Phytosterol

Phytosterols are phytosteroids, similar to cholesterol, that serve as structural components of biological membranes of plants.^[1] They encompass plant sterols and stanols.^[1] More than 250 sterols and related compounds have been identified.^[2] Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.

β-sitosterol, a prototypical phytosterol

Phytosterol-enriched foods and dietary supplements have been marketed for decades.^[3] Despite well-documented LDL cholesterol-lowering effects from long-term consumption of phytosterols, there is insufficient evidence for an effect on cardiovascular diseases, fasting blood sugar, glycated hemoglobin, or overall mortality rate.^[4][5]

Structure

 

Nomenclature of the structure of a tetracyclic damarane triterpene

They have a fused polycyclic structure and vary in carbon side chains and / or presence or absence of a double bond (saturation).^[3] They^{[clarification needed]} are divided into 4,4-dimethyl phytosterols, 4-monomethyl phytosterols, and 4-desmethyl phytosterols based on the location of methyl groups at the carbon-4 position.^[6] Stanols are saturated sterols, having no double bonds in the sterol ring structure.

The molecule in the article lead is β-sitosterol. The nomenclature is shown on the right.

• By removing carbon 24², campesterol is obtained.
• By removing carbons 24¹ and 24², cholesterol is obtained.
• Removing a hydrogen from carbons 22 and 23 yields stigmasterol (stigmasta-5,22-dien-3β-ol).
• By hydrogenating the double bond between carbons 5 and 6, β-sitostanol (Stigmastanol) is obtained.
• By hydrogenating the double bond between carbons 5 and 6 and removing carbon 24², campestanol is obtained.
• Removing carbon 24² and hydrogens from carbons 22 and 23, and inverting the stereochemistry at C-24 yields brassicasterol (ergosta-5,22-dien-3β-ol).
• Further removal of hydrogens from carbons 7 and 8 from brassicasterol yields ergosterol (ergosta-5,7,22-trien-3β-ol). Important: Ergosterol is not a plant sterol. Ergosterol is a component of fungal cell membranes, serving the same function in fungi that cholesterol serves in animal cells.

In addition:

• Esterification of the hydroxyl group at carbon 3 with fatty/organic acids or carbohydrates results in plant sterol esters, i.e. oleates, ferulates and (acyl) glycosides.

• Structures of some common phytosterols
•  
  β-sitosterol
•  
  Campesterol
•  
  Stigmasterol
•  
  Stigmastanol
•  
  Campestanol
•  
  Brassicasterol
•  
  Cycloartenol

• Structures of some common sterols, for comparison
•  
  Cholesterol
•  
  Ergosterol

Dietary phytosterols

The richest naturally occurring sources of phytosterols are vegetable oils and products made from them. Sterols can be present in the free form and as fatty acid esters and glycolipids. The bound form is usually hydrolyzed in the small intestines by pancreatic enzymes.^[7] Some of the sterols are removed during the deodorization step of refining oils and fats, without, however, changing their relative composition. Sterols are therefore a useful tool in checking authenticity.

As common sources of phytosterols, vegetable oils have been developed as margarine products highlighting phytosterol content.^[3] 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.^[8]

The intake of naturally occurring phytosterols ranges between ~200–300 mg/day depending on eating habits.^[9] Specially designed vegetarian experimental diets have been produced yielding upwards of 700 mg/day.^[10] The most commonly occurring phytosterols in the human diet are β-sitosterol, campesterol and stigmasterol,^[3] which account for about 65%, 30% and 3% of diet contents, respectively.^[11] The most common plant stanols in the human diet are sitostanol and campestanol, which combined make up about 5% of dietary phytosterol.^[12]

Sterol composition in crude oils (as percentage of total sterol fraction)^[13]

	Cholesterol	Brassicasterol	Campesterol	Stigmasterol	β-Sitosterol	∆5-Avenasterol	∆7-Avenasterol	∆7-Stigmasterol
Coconut oil	0.6 – 2	0 – 0.9	7 – 10	12 – 18	50 – 70	5 – 16	0.6 – 2	2 – 8
Corn oil	0.2 – 0.6	0 – 0.2	18 – 24	4 – 8	55 – 67	4 – 8	1 – 3	1 – 4
Cottonseed oil	0.7 – 2.3	0.1 – 0.9	7.2 – 8.4	1.2 – 1.8	80 – 90	1.9 – 3.8	1.4 – 3.3	0.7 – 1.4
Olive oil	0 – 0.5		2.3 – 3.6	0.6 – 2	75.6 – 90	3.1 – 14		0 – 4
Palm oil	2.2 – 6.7		18.7 – 29.1	8.9 – 13.9	50.2 – 62.1	0 – 2.8	0 – 5.1	0.2 – 2.4
Palm kernel oil	1 – 3.7	0 – 0.3	8.4 – 12.7	12.3 – 16.1	62.6 – 70.4	4 – 9	0 – 1.4	0 – 2.1
Peanut oil	0.6 – 3.8	0 – 0.2	12 – 20	5 – 13	48 – 65	7 – 9	0 – 5	0 – 5
Rapeseed oil	0.4 – 2	5 – 13	18 – 39	0 – 0.7	45 – 58	0 – 6.6	0 – 0.8	0 – 5
Soybean oil	0.6 – 1.4	0 – 0.3	16 – 24	16 – 19	52 – 58	2 – 4	1 – 4.5	1.5 – 5
Sunflower oil	0.2 – 1.3	0 – 0.2	7 – 13	8 – 11	56 – 63	2 – 7	7 – 13	3 – 6

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.^[14] 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".^[15]

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.^[16] 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.^[17] 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.^[18]

Health Canada

Health Canada reviewed the evidence of 84 randomized controlled trials published between 1994 and 2007 involving phytosterol supplementation. An average 8.8% reduction in LDL-cholesterol was observed at a mean intake of 2 grams per day.^[19] 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.^[20][21] From 1954 to 1982, phytosterols were subsequently marketed as a pharmaceutical under the name Cytellin as a treatment for elevated cholesterol.^[22]

Unlike the statins, where cholesterol lowering has been proven to reduce risk of cardiovascular diseases (CVD) and overall mortality under well-defined circumstances, the evidence has been inconsistent for phytosterol-enriched foods or supplements to lower risk of CVD, with two reviews indicating no or marginal effect,^[23][4] and another review showing evidence for use of dietary phytosterols to attain a cholesterol-lowering effect.^[24]

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.^[23] 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,^[25][26][27] an effect that complements statins. Phytosterols further reduce cholesterol levels by about 9% to 17% in statin users.^[28] The type or dose of statin does not appear to affect the cholesterol-lowering efficacy of phytosterols.^[29]

Because of their cholesterol reducing properties, some manufacturers are using sterols or stanols as a food additive.^[3][30]

Safety

Phytosterols have a long history of safe use,^[3] dating back to Cytellin, the pharmaceutical preparation of phytosterols marketed in the US from 1954 to 1982.^[22] 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).^{[citation needed]}

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. Phytostanols have a lower estimated intestinal absorption rate (0.02 - 0.3%) than phytosterols (0.4 - 5%) and consequently blood phytostanol concentration is generally lower than phytosterol concentration.^[23]

Research

Phytosterols are under preliminary research for their potential to inhibit lung, stomach, ovarian and breast cancers,^[45][46] as well as colon and prostate cancers.^[47]

Functions in plants

Sterols are essential for all eukaryotes. In contrast to animal and fungal cells, which contain only one major sterol, plant cells synthesize an array of sterol mixtures in which sitosterol and stigmasterol predominate.^[48] Sitosterol regulates membrane fluidity and permeability in a similar manner to cholesterol in mammalian cell membranes.^[49] Plant sterols can also modulate the activity of membrane-bound enzymes.^[49] Phytosterols are also linked to plant adaptation to temperature and plant immunity against pathogens.^[50]

References

1. Moreau, Robert A.; Nyström, Laura; Whitaker, Bruce D.; Winkler-Moser, Jill K.; Baer, David J.; Gebauer, Sarah K.; Hicks, Kevin B. (2018). "Phytosterols and their derivatives: Structural diversity, distribution, metabolism, analysis, and health-promoting uses". Progress in Lipid Research. 70: 35–61. doi:10.1016/j.plipres.2018.04.001. ISSN 1873-2194. PMID 29627611.
2. Akhisa, T.; Kokke, W. (1991). "Naturally occurring sterols and related compounds from plants". In Patterson, G. W.; Nes, W. D. (eds.). Physiology and Biochemistry of Sterols. Champaign, IL: American Oil Chemists' Society. pp. 172–228.
3. Patterson, CA (July 2006). "Phytosterols and stanols: Topic 10075E" (PDF). Agriculture and Agri-Food Canada, Government of Canada. Retrieved 7 November 2017.
4. 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.
5. Salehi-Sahlabadi A, Varkaneh HK, Shahdadian F, Ghaedi E, Nouri M, Singh A, Farhadnejad H, Găman MA, Hekmatdoost A, Mirmiran P (2020). "Effects of Phytosterols supplementation on blood glucose, glycosylated hemoglobin (HbA1c) and insulin levels in humans: a systematic review and meta-analysis of randomized controlled trials". J Diabetes Metab Disord. 19 (1): 625–632. doi:10.1007/s40200-020-00526-z. PMC 7270433. PMID 32550215.
6. Zhang, Tao; Liu, Ruijie; Chang, Ming; Jin, Qingzhe; Zhang, Hui; Wang, Xingguo (2020). "Health benefits of 4,4-dimethyl phytosterols: an exploration beyond 4-desmethyl phytosterols". Food & Function. 11 (1): 93–110. doi:10.1039/C9FO01205B. ISSN 2042-6496. PMID 31804642. S2CID 208646899.
7. Moreau RA, Hicks KB (2004). "The in vitro hydrolysis of phytosterol conjugates in food matrices by mammalian digestive enzymes". Lipids. 39 (8): 769–76. doi:10.1007/s11745-004-1294-3. PMID 15638245. S2CID 4043005.
8. 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.
9. Jesch ED, Carr TP (2017). "Food Ingredients That Inhibit Cholesterol Absorption". Prev Nutr Food Sci. 22 (2): 67–80. doi:10.3746/pnf.2017.22.2.67. PMC 5503415. PMID 28702423.
10. 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.
11. Weihrauch, JL; Gardner, JM (1978). "Sterol content of foods of plant origin". Journal of the American Dietetic Association. 73 (1): 39–47. doi:10.1016/S0002-8223(21)05668-6. PMID 659760. S2CID 43470157.
12. 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. S2CID 19049641.
13. Alfred Thomas (2007), "Fats and Fatty Oils", Ullmann's Encyclopedia of Industrial Chemistry (7th ed.), Wiley, p. 9, doi:10.1002/14356007.a10_173, ISBN 978-3527306732
14. European Food Safety Authority (2009-07-31). "Blood cholesterol reduction health claims on phytosterols can now be judged against EFSA new scientific advice".
15. European Food Safety Authority (2008-08-21). "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]".
16. FDA (8 September 2000). "Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD)".
17. FDA. . Archived from the original on 2012-10-09. Retrieved 2011-09-06.
18. FDA. "Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease; Proposed Rule" (PDF).
19. Health Canada. "Plant Sterols and Blood Cholesterol Lowering" (PDF).
20. Pollak, OJ (1953). "Reduction of blood cholesterol in man". Circulation. 7 (5): 702–6. doi:10.1161/01.CIR.7.5.702. PMID 13042924. S2CID 3165910.
21. Tilvis, RS; Miettinen, TA (1986). "Serum plant sterols and their relation to cholesterol absorption". The American Journal of Clinical Nutrition. 43 (1): 92–7. doi:10.1093/ajcn/43.1.92. PMID 3942097.
22. Jones, PJ (2007). "Ingestion of phytosterols is not potentially hazardous". The Journal of Nutrition. 137 (11): 2485, author reply 2486. doi:10.1093/jn/137.11.2485. PMID 17951490.
23. 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.
24. Gylling, H; Plat, J; Turley, S; Ginsberg, H. N; Ellegård, L; Jessup, W; Jones, P. J; Lütjohann, D; Maerz, W; Masana, L; Silbernagel, G; Staels, B; Borén, J; Catapano, A. L; De Backer, G; Deanfield, J; Descamps, O. S; Kovanen, P. T; Riccardi, G; Tokgözoglu, L; Chapman, M. J; European Atherosclerosis Society Consensus Panel on Phytosterols (2014). "Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease". Atherosclerosis. 232 (2): 346–60. doi:10.1016/j.atherosclerosis.2013.11.043. PMID 24468148.
25. Nguyen, Tu T. (1999). "The Cholesterol-Lowering Action of Plant Stanol Esters". The Journal of Nutrition. 129 (12): 2109–2112. doi:10.1093/jn/129.12.2109. PMID 10573535.
26. 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.
27. 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.
28. 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. S2CID 41438503.
29. 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.
30. 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?". WebMD. Retrieved 6 July 2013.
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. 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. PMID 18769018.
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. 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. 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. 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 (1): 139–44. doi:10.1194/jlr.M600371-JLR200. PMID 17074925.
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. S2CID 19548242.
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. PMID 15330272.
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. doi:10.1093/ajcn/76.6.1272. 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. Ramprasath, VR; Awad, AB (2015). "Role of Phytosterols in Cancer Prevention and Treatment" (PDF). Journal of AOAC International. 98 (3): 735–8. doi:10.5740/jaoacint.SGERamprasath. PMID 26086253.
46. Woyengo, T.A.; Ramprasath, V.R.; Jones, P.J.H. (June 2009). "Anticancer effects of phytosterols". European Journal of Clinical Nutrition. 63 (7): 813–820. doi:10.1038/ejcn.2009.29. PMID 19491917. S2CID 23962957.
47. Bradford, P.G.; Awad, A.B. (February 2007). "Phytosterols as anticancer compounds". Molecular Nutrition & Food Research. 51 (2): 161–170. doi:10.1002/mnfr.200600164. PMID 17266177.
48. Hartmann, Marie-Andrée (1998). "Plant sterols and the membrane environment". Trends in Plant Science. 3 (5): 170–175. doi:10.1016/S1360-1385(98)01233-3.
49. De Smet, E; Mensink, R. P; 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.
50. De Bruyne, L; Höfte, M; De Vleesschauwer, D (2014). "Connecting growth and defense: The emerging roles of brassinosteroids and gibberellins in plant innate immunity". Molecular Plant. 7 (6): 943–59. doi:10.1093/mp/ssu050. PMID 24777987.