{{Short description|Class of steroids derived from plants}} [[File:Sitosterol structure.svg|thumb|right|[[β-sitosterol]], a prototypical phytosterol]] '''Phytosterols''' are [[phytosteroid]]s, similar to [[cholesterol]], that serve as structural components of biological membranes of [[plant]]s.<ref name="moreau">{{Cite journal|last1=Moreau|first1=Robert A.|last2=Nyström|first2=Laura|last3=Whitaker|first3=Bruce D.|last4=Winkler-Moser|first4=Jill K.|last5=Baer|first5=David J.|last6=Gebauer|first6=Sarah K.|last7=Hicks|first7=Kevin B.|title=Phytosterols and their derivatives: Structural diversity, distribution, metabolism, analysis, and health-promoting uses|pmid=29627611|journal=Progress in Lipid Research|volume=70|year=2018|pages=35–61|doi=10.1016/j.plipres.2018.04.001|bibcode=2018PLipR..70...35M |issn=1873-2194}}</ref> They encompass plant [[sterol]]s and [[stanol ester|stanols]].<ref name=moreau/> More than 250 sterols and related compounds have been identified.<ref>{{cite book |title=Physiology and Biochemistry of Sterols |year=1991 |publisher=American Oil Chemists' Society |location=Champaign, IL |pages=172–228 |last1=Akhisa |first1=T. |last2=Kokke |first2=W. |editor1-first=G. W. |editor1-last=Patterson |editor2-first=W. D. |editor2-last=Nes |chapter=Naturally occurring sterols and related compounds from plants}}</ref> Free phytosterols extracted from oils are insoluble in water, relatively insoluble in oil, and soluble in alcohols.

Phytosterol-enriched foods and [[dietary supplement]]s have been marketed for decades.<ref name="aafc"/> Despite well-documented [[LDL cholesterol]]-lowering effects from long-term consumption of phytosterols, typically in the range of about 5-10%, there is no conclusive evidence from long‑term outcome trials that phytosterols themselves reduce the incidence of [[cardiovascular disease]]s, improve [[fasting blood sugar]], or [[glycated hemoglobin]] levels, or overall [[mortality rate]].<ref name="Genser_2012"/><ref>{{cite journal|vauthors=Salehi-Sahlabadi A, Varkaneh HK, Shahdadian F, Ghaedi E, Nouri M, Singh A, Farhadnejad H, Găman MA, Hekmatdoost A, Mirmiran P |title=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|journal=J Diabetes Metab Disord|year=2020|volume=19|issue=1|pages=625–632|doi=10.1007/s40200-020-00526-z|pmid=32550215|pmc=7270433}}</ref>

Expert reviews have therefore emphasized that phytosterol‑enriched products can be considered a dietary option for LDL‑cholesterol reduction, but that their impact on ‘hard’ cardiovascular endpoints and mortality remains to be established.<ref>{{Cite journal |last1=Windler |first1=Eberhard |last2=Beil |first2=Frank-Ulrich |last3=Berthold |first3=Heiner K. |last4=Gouni-Berthold |first4=Ioanna |last5=Kassner |first5=Ursula |last6=Klose |first6=Gerald |last7=Lorkowski |first7=Stefan |last8=März |first8=Winfried |last9=Parhofer |first9=Klaus G. |last10=Plat |first10=Jogchum |last11=Silbernagel |first11=Günter |last12=Steinhagen-Thiessen |first12=Elisabeth |last13=Weingärtner |first13=Oliver |last14=Zyriax |first14=Birgit-Christiane |last15=Lütjohann |first15=Dieter |date=2023-02-06 |title=Phytosterols and Cardiovascular Risk Evaluated against the Background of Phytosterolemia Cases—A German Expert Panel Statement |journal=Nutrients |language=en |volume=15 |issue=4 |pages=828 |doi=10.3390/nu15040828 |doi-access=free |issn=2072-6643 |pmc=9963617 |pmid=36839186}}</ref>

== Structure == [[File:Steroid numbering.svg|thumb|right|275px|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).<ref name="aafc">{{cite web|author1=Patterson, CA|title=Phytosterols and stanols: Topic 10075E|url=https://www5.agr.gc.ca/resources/prod/doc/misb/fb-ba/nutra/pdf/aug_31_06_phystosterol_en.pdf|publisher=Agriculture and Agri-Food Canada, Government of Canada|access-date=7 November 2017|date=July 2006}}</ref> They{{clarify|reason=None of the example phytosterols given here have a 4-methyl group, so what are "they" and what are some examples of natural ones with such a group? Lupeol does not count.|date=April 2022}} 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.<ref>{{Cite journal|last1=Zhang|first1=Tao|last2=Liu|first2=Ruijie|last3=Chang|first3=Ming|last4=Jin|first4=Qingzhe|last5=Zhang|first5=Hui|last6=Wang|first6=Xingguo|date=2020|title=Health benefits of 4,4-dimethyl phytosterols: an exploration beyond 4-desmethyl phytosterols|url=https://xlink.rsc.org/?DOI=C9FO01205B|journal=Food & Function|language=en|volume=11|issue=1|pages=93–110|doi=10.1039/C9FO01205B|pmid=31804642|s2cid=208646899|issn=2042-6496|url-access=subscription}}</ref> Stanols are [[saturated fat|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 24<sup>2</sup>, [[campesterol]] is obtained. * By removing carbons 24<sup>1</sup> and 24<sup>2</sup>, [[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 24<sup>2</sup>, [[campestanol]] is obtained. * Removing carbon 24<sup>2</sup> 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 ester]]s, i.e. oleates, ferulates and (acyl) glycosides.

<gallery mode="nolines" caption="Structures of some common phytosterols"> File:Sitosterol structure.svg|[[β-sitosterol]] File:campesterol.svg|[[Campesterol]] File:Stigmasterin.svg|[[Stigmasterol]] File:Stigmastanol.svg|[[Stigmastanol]] File:campestanol.svg|[[Campestanol]] File:brassicasterol.svg|[[Brassicasterol]] File:Cycloartenol.svg|[[Cycloartenol]] </gallery> <gallery mode="nolines" caption="Structures of some common sterols, for comparison"> File:cholesterol.svg|[[Cholesterol]] Image:ergosterol.svg|[[Ergosterol]] </gallery>

==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 ester]]s and [[glycolipids]]. The bound form is usually hydrolyzed in the small intestines by [[pancreatic enzyme]]s.<ref>{{cite journal |vauthors=Moreau RA, Hicks KB | year = 2004 | title = The in vitro hydrolysis of phytosterol conjugates in food matrices by mammalian digestive enzymes | doi = 10.1007/s11745-004-1294-3 | journal = Lipids | volume = 39 | issue = 8| pages = 769–76 | pmid = 15638245 | bibcode = 2004Lipid..39..769M | s2cid = 4043005 }}</ref> Some of the sterols are removed during the deodorization step of [[Hydrotreated vegetable oil|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 oil]]s have been developed as [[margarine]] products highlighting phytosterol content.<ref name=aafc/> 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.<ref>{{cite journal |pages=671–8 |doi=10.1079/BJN20041234 |title=Estimation of plant sterol and cholesterol intake in Finland: Quality of new values and their effect on intake |year=2007 |last1=Valsta |first1=L. M. |last2=Lemström |first2=A. |last3=Ovaskainen |first3=M.-L. |last4=Lampi |first4=A.-M. |last5=Toivo |first5=J. |last6=Korhonen |first6=T. |last7=Piironen |first7=V. |journal=British Journal of Nutrition |volume=92 |issue=4 |pmid=15522137|doi-access=free }}</ref>

The intake of naturally occurring phytosterols ranges between ~200–300&nbsp;mg/day depending on eating habits.<ref>{{cite journal |vauthors=Jesch ED, Carr TP |title=Food Ingredients That Inhibit Cholesterol Absorption |journal=Prev Nutr Food Sci |volume=22 |issue=2 |pages=67–80 |year=2017 |pmid=28702423 |pmc=5503415 |doi=10.3746/pnf.2017.22.2.67 }}</ref> Specially designed vegetarian experimental diets have been produced yielding upwards of 700&nbsp;mg/day.<ref>{{cite journal |pages=137–9 |doi=10.1079/BJN2000234 |title=Divergent changes in serum sterols during a strict uncooked vegan diet in patients with rheumatoid arthritis |year=2007 |last1=Ågren |first1=J. J. |last2=Tvrzicka |first2=E. |last3=Nenonen |first3=M. T. |last4=Helve |first4=T. |last5=Hänninen |first5=O. |journal=British Journal of Nutrition |volume=85 |issue=2 |pmid=11242480|doi-access=free }}</ref> The most commonly occurring phytosterols in the human diet are β-sitosterol, campesterol and stigmasterol,<ref name="aafc"/> which account for about 65%, 30% and 3% of diet contents, respectively.<ref>{{cite journal |pmid=659760 |year=1978 |last1=Weihrauch |first1=JL |last2=Gardner |first2=JM |title=Sterol content of foods of plant origin |volume=73 |issue=1 |pages=39–47 |journal=Journal of the American Dietetic Association|doi=10.1016/S0002-8223(21)05668-6 |s2cid=43470157 }}</ref> The most common plant ''stanols'' in the human diet are sitostanol and campestanol, which combined make up about 5% of dietary phytosterol.<ref>{{cite journal |pages=1378–85 |doi=10.1038/sj.ejcn.1601980 |title=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 |year=2004 |last1=Andersson |first1=S W |last2=Skinner |first2=J |last3=Ellegård |first3=L |last4=Welch |first4=A A |last5=Bingham |first5=S |last6=Mulligan |first6=A |last7=Andersson |first7=H |last8=Khaw |first8=K-T |journal=European Journal of Clinical Nutrition |volume=58 |issue=10 |pmid=15054420|s2cid=19049641 |doi-access= }}</ref>

{| class="wikitable" |+ Sterol composition in crude oils (as percentage of total sterol fraction)<ref>{{citation | author=Alfred Thomas | contribution=Fats and Fatty Oils | title=Ullmann's Encyclopedia of Industrial Chemistry | edition=7th | publisher=Wiley | year=2007 | page=9 | doi=10.1002/14356007.a10_173| title-link=Ullmann's Encyclopedia of Industrial Chemistry | isbn=978-3527306732 }}</ref> |- ! ! [[Cholesterol]] ! [[Brassicasterol]] ! [[Campesterol]] ! [[Stigmasterol]] ! [[β-Sitosterol]] ! ∆5-[[Avenasterol]] ! [[Isofucosterol|∆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.<ref>{{cite web|last=European Food Safety Authority|title=Blood cholesterol reduction health claims on phytosterols can now be judged against EFSA new scientific advice|url=https://www.efsa.europa.eu/en/press/news/nda090731|date=2009-07-31}}</ref> 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 artery disease|coronary heart disease]]".<ref>{{cite journal|last=European Food Safety Authority|title=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]|journal=EFSA Journal |url=https://www.efsa.europa.eu/en/efsajournal/pub/781|date=2008-08-21 |volume=6 |issue=8 |page=781 |doi=10.2903/j.efsa.2008.781 |doi-access=free }}</ref>

===FDA=== The [[Food and Drug Administration|FDA]] has approved the following claim for phytosterols: ''For plant [[sterol ester]]s'': (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.<ref name="fda">{{cite web|last=FDA|title=Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD)|url=https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.83|date=8 September 2000|access-date=7 November 2017|archive-date=14 September 2003|archive-url=https://web.archive.org/web/20030914052329/http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?FR=101.83|url-status=dead}}</ref> ''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.<ref>{{cite web|last=FDA|title=Health claims: plant sterol/stanol esters and risk of coronary heart disease (CHD)|url=http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr;sid=502078d8634923edc695b394a357d189;rgn=div8;view=text;node=21%3A2.0.1.1.2.5.1.14;idno=21;cc=ecfr|access-date=2011-09-06|archive-url=https://web.archive.org/web/20121009113337/http://ecfr.gpoaccess.gov/cgi/t/text/text-idx?c=ecfr;sid=502078d8634923edc695b394a357d189;rgn=div8;view=text;node=21:2.0.1.1.2.5.1.14;idno=21;cc=ecfr|archive-date=2012-10-09|url-status=dead}}</ref> 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.<ref>{{cite web|last=FDA|title=Food Labeling; Health Claim; Phytosterols and Risk of Coronary Heart Disease; Proposed Rule|url=https://edocket.access.gpo.gov/2010/pdf/2010-30386.pdf}}</ref>

===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.<ref>{{cite web|last=Health Canada|title=Plant Sterols and Blood Cholesterol Lowering|url=https://www.hc-sc.gc.ca/fn-an/alt_formats/pdf/label-etiquet/claims-reclam/assess-evalu/phytosterols-claim-allegation-eng.pdf}}</ref> 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 [[hypercholesterolemia|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.<ref>{{cite journal |pmid=13042924 |year=1953 |last1=Pollak |first1=OJ |title=Reduction of blood cholesterol in man |volume=7 |issue=5 |pages=702–6 |journal=Circulation |doi=10.1161/01.CIR.7.5.702|bibcode=1953Circu...7..702P |s2cid=3165910 |doi-access= }}</ref><ref>{{cite journal |pmid=3942097 |year=1986 |last1=Tilvis |first1=RS |last2=Miettinen |first2=TA |title=Serum plant sterols and their relation to cholesterol absorption |volume=43 |issue=1 |pages=92–7 |journal=The American Journal of Clinical Nutrition|doi=10.1093/ajcn/43.1.92 |doi-access=free }}</ref> From 1954 to 1982, phytosterols were subsequently marketed as a pharmaceutical under the name Cytellin as a treatment for elevated cholesterol.<ref name="Jones2007">{{cite journal |pmid=17951490 |year=2007 |last1=Jones |first1=PJ |title=Ingestion of phytosterols is not potentially hazardous |volume=137 |issue=11 |pages=2485; author reply 2486 |journal=The Journal of Nutrition|doi=10.1093/jn/137.11.2485 |doi-access=free }}</ref>

'''Cholesterol lowering mechanisms'''

Phytosterols reduce intestinal cholesterol absorption, and two main mechanisms have been proposed: (1) reduced micellar solubilization of cholesterol in the intestinal lumen (“mixed micelle hypothesis”)<ref name=":0">{{Cite journal |last1=Ikeda |first1=Ikuo |last2=Sugano |first2=Michihiro |date=August 1983 |title=Some aspects of mechanism of inhibition of cholesterol absorption by β-sitosterol |url=https://linkinghub.elsevier.com/retrieve/pii/0005273683902432 |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |language=en |volume=732 |issue=3 |pages=651–658 |doi=10.1016/0005-2736(83)90243-2 |pmid=6615593 |url-access=subscription }}</ref><ref name=":1">{{Cite journal |last=Ikeda |first=Ikuo |date=2015 |title=Factors Affecting Intestinal Absorption of Cholesterol and Plant Sterols and Stanols |url=https://www.jstage.jst.go.jp/article/jos/64/1/64_ess14221/_article |journal=Journal of Oleo Science |language=en |volume=64 |issue=1 |pages=9–18 |doi=10.5650/jos.ess14221 |pmid=25742922 |issn=1345-8957|doi-access=free }}</ref> and (2) modulation of cholesterol handling at the enterocyte brush border membrane (microvilli), where absorption and efflux compete (“trans-intestinal sterol efflux (TISE)” model).<ref name=":2">{{Cite journal |last1=Nakano |first1=Takanari |last2=Inoue |first2=Ikuo |last3=Murakoshi |first3=Takayuki |date=2019-02-01 |title=A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Reappraises How Plant Sterol Intake Reduces Circulating Cholesterol Levels |journal=Nutrients |language=en |volume=11 |issue=2 |pages=310 |doi=10.3390/nu11020310 |doi-access=free |issn=2072-6643 |pmc=6412963 |pmid=30717222}}</ref>

''Mechanism 1: Mixed micelle hypothesis (lumen)''

Ikeda and colleagues proposed that bile salt mixed micelles have a limited capacity to solubilize sterols;<ref name=":0" /><ref name=":1" /> when phytosterols enter the micelles, they can reduce the micellar solubility of cholesterol in vitro, suggesting decreased cholesterol availability for uptake. In this framing, the key site of action is the intestinal lumen (the contents of the gut), i.e., before cholesterol interacts with the brush border membrane. This luminal competition does not translate into an inhibitory effect in in situ intestinal loop experiments: in rat jejunal loops, β-sitosterol had no inhibitory effect on cholesterol absorption from a preformed micellar solution.

''Mechanism 2: Brush border membrane (microvilli) model''

Nakano and colleagues proposed that the brush border membrane (BBM) acts as a “dividing ridge” for opposing cholesterol fluxes—movement toward absorption (cell interior) versus movement back to the lumen (efflux, including TICE).<ref name=":2" /><ref>{{Cite journal |last1=Nakano |first1=Takanari |last2=Inoue |first2=Ikuo |last3=Takenaka |first3=Yasuhiro |last4=Ono |first4=Hiraku |last5=Katayama |first5=Shigehiro |last6=Awata |first6=Takuya |last7=Murakoshi |first7=Takayuki |date=2016-03-29 |title=Ezetimibe Promotes Brush Border Membrane-to-Lumen Cholesterol Efflux in the Small Intestine |journal=PLOS ONE |language=en |volume=11 |issue=3 |article-number=e0152207 |doi=10.1371/journal.pone.0152207 |doi-access=free |issn=1932-6203 |pmc=4811413 |pmid=27023132 |bibcode=2016PLoSO..1152207N }}</ref><ref>{{Cite journal |last1=Nakano |first1=Takanari |last2=Inoue |first2=Ikuo |last3=Takenaka |first3=Yasuhiro |last4=Ikegami |first4=Yuichi |last5=Kotani |first5=Norihiro |last6=Shimada |first6=Akira |last7=Noda |first7=Mitsuhiko |last8=Murakoshi |first8=Takayuki |date=2018 |title=Luminal plant sterol promotes brush border membrane-to-lumen cholesterol efflux in the small intestine |url=https://www.jstage.jst.go.jp/article/jcbn/63/2/63_17-116/_article |journal=Journal of Clinical Biochemistry and Nutrition |language=en |volume=63 |issue=2 |pages=102–105 |doi=10.3164/jcbn.17-116 |pmid=30279620 |pmc=6160726 |issn=0912-0009}}</ref> In this model, phytosterols are taken up by the BBM diffusively, and because they are poorly assimilated, they are excreted by ABCG5/G8 and/or back-diffused, repeating this shuttle between the lumen and the BBM. Through repeated interactions at the microvillar membrane, phytosterols are proposed to promote concomitant cholesterol efflux and reduce net absorption (potentially also by disturbing NPC1L1-associated trafficking of cholesterol toward the cell interior).

'''Complementary to Statin Therapy: Added LDL Lowering, Uncertain Clinical Benefit'''

Unlike the [[statin]]s, 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,<ref name="Weingaertner_2008" /><ref name="Genser_2012">{{Cite journal | last1 = Genser | first1 = B. | last2 = Silbernagel | first2 = G. | last3 = De Backer | first3 = G. | last4 = Bruckert | first4 = E. | last5 = Carmena | first5 = R. | last6 = Chapman | first6 = M. J. | last7 = Deanfield | first7 = J. | last8 = Descamps | first8 = O. S. | last9 = Rietzschel | first9 = E. R. | last10 = Dias | doi = 10.1093/eurheartj/ehr441 | first10 = K. C. | last11 = März | first11 = W. | title = Plant sterols and cardiovascular disease: A systematic review and meta-analysis | journal = European Heart Journal | volume = 33 | issue = 4 | pages = 444–451 | year = 2012 | pmid = 22334625 | pmc =3279314 }}</ref> and another review showing evidence for use of dietary phytosterols to attain a cholesterol-lowering effect.<ref>{{cite journal|pmid=24468148|url=http://www.atherosclerosis-journal.com/article/S0021-9150(13)00694-1/fulltext|year=2014|last1=Gylling|first1=H|title=Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease|journal=Atherosclerosis|volume=232|issue=2|pages=346–60|last2=Plat|first2=J|last3=Turley|first3=S|last4=Ginsberg|first4=H. N|last5=Ellegård|first5=L|last6=Jessup|first6=W|last7=Jones|first7=P. J|last8=Lütjohann|first8=D|last9=Maerz|first9=W|last10=Masana|first10=L|last11=Silbernagel|first11=G|last12=Staels|first12=B|last13=Borén|first13=J|last14=Catapano|first14=A. L|last15=De Backer|first15=G|last16=Deanfield|first16=J|last17=Descamps|first17=O. S|last18=Kovanen|first18=P. T|last19=Riccardi|first19=G|last20=Tokgözoglu|first20=L|last21=Chapman|first21=M. J|author22=European Atherosclerosis Society Consensus Panel on Phytosterols|doi=10.1016/j.atherosclerosis.2013.11.043|doi-access=free|hdl=11655/15574|hdl-access=free}}</ref>

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]] (though statins also have adverse effects such as [[myopathy]] and digestive problems).<ref name="Weingaertner_2008" /> 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,<ref name="nguyen">{{cite journal|last1=Nguyen|first1=Tu T.|title=The Cholesterol-Lowering Action of Plant Stanol Esters|journal=The Journal of Nutrition|date=1999|volume=129|issue=12|pages=2109–2112|doi=10.1093/jn/129.12.2109|pmid=10573535|doi-access=free}}</ref><ref>{{cite journal|last1=Trautwein|first1=Elke A.|last2=Duchateau|first2=Guus S. M. J. E.|last3=Lin|first3=Yuguang|last4=Mel'nikov|first4=Sergey M.|last5=Molhuizen|first5=Henry O.F.|last6=Ntanios|first6=Fady Y.|title=Proposed mechanisms of cholesterol-lowering action of plant sterols|journal=European Journal of Lipid Science and Technology|date=2003|volume=105|issue=3–4|pages=171–185|doi=10.1002/ejlt.200390033}}</ref><ref>{{cite journal|last1=De Smet|first1=E|last2=Mensink|first2=RP|last3=Plat|first3=J|title=Effects of plant sterols and stanols on intestinal cholesterol metabolism: suggested mechanisms from past to present|journal=Molecular Nutrition & Food Research|date=2012|volume=56|issue=7|pages=1058–72|doi=10.1002/mnfr.201100722|pmid=22623436|url=https://cris.maastrichtuniversity.nl/en/publications/05119257-24a9-4aa6-b6f8-14de74964f3e|doi-access=}}</ref> an effect that complements statins. Phytosterols further reduce cholesterol levels by about 9% to 17% in statin users.<ref>{{cite journal |pmid=20439548 |year=2009 |last1=Scholle |first1=JM |last2=Baker |first2=WL |last3=Talati |first3=R |last4=Coleman |first4=CI |title=The effect of adding plant sterols or stanols to statin therapy in hypercholesterolemic patients: Systematic review and meta-analysis |volume=28 |issue=5 |pages=517–24 |journal=Journal of the American College of Nutrition |doi=10.1080/07315724.2009.10719784|s2cid=41438503 }}</ref> The type or dose of statin does not appear to affect the cholesterol-lowering efficacy of phytosterols.<ref name="Katan2003">{{cite journal |pages=965–78 |doi=10.4065/78.8.965 |title=Efficacy and Safety of Plant Stanols and Sterols in the Management of Blood Cholesterol Levels |year=2003 |last1=Katan |first1=M. B. |last2=Grundy |first2=S. M. |last3=Jones |first3=P. |last4=Law |first4=M. |last5=Miettinen |first5=T. |last6=Paoletti |first6=R. |journal=Mayo Clinic Proceedings |volume=78 |issue=8 |pmid=12911045 |last7=Stresa Workshop |first7=Participants|doi-access=free }}</ref>

Similarly, fixed-dose combinations of a statin with ezetimibe target complementary pathways—statins reduce hepatic cholesterol synthesis, whereas ezetimibe inhibits intestinal cholesterol absorption similarly to phytosterols —thereby producing additional LDL-C lowering compared with statin monotherapy. Ezetimibe added to statin therapy has demonstrated clinical outcome benefit in high-risk patients (e.g., IMPROVE-IT).

Because of their cholesterol reducing properties, some manufacturers are using sterols or stanols as a food additive.<ref name="aafc" /><ref>{{cite web|url=http://www.webmd.com/cholesterol-management/features/low-cholesterol-diet-plant-sterols-stanols|title= The New Low-Cholesterol Diet: Plant Sterols and Stanols: What are sterols and stanols, and does anyone like to eat them?|last1=Griffin |first1=RM |date=Feb 2, 2009 |publisher=WebMD |access-date=6 July 2013}}</ref>

==Safety== Phytosterols have a long history of safe use,<ref name="aafc"/> dating back to Cytellin, the pharmaceutical preparation of phytosterols marketed in the US from 1954 to 1982.<ref name="Jones2007" /> Phytosterol esters have [[generally recognized as safe]] (GRAS) status in the US.<ref>{{cite web|last=FDA|title=GRAS Notice 000181: Phytosterols|url=http://www.accessdata.fda.gov/scripts/fcn/gras_notices/grn000181.pdf}}{{dead link|date=May 2025|bot=medic}}{{cbignore|bot=medic}}</ref> Phytosterol-containing [[functional food]]s were subject to postlaunch monitoring after being introduced to the EU market in 2000, and no unpredicted side effects were reported.<ref>{{cite journal |pages=1213–22 |doi=10.1016/j.fct.2006.01.017 |title=Safety evaluation of phytosterol-esters. Part 9: Results of a European post-launch monitoring programme |year=2006 |last1=Lea |first1=L.J. |last2=Hepburn |first2=P.A. |journal=[[Food and Chemical Toxicology]] |volume=44 |issue=8 |pmid=16542769}}</ref>

A potential safety concern regarding phytosterol consumption is in patients with [[sitosterolemia|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. However, there is no direct evidence that phytosterols accelerate the development of atherosclerosis. On the other hand, a meta-analysis showed that premature atherosclerosis and resulting CVD observed in patients with sitosterolemia are attributable to severe hypercholesterolemia in their childhood.<ref name=":3">{{Cite journal |last1=Nakano |first1=Takanari |last2=Takashima |first2=Erina |last3=Yu |first3=Liqing |date=2025 |title=Factors Affecting Circulating Phytosterol Levels: Toward an Integrated Understanding of Atherogenicity and Atheroprotection by Dietary and Circulating Phytosterols |journal=Current Atherosclerosis Reports |language=en |volume=27 |issue=1 |article-number=104 |doi=10.1007/s11883-025-01334-7 |issn=1523-3804 |pmc=12540574 |pmid=41118071}}</ref> Also, one should keep in mind that dietary phytosterols do not meaningfully raise circulating phytosgterollevels even with having phytosterol-supplemented foods.<ref name=":3" />

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.<ref name="Silbernagel2009">{{cite journal |pages=334–41 |doi=10.1194/jlr.P800013-JLR200 |pmid=18769018 |title=The relationships of cholesterol metabolism and plasma plant sterols with the severity of coronary artery disease |year=2008 |last1=Silbernagel |first1=G. |last2=Fauler |first2=G. |last3=Renner |first3=W. |last4=Landl |first4=E. M. |last5=Hoffmann |first5=M. M. |last6=Winkelmann |first6=B. R. |last7=Boehm |first7=B. O. |last8=Marz |first8=W. |journal=The Journal of Lipid Research |volume=50 |issue=2|doi-access=free }}</ref><ref>{{cite journal |pages=2384–93 |doi=10.1194/jlr.P002899 |doi-access=free |pmc=2903788 |title=The associations of cholesterol metabolism and plasma plant sterols with all-cause and cardiovascular mortality |year=2010 |last1=Silbernagel |first1=G. |last2=Fauler |first2=G. |last3=Hoffmann |first3=M. M. |last4=Lutjohann |first4=D. |last5=Winkelmann |first5=B. R. |last6=Boehm |first6=B. O. |last7=Marz |first7=W. |journal=The Journal of Lipid Research |volume=51 |issue=8 |pmid=20228406}}</ref><ref>{{cite journal |pages=282–7 |doi=10.1016/j.atherosclerosis.2009.11.007 |title=Serum plant and other noncholesterol sterols, cholesterol metabolism and 22-year mortality among middle-aged men |year=2010 |last1=Strandberg |first1=Timo E. |last2=Gylling |first2=Helena |last3=Tilvis |first3=Reijo S. |last4=Miettinen |first4=Tatu A. |journal=Atherosclerosis |volume=210 |pmid=19962145 |issue=1}}</ref><ref>{{cite journal |pages=283–8 |doi=10.1016/j.atherosclerosis.2006.10.032 |title=Moderately elevated plant sterol levels are associated with reduced cardiovascular risk—The LASA study |year=2008 |last1=Fassbender |first1=Klaus |last2=Lütjohann |first2=Dieter |last3=Dik |first3=Miranda G. |last4=Bremmer |first4=Marijke |last5=König |first5=Jochem |last6=Walter |first6=Silke |last7=Liu |first7=Yang |last8=Letièmbre |first8=Maryse |last9=Von Bergmann |first9=Klaus |journal=Atherosclerosis |volume=196 |pmid=17137582 |issue=1 }}</ref><ref name="Rajaratnam2000">{{cite journal |pages=1185–91 |doi=10.1016/S0735-1097(00)00527-1 |title=Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women |year=2000 |last1=Rajaratnam |first1=Radhakrishnan A |last2=Gylling |first2=Helena |last3=Miettinen |first3=Tatu A |journal=Journal of the American College of Cardiology |volume=35 |issue=5 |pmid=10758959|doi-access= }}</ref><ref name="Assmann2006">{{cite journal |pages=13–21 |doi=10.1016/j.numecd.2005.04.001 |title=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 |year=2006 |last1=Assmann |first1=Gerd |last2=Cullen |first2=Paul |last3=Erbey |first3=John |last4=Ramey |first4=Dena R. |last5=Kannenberg |first5=Frank |last6=Schulte |first6=Helmut |journal=Nutrition, Metabolism and Cardiovascular Diseases |volume=16 |pmid=16399487 |issue=1}}</ref><ref name="Sudhop2002">{{cite journal |pages=1519–21 |doi=10.1053/meta.2002.36298 |title=Serum plant sterols as a potential risk factor for coronary heart disease |year=2002 |last1=Sudhop |first1=Thomas |last2=Gottwald |first2=Britta M. |last3=Von Bergmann |first3=Klaus |journal=Metabolism |volume=51 |issue=12 |pmid=12489060}}</ref><ref>{{cite journal |pages=139–44 |doi=10.1194/jlr.M600371-JLR200 |pmid=17074925 |title=Plasma levels of plant sterols and the risk of coronary artery disease: The prospective EPIC-Norfolk Population Study |year=2006 |last1=Pinedo |first1=S. |last2=Vissers |first2=M. N. |last3=Bergmann |first3=K. v. |last4=Elharchaoui |first4=K. |last5=Lutjohann |first5=D. |last6=Luben |first6=R. |last7=Wareham |first7=N. J. |last8=Kastelein |first8=J. J. P. |last9=Khaw |first9=K.-T. |journal=The Journal of Lipid Research |volume=48|issue=1 |last10=Boekholdt |first10=S. M. |doi-access=free }}</ref> 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|Phytosterols as a marker for cholesterol absorption]]).<ref name=":3" />

'''Sterols and stanols'''

The equivalent ability and safety of plant sterols and plant [[stanol]]s 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.<ref>{{cite journal |pages=715–25 |doi=10.1038/sj.ejcn.1601083 |title=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 |year=2000 |last1=Hallikainen |first1=M A |last2=Sarkkinen |first2=E S |last3=Gylling |first3=H |last4=Erkkilä |first4=A T |last5=Uusitupa |first5=M I J |journal=European Journal of Clinical Nutrition |volume=54 |issue=9 |pmid=11002384|s2cid=19548242 |doi-access=free }}</ref><ref>{{cite journal |pages=133–42 |doi=10.1016/S0939-4753(04)80033-4 |pmid=15330272 |title=Comparison of the effects of dietary plant sterol and stanol esters on lipid metabolism |year=2004 |last1=O'Neill |first1=F.H. |last2=Brynes |first2=A. |last3=Mandeno |first3=R. |last4=Rendell |first4=N. |last5=Taylor |first5=G. |last6=Seed |first6=M. |last7=Thompson |first7=G.R. |journal=Nutrition, Metabolism and Cardiovascular Diseases |volume=14 |issue=3}}</ref><ref>{{cite journal |pmid=12450893 |year=2002 |last1=Vanstone |first1=CA |last2=Raeini-Sarjaz |first2=M |last3=Parsons |first3=WE |last4=Jones |first4=PJ |title=Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons |volume=76 |issue=6 |pages=1272–8 |journal=The American Journal of Clinical Nutrition|doi=10.1093/ajcn/76.6.1272 |doi-access=free }}</ref> 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.<ref>{{cite journal |pages=719–26 |doi=10.1016/j.jada.2010.02.011 |title=The Comparative Efficacy of Plant Sterols and Stanols on Serum Lipids: A Systematic Review and Meta-Analysis |year=2010 |last1=Talati |first1=Ripple |last2=Sobieraj |first2=Diana M. |last3=Makanji |first3=Sagar S. |last4=Phung |first4=Olivia J. |last5=Coleman |first5=Craig I. |journal=Journal of the American Dietetic Association |volume=110 |issue=5 |pmid=20430133}}</ref> 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.<ref name="Weingaertner_2008">{{cite journal |pages=404–9 |doi=10.1093/eurheartj/ehn580 |pmc=2642922 |title=Controversial role of plant sterol esters in the management of hypercholesterolaemia |year=2008 |last1=Weingartner |first1=O. |last2=Bohm |first2=M. |last3=Laufs |first3=U. |journal=European Heart Journal |volume=30 |issue=4 |pmid=19158117}}</ref>

==Functions in plants== Sterols are essential for all [[eukaryote]]s. In contrast to animal and [[fungus|fungal]] cells, which contain only one major sterol, plant cells synthesize an array of sterol mixtures in which [[sitosterol]] and [[stigmasterol]] predominate.<ref>{{cite journal |pages=170–175 |doi=10.1016/S1360-1385(98)01233-3 |title=Plant sterols and the membrane environment |year=1998|last1=Hartmann|first1=Marie-Andrée |journal=Trends in Plant Science |volume=3 |issue=5 |bibcode=1998TPS.....3..170H }}</ref> Sitosterol regulates membrane fluidity and permeability in a similar manner to cholesterol in mammalian cell membranes.<ref name="mnfr">{{cite journal|pmid=22623436|year=2012|last1=De Smet|first1=E|title=Effects of plant sterols and stanols on intestinal cholesterol metabolism: Suggested mechanisms from past to present|journal=Molecular Nutrition & Food Research|volume=56|issue=7|pages=1058–72|last2=Mensink|first2=R. P|last3=Plat|first3=J|doi=10.1002/mnfr.201100722|url=https://cris.maastrichtuniversity.nl/en/publications/05119257-24a9-4aa6-b6f8-14de74964f3e |doi-access=}}</ref> Plant sterols can also modulate the activity of membrane-bound enzymes.<ref name="mnfr"/> Phytosterols are also linked to plant adaptation to temperature and plant immunity against pathogens.<ref>{{cite journal|pmid=24777987|year=2014|last1=De Bruyne|first1=L|title=Connecting growth and defense: The emerging roles of brassinosteroids and gibberellins in plant innate immunity|journal=Molecular Plant|volume=7|issue=6|pages=943–59|last2=Höfte|first2=M|last3=De Vleesschauwer|first3=D|doi=10.1093/mp/ssu050|url=http://www.cell.com/molecular-plant/fulltext/S1674-2052(14)60799-1|doi-access=free}}</ref>

== References == {{Reflist|35em}}

{{Sterols}} {{Phytochemical}} {{Phytosterols}} {{Cholesterol metabolism intermediates}}

[[Category:Phytosterols| ]] [[Category:Food additives]] [[Category:Lipid-lowering agents]] [[Category:Phytochemicals]] [[Category:Tree-derived bioactive compounds]]