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. Phytosterols are widely recognized as a food additive with proven cholesterol-lowering efficacy.[2]

Contents

Structure

Nomenclature for steroid skeleton (on right)

Dietary phytosterols

The richest naturally occurring sources of phytosterols are vegetable oils and products made from them. Nuts, which are rich in phytosterols are often eaten in smaller amounts can still significantly contribute to total phytosterol intake, while 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.[3] The intake of naturally occurring phytosterols ranges between ~150-450 mg/day[4] depending on eating habit. Specially designed vegetarian experimental diets having been produced yielding upwards of 700mg/day.[5] The most commonly occurring phytosterols in the human diet are β-sitosterol, Campesterol and Stigmasterol which account for approximately 65%, 30% and 3% of diet contents, respectively.[6] The most common plant stanols in the human diet are sitostanol and campestanol which combined make up about ~5% of dietary phytosterol.[7]

Cholesterol lowering

The ability of phytosterols to reduce cholesterol levels was first demonstrated in humans in 1953.[8] They were subsequently marketed as a pharmaceutical under the name Cytellin as a treatment for elevated cholesterol from 1954-1982.[9] Functional foods containing phytosterols, marketed to reduce cholesterol, were first introduced in Finland in 1995 by Raisio group. Phytosterol-supplemented functional foods have been subsequently shown to reduce total and LDL-cholesterol levels in hundreds of subsequent clinical trials.[10][11] Phytosterols are also currently available in capsules and tablets, formulated with phytosterols alone or combined with multivitamins.

Mechanism of action

Phytosterols lower cholesterol levels by competing with cholesterol for absorption in the intestine (see cholesterol absorption inhibitor).[12] Having a similar structure to cholesterol, phytosterols compete with cholesterol of dietary and biliary origin for incorporation into micelles in the gastrointestinal tract. Cholesterol displaced from the micelles is not absorbed and is destined for fecal excretion.

Efficacy/Dosage

Phytosterol reduce total and LDL cholesterol in a dose dependant manner.[10] Current supplemental guidelines recommend doses of phytosterols in the 1.6-3.0 grams per day range (Health Canada, EFSA, ATP III,FDA) with a recent meta-analysis demonstrating an 8.8% reduction in LDL-cholesterol at a mean dose of 2.15 gram per day.[10] A recent meta-analysis by Musa-Veloso et al.[13] also reported a dose response in cholesterol lowering following phytosterol supplementation and suggested that phytosterols in the stanol form may be more effective than phytosterols in the sterol form, but only at doses well above the currently recommended level (See Sterol vs Stanol).

Phytosterols in functional foods

Functional foods containing phytosterols, rather than nutraceutical delivery, are the most commonly used mechanism of phytosterol supplementation. Foods enriched in phytosterols replace foods already in the diet to enrich the phytosterol intake without having to change eating patterns. Functional foods containing phytosterols were named the 10th greatest nutritional discovery since 1976 in the European Journal of Clinical Nutrition.[14]

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 every day. The scientists found that the effect is usually established within the first 2-3 weeks. Longer-term studies extending up to 85 weeks showed that the cholesterol-lowering effect could be sustained.[15]

Based on this and other efficacy data the EFSA scientists consider the following health claims to reflect the available scientific knowledge: “Plant sterols have been shown to lower/reduce blood cholesterol. Blood cholesterol lowering may reduce the risk of coronary heart disease" and “Plant stanol esters have been shown to lower/reduce blood cholesterol. Blood cholesterol lowering may reduce the risk of coronary heart disease".[16]

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 [17]. 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] The FDA is currently reviewing the health claims for phytosterols.[18] When 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 make an authorized health claim relating phytosterol consumption to cholesterol lowering and CVD risk.[18]

Health Canada

Health Canada reviewed the evidence of 84 randomized controlled trials published between 1994-2007 involving phytosterol supplementation. An average of 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 moderately to highly 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." and "High cholesterol is a risk factor for heart disease."[19]

Safety

Phytosterol have a long history of safe use dating back to Cytellin, the pharmaceutical preparation of phytosterols marketed in the U.S from 1954-1982[9]. Phytosterol esters have generally recognized as safe (GRAS) status in the US[20]. Phytosterol containing functional foods were subject to post-launch monitoring after being introduced to the E.U market in 2000 and no unpredicted side-effects were reported.[21]

A potential safety concern regarding phytosterol consumption is in patients with phytosterolaemia(or sitosterolemia) a rare genetic disorder which results in a 50-100 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 un-associated with CVD risk depending on the study population investigated.[22][23][24][25][26][27][28][29]

The link between plant sterols and CVD or CHD risk is complicated by the fact that 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 plant stanols when compared head to head in clinical trials have been shown to equally reduce cholesterol levels.[30][31][32] 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.[33] Trials looking at high doses (> 4g/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. Only when a direct comparison between high dose plant sterol to plant stanol supplementation has been completed could it be said that either is more efficacious than the other at lowering cholesterol.

The debate regarding sterol vs. stanol safety is centered on their differing intestinal absorption and resulting plasma concentrations.[34] 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.[35][36] suggested that 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 that elevated plant sterol levels may be a risk factor for CVD.[26][28][27] However, it must be noted that in these studies 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.[4] Due to the fact that plant sterol levels actually reflect cholesterol absorption some have concluded that elevated cholesterol absorption, not plant sterol themselves are atherogenic or otherwise associated with CVD risk.[22]

Effects in conjunction with statins

Currently, statins are the most widely prescribed pharmaceutical in the world for cholesterol-lowering (see List of bestselling drugs). Statins work by reducing cholesterol synthesis by inhibiting the rate-limiting HMG-CoA reductase enzyme. Phytosterols reduce cholesterol levels by competing with cholesterol absorption in the gut, a mechanism which complements statins. Both plant sterol and stanol forms of phytosterols reduced LDL cholesterol by 0.34 mmol/L on average when supplemented at 2.5g/day in individuals on statin treatment.[37] These results were supported in a meta-analysis by Scholle et al.(2009).[38] showing that phytosterols further reduces cholesterol levels by 9.18-17.34 % in statin users. The type or dose of statin does not appear to affect phytosterols’ cholesterol lowering efficacy. These data suggest that phytosterols are a viable adjunct to statin therapy, and statin users may benefit more from phytosterol supplementation than increasing their current statin dose, especially with regards to potential side-effects associated with statin use.[11]

Potential for TAG lowering

Elevated triglyceride levels are a risk factor for CVD.[39] Beyond LDL-C lowering, growing evidence suggest that phytosterols reduce triglyceride levels as well. Triglycerides were found to be reduced by 14% in individual supplementing 1.6g/day of plant sterols in a fermented milk beverage for 6 weeks.[40] The proposed mechanism behind the triglyceride lowering effect of phytosterols is due to a reduction in triglyceride rich VLDL particle produced by the liver.[41] It is believed that the triglyceride lowering effects of phytosterols are more pronounced in individuals with elevated triglycerides.[42]

Phytosterols as a marker for cholesterol absorption

The use of serum plant sterol levels to predict cholesterol absorption was first proposed by Tilvis and Miettinen (1986).[43] These researchers showed that serum levels of campesterol, when normalized for total serum cholesterol, correlated positively with cholesterol absorption in healthy populations. Recently it has also been shown that serum plant sterol concentrations fail to accurately reflect cholesterol absorption in individuals with Smith-Lemli-Opitz syndrome.[44] Phytosterols should also not be used as surrogates for cholesterol absorption in situations when phytosterols are being supplemented.[45] Therefore, the use of serum plant sterols as surrogates for cholesterol absorption should be carefully verified and validated prior to its use within a particular population.

Phytosterols and Cancer risk

Considerable emerging evidence supports the inhibitory actions of phytosterols on lung, stomach, as well as ovarian and breast cancer.[46] Phytosterols seem to act through multiple mechanisms of action, including inhibition of carcinogen production, cancer-cell growth, angiogenesis, invasion and metastasis, and through the promotion of apoptosis of cancerous cells. Phytosterol consumption may also increase the activity of antioxidant enzymes and thereby reduce oxidative stress.

References

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Phytochemicals
Natural phenols and Polyphenols • Phytosterols • Saponins
Misc:
biochemical families: prot · nucl · carb (glpr, alco, glys) · lipd (fata/i, phld, strd, gllp, eico) · amac/i · ncbs/i · ttpy/i
Phytosterols
β-Sitosterol • Campesterol • Stigmasterol • Brassicasterol • Delta-7-stigmasterol • Delta-7-avenasterol • Ergosterol (Vitamin D2)