. Am. J. Clin. Nutr. 72:1095-100
54. Laakso M. 2015. Is insulin resistance a feature of or a primary risk factor for cardiovascular disease? Curr. Diab. Rep. 15:105
55. LeeCH, JeongTS, Choi YK,Hyun BH, Oh GT, et al. 2001. 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. 284:681-88
56. Lee EJ, Kim DI, Kim WJ, Moon SK. 2009. Naringin inhibits matrix metalloproteinase-9 expression and AKT phosphorylation in tumor necrosis factor-α-induced vascular smooth muscle cells. Mol. Nutr. Food Res. 53:1582-91
57. Lee JJ, Yi H, Kim IS, Kim Y, Nhiem NX, et al. 2012. 2S-naringenin from Typha angustata inhibits vascular smooth muscle cell proliferation via a G0/G1 arrest. J. Ethnopharmacol. 139:873-78
58. Lee MK, Moon SS, Lee SE, Bok SH, Jeong TS, et al. 2003. Naringenin 7-O-cetyl ether as inhibitor of HMG-CoA reductase and modulator of plasma and hepatic lipids in high cholesterol-fed rats. Bioorg. Med. Chem. Lett. 11:393-98
59. Lee S, Lee CH, Moon SS, Kim E, Kim CT, et al. 2003. Naringenin derivatives as anti-atherogenic agents. Bioorg. Med. Chem. Lett. 13:3901-3
60. Lee SH, Park YB, Bae KH, Bok SH, Kwon YK, et al. 1999. Cholesterol-lowering activity of naringenin via inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase and acyl coenzyme A:cholesterol acyltransferase in rats. Ann. Nutr. Metab. 43:173-80
61. Li RW, Theriault AG, Au K, Douglas TD, Casaschi A, et al. 2006. Citrus polymethoxylated flavones improve lipid and glucose homeostasis and modulate adipocytokines in fructose-induced insulin resistant hamsters. Life Sci. 79:365-73
62. Lin N, Sato T, Takayama Y, Mimaki Y, Sashida Y, et al. 2003. Novel anti-inflammatory actions of nobiletin, a citrus polymethoxy flavonoid, on human synovial fibroblasts and mouse macrophages. Biochem. Pharmacol. 65:2065-71
63. Lin SP, Hou YC, Tsai SY, Wang MJ, Chao PD. 2014. Tissue distribution of naringenin conjugated metabolites following repeated dosing of naringin to rats. Biomedicine (Taipei) 4:16
64. Mahmoud AM, Ashour MB, Abdel-Moneim A, Ahmed OM. 2012. Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J. Diabetes Complicat. 26:483-90
65. Manach C, Scalbert A,Morand C, Remesy C, Jimenez L. 2004. Polyphenols: food sources and bioavailability. Am. J. Clin. Nutr. 79:727-47
66. Mink PJ, Scrafford CG,BarrajLM, Harnack L, Hong CP, et al. 2007. Flavonoid intake and cardiovascular disease mortality a prospective study in postmenopausal women. Am. J. Clin. Nutr. 85:895-909
67. Miwa Y, Mitsuzumi H, Sunayama T, Yamada M, Okada K, et al. 2005. Glucosyl hesperidin lowers serum triglyceride level in hypertriglyceridemic subjects through the improvement of very low-density lipoprotein metabolic abnormality. J. Nutr. Sci. Vitaminol. (Tokyo) 51:460-70
68. Mollace V, Sacco I, Janda E,Malara C, Ventrice D, et al. 2011. Hypolipemic and hypoglycaemic activity of bergamot polyphenols: from animal models to human studies. Fitoterapia 82:309-16
69. Morand C, Dubray C, Milenkovic D, Lioger D, Martin JF, et al. 2011. Hesperidin contributes to the vascular protective effects of orange juice a randomized crossover study in healthy volunteers. Am. J. Clin. Nutr. 93:73-80
70. Mortensen A, Breinholt V, Dalsgaard T, Frandsen H, Lauridsen ST, et al. 2001. 17β-Estradiol but not the phytoestrogen naringenin attenuates aortic cholesterol accumulation inWHHL rabbits. J. Lipid Res. 42:834-43
71. Mulvihill EE, Allister EM, Sutherland BG, Telford DE, Sawyez CG, et al. 2009. Naringenin prevents dyslipidemia, apolipoprotein B overproduction, and hyperinsulinemia in LDL receptor-null mice with diet-induced insulin resistance. Diabetes 58:2198-210
72. Mulvihill EE, Assini JM, Lee JK, Allister EM, Sutherland BG, et al. 2011. Nobiletin attenuates VLDL overproduction, dyslipidemia, and atherosclerosis in mice with diet-induced insulin resistance. Diabetes 60:1446-57
73. Mulvihill EE, Assini JM, Sutherland BG, DiMattia AS, KhamiM, et al. 2010. Naringenin decreases progression of atherosclerosis by improving dyslipidemia in high-fat-fed low-density lipoprotein receptor-null mice. Arterioscler. Thromb. Vasc. Biol. 30:742-48
74. Mulvihill EE, Huff MW. 2010. Antiatherogenic properties of flavonoids: implications for cardiovascular health. Can. J. Cardiol. 26(Suppl):17-21A
75. Mulvihill EE, HuffMW.2011.Howcan nobiletin prevent obesity? Expert Rev. Endocrinol.Metab. 6:501-3
76. Mulvihill EE, Huff MW. 2012. Citrus flavonoids and the prevention of atherosclerosis. Cardiovasc. Hematol. Disord. Drug Targets 12:84-91
77. Mursu J, Voutilainen S, Nurmi T, Tuomainen TP, Kurl S, Salonen JT. 2008. Flavonoid intake and the risk of ischaemic stroke and CVD mortality in middle-aged Finnish men: the Kuopio Ischaemic Heart Disease Risk Factor Study. Br. J. Nutr. 100:890-95
78. Nielsen IL, Chee WS, Poulsen L,Offord-Cavin E, Rasmussen SE, et al. 2006. Bioavailability is improved by enzymatic modification of the citrus flavonoid hesperidin in humans a randomized, double-blind, crossover trial. J. Nutr. 136:404-8
79. Owen BM, Mangelsdorf DJ, Kliewer SA. 2015. Tissue-specific actions of the metabolic hormones FGF15/19 and FGF21. Trends Endocrinol. Metab. 26:22-29
80. Park HJ, Jung UJ, Cho SJ, Jung HK, Shim S, Choi MS. 2013. Citrus unshiu peel extract ameliorates hyperglycemia and hepatic steatosis by altering inflammation and hepatic glucose-and lipid-regulating enzymes in db/db mice. J. Nutr. Biochem. 24:419-27
81. Pu P, Gao DM, Mohamed S, Chen J, Zhang J, et al. 2012. Naringin ameliorates metabolic syndrome by activating AMP-activated protein kinase in mice fed a high-fat diet. Arch. Biochem. Biophys. 518:61-70
82. Punithavathi VR, Anuthama R, Prince PS. 2008. Combined treatment with naringin and vitamin C ameliorates streptozotocin-induced diabetes in male Wistar rats. J. Appl. Toxicol. 28:806-13
83. Ramful D, Tarnus E, Rondeau P,Da Silva CR, Bahorun T, Bourdon E. 2010. Citrus fruit extracts reduce advanced glycation end products (AGEs)-and H2O2-induced oxidative stress in human adipocytes. J. Agric. Food Chem. 58:11119-29
84. Reshef N, Hayari Y, Goren C, Boaz M, Madar Z, Knobler H. 2005. Antihypertensive effect of sweetie fruit in patients with stage I hypertension. Am. J. Hypertens. 18:1360-63
85. Rice-Evans CA, Miller NJ, Paganga G. 1996. Structure-antioxidant activity relationships of flavonoids and phenolic acids. Free Radic. Biol. Med. 20:933-56
86. Richard AJ, Amini-Vaughan Z, Ribnicky DM, Stephens JM. 2013. Naringenin inhibits adipogenesis and reduces insulin sensitivity and adiponectin expression in adipocytes. Evid.-Based Complement. Altern. Med. 2013:549750
87. Rizza S, Muniyappa R, Iantorno M, Kim JA, Chen H, et al. 2011. 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. 96:E782-92
88. Roza JM, Xian-Liu Z, GuthrieN. 2007. Effect of citrus flavonoids and tocotrienols on serum cholesterol levels in hypercholesterolemic subjects. Altern. Ther. Health Med. 13:44-48
89. Sattar NA, Ginsberg H, Ray K, Chapman MJ, ArcaM, et al. 2014. The use of statins in people at risk of developing diabetes mellitus: evidence and guidance for clinical practice. Atheroscler. Suppl. 15:1-15
90. Seo J, Lee HS, Ryoo S, Seo JH, Min BS, Lee JH. 2011. Tangeretin, a citrus flavonoid, inhibits PGDFBB-induced proliferation and migration of aortic smooth muscle cells by blocking AKT activation. Eur. J. Pharmacol. 673:56-64
91. Sharma AK, Bharti S, Ojha S, Bhatia J, KumarN, et al. 2011. Up-regulation of PPARgamma, heat shock protein-27 and-72 by naringin attenuates insulin resistance, beta-cell dysfunction, hepatic steatosis and kidney damage in a rat model of type 2 diabetes. Br. J. Nutr. 106:1713-23
92. Shin YW, Bok SH, Jeong TS, Bae KH, Jeoung NH, et al. 1999. Hypocholesterolemic effect of naringin associated with hepatic cholesterol regulating enzyme changes in rats. Int. J. Vitam. Nutr. Res. 69:341-47
93. Sugiura M, Ogawa K, Yano M. 2006. Effect of chronic administration of fruit extract (Citrus unshiu Marc.) on glucose tolerance in GK rats, a model of type 2 diabetes. Biosci. Biotechnol. Biochem. 70:293-95
94. Sun Y, Qiao L, Shen Y, Jiang P, Chen J, Ye X. 2013. Phytochemical profile and antioxidant activity of physiological drop of citrus fruits. J. Food Sci. 78:C37-42
95. Vaiyapuri S, Ali MS, Moraes LA, Sage T, Lewis KR, et al. 2013. Tangeretin regulates platelet function through inhibition of phosphoinositide 3-kinase and cyclic nucleotide signaling. Arterioscler. Thromb. Vasc. Biol. 33:2740-49
96. Whitman SC, Kurowska EM, Manthey JA, Daugherty A. 2005. Nobiletin, a citrus flavonoid isolated from tangerines, selectively inhibits class A scavenger receptor-mediated metabolism of acetylated LDL by mouse macrophages. Atherosclerosis 178:25-32
97. Wilcox LJ, Borradaile NM, de Dreu LE, Huff MW. 2001. Secretion of hepatocyte apoB is inhibited by the flavonoids, naringenin and hesperetin, via reduced activity and expression of ACAT2 and MTP. J. Lipid Res. 42:725-34
98. Xiong Y,WangGF, Zhang JY,WuSY, XuW, et al. 2010. [Naringin inhibits monocyte adhesion to high glucose-induced human umbilical vein endothelial cells.] Nan Fang Yi Ke Da Xue Xue Bao 30:321-25
99. Yamada T, Hayasaka S, Shibata Y, Ojima T, Saegusa T, et al. 2011. Frequency of citrus fruit intake is associated with the incidence of cardiovascular disease: the Jichi Medical School cohort study. J. Epidemiol. 21:169-75
100. Zygmunt K, Faubert B, MacNeil J, Tsiani E. 2010. Naringenin, a citrus flavonoid, increases muscle cell glucose uptake via AMPK. Biochem. Biophys. Res. Commun. 398:178-83