Phytosterol

Phytosterols, which encompass plant sterols and stanols, are steroid compounds similar to cholesterol which occur in plants and vary only in carbon side chains and/or presence or absence of a double bond. Stanols are saturated sterols, having no double bonds in the sterol ring structure. More than 200 sterols and related compounds have been identified.[1] Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.

Phytosterol-enriched foods and dietary supplements have been marketed for decades. Despite well documented LDL cholesterol lowering effects, no scientifically proven evidence of any beneficial effect on cardiovascular disease (CVD) or overall mortality exists.[2]

Structure

β-sitosterol campesterol cholesterol
stigmasterol Stigmastanol
Nomenclature for steroid skeleton

The molecule on the left is β-sitosterol. Nomenclature for steroid skeleton is on the right.

campestanol brassicasterol ergosterol
lupeol cycloartenol

Dietary phytosterols

The richest naturally occurring sources of phytosterols are vegetable oils and products made from them. They can be present in the free form and as esters of fatty acid/cinnamic acid or as glycosides, respectively. The bound form is usually hydrolyzed in the small intestines by pancreatic enzymes.[3] Nuts, which are rich in phytosterols, are often eaten in smaller amounts, but can still significantly contribute to total phytosterol intake. Cereal products, vegetables, fruit and berries, which are not as rich in phytosterols, may also be significant sources of phytosterols due to their higher intakes.[4] The intake of naturally occurring phytosterols ranges between ~150–450 mg/day[5] depending on eating habits. Specially designed vegetarian experimental diets have been produced yielding upwards of 700 mg/day.[6] The most commonly occurring phytosterols in the human diet are β-sitosterol, campesterol and stigmasterol, which account for about 65%, 30% and 3% of diet contents, respectively.[7] The most common plant stanols in the human diet are sitostanol and campestanol, which combined make up about 5% of dietary phytosterol.[8]

Health claims

EFSA

The European Foods Safety Authority (EFSA) concluded that blood cholesterol can be reduced on average by 7 to 10.5% if a person consumes 1.5 to 2.4 grams of plant sterols and stanols per day, an effect usually established within 2–3 weeks. Longer-term studies extending up to 85 weeks showed that the cholesterol-lowering effect could be sustained.[9] Based on this and other efficacy data, the EFSA scientific panel provided the following health advisory: “Plant sterols have been shown to lower/reduce blood cholesterol. Blood cholesterol lowering may reduce the risk of coronary heart disease".[10]

FDA

The FDA has approved the following claim for phytosterols: For plant sterol esters: (i) Foods containing at least 0.65 g per serving of plant sterol esters, eaten twice a day with meals for a daily total intake of at least 1.3 g, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. A serving of [name of the food] supplies ___grams of vegetable oil sterol esters.[11] For plant stanol esters: (i) Foods containing at least 1.7 g per serving of plant stanol esters, eaten twice a day with meals for a total daily intake of at least 3.4 g, as part of a diet low in saturated fat and cholesterol, may reduce the risk of heart disease. A serving of [name of the food] supplies ___grams of plant stanol esters.[12] The FDA is currently reviewing the health claims for phytosterols.[13] Reviewing clinical trials involving phytosterol supplementation, the FDA concluded that when consumed in the range of 1 to 3 grams in enriched foods, phytosterols resulted in statistically significant (5-15%) reductions in blood LDL cholesterol levels relative to placebo. The FDA also concluded that a daily dietary intake of 2 grams a day of phytosterols (expressed as non-esterified phytosterols) is required to demonstrate a relationship between phytosterol consumption and cholesterol lowering for reduced CVD risk.[14]

Health Canada

Health Canada reviewed the evidence of 84 randomized controlled trials published between 1994-2007 involving phytosterol supplementation. An average 8.8% reduction in LDL-cholesterol was observed at a mean intake of 2 grams per day.[15] Health Canada concluded that sufficient scientific evidence exists to support a relationship between phytosterol consumption and blood cholesterol lowering. Based on this evidence, Health Canada approved the following statements for qualifying foods intended for hypercholesterolemic individuals: Primary statement: "[serving size from Nutrition Facts table in metric and common household measures] of [naming the product] provides X% of the daily amount* of plant sterols shown to help reduce/lower cholesterol in adults." Two additional statements that could be used in combination or alone, adjacent to the primary statement, without any intervening printed, written or graphic material: "Plant sterols help reduce [or help lower] cholesterol." This statement when used, shall be shown in letters up to twice the size and prominence as those of the primary statement. "High cholesterol is a risk factor for heart disease." This statement when used, shall be shown in letters up to the same size and prominence as those of the primary statement.

Cholesterol lowering

The ability of phytosterols to reduce cholesterol levels was first demonstrated in humans in 1953.[16][17] From 1954-82, phytosterols were subsequently marketed as a pharmaceutical under the name Cytellin as a treatment for elevated cholesterol.[18]

Unlike the statins, where cholesterol lowering has been proven to reduce CVD risk and overall mortality under well-defined circumstances, no such effect has ever been documented with phytosterol-enriched foods or supplements.[2][19] While cholesterol lowering was frequently used as a surrogate endpoint for beneficial effects on CVD, examples exist where specific medications for cholesterol lowering were found to have no significant effect on clinical endpoints, such as with ezetimibe.

Coadministration of statins with phytosterol-enriched foods increases the cholesterol-lowering effect of phytosterols, again without any proof of clinical benefit and with anecdotal evidence of potential adverse effects.[2]

Statins work by reducing cholesterol synthesis via inhibition of the rate-limiting HMG-CoA reductase enzyme. Phytosterols reduce cholesterol levels by competing with cholesterol absorption in the gut via one or several possible mechanisms,[20][21][22] an effect that complements statins. Phytosterols further reduce cholesterol levels by about 9% to 17% in statin users.[23] The type or dose of statin does not appear to affect the cholesterol-lowering efficacy of phytosterols.[24]

Because of their cholesterol reducing properties, some manufacturers are using sterols or stanols as a food additive.[25]

Triglycerides lowering

Elevated triglyceride levels are a risk factor for CVD.[26] Triglycerides were found to be reduced by 14% by supplementing 1.6 g/day of plant sterols in a fermented milk beverage for six weeks.[27] The proposed mechanism behind the triglyceride-lowering effect of phytosterols is a reduction in triglyceride-rich very low-density lipoprotein particles produced by the liver.[28] These effects of phytosterols may be more pronounced in people with elevated triglycerides.[29]

Cancer risk

Phytosterols are under preliminary research for their potential to inhibit lung, stomach, ovarian and breast cancers.[30]

Safety

Phytosterols have a long history of safe use dating back to Cytellin, the pharmaceutical preparation of phytosterols marketed in the US from 1954-82.[18] Phytosterol esters have generally recognized as safe (GRAS) status in the US.[31] Phytosterol-containing functional foods were subject to postlaunch monitoring after being introduced to the EU market in 2000, and no unpredicted side effects were reported.[32]

A potential safety concern regarding phytosterol consumption is in patients with phytosterolaemia, a rare genetic disorder which results in a 50- to 100-fold increase in blood plant sterol levels and is associated with rapid development of coronary atherosclerosis. Phytosterolaemia has been linked to mutations in the ABCG5/G8 proteins which pump plant sterols out of enterocytes and hepatocytes into the lumen and bile ducts, respectively. Plant sterol levels in the blood have been shown to be positively, negatively or not associated with CVD risk, depending on the study population investigated.[33][34][35][36][37][38][39][40]

The link between plant sterols and CVD or CHD risk is complicated because phytosterol levels reflect cholesterol absorption. (See Phytosterols as a marker for cholesterol absorption).

Sterol vs stanol

The equivalent ability and safety of plant sterols and plant stanols to lower cholesterol continues to be a hotly debated topic. Plant sterols and stanols, when compared head to head in clinical trials, have been shown to equally reduce cholesterol levels.[41][42][43] A meta-analysis of 14 randomized, controlled trials comparing plant sterols to plant stanols directly at doses of 0.6 to 2.5 g/day showed no difference between the two forms on total cholesterol, LDL cholesterol, HDL cholesterol, or triglyceride levels.[44] Trials looking at high doses (> 4 g/day) of plant sterols or stanols are very limited, and none have yet to be completed comparing the same high dose of plant sterol to plant stanol.

The debate regarding sterol vs. stanol safety is centered on their differing intestinal absorption and resulting plasma concentrations.[2] Due to the extremely elevated levels of phytosterols seen in the rare genetic disorder phytosterolemia (sitosterolemia), which is associated with rapidly progressing CVD, it was hypothesized that plant sterols themselves may be atherogenic.[45][46] suggested elevated plant sterol levels may be related to increased CVD risk because campesterol and total plant sterols correlated positively with cholesterol. Several other studies have suggested elevated plant sterol levels may be a risk factor for CVD.[37][38][39] In these studies, though, the plant sterol levels were not as high as those seen in phytosterolemia. In phytosterolemia, the rapid development of CVD is most likely due to the improper handling of cholesterol, which is elevated and accounts for the vast majority of sterols in phytosterolemics.[5] Because plant sterol levels actually reflect cholesterol absorption, some have concluded elevated cholesterol absorption, not plant sterols are atherogenic or otherwise associated with CVD risk.[33][47]

References

  1. ↑ Akhisa, T.; Kokke, W. (1991). "Naturally occurring sterols and related compounds from plants". In Patterson, G. W.; Nes, W. D. Physiology and Biochemistry of Sterols. Champaign, IL: American Oil Chemists' Society. pp. 172–228.
  2. 1 2 3 4 Weingartner, O.; Bohm, M.; Laufs, U. (2008). "Controversial role of plant sterol esters in the management of hypercholesterolaemia". European Heart Journal 30 (4): 404–9. doi:10.1093/eurheartj/ehn580. PMC 2642922. PMID 19158117.
  3. ↑ Moreau RA, Hicks KB (2004). "The in vitro hydrolysis of phytosterol conjugates in food matrices by mammalian digestive enzymes". Lipids 39 (8): 769–76. PMID 15638245.
  4. ↑ Valsta, L. M.; Lemström, A.; Ovaskainen, M.-L.; Lampi, A.-M.; Toivo, J.; Korhonen, T.; Piironen, V. (2007). "Estimation of plant sterol and cholesterol intake in Finland: Quality of new values and their effect on intake". British Journal of Nutrition 92 (4): 671–8. doi:10.1079/BJN20041234. PMID 15522137.
  5. 1 2 Ostlund, Richard E. (2002). "Phytosterols Inhumannutrition". Annual Review of Nutrition 22: 533–49. doi:10.1146/annurev.nutr.22.020702.075220. PMID 12055357.
  6. ↑ Ågren, J. J.; Tvrzicka, E.; Nenonen, M. T.; Helve, T.; Hänninen, O. (2007). "Divergent changes in serum sterols during a strict uncooked vegan diet in patients with rheumatoid arthritis". British Journal of Nutrition 85 (2): 137–9. doi:10.1079/BJN2000234. PMID 11242480.
  7. ↑ Weihrauch, JL; Gardner, JM (1978). "Sterol content of foods of plant origin". Journal of the American Dietetic Association 73 (1): 39–47. PMID 659760.
  8. ↑ Andersson, S W; Skinner, J; Ellegård, L; Welch, A A; Bingham, S; Mulligan, A; Andersson, H; Khaw, K-T (2004). "Intake of dietary plant sterols is inversely related to serum cholesterol concentration in men and women in the EPIC Norfolk population: A cross-sectional study". European Journal of Clinical Nutrition 58 (10): 1378–85. doi:10.1038/sj.ejcn.1601980. PMID 15054420.
  9. ↑ European Food Safety Authority. "Blood cholesterol reduction health claims on phytosterols can now be judged against EFSA new scientific advice".
  10. ↑ European Food Safety Authority. "Plant Sterols and Blood Cholesterol - Scientific substantiation of a health claim related to plant sterols and lower/reduced blood cholesterol and reduced risk of (coronary) heart disease pursuant to Article 14 of Regulation (EC) No 1924/2006[1]" (PDF).
  11. ↑ FDA. "Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD)".
  12. ↑ FDA. "Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD)".
  13. ↑ FDA. "Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease; Proposed Rule" (PDF).
  14. ↑ FDA. "Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease; Proposed Rule" (PDF).
  15. ↑ Health Canada. "Plant Sterols and Blood Cholesterol Lowering" (PDF).
  16. ↑ Pollak, OJ (1953). "Reduction of blood cholesterol in man". Circulation 7 (5): 702–6. doi:10.1161/01.CIR.7.5.702. PMID 13042924.
  17. ↑ Tilvis, RS; Miettinen, TA (1986). "Serum plant sterols and their relation to cholesterol absorption". The American Journal of Clinical Nutrition 43 (1): 92–7. PMID 3942097.
  18. 1 2 Jones, PJ (2007). "Ingestion of phytosterols is not potentially hazardous". The Journal of Nutrition 137 (11): 2485; author reply 2486. PMID 17951490.
  19. ↑ Genser, B.; Silbernagel, G.; De Backer, G.; Bruckert, E.; Carmena, R.; Chapman, M. J.; Deanfield, J.; Descamps, O. S.; Rietzschel, E. R.; Dias, K. C.; März, W. (2012). "Plant sterols and cardiovascular disease: A systematic review and meta-analysis". European Heart Journal 33 (4): 444–451. doi:10.1093/eurheartj/ehr441. PMC 3279314. PMID 22334625.
  20. ↑ Nguyen, Tu T. (1999). "The Cholesterol-Lowering Action of Plant Stanol Esters". The Journal of Nutrition (The American Society for Nutritional Sciences) 129 (12): 2109–2112. Retrieved 10 April 2015.
  21. ↑ Trautwein, Elke A.; Duchateau, Guus S. M. J. E.; Lin, Yuguang; Mel'nikov, Sergey M.; Molhuizen, Henry O.F.; Ntanios, Fady Y. (2003). "Proposed mechanisms of cholesterol-lowering action of plant sterols". European Journal of Lipid Science and Technology 105 (3-4): 171–185. doi:10.1002/ejlt.200390033. Retrieved 16 April 2015.
  22. ↑ De Smet, E; Mensink, RP; Plat, J (2012). "Effects of plant sterols and stanols on intestinal cholesterol metabolism: suggested mechanisms from past to present". Molecular Nutrition & Food Research 56 (7): 1058–72. doi:10.1002/mnfr.201100722. PMID 22623436. Retrieved 16 April 2015.
  23. ↑ Scholle, JM; Baker, WL; Talati, R; Coleman, CI (2009). "The effect of adding plant sterols or stanols to statin therapy in hypercholesterolemic patients: Systematic review and meta-analysis". Journal of the American College of Nutrition 28 (5): 517–24. doi:10.1080/07315724.2009.10719784. PMID 20439548.
  24. ↑ Katan, M. B.; Grundy, S. M.; Jones, P.; Law, M.; Miettinen, T.; Paoletti, R.; Stresa Workshop, Participants (2003). "Efficacy and Safety of Plant Stanols and Sterols in the Management of Blood Cholesterol Levels". Mayo Clinic Proceedings 78 (8): 965–78. doi:10.4065/78.8.965. PMID 12911045.
  25. ↑ Griffin, RM (Feb 2, 2009). "The New Low-Cholesterol Diet: Plant Sterols and Stanols: What are sterols and stanols, and does anyone like to eat them?". http://webmd.com. WebMD. Retrieved 6 July 2013. External link in |website= (help)
  26. ↑ Malloy, MJ; Kane, JP (2001). "A risk factor for atherosclerosis: Triglyceride-rich lipoproteins". Advances in internal medicine 47: 111–36. PMID 11795072.
  27. ↑ Plana, Nuria; Nicolle, Catherine; Ferre, Raimon; Camps, Jordi; Cos, Rosa; Villoria, Jesus; Masana, Luis; Danacol, Group (2008). "Plant sterol-enriched fermented milk enhances the attainment of LDL-cholesterol goal in hypercholesterolemic subjects". European Journal of Nutrition 47 (1): 32–9. doi:10.1007/s00394-007-0693-4. PMID 18193377.
  28. ↑ Plat, Jogchum; Mensink, Ronald P. (2009). "Plant Stanol Esters Lower Serum Triacylglycerol Concentrations via a Reduced Hepatic VLDL-1 Production". Lipids 44 (12): 1149–53. doi:10.1007/s11745-009-3361-z. PMC 2779439. PMID 19856194.
  29. ↑ Theuwissen, Elke; Plat, Jogchum; Kallen, Carla J.; Greevenbroek, Marleen M.; Mensink, Ronald P. (2009). "Plant Stanol Supplementation Decreases Serum Triacylglycerols in Subjects with Overt Hypertriglyceridemia". Lipids 44 (12): 1131–40. doi:10.1007/s11745-009-3367-6. PMID 19904567.
  30. ↑ Woyengo, T A; Ramprasath, V R; Jones, P J H (2009). "Anticancer effects of phytosterols". European Journal of Clinical Nutrition 63 (7): 813–20. doi:10.1038/ejcn.2009.29. PMID 19491917.
  31. ↑ FDA. "GRAS Notice 000181: Phytosterols" (PDF).
  32. ↑ Lea, L.J.; Hepburn, P.A. (2006). "Safety evaluation of phytosterol-esters. Part 9: Results of a European post-launch monitoring programme". Food and Chemical Toxicology 44 (8): 1213–22. doi:10.1016/j.fct.2006.01.017. PMID 16542769.
  33. 1 2 Silbernagel, G.; Fauler, G.; Renner, W.; Landl, E. M.; Hoffmann, M. M.; Winkelmann, B. R.; Boehm, B. O.; Marz, W. (2008). "The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease". The Journal of Lipid Research 50 (2): 334–41. doi:10.1194/jlr.P800013-JLR200.
  34. ↑ Silbernagel, G.; Fauler, G.; Hoffmann, M. M.; Lutjohann, D.; Winkelmann, B. R.; Boehm, B. O.; Marz, W. (2010). "The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality". The Journal of Lipid Research 51 (8): 2384–93. doi:10.1194/jlr.P002899. PMC 2903788. PMID 20228406.
  35. ↑ Strandberg, Timo E.; Gylling, Helena; Tilvis, Reijo S.; Miettinen, Tatu A. (2010). "Serum plant and other noncholesterol sterols, cholesterol metabolism and 22-year mortality among middle-aged men". Atherosclerosis 210 (1): 282–7. doi:10.1016/j.atherosclerosis.2009.11.007. PMID 19962145.
  36. ↑ Fassbender, Klaus; Lütjohann, Dieter; Dik, Miranda G.; Bremmer, Marijke; König, Jochem; Walter, Silke; Liu, Yang; Letièmbre, Maryse; Von Bergmann, Klaus (2008). "Moderately elevated plant sterol levels are associated with reduced cardiovascular risk—The LASA study". Atherosclerosis 196 (1): 283–8. doi:10.1016/j.atherosclerosis.2006.10.032. PMID 17137582.
  37. 1 2 Rajaratnam, Radhakrishnan A; Gylling, Helena; Miettinen, Tatu A (2000). "Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women". Journal of the American College of Cardiology 35 (5): 1185–91. doi:10.1016/S0735-1097(00)00527-1. PMID 10758959.
  38. 1 2 Assmann, Gerd; Cullen, Paul; Erbey, John; Ramey, Dena R.; Kannenberg, Frank; Schulte, Helmut (2006). "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". Nutrition, Metabolism and Cardiovascular Diseases 16 (1): 13–21. doi:10.1016/j.numecd.2005.04.001. PMID 16399487.
  39. 1 2 Sudhop, Thomas; Gottwald, Britta M.; Von Bergmann, Klaus (2002). "Serum plant sterols as a potential risk factor for coronary heart disease". Metabolism 51 (12): 1519–21. doi:10.1053/meta.2002.36298. PMID 12489060.
  40. ↑ Pinedo, S.; Vissers, M. N.; Bergmann, K. v.; Elharchaoui, K.; Lutjohann, D.; Luben, R.; Wareham, N. J.; Kastelein, J. J. P.; Khaw, K.-T.; Boekholdt, S. M. (2006). "Plasma levels of plant sterols and the risk of coronary artery disease: The prospective EPIC-Norfolk Population Study". The Journal of Lipid Research 48: 139–44. doi:10.1194/jlr.M600371-JLR200.
  41. ↑ Hallikainen, M A; Sarkkinen, E S; Gylling, H; Erkkilä, A T; Uusitupa, M I J (2000). "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". European Journal of Clinical Nutrition 54 (9): 715–25. doi:10.1038/sj.ejcn.1601083. PMID 11002384.
  42. ↑ O'Neill, F.H.; Brynes, A.; Mandeno, R.; Rendell, N.; Taylor, G.; Seed, M.; Thompson, G.R. (2004). "Comparison of the effects of dietary plant sterol and stanol esters on lipid metabolism". Nutrition, Metabolism and Cardiovascular Diseases 14 (3): 133–42. doi:10.1016/S0939-4753(04)80033-4.
  43. ↑ Vanstone, CA; Raeini-Sarjaz, M; Parsons, WE; Jones, PJ (2002). "Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons". The American Journal of Clinical Nutrition 76 (6): 1272–8. PMID 12450893.
  44. ↑ Talati, Ripple; Sobieraj, Diana M.; Makanji, Sagar S.; Phung, Olivia J.; Coleman, Craig I. (2010). "The Comparative Efficacy of Plant Sterols and Stanols on Serum Lipids: A Systematic Review and Meta-Analysis". Journal of the American Dietetic Association 110 (5): 719–26. doi:10.1016/j.jada.2010.02.011. PMID 20430133.
  45. ↑ Glueck et al. 1992
  46. ↑ Glueck, Charles J.; Streicher, Patricia; Illig, Ellen (1992). "Serum and dietary phytosterols, cholesterol, and coronary heart disease in hyperphytosterolemic probands". Clinical Biochemistry 25 (5): 331–4. doi:10.1016/0009-9120(92)80009-6. PMID 1490292.
  47. ↑ Vanstone, CA; Jones, PJ (2004). "Limitations of plasma plant sterols as indicators of cholesterol absorption". Am J Clin Nutr 79 (2): 340–1. PMID 14749249.
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