Nutrition Research
Volume 25, Issue 5 , Pages 413-428 , May 2005

Phytosterols—health benefits and potential concerns: a review

  • David Kritchevsky

      Affiliations

    • The Wistar Institute, Philadelphia, PA 19104, USA
    • Corresponding Author InformationCorresponding author. Tel.: +1 215 898 3713; fax: +1 215 898 3995.
  • ,
  • Shirley C. Chen

      Affiliations

    • Ellicott City, MD 21042, USA

Received 13 October 2004 ,Revised 23 February 2005 ,Accepted 28 February 2005.

References 

  1. Bean GA. Phytosterols. Adv Lipid Res. 1973;11:193–218
  2. Moreau RA, Whitaker BD, Hicks KB. Phytosterols, phytostanols, and their conjugates in foods: structural diversity, quantitative analysis and health-promoting uses. Prog Lipid Res. 2002;41:457–500
  3. Weihrauch JL, Gardner JM. Sterol content of foods of plant origin. J Am Diet Assoc. 1978;73:39–47
  4. Itoh T, Tamura T, Matsumoto T. Sterol composition of 19 vegetable oils. J Am Oil Chem Soc. 1973;50:122–125
  5. Piironen V, Lindsay DG, Miettinen TA, et al. Plant sterols: biosynthesis, biological function and their importance to human nutrition. J Sci Food Agric. 2000;80:939–966
  6. Ellis GW, Gardner JA. The origin and destiny of cholesterol in the organism VIII. On the cholesterol content of the liver of rabbits under various diets and during inanition. Proc R Soc Lond. 1912;B84:461–470
  7. Schönheimer R. New contributions in sterol metabolism. Science. 1931;74:579–584
  8. Pollak OJ, Kritchevsky D. Sitosterol. Basel: S. Karger; 1981;
  9. Salen G, Ahrens EH, Grundy SM. Metabolism of beta-sitosterol in man. J Clin Invest. 1949;49:952–967
  10. Ostlund RE, McGill JB, Zeng C-M, et al. Gastrointestinal absorption and plasma kinetics of soy δ-5-phytosterols and phytostanols in humans. Am J Physiol Endocrinol Metab. 2002;282:E911–E916
  11. Kritchevsky D, Werthessen NT, Shapiro IL, et al. Transfer of radioactivity of cholesterol-7-α-3H to fatty acids in tissue lipids in vivo. Nature. 1965;207:194–195
  12. Boberg KM, Einarsson K, Bjorkhem I. Apparent lack of conversion of sitosterol into C24 bile acids in humans. J Lipid Res. 1990;31:1083–1088
  13. Kritchevsky D, Davidson LM, Mosbach EM, et al. Identification of acidic steroids in feces of monkeys fed β-sitosterol. Lipids. 1981;16:77–78
  14. Boberg KM, Lund E, Olund J, et al. Formation of C21 bile acids from plant sterols in the rat. J Biol Chem. 1990;265:7967–7975
  15. Subbiah MTR, Kuksis A. Differences in metabolism of cholesterol and sitosterol following intravenous injection in rats. Biochim Biophys Acta. 1973;306:95–105
  16. Peterson DW. Effect of soybean sterols in the diet on plasma and liver cholesterol in chicks. Proc Soc Exp Biol Med. 1951;78:143–147
  17. Peterson DW, Nichols CW, Shneour EA. Some relationships among dietary sterols, plasma and liver cholesterol levels, and atherosclerosis in chicks. J Nutr. 1952;47:57–65
  18. Peterson DW, Shneour EA, Peek NF, et al. Dietary constituents affecting plasma and liver cholesterol in cholesterol-fed chicks. J Nutr. 1953;50:191–201
  19. Pollak OJ. Reduction of blood cholesterol in man. Circulation. 1953;7:702–706
  20. Ahrens EH, Hirsch J, Insull W, et al. The influence of dietary fats on serum lipid levels in man. Lancet. 1957;i:943–953
  21. Ahrens EH, Hirsch J, Insull W, et al. Dietary control of serum lipids in relation to atherosclerosis. JAMA. 1957;164:1905–1911
  22. Engelberg H. Studies of serum cholesterol and low density lipoproteins, previously lowered by a reduced fat intake, after the addition of corn oil to the diet. J Chronic Dis. 1957;6:229–233
  23. Beveridge JMR, Connell WF, Mayer GA, et al. The effect of certain vegetable and animal fats on the plasma lipids of humans. J Nutr. 1955;56:311–320
  24. Beveridge JMR, Connell WF, Mayer GA. Dietary factors affecting the level of plasma cholesterol in humans: the role of fat. Can J Biochem Physiol. 1956;34:441–455
  25. Beveridge JMR, Connell WF, Mayer GA, et al. Plant sterols, degree of unsaturation, and hypocholesterolemic action of certain fats. Can J Biochem Physiol. 1958;36:895–911
  26. Ostlund RE, Racette SB, Okeke A, et al. Phytosterols that are naturally present in commercial corn oil significantly reduce cholesterol absorption in humans. Am J Clin Nutr. 2002;75:1000–1004
  27. Howell TJ, MacDougall DE, Jones PJH. Phytosterols partially explain differences in cholesterol metabolism caused by corn or olive oil feeding. J Lipid Res. 1998;39:892–900
  28. Peterson DW, Nichols CW, Peek NF, et al. Depression of plasma cholesterol in human subjects consuming butter containing soy sterols. Fed Proc. 1956;65–69
  29. Miettinen TA, Puska P, Gylling H, et al. Reduction of serum cholesterol with sitostanol-ester margarine in a mildly hypercholesterolemic population. N Engl J Med. 1995;333:1308–1312
  30. Weststrate JA, Meijer GW. Plant sterol enriched margarines and reduction of plasma total- and LDL-cholesterol concentrations in normocholesterolemic and mildly hypercholesterolemic subjects. Eur J Clin Nutr. 1998;52:334–343
  31. Plat J, Mensink RP. 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
  32. Hallikainen MA, Sarkkinen ES, Gylling H, et al. Comparison of the effects of plant sterol ester and plant stanol ester–enriched margarines in lowering serum cholesterol concentrations in hypercholesterolaemic subjects on a low fat diet. Eur J Clin Nutr. 2000;54:715–725
  33. Vanstone CA, Raeini-Sarjaz M, Parsons WE, et al. Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons. Am J Clin Nutr. 2002;76:1271–1278
  34. Duncan DH, Best MM. Comparative effects of free and esterified sitosterol on serum and liver cholesterol in rats. J Clin Invest. 1956;35:700–709
  35. Mattson FH, Grundy SM, Crouse JR. Optimizing the effect of plant sterols on cholesterol absorption in man. Am J Clin Nutr. 1982;35:696–700
  36. Normén L, Frohlich J, Trautwein E. Role of plant sterols in cholesterol lowering. In:  Dutta PC editors. Phytosterols as functional food components and nutraceuticals. New York: Marcel Dekker, Inc; 2004;p. 243–315
  37. Katan MB, Grundy SM, Jones P, et al. Efficacy and safety of plant stanols and sterols in the management of blood cholesterol levels. Mayo Clin Proc. 2003;78:965–978
  38. Pollak OJ. Effect of plant sterols on serum lipids and atherosclerosis. Pharmacol Ther. 1985;31:177–208
  39. Shipley RE, Pfieffer RR, Marsh MM, et al. Sitosterol feeding: chronic animal and clinical toxicity and tissue analysis. Circ Res. 1958;6:373–382
  40. Baker VA, Hepburn PA, Kennedy SJ, et al. Safety evaluation of sitosterol esters. Part 1. Assessment of oestrogenicity using a combination of in vivo and in vitro assays. Food Chem Toxicol. 1999;37:13–22
  41. Hepburn PA, Horner SA, Smith M. Safety evaluation of phytosterol esters. Part 2. Subchronic 90-day oral toxicity study on phytosterol esters—a novel functional food. Food Chem Toxicol. 1999;37:521–532
  42. Waalkens-Berendsen HD, Wolterbeek APM, Wijnands MVW, et al. Safety evaluation of phytosterol esters. Part 3. Two-generation reproduction study in rats with phytosterol esters—a novel functional food. Food Chem Toxicol. 1999;37:683–696
  43. Weststrate JA, Ayesh R, Bauer-Plank C, et al. Safety evaluation of phytosterol esters. Part 4. Faecal concentrations of bile acids and neutral sterols in healthy normolipaedemic volunteers consuming a controlled diet either with or without a phytosterol ester–enriched margarine. Food Chem Toxicol. 1999;37:1063–1071
  44. Ayesh R, Weststrate JA, Drewitt PN, et al. Safety evaluation of phytosterol esters. Part 5. Faecal short-chain fatty acid and microflora content, faecal bacterial enzyme activity and serum female sex hormones in healthy normolipaedemic volunteers consuming a controlled diet either with or without a phytosterol ester–enriched margarine. Food Chem Toxicol. 1999;37:1127–1138
  45. Sanders DJ, Minter HJ, Hower D, et al. The safety evaluation of phytosterol esterol. Part 6. The comparative absorption and tissue distribution of phytosterols in the rat. Food Chem Toxicol. 2000;38:485–491
  46. Wolfreys AM, Hepburn PA. 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
  47. Lea LJ, Hepburn PA, Wolfreys AM, et al. Safety evaluation of phytosterol esters. Part 8. Lack of genotoxicity and subchronic toxicity with phytosterol oxides. Food Chem Toxicol. 2004;42:771–783
  48. Whittaker MH, Frankos VH, Wolterbeek APM, et al. Two-generation reproductive toxicity study of plant stanol esters in rats. Regul Toxicol Pharmacol. 1999;29:196–204
  49. Turnbull D, Frankos VH, van Delft JHM, et al. Genotoxicity evaluation of wood-derived and vegetable oil–derived stanol esters. Regul Toxicol Pharmacol. 1999;29:205–210
  50. Turnbull D, Whittaker MH, Frankos VH, et al. 13-Week oral toxicity study with stanol esters in rats. Regul Toxicol Pharmacol. 1999;29:216–226
  51. Slesinski RS, Turnbull D, Frankos VH, et al. Developmental toxicity study of vegetable oil–derived stanol fatty acid esters. Regul Toxicol Pharmacol. 1999;29:227–233
  52. Malini T, Vanithakumari G. Rat toxicity studies with β sitosterol. J Ethnopharmacol. 1990;28:221–234
  53. Richelle M, Enslen M, Hager C, et al. Both free and esterified plant sterols reduce cholesterol absorption and the bioavailability of β-carotene and β-tocopherol in normocholesterolemic humans. Am J Clin Nutr. 2004;171–177
  54. Hallikainen MA, Uusitupa MIJ. Effects of 2 low-fat stanol-esterol containing margarines on serum cholesterol concentrations as part of a low fat diet in hypercholesterolemic subjects. Am J Clin Nutr. 1999;403–410
  55. Maki C, Davidson MH, Umporowicz DM, et al. Lipid responses to plant-sterol–enriched reduced-fat spreads incorporated into a National Cholesterol Education Program Step 1 diet. Am J Clin Nutr. 2001;74:33–43
  56. Nestel P, Cehun M, Pomeroy S, et al. Cholesterol-lowering effects of plant sterol esters and non-esterified stanols in margarine, butter and low fat foods. Eur J Clin Nutr. 2001;55:1084–1090
  57. Hendricks HFJ, Weststrate JA, van Vliet T, et al. Spreads enriched with three different levels of vegetable oil sterols and the degree of cholesterol lowering in normocholesterolaemic and mildly hypercholesterolaemic subjects. Eur J Clin Nutr. 1999;53:319–327
  58. Judd JT, Baer DJ, Chen SC, et al. Plant sterol esters lower plasma lipids and most carotenoids in mildly hypercholesterolemic adults. Lipids. 2002;37:33–42
  59. Ntanios F, Homma Y, Ushiro S. A spread enriched with plant sterol-esters lowers blood cholesterol and lipoproteins without affecting vitamins A and E in normal and hypercholesterolemic Japanese men and women. J Nutr. 2002;132:3650–3655
  60. Amundsen AL, Ose L, Nenseter MS, et al. Plant sterol ester–enriched spread lowers plasma total and LDL cholesterol in children with familial hypercholesterolemia. Am J Clin Nutr. 2002;76:338–344
  61. Noakes M, Clifton P, Ntanios F, et al. 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
  62. Lipid Research Clinics Program . The Lipid Research Clinics Coronary Primary Prevention Trial results. I. Reduction in incidence of coronary heart disease. JAMA. 1984;251:351–364
  63. Bhattacharyya AK, Connor WE. Beta sitosterolemia and xanthomatosis. A newly described lipid storage disease in two sisters. J Clin Invest. 1974;53:1033–1043
  64. Salen G, Shefer S, Nguygen L, et al. Sitosterolemia. J Lipid Res. 1992;33:945–955
  65. Sehayek E. Genetic regulation of cholesterol absorption and plasma plant sterol levels: commonalities and differences. J Lipid Res. 2003;44:2030–2034
  66. Berger GMB, Pegoraro RJ, Patel SA, et al. HMG-CoA reductase is not the site of the primary defect in phytosterolemia. J Lipid Res. 1998;39:1046–1054
  67. Lee MH, Lu K, Patel SB. Genetic basis of sitosterolemia. Curr Opin Lipidol. 2001;12:141–149
  68. Stalenhoef AFH, Hectors M, Demacker PNM. Effect of plant sterol–enriched margarine on plasma lipids and sterols in subjects heterozygous for phytosterolaemia. J Int Med. 2001;249:163–166
  69. Kwiterovich PO, Chen SC, Virgil DG, et al. Response of obligate heterozygotes for phytosterolemia to a low-fat diet and to a plant sterol esterol dietary challenge. J Lipid Res. 2003;44:1143–1155
  70. Lees RS, Lees AM. Effect of sitosterol therapy on plasma lipid and lipoprotein concentration. In:  Greten H editors. Lipoprotein metabolism. Berlin: Springer Verlag; 1976;p. 119–124
  71. Lees AM, Mok HYI, Lees RS, et al. Plant sterols as cholesterol lowering agents: clinical trials in patients with hypercholesterolemia and studies of sterol balance. Atherosclerosis. 1977;28:325–338
  72. Glueck CJ, Speirs J, Tracy T, et al. Relationship of serum plant sterols (phytosterol) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hypercholesterolemic probands and their first degree relatives. Metabolism. 1991;40:842–848
  73. Glueck CJ, Streicher P, Illig E. Serum and dietary phytosterols, cholesterol and coronary heart disease in hypercholesterolemic probands. Clin Biochem. 1992;25:331–334
  74. Heinemann T, Axtmann G, von Bergmann K. Comparison of intestinal absorption of cholesterol with different plant sterols in man. Eur J Clin Invest. 1993;23:827–831
  75. Hendricks HFJ, Brink EJ, Meijer GW, et al. Safety of long-term consumption of plant sterol esters–enriched spread. Eur J Clin Nutr. 2003;57:681–692
  76. Sudhop T, Gottwald BM, von Bergmann K. Serum plant sterols as a potential risk factor for coronary heart disease. Metabolism. 2002;51:1519–1521
  77. Rajaratnam RA, Gylling H, Miettinen TA. Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol. 2000;35:1185–1191
  78. Sutherland WHF, Williams MJA, Trye ER, et al. Association of plasma noncholesterol sterol levels with severity of CAD. Nutr Metab Cardiovasc Dis. 1998;8:386–391
  79. Sarkkinen ES, Uusitupa MIJ, Gylling H, et al. Fat-modified diets influence serum concentrations of cholesterol precursors and plant sterols in hypercholesterolemic subjects. Metabolism. 1998;47:744–750
  80. Dyer RG, Stewart MW, Game FL, et al. Phytosterols and lipoprotein composition of patients with non-insulin dependent diabetes and patients with peripheral vascular disease. Diabetes Nutr Metab. 1995;8:234–24181
  81. Neil HAW, Meijer GW, Roe LS. Randomized control trial of use by hypercholesterolaemic patients of a vegetable oil sterol–enriched fat spread. Atherosclerosis. 2001;156:329–337
  82. Hendriks HFJ, Brink EJ, Meijer GW, et al. Safety of long term consumption of plant sterol esters–enriched spread. Eur J Clin Nutr. 2003;57:681–692
  83. Jones PJ, Raeini-Sarjaz M, Ntanios F, et al. Modulation of plasma lipid levels and cholesterol kinetics by phytosterol versus phytostanol esters. J Lipid Res. 2000;41:697–705
  84. Mussner MJ, Parhofer KG, von Bergmann K, et al. Effects of phytosterol ester–enriched margarine on plasma lipoproteins in mild to moderate hypocholesterolemia are related to both cholesterol and fat intakes. Metabolism. 2002;51:189–194
  85. Amundsen AL, Ntanios F, van der Put N, et al. Long-term compliance and changes in plasma lipids, plant sterols and carotenoids in children and parents with FH consuming plant sterol ester–enriched spread. Eur J Clin Nutr. 2004;[Advanced online publication 16. June 2004]
  86. de Graaf J, de Sauvage-Nolting PRW, van Dam M, et al. Consumption of tall oil–derived phytosterols in a chocolate matrix significantly decreases plasma total and low density lipoprotein levels. Br J Nutr. 2002;88:479–488
  87. Christiansen LI, Laheetnmaki PLA, Mannelien MR, et al. Cholesterol-lowering effect of spreads enriched with microcrystalline plant sterols in hypercholesterolemic subjects. Eur J Nutr. 2001;40:66–73
  88. Brooks CJW, Steel G, Gilbert JD, et al. Lipids of human atheroma. Part 4. Characterization of a new group of polar sterol esters from human atherosclerotic plaques. Atherosclerosis. 1971;13:223–237
  89. Hodes HN, Crawford DW, Sevanian A. Cholesterol feeding increases plasma and aortic tissue cholesterol oxide levels in parallel: further evidence for the role of cholesterol oxidation in atherosclerosis. Atherosclerosis. 1991;89:117–126
  90. Vaya J, Aviram M, Mahmood S, et al. Selective distribution of oxysterols in atherosclerotic lesions and human plasma lipoproteins. Free Radic Res. 2001;34:485–497
  91. Kritchevsky D, Fumagalli R, Cattabeni F, et al. Effect of triparanol on sterol composition in normal and atherosclerotic rabbit aorta. Riv Farmacol Ter. 1970;1:455–463
  92. Kritchevsky D, Tepper SA, Czarnecki SK, et al. Serum and aortic levels of phytosterols in rabbits fed sitosterol or sitostanol ester preparations. Lipids. 2003;38:1115–1118
  93. Moghadasian MH, McManus BM, Pritchard PH, et al. Tall oil–derived phytosterols reduce atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 1997;17:119–126
  94. Moghadasian MH, McManus BM, Godin DV, Rodrigues B, et al. Proatherogenic and antiatherogenic effects of probucol and phytosterols in apolipoprotein E–deficient mice. Possible mechanisms of action. Circulation. 1999;99:1733–1739
  95. Ntanios FY, Jones PJ, Frohlich JJ. Dietary sitostanol reduces plaque formation but not lecithin cholesterol acyl transferase activity in rabbits. Atherosclerosis. 1998;138:101–110
  96. Volger OL, Mensink RP, Plat J, et al. Dietary vegetable oil and wood derived plant stanol esters reduce atherosclerotic lesion size and severity in apoE*3-Leiden transgenic mice. Atherosclerosis. 2001;157:375–381
  97. Ntanios FY, van de Kooij AJ, de Deckere EAM, et al. Effects of various amounts of dietary plant sterol esters on plasma and hepatic sterol concentration and aortic foam cell formation of cholesterol-fed hamsters. Atherosclerosis. 2003;169:41–50
  98. de Vries JHM, Jansen M, Kromhout D, et al. The fatty acid and sterol content of food composites of middle-aged men in seven countries. J Food Compos Anal. 1997;10:115–141
  99. Keys A. Coronary heart disease in seven countries. Circulation. 1997;41(Suppl 1):1–211
  100. Salen G, Xu G, Tint GS, et al. Hyperabsorption and retention of campestanol in a sitosterolemic homozygote: comparison with her mother and three control subjects. J Lipid Res. 2000;41:1883–1889
  101. Ratnayake WMN, Plouffe L, Hollywood R, et al. Influence of sources of dietary oils on the life-span of stroke-prone spontaneously hypertensive rats. Lipids. 2000;35:409–420
  102. Kagan A, Poppler JS, Rhodes GG. Factors related to stroke incidence in Hawaiian Japanese men: the Honolulu Heart Study. Stroke. 1982;13:62–72
  103. Neaton JD, Blackburn H, Jacobs D, et al. Serum cholesterol level and mortality findings for men screened in the multiple risk factor intervention trial. Arch Intern Med. 1992;152:1490–1500
  104. Ratnayake WMN, L'Abbe MR, Mueller R, et al. Vegetable oils high in phytosterols make erythrocytes less deformable and shorten life in stroke-prone spontaneously hypertensive rats. J Nutr. 2000;130:1166–1178
  105. Ratnayake WMN, Plouffe L, L'Abbe MR, et al. Comparative health effects of margarines fortified with plant sterols and stanols on a rat model for hemorrhagic stroke. Lipids. 2003;38:1237–1247
  106. Ikeda I, Nakagiri N, Sugano M, et al. Mechanisms of phytosterolemia in stroke-prone spontaneously hypertensive and WKY rats. Metabolism. 2001;50:1361–1368
  107. Scoggan KA, Gruber H, Lariviere K. A missense mutation in the Abcg5 gene causes phytosterolemia in SHR, stroke-prone SHR, and WKY rats. J Lipid Res. 2003;44:911–916
  108. Jenkins DJA, Kendall CWC. Plant sterols: health claims and strategies to reduce cardiovascular risk. J Am Coll Nutr. 1999;18:559–562
  109. Ling WH, Jones PJH. Dietary phytosterols: a review of metabolism, benefits and side effects. Life Sci. 1995;57:195–206
  110. Moghadasian MH. Pharmacological properties of plant sterols: in vivo and in vitro observations. Life Sci. 2000;67:605–615
  111. Wilund KR, Yu L, Xu F, et al. No association between plasma levels of plant sterols and atherosclerosis in mice and men. Arterioscler Thromb Vasc Biol. 2004;24:2322–2326

PII: S0271-5317(05)00083-7

doi: 10.1016/j.nutres.2005.02.003

Nutrition Research
Volume 25, Issue 5 , Pages 413-428 , May 2005