Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease

Atherosclerosis

Volumn 232, Issue 2, 2014, Pages 346-360

  Gylling, Helena ^a   Plat, Jogchum ^b   Turley, Stephen ^c   Ginsberg, Henry N ^d   Ellegård, Lars ^e   Jessup, Wendy ^f   Jones, Peter J ^g   Lütjohann, Dieter ^h   Maerz, Winfried ^i,j,k   Masana, Luis ^l   Silbernagel, Günther ^m   Staels, Bart ⁿ   Borén, Jan ^o   Catapano, Alberico L ^p,q   De Backer, Guy ^r   Deanfield, John ^s   Descamps, Olivier S ^t   Kovanen, Petri T ^u   Riccardi, Gabriele ^v   Tokgözoglu, Lale ^w   Chapman, M John ^x,y   more..

^a UNIVERSITY OF HELSINKI   (Finland)

^b MAASTRICHT UNIVERSITY   (Netherlands)

^c UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER   (United States)

^d Och Spine at New York Presbyterian Hospitals   (United States)

^e UNIVERSITY OF GOTHENBURG   (Sweden)

^f Department of Microbiology and Infectious Diseases   (Australia)

^g UNIVERSITY OF MANITOBA   (Canada)

^h UNIVERSITY HOSPITAL BONN   (Germany)

ⁱ SYNLAB ACADEMY   (Germany)

^j UNIVERSITY OF HEIDELBERG   (Germany)

^k MEDICAL UNIVERSITY OF GRAZ   (Austria)

^l UNIVERSITAT ROVIRA I VIRGILI   (Spain)

^m UNIVERSITY OF BERN   (Switzerland)

ⁿ UNIV LILLE   (France)

^o UNIVERSITY OF GOTHENBURG   (Sweden)

^p UNIVERSITY OF MILAN   (Italy)

^q IRCCS MULTIMEDICA   (Italy)

^r GHENT UNIVERSITY HOSPITAL   (Belgium)

^s UNIVERSITY COLLEGE LONDON   (United Kingdom)

^t Hospital de Jolimont   (Belgium)

^u WIHURI RESEARCH INSTITUTE   (Finland)

^v UNIVERSITY OF NAPLES FEDERICO II   (Italy)

^w HACETTEPE UNIVERSITY   (Turkey)

^x SORBONNE UNIVERSITÉ   (France)

^y PITIÉ SALPÊTRIÈRE HOSPITAL   (France)

more..

Author keywords

Cardiovascular risk; Functional foods with added plant sterols and plant stanols; Hypercholesterolaemia; Intestinal cholesterol absorption; Phytosterols; Safety

Indexed keywords

CHOLESTEROL; EZETIMIBE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; LIPID; LOW DENSITY LIPOPROTEIN CHOLESTEROL; PHYTOSTEROL; STANOZOLOL; TRIACYLGLYCEROL;

ATHEROSCLEROSIS; CARDIOVASCULAR DISEASE; CARDIOVASCULAR RISK; CELL METABOLISM; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL METABOLISM; COHORT ANALYSIS; DRUG ABSORPTION; DRUG SAFETY; DRUG TISSUE LEVEL; DYSLIPIDEMIA; FUNCTIONAL FOOD; HIGH RISK PATIENT; HUMAN; LIPID ANALYSIS; LIPID BLOOD LEVEL; NONHUMAN; POSTPRANDIAL STATE; PRIORITY JOURNAL; REVIEW; RISK BENEFIT ANALYSIS; TRIACYLGLYCEROL BLOOD LEVEL;

CARDIOVASCULAR RISK; FUNCTIONAL FOODS WITH ADDED PLANT STEROLS AND PLANT STANOLS; HYPERCHOLESTEROLAEMIA; INTESTINAL CHOLESTEROL ABSORPTION; PHYTOSTEROLS; SAFETY;

ANIMALS; ANTICHOLESTEREMIC AGENTS; CARDIOVASCULAR DISEASES; CHOLESTEROL; CHOLESTEROL, LDL; DYSLIPIDEMIAS; HUMANS; INFLAMMATION; LIPIDS; PHYTOSTEROLS; SITOSTEROLS; TRIGLYCERIDES;

EID: 84892882894     PISSN: 00219150     EISSN: 18791484     Source Type: Journal    
DOI: 10.1016/j.atherosclerosis.2013.11.043     Document Type: Review

References (164)

1. Nichols M., Townsend N., Luengo-Fernandez R., et al. European cardiovascular disease statistics 2012 2012, European Heart Network, European Society of Cardiology, Brussels/Sophia Antipolis.
2. Berry J.D., Dyer A., Cai X., et al. Lifetime risks of cardiovascular disease. NEngl J Med 2012, 366:321-329.
3. Yusuf S., Hawken S., Ounpuu S., et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet 2004, 364:937-952.
4. Baigent C., Keech A., Kearney P.M., et al. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005, 366:1267-1278. Cholesterol Treatment Trialists' (CTT) Collaborators.
5. Robinson J.G., Smith B., Maheshwari N., Schrott H. Pleiotropic effects of statins: benefit beyond cholesterol reduction? A meta-regression analysis. JAm Coll Cardiol 2005, 46:1855-1862.
6. Ference B.A., Yoo W., Alesh I., et al. Effect of long-term exposure to lower low-density lipoprotein cholesterol beginning early in life on the risk of coronary heart disease: a Mendelian randomization analysis. JAm Coll Cardiol 2012, 60:2631-2639.
7. Estruch R., Martínez-González M.A., Corella D., et al. Effects of a Mediterranean-style diet on cardiovascular risk factors: a randomized trial. Ann Intern Med 2006, 145:1-11.
8. Dietschy J.M., Turley S.D., Spady D.K. Role of liver in the maintenance of cholesterol and low density lipoprotein homeostasis in different animal species, including humans. JLipid Res 1993, 34:1637-1659.
9. Cooper A.D. Hepatic uptake of chylomicron remnants. JLipid Res 1997, 38:2173-2192.
10. Davis H.R., Compton D.S., Hoos L., Tetzloff G. Ezetimibe, a potent cholesterol absorption inhibitor, inhibits the development of atherosclerosis in ApoE knockout mice. Arterioscler Thromb Vasc Biol 2001, 21:2032-2038.
11. Chan D.C., Watts G.F., Gan S.K., Ooi E.M., Barrett P.H. Effect of ezetimibe on hepatic fat, inflammatory markers, and apolipoprotein B-100 kinetics in insulin-resistant obese subjects on a weight loss diet. Diabetes Care 2010, 33:1134-1139.
12. Tremblay A.J., Lamarche B., Cohn J.S., Hogue J.C., Couture P. Effect of ezetimibe on the invivo kinetics of apoB-48 and apoB-100 in men with primary hypercholesterolemia. Arterioscler Thromb Vasc Biol 2006, 26:1101-1106.
13. Klingberg S., Andersson H., Mulligan A., et al. Food sources of plant sterols in the EPIC Norfolk population. Eur J Clin Nutr 2008, 62:695-703.
14. Valsta L.M., Lemström A., Ovaskainen M.L., et al. Estimation of plant sterol and cholesterol intake in Finland: quality of new values and their effect on intake. Br J Nutr 2004, 92:671-678.
15. Piironen V., Lampi A.M. Occurrence and levels of phytosterols in foods. Phytosterols as functional food components and nutraceuticals 2004, 1-32. Marcel Dekker, Inc, New York. P.C. Dutta (Ed.).
16. Vuoristo M., Miettinen T.A. Absorption, metabolism, and serum concentrations of cholesterol in vegetarians: effects of cholesterol feeding. Am J Clin Nutr 1994, 59:1325-1331.
17. Ostlund R.E., McGill J.B., Zeng C.-M., et al. Gastro-intestinal absorption and plasma kinetics of soy δ5-phytosterols and phytostanols in humans. Am J Physiol Endocrinol Metab 2002, 282:E911-E916.
18. Björkhem I., Boberg K.M., Leitersdorf E. Inborn errors in bile acid biosynthesis and storage of sterols other than cholesterol. The metabolic and molecular bases of inherited disease 2001, 2961-2988. McGraw-Hill, New York. 8th ed. C.R. Scriver, A.L. Beaudet, W.S. Sly, D. Valle (Eds.).
19. Fransen H.P., de Jong N., Wolfs M., et al. Customary use of plant sterol and plant stanol enriched margarine is associated with changes in serum plant sterol and stanol concentrations in humans. JNutr 2007, 137:1301-1306.
20. Berge K.E., Tian H., Graf G.A., et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science 2000, 290:1771-1775.
21. Lee M.H., Lu K., Hazard S., et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet 2001, 27:79-83.
22. Salen G., von Bergmann K., Lütjohann D., et al. Ezetimibe effectively reduces plasma plant sterols in patients with sitosterolemia. Circulation 2004, 109:966-971. Multicenter Sitosterolemia Study Group.
23. Vanmierlo T., Popp J., Kölsch H., et al. The plant sterol brassicasterol as additional CSF biomarker in Alzheimer's disease. Acta Psychiatr Scand 2011, 124:184-192.
24. Salen G., Horak I., Rothkopf M., et al. Lethal atherosclerosis associated with abnormal plasma and tissue sterol composition in sitosterolemia with xanthomatosis. JLipid Res 1985, 26:1126-1133.
25. Helske S., Miettinen T., Gylling H., et al. Accumulation of cholesterol precursors and plant sterols in human stenotic aortic valves. JLipid Res 2008, 49:1511-1518.
26. Miettinen T.A., Railo M., Lepäntalo M., Gylling H. Plant sterols in serum and in atherosclerotic plaques of patients undergoing carotid endarterectomy. JAm Coll Cardiol 2005, 45:1792-1801.
27. Miettinen T.A., Nissinen M., Lepäntalo M., et al. Non-cholesterol sterols in serum and endarterectomized carotid arteries after a short-term plant stanol and sterol ester challenge. Nutr Metab Cardiovasc Dis 2011, 21:182-188.
28. Weingärtner O., Lütjohann D., Ji S., et al. Vascular effects of diet supplementation with plant sterols. JAm Coll Cardiol 2008, 51:1553-1561.
29. Mellies M.J., Ishikawa T.T., Glueck C.J., Bove K., Morrison J. Phytosterols in aortic tissue in adults and infants. JLab Clin Med 1976, 88:914-921.
30. Jessup W., Herman A., Chapman M.J. Phytosterols in cardiovascular disease: innocuous dietary components, or accelerators of atherosclerosis?. Fut Lipidol 2008, 3:301-310.
31. Gylling H., Radhakrishnan R., Miettinen T.A. Reduction of serum cholesterol in postmenopausal women with previous myocardial infarction and cholesterol malabsorption induced by dietary sitostanol ester margarine: women and dietary sitostanol. Circulation 1997, 96:4226-4231.
32. Miettinen T.A., Gylling H., Nissinen M.J. The role of serum non-cholesterol sterols as surrogate markers of absolute cholesterol synthesis and absorption. Nutr Metab Cardiovasc Dis 2011, 21:765-769.
33. Descamps O.S., De Sutter J., Guillaume M., Missault L. Where does the interplay between cholesterol absorption and synthesis in the context of statin and/or ezetimibe treatment stand today?. Atherosclerosis 2011, 217:308-321.
34. Rozner S., Garti N. The activity and absorption relationship of cholesterol andphytosterols. Colloids Surf A: Physicochem Eng Aspects 2006, 282-283:435-456.
35. Wang D.Q.-H. Regulation of intestinal cholesterol absorption. Annu Rev Physiol 2007, 69:221-248.
36. Turley S.D. Role of Niemann-Pick C1-Like 1 (NPC1L1) in intestinal sterol absorption. JClin Lipidol 2008, 2:S20-S28.
37. Nissinen M., Gylling H., Vuoristo M., Miettinen T.A. Micellar distribution of cholesterol and phytosterols after duodenal plant stanol ester infusion. Am J Physiol Gastrointest Liver Physiol 2002, 282:G1009-G1015.
38. Nguyen T.M., Sawyer J.K., Kelley K.L., Davis M.A., Rudel L.L. Cholesterol esterification by ACAT2 is essential for efficient intestinal cholesterol absorption: evidence from thoracic lymph duct cannulation. JLipid Res 2012, 53:95-104.
39. Gylling H.K., Hallikainen M., Vidgren H., Ågren J., Miettinen T.A. Ester percentages of plant sterols and cholesterol in chylomicrons and VLDL of humans with low and high sterol absorption. Atherosclerosis 2006, 187:150-152.
40. Calandra S., Tarugi P., Speedy H.E., Dean A.F., Bertolini S., Shoulders C.C. Mechanisms and genetic determinants regulating sterol absorption, circulating LDL levels, and sterol elimination: implications for classification and disease risk. JLipid Res 2011, 52:1885-1926.
41. Lee S., Gershkovich P., Darlington J., Wasan K. Inhibition of cholesterol absorption: targeting the intestine. Pharm Res 2012, 29:3235-3250.
42. De Smet E., Mensink R.P., Plat J. Effects of plant sterols and stanols on intestinal cholesterol metabolism: suggested mechanisms from past to present. Mol Nutr Food Res 2012, 56:1058-1072.
43. Teupser D., Baber R., Ceglarek U., et al. Genetic regulation of serum phytosterol levels and risk of coronary artery disease. Circ Cardiovasc Genet 2010, 3:331-339.
44. Silbernagel G., Chapman M.J., Genser B., et al. High intestinal cholesterol absorption is associated with risk alleles in ABCG8 and ABO and with cardiovascular disease: evidence from the LURIC and YFS Cohorts and from a meta-analysis. JAm Coll Cardiol 2013, 62:291-299.
45. Andersson S.W., Skinner J., Ellegård L., et al. Intake of plant sterols is inversely related to serum cholesterol concentration in men and women in the EPIC Norfolk population: a cross-sectional study. Eur J Clin Nutr 2004, 58:1378-1385.
46. Klingberg S., Ellegård L., Johansson I., et al. Inverse relation between naturally occurring dietary plant sterols and serum cholesterol in northern Sweden. Am J Clin Nutr 2008, 87:993-1002.
47. Wang P., Chen Y.M., He L.P., et al. Association of natural intake of dietary plant sterols with carotid intima-media thickness and blood lipids in Chinese adults: a cross-section study. PLoS ONE 2012, 7:e32736.
48. Lin X., Racette S.B., Lefevre M., et al. The effects of phytosterols present in natural food matrices on cholesterol metabolism and LDL-cholesterol: a controlled feeding trial. Eur J Clin Nutr 2010, 64:1481-1487.
49. Racette S.B., Lin X., Lefevre M., et al. Dose effects of dietary phytosterols on cholesterol metabolism: a controlled feeding study. Am J Clin Nutr 2010, 91:32-38.
50. Farquhar J.W., Smith R.E., Dempsey M.E. The effect of beta sitosterol on the serum lipids of young men with arteriosclerotic heart disease. Circulation 1956, 14:77-82.
51. Miettinen T.A., Puska P., Gylling H., Vanhanen H., Vartiainen E. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. NEngl J Med 1995, 333:1308-1312.
52. Katan M.B., Grundy S.M., Jones P., Law M., Miettinen T., Paoletti R. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc 2003, 78:965-978. Stresa Workshop Participants.
53. Demonty I., Ras R.T., van der Knaap H.C., et al. Continuous dose-response relationship of the LDL-cholesterol-lowering effect of phytosterol intake. JNutr 2009, 139:271-284.
54. Musa-Veloso K., Poon T.H., Elliot J.A., Chung C. Acomparison of the LDL-cholsterol efficacy of plant stanols and plant sterols over a continuous range: Results of a meta-analysis of randomized, placebo-controlled trials. Prostaglandins Leukot Essent Fatty Acids 2011, 85:9-28.
55. Demonty I., Ras R.T., Trautwein E.A. Comment on: "A comparison of the LDL-cholesterol lowering efficacy of plant stanols and plant sterols over a continuous dose range: results of a meta-analysis of randomized, placebo controlled trials" by Musa-Veloso K, Poon T H, Elliot JA, Chung C. Prostaglandins Leukot Essent Fatty Acids 2011;85:9-28. Prostaglandins Leukot Essent Fatty Acids 2011, 85:7-8.
56. Reiner Z., Catapano A.L., De Backer G., et al. ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J 2011, 32:1769-1818.
57. Williams C.L., Bollella M.C., Strobino B.A., Boccia L., Campanaro L. Plant stanol ester and bran fiber in childhood: effects on lipids, stool weight and stool frequency in preschool children. JAm Coll Nutr 1999, 18:572-581.
58. Tammi A., Rönnemaa T., Miettinen T.A., et al. Effects of gender, apolipoprotein E phenotype and cholesterol-lowering by plant stanol esters in children: The STRIP study. Acta Paediatr 2002, 91:1155-1162.
59. Guardamagna O., Abello F., Baracco V., et al. Primary hyperlipidemias in children: effect of plant sterol supplementation on plasma lipids and markers of cholesterol synthesis and absorption. Acta Diabetol 2011, 48:127-133.
60. Becker M., Staab D., von Bergmann K. Treatment of severe familial hypercholesterolemia in childhood with sitosterol and sitostanol. JPediatr 1993, 122:292-296.
61. Gylling H., Siimes M.A., Miettinen T.A. Sitostanol ester margarine in dietary treatment of children with familial hypercholesterolemia. JLipid Res 1995, 36:1807-1812.
62. Vuorio A.F., Gylling H., Turtola H., Kontula K., Ketonen P., Miettinen T.A. Stanol ester margarine alone and with simvastatin lowers serum cholesterol in families with familial hypercholesterolemia caused by the FH-North Karelia mutation. Arterioscler Thromb Vasc Biol 2000, 20:500-506.
63. Amundsen A.L., Ose L., Nenseter M.S., Ntanios F.Y. Plant sterol ester-enriched spread lowers plasma total and LDL cholesterol in children with familial hypercholesterolemia. Am J Clin Nutr 2002, 76:338-344.
64. de Jongh S., Vissers M.N., Rol P., Bakker H.D., Kastelein J.J., Stroes E.S. Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolemia. JInherit Metab Dis 2003, 26:343-351.
65. Ketomäki A.M., Gylling H., Antikainen M., Siimes M.A., Miettinen T.A. Red cell and plasma plant sterols are related during consumption of plant stanol and sterol ester spreads in children with hypercholesterolemia. JPediatr 2003, 142:524-531.
66. Jakulj L., Vissers M.N., Rodenburg J., Wiegman A., Trip M.D., Kastelein J.J. Plant stanols do not restore endothelial function in prepubertal children with familial hypercholesterolemia despite reduction of low-density lipoprotein cholesterol levels. JPediatr 2006, 148:495-500.
67. Plat J., Mensink R.P. Plant stanol esters lower serum triacylglycerol concentrations via a reduced hepatic VLDL-1 production. Lipids 2009, 44:1149-1153.
68. Sialvera T.E., Pounis G.D., Koutelidakis A.E., et al. Phytosterols supplementation decreases plasma small and dense LDL levels in metabolic syndrome patients on a westernized type diet. Nutr Metab Cardiovasc Dis 2012, 22:843-848.
69. Demonty I., Ras R.T., van der Knaap H.C., et al. The effect of plant sterols on serum triglyceride concentrations is dependent on baseline concentrations: a pooled analysis of 12 randomised controlled trials. Eur J Nutr 2013, 52:153-160.
70. Naumann E., Plat J., Kester A.D.M., Mensink R.P. The baseline serum lipoprotein profile is related to plant stanol induced changes in serum lipoprotein cholesterol and triacylglycerol concentrations. JAm Coll Nutr 2008, 27:117-126.
71. Gylling H., Miettinen T.A. Serum cholesterol and cholesterol and lipoprotein metabolism in hypercholesterolaemic NIDDM patients before and during sitostanol ester-margarine treatment. Diabetologia 1994, 37:773-780.
72. Plat J., Mensink R.P. Vegetable oil based versus wood based stanol ester mixtures: effects on serum lipids and hemostatic factors in non-hypercholesterolemic subjects. Atherosclerosis 2000, 148:101-112.
73. Mayne J., Dewpura T., Raymond A., et al. Plasma PCSK9 levels are significantly modified by statins and fibrates in humans. Lipids Health Dis 2008, 7:22.
74. Kritchevsky D., Chen S.C. Phytosterols - health benefits and potential concerns: a review. JNutr Res 2005, 25:413-428.
75. Plat J., Beugels I., Gijbels M.J., de Winther M.P., Mensink R.P. Plant sterol or stanol esters retard lesion formation in LDL receptor-deficient mice independent of changes in serum plant sterols. JLipid Res 2006, 47:2762-2771.
76. Weingärtner O., Ulrich C., Lutjohann D., et al. Differential effects on inhibition of cholesterol absorption by plant stanol and plant sterol esters in apoE-/- mice. Cardiovasc Res 2011, 90:484-492.
77. Hovenkamp E., Lourbakos A., Duchateau G.S., Tareilus E.W., Trautwein E.A. Preferential efflux of phytosterols over cholesterol from macrophages. Lipids 2007, 42:1125-1132.
78. Bao L., Li Y., Deng S.X., Landry D., Tabas I. Sitosterol-containing lipoproteins trigger free sterol-induced caspase-independent death in ACAT-competent macrophages. JBiol Chem 2006, 281:33635-33649.
79. Tabas I., Feinmark S.J., Beatini N. The reactivity of desmosterol and other shellfish- and xanthomatosis-associated sterols in the macrophage sterol esterification reaction. JClin Invest 1989, 84:1713-1721.
80. Plat J., Nichols J.A., Mensink R.P. Plant sterols and stanols: effects on mixed micellar composition and LXR (target gene) activation. JLipid Res 2005, 46:2468-2476.
81. Brauner R., Johannes C., Ploessl F., Bracher F., Lorenz R.L. Phytosterols reduce cholesterol absorption by inhibition of 27-hydroxycholesterol generation, liver X receptor α activation, and expression of the basolateral sterol exporter ATP-binding cassette A1 in Caco-2 enterocytes. JNutr 2012, 142:981-989.
82. Kaneko E., Matsuda M., Yamada Y., Tachibana Y., Shimomura I., Makishima M. Induction of intestinal ATP-binding cassette transporters by a phytosterol-derived liver X receptor agonist. JBiol Chem 2003, 278:36091-36098.
83. Yang C., Yu L., Li W., Xu F., Cohen J.C., Hobbs H.H. Disruption of cholesterol homeostasis by plant sterols. JClin Invest 2004, 114:813-822.
84. Sabeva N.S., McPhaul C.M., Li X., Cory T.J., Feola D.J., Graf G.A. Phytosterols differentially influence ABC transporter expression, cholesterol efflux and inflammatory cytokine secretion in macrophage foam cells. JNutr Biochem 2011, 22:777-783.
85. Calpe-Berdiel L., Escolá-Gil J.C., Blanco-Vaca F. Are LXR-regulated genes a major molecular target of plant sterols/stanols?. Atherosclerosis 2007, 195:210-211.
86. Joseph S.B., Castrillo A., Laffitte B.A., Mangelsdorf D.J., Tontonoz P. Reciprocal regulation of inflammation and lipid metabolism by liver X receptors. Nat Med 2003, 9:213-219.
87. Spann N.J., Garmire L.X., McDonald J.G., et al. Regulated accumulation of desmosterol integrates macrophage lipid metabolism and inflammatory responses. Cell 2012, 151:138-152.
88. Bouic P.J., Lamprecht J.H. Plant sterols and sterolins: a review of their immune-modulating properties. Altern Med Rev 1999, 4:170-177.
89. Ding Y., Nguyen H.T., Kim S.I., Kim H.W., Kim Y.H. The regulation of inflammatory cytokine secretion in macrophage cell line by the chemical constituents of Rhus sylvestris. Bioorg Med Chem Lett 2009, 19:3607-3610.
90. Alappat L., Valerio M., Awad A.B. Effect of vitamin D and β-sitosterol on immune function of macrophages. Int Immunopharmacol 2010, 10:1390-1396.
91. Kurano M., Iso O.N., Hara M., et al. Plant sterols increased IL-6 and TNF-α secretion from macrophages, but to a lesser extent than cholesterol. JAtheroscler Thromb 2011, 18:373-383.
92. Brüll F., Mensink R.P., van den Hurk K., Duijvestijn A., Plat J. TLR2 activation is essential to induce a Th1 shift in human peripheral blood mononuclear cells by plant stanols and plant sterols. JBiol Chem 2010, 285:2951-2958.
93. Moreno J.J. Effect of olive oil minor components on oxidative stress and arachidonic acid mobilization and metabolism by macrophages RAW 264.7. Free Radic Biol Med 2003, 35:1073-1081.
94. Vivancos M., Moreno J.J. Beta-sitosterol modulates antioxidant enzyme response in RAW 264.7 macrophages. Free Radic Biol Med 2005, 39:91-97.
95. Vivancos M., Moreno J.J. Effect of resveratrol, tyrosol and beta-sitosterol on oxidised low-density lipoprotein-stimulated oxidative stress, arachidonic acid release and prostaglandin E2 synthesis by RAW 264.7 macrophages. Br J Nutr 2008, 99:1199-1207.
96. Awad A.B., Toczek J., Fink C.S. Phytosterols decrease prostaglandin release in cultured P388D1/MAB macrophages. Prostaglandins Leukot Essent Fatty Acids 2004, 70:511-520.
97. Tedgui A., Mallat Z. Cytokines in atherosclerosis: pathogenic and regulatory pathways. Physiol Rev 2006, 86:515-581.
98. Raitakari O.T., Salo P., Gylling H., Miettinen T.A. Plant stanol ester consumption and arterial elasticity and endothelial function. Br J Nutr 2008, 100:603-608.
99. Gylling H., Hallikainen M., Raitakari O.T., et al. Long-term consumption of plant stanol and sterol esters, vascular function and genetic regulation. Br J Nutr 2009, 101:1688-1695.
100. Hallikainen M., Lyyra-Laitinen T., Laitinen T., et al. Endothelial function in hypercholesterolemic subjects: effects of plant stanol and sterol esters. Atherosclerosis 2006, 188:425-432.
101. Hallikainen M., Lyyra-Laitinen T., Laitinen T., Moilanen L., Miettinen T.A., Gylling H. Effects of plant stanol esters on serum cholesterol concentrations, relative markers of cholesterol metabolism and endothelial function in type 1 diabetes. Atherosclerosis 2008, 199:432-439.
102. Gylling H., Halonen J., Lindholm H., et al. The effects of plant stanol ester consumption on arterial stiffness and endothelial function in adults: a randomised controlled clinical trial. BMC Cardiovasc Disord 2013, 13:50.
103. Raitakari O.T., Salo P., Ahotupa M. Carotid artery compliance in users of plant stanol ester margarine. Eur J Clin Nutr 2008, 62:218-224.
104. Wang J.J., Liew G., Wong T.Y., et al. Retinal vascular calibre and the risk of coronary heart disease-related death. Heart 2006, 92:1583-1587.
105. Kelly E.R., Plat J., Mensink R.P., Berendschot T.T.J.M. Effects of long term plant sterol and -stanol consumption on the retinal vasculature: a randomized controlled trial in statin users. Atherosclerosis 2011, 214:225-230.
106. Kozłowska-Wojciechowska M., Jastrzebska M., Naruszewicz M., Foltyńska A. Impact of margarine enriched with plant sterols on blood lipids, platelet function, and fibrinogen level in young men. Metabolism 2003, 52:1373-1378.
107. De Jong A., Plat J., Bast A., Godschalk R.W., Basu S., Mensink R.P. Effects of plant sterol and stanol ester consumption on lipid metabolism, antioxidant status and markers of oxidative stress, endothelial function and low-grade inflammation in patients on current statin treatment. Eur J Clin Nutr 2008, 62:263-273.
108. Othman R.A., Moghadasian M.H. Beyond cholesterol-lowering effects of plant sterols: clinical and experimental evidence of anti-inflammatory properties. Nutr Rev 2011, 69:371-382.
109. Sudhop T., Gottwald B.M., von Bergmann K. Serum plant sterols as a potential risk factor for coronary heart disease. Metabolism 2002, 51:1519-1521.
110. Assmann G., Cullen P., Erbey J., Ramey D.R., Kannenberg F., Schulte H. Plasma sitosterol elevations are associated with an increased incidence of coronary events in men: results of a nested case-control analysis of the Prospective Cardiovascular Münster (PROCAM) study. Nutr Metab Cardiovasc Dis 2006, 16:13-21.
111. Pinedo S., Vissers M.N., von Bergmann K., et al. Plasma levels of plant sterols and the risk of coronary artery disease: the prospective EPIC-Norfolk Population Study. JLipid Res 2007, 48:139-144.
112. Windler E., Zyriax B.C., Kuipers F., Linseisen J., Boeing H. Association of plasma phytosterol concentrations with incident coronary heart disease Data from the CORA study, a case-control study of coronary artery disease in women. Atherosclerosis 2009, 203:284-290.
113. Escurriol V., Cofán M., Moreno-Iribas C., et al. Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort. JLipid Res 2010, 51:618-624.
114. Genser B., Silbernagel G., De Backer G., et al. Plant sterols and cardiovascular disease: a systematic review and meta-analysis. Eur Heart J 2012, 33:444-451.
115. Tilvis R.S., Valvanne J.N., Strandberg T.E., Miettinen T.A. Prognostic significance of serum cholesterol, lathosterol, and sitosterol in old age; a 17-year population study. Ann Med 2011, 43:292-301.
116. Weingärtner O., Pinsdorf T., Rogacev K.S., et al. The relationships of markers of cholesterol homeostasis with carotid intima-media thickness. PLoS ONE 2010, 5:e13467.
117. Weingärtner O., Lütjohann D., Vanmierlo T., et al. Markers of enhanced cholesterol absorption are a strong predictor for cardiovascular diseases in patients without diabetes mellitus. Chem Phys Lipids 2011, 164:451-456.
118. Fukushima M., Miura S., Mitsutake R., Fukushima T., Fukushima K., Saku K. Cholesterol metabolism in patients with hemodialysis in the presence or absence of coronary artery disease. Circ J 2012, 76:1980-1986.
119. Large-scale gene-centric analysis identifies novel variants for coronary artery disease. PLoS Genet 2011, 7:e1002260. IBC 50K CAD Consortium.
120. Reilly M.P., Li M., He J., et al. Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies. Lancet 2011, 377:383-392. Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control ConsortiumWellcome Trust Case Control Consortium.
121. Schunkert H., König I.R., Kathiresan S., et al. Large scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nat Genet 2011, 43:333-338. CARDIoGRAM Consortium.
122. Deloukas P., Kanoni S., Willenborg C. Large-scale association analysis identifies new risk loci for coronary artery disease. Nat Genet 2013, 45:25-33. CARDIoGRAMplusC4D Consortium, DIAGRAM ConsortiumDIAGRAM Consortium, CARDIOGENICS ConsortiumCARDIOGENICS Consortium, MuTHER ConsortiumMuTHER Consortium, Wellcome Trust Case Control ConsortiumWellcome Trust Case Control Consortium.
123. Strandberg T.E., Tilvis R.S., Pitkala K.H., Miettinen T.A. Cholesterol and glucose metabolism and recurrent cardiovascular events among the elderly: a prospective study. JAm Coll Cardiol 2006, 48:708-714.
124. Silbernagel G., Fauler G., Renner W., et al. The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease. JLipid Res 2009, 50:334-341.
125. Matthan N.R., Pencina M., LaRocque J.M., et al. Alterations in cholesterol absorption/synthesis markers characterize Framingham offspring study participants with CHD. JLipid Res 2009, 50:1927-1935.
126. Silbernagel G., Fauler G., Hoffmann M.M., et al. The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality. JLipid Res 2010, 51:2384-2393.
127. Smith N.L., Chen M.H., Dehghan A., et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: the CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation 2010, 121:1382-1392. Wellcome Trust Case Control Consortium.
128. Kiechl S., Paré G., Barbalic M., et al. Association of variation at the ABO locus with circulating levels of soluble intercellular adhesion molecule-1, soluble P-selectin, and soluble E-selectin: a meta-analysis. Circ Cardiovasc Genet 2011, 4:681-686.
129. Karakas M., Baumert J., Kleber M.E., et al. Avariant in the abo gene explains the variation in soluble e-selectin levels-results from dense genotyping in two independent populations. PLoS ONE 2012, 7:e51441.
130. Fassbender K., Lütjohann D., Dik M.G., et al. Moderately elevated plant sterol levels are associated with reduced cardiovascular risk-the LASA study. Atherosclerosis 2008, 196:283-288.
131. Buchwald H., Varco R.L., Boen J.R., et al. Effective lipid modification by partial ileal bypass reduced long-term coronary heart disease mortality and morbidity: five-year posttrial follow-up report from the POSCH. Program on the Surgical Control of the Hyperlipidemias. Arch Intern Med 1998, 158:1253-1261.
132. Brown L., Rosner B., Willett W.W., Sacks F.M. Cholesterol-lowering effects of dietary fiber: a meta-analysis. Am J Clin Nutr 1999, 69:30-42.
133. Pereira M.A., O'Reilly E., Augustsson K., et al. Dietary fiber and risk of coronary heart disease: a pooled analysis of cohort studies. Arch Intern Med 2004, 164:370-376.
134. Willems J.I., Blommaert M.A.E., Trautwein E.A. Results from a post-launch monitoring survey on consumer purchases of foods with added phytosterols in five European countries. Food Chem Toxicol 2013, 62:48-53.
135. Lea L.J., Hepburn P.A. Safety evaluation of phytosterol-esters. Part 9: Results of a European post-launch monitoring programme. Food Chem Toxicol 2006, 44:1213-1222.
136. EFSA Panel on Food Additives and Nutrient Sources added to Food (ANS) Scientific opinion on the safety of stigmasterol-rich plant sterols as food additive. EFSA J 2012, 10:2659.
137. Hendriks H.F., Brink E.J., Meijer G.W., Princen H.M., Ntanios F.Y. Safety of long-term consumption of plant sterol esters-enriched spread. Eur J Clin Nutr 2003, 57:681-692.
138. de Jong A., Plat J., Lütjohann D., Mensink R.P. Effects of long-term plant sterol or stanol ester consumption on lipid and lipoprotein metabolism in subjects on statin treatment. Br J Nutr 2008, 100:937-941.
139. Noakes M., Clifton P., Ntanios F., Shrapnel W., Record I., McInerney J. An increase in dietary carotenoids when consuming plant sterols or stanols is effective in maintaining plasma carotenoid concentrations. Am J Clin Nutr 2002, 75:79-86.
140. Tuomilehto J., Tikkanen M.J., Högström P., et al. Safety assessment of common foods enriched with natural nonesterified plant sterols. Eur J Clin Nutr 2009, 63:684-691.
141. Plat J., Mensink R.P. Effects of diets enriched with two different plant stanol ester mixtures on plasma ubiquinol-10 and fat-soluble antioxidant concentrations. Metabolism 2001, 50:520-529.
142. Baskar A.A., Ignacimuthu S., Paulraj G.M., Al Numair K.S. Chemopreventive potential of beta-sitosterol in experimental colon cancer model - an invitro and invivo study. BMC Compl Altern Med 2010, 10:24.
143. Lea L.J., Hepburn P.A., Wolfreys A.M., Baldrick P. Safety evaluation of phytosterol esters. Part 8. Lack of genotoxicity and subchronic toxicity with phytosterol oxides. Food Chem Toxicol 2004, 42:771-783.
144. Wolfreys A.M., Hepburn P.A. Safety evaluation of phytosterol esters. Part 7. Assessment of mutagenic activity of phytosterols, phytosterol esters and the cholesterol derivative, 4-cholesten-3-one. Food Chem Toxicol 2002, 40:461-470.
145. Woyengo T.A., Ramprasath V.R., Jones P.J. Anticancer effects of phytosterols. Eur J Clin Nutr 2009, 63:813-820.
146. De Stefani E., Boffetta P., Ronco A.L., et al. Plant sterols and risk of stomach cancer: a case-control study in Uruguay. Nutr Cancer 2000, 37:140-144.
147. Mendilaharsu M., De Stefani E., Deneo-Pellegrini H., Carzoglio J., Ronco A. Phytosterols and risk of lung cancer: a case-control study in Uruguay. Lung Cancer 1998, 21:37-45.
148. Blair S.N., Capuzzi D.M., Gottlieb S.O., Nguyen T., Morgan J.M., Cater N.B. Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy. Am J Cardiol 2000, 86:46-52.
149. Neil H.A., Meijer G.W., Roe L.S. Randomised controlled trial of use by hypercholesterolaemic patients of a vegetable oil sterol-enriched fat spread. Atherosclerosis 2001, 156:329-337.
150. Castro Cabezas M., de Vries J.H., Van Oostrom A.J., Iestra J., van Staveren W.A. Effects of a stanol-enriched diet on plasma cholesterol and triglycerides in patients treated with statins. JAm Diet Assoc 2006, 106:1564-1569.
151. Simons L.A. Additive effect of plant sterol-ester margarine and cerivastatin in lowering low-density lipoprotein cholesterol in primary hypercholesterolemia. Am J Cardiol 2002, 90:737-740.
152. Gylling H., Miettinen T.A. Effects of inhibiting cholesterol absorption and synthesis on cholesterol and lipoprotein metabolism in hypercholesterolemic non-insulin-dependent diabetic men. JLipid Res 1996, 37:1776-1785.
153. Lin X., Racette S.B., Lefevre M., et al. Combined effects of ezetimibe and phytosterols on cholesterol metabolism: a randomized, controlled feeding study in humans. Circulation 2011, 124:596-601.
154. Becker M., Staab D., Von Bergman K. Long-term treatment of severe familial hypercholesterolemia in children: effect of sitosterol and bezafibrate. Pediatrics 1992, 89:138-142.
155. Nigon F., Serfaty-Lacrosnière C., Beucler I., et al. Plant sterol-enriched margarine lowers plasma LDL in hyperlipidemic subjects with low cholesterol intake: effect of fibrate treatment. Clin Chem Lab Med 2001, 39:634-640.
156. Micallef M.A., Garg M.L. Beyond blood lipids: phytosterols, statins and omega-3 polyunsaturated fatty acid therapy for hyperlipidemia. JNutr Biochem 2009, 20:927-939.
157. O'Neill F.H., Brynes A., Mandeno R., et al. Comparison of the effects of dietary plant sterol and stanol esters on lipid metabolism. Nutr Metab Cardiovasc Dis 2004, 14:133-142.
158. Relas H., Gylling H., Miettinen T.A. Effect of stanol ester on postabsorptive squalene and retinyl palmitate. Metabolism 2000, 49:473-478.
159. Gylling H., Hallikainen M., Simonen P., Miettinen H.E., Nissinen M.J., Miettinen T.A. Serum and lipoprotein sitostanol and non-cholesterol sterols after an acute dose of plant stanol ester on its long-term consumption. Eur J Nutr 2012, 56:663-670.
160. Demonty I., Chan Y.M., Pelled D., Jones P.J. Fish-oil esters of plant sterols improve the lipid profile of dyslipidemic subjects more than do fish-oil or sunflower oil esters of plant sterols. Am J Clin Nutr 2006, 84:1534-1542.
161. Darmon N., Drewnowski A. Does social class predict diet quality?. Am J Clin Nutr 2008, 87:1107-1117.
162. Bonaccio M., Bonanni A.E., Di Castelnuovo A., et al. Low income is associated with poor adherence to a Mediterranean diet and a higher prevalence of obesity: cross-sectional results from the Moli-sani study. BMJ Open 2012, 2:e001685. 10.1136/bmjopen-2012-001685.
163. European Food Safety Authority Areport from the data collection and exposure unit in response to a request from the European Commission. EFSA J 2008, 133:1-21. [accessed 04.07.13]. http://www.efsa.europa.eu/en/scdocs/doc/datex_report_ej133_phytosterols_en.pdf.
164. Bes-Rastrollo M. Costs of Mediterranean and Western dietary patterns and their relationship with prospective weight change. EuroPRevent 2013, [abstract 610].