Sterols are important constituents of cell membranes. Cholesterol is the sterol of mammalian cells, whereas the plant equivalents are called phytosterols. Phytosterols are known since the early 1930s and the most common plant sterols are sitosterol, campesterol, and stigmasterol. Plant sterols can be further divided into sterols and stanols depending on their molecular structure.  Plant sterols and stanols are found in all plant foods. The highest concentrations of plant sterols can be found in vegetable oils.

Plant stanol ester used in Benecol products is produced by esterifying the plant stanols with unsaturated fatty acids of vegetable oils. This is done in order to increase the fat solubility and enable the maximal incorporation into foods.

Small amounts of plant stanols occur naturally in many foods in both free and esterified forms. The main dietary sources are whole-grain foods, mostly wheat and rye. The daily intake of stanols in the average Western diet is about 30-50 mg/d [1], whereas the intake of plant sterols is about 300-500 mg/d [2] and that of cholesterol is 500-800 mg/d.

However, the natural levels of plant sterols and stanols of the normal every day diet are a way too low to have a significant effect on serum cholesterol levels. Therefore functional foods containing enough Plant stanol ester have the potential to become the basis of cholesterol management of the people.

Plant sterols are derived either from vegetable sources (mainly soy, but also corn and rapeseed) or from tall oil. Plant sterols are saturated into plant stanols, which are then esterified with unsaturated fatty acids of vegetable oils.

Adding Plant stanol ester to the foods

Plant stanol ester has typical properties of edible fats and it can be easily incorporated into fat containing foods. Plant stanol ester can also be added to various low-fat and fat-free foods. Different potential food applications are described more in detail here.

The production process of Plant stanol ester

Difference between plant sterols and plant stanols

Even though plant sterols and stanols are structurally very similar, the following differences have been found between them:

Efficacy
Until recently, it was thought that increasing the intake of plant stanols or sterols above the recommended  2 grams per day would not result in an enhanced cholesterol lowering efficacy. However, the most recent studies show that the LDL lowering efficacy of Plant stanol ester is dose dependent, but the same effect was not found with plant sterols. When increasing plant stanol ester dose up to 9 grams plant stanols per day, the maximal LDL cholesterol lowering efficacy was -17% [3],[4]. In the recent meta-analyses [5] the maximal LDL lowering efficacy of plant sterol ester was -18,3%, whereas the corresponding maximal LDL lowering of plant sterol remained at 10,7%. Increased daily doses of plant stanol ester were found to be safe without adverse effects.

Absorption
The intestinal absorption of plant stanols is very low, varying from 0.04 to 0.1% compared with 0.5 to 1.9% of plant sterols [1]. Serum and tissue levels of plant stanols are less than 1/10 compared with concentrations of corresponding plant sterols. However, it is worth noticing that the serum levels of both plant stanols and plant sterols are still very low compared with the serum cholesterol levels.

Plant stanol ester is shown to be safe, well-tolerated and without adverse effects in clinical studies, in assessments by food authorities and by the experience of thousands of consumers.

Plant stanols are practically unabsorbed and are effectively excreted from the body. As a result of the low absorption, the amount of plant stanol in the blood remains very low even after continuous long-term use of Benecol products, and also when the daily intake of plant stanols exceeds the currently recommenced dose of 2 grams per day (i.e. up to 9 gram per day). [1], [6]

Plasma levels of fat-soluble vitamins and other vegetable-derived compounds have been studied following plant sterol and stanol ingestion due to concerns about the possibility of reduced absorption. Serum concentrations of alpha- and beta-carotene were found to slightly reduced after long-term use, although results have been inconsistent. However, no reduction in beta-carotene level was seen when plant sterols or plant stanols were consumed as part of a healthy diet containing fruits and vegetables. [7-11]

Based on the evidence from toxicological studies and numerous clinical trials, plant stanols are characterized as safe by authorities in the EU as well as by the FDA (USA).

Plant stanol ester added to foods reduces serum levels of total and LDL cholesterol by partly inhibiting the absorption of dietary cholesterol and the re-absorption of biliary cholesterol in the human intestine.

Plant stanols reduce blood concentrations of both cholesterol and plant sterols. This may be of importance since elevated plant sterol concentrations have been identified as a potential independent risk factor for coronary heart disease (CHD). Two ABC transporters (ABCG5 and ABCG8) play an important role in the regulating the intestinal absorption of plant sterols by secreting absorbed plant sterols from the enterocytes back into the intestinal lumen. Mutations in these transporter proteins lead to a rare congenital disease called sitosterolaemia, which is characterised by:

•    severely elevated serum plant sterol concentrations,
•    normal to moderately increased serum cholesterol concentrations, and
•    a high risk of developing CHD at a very early age.

Polymorphisms in the ABCG5 and ABCG8 genes contribute to modifying serum plant sterol levels in healthy, non-sitosterolaemic individuals. Furthermore, several epidemiological studies have shown that the risk of developing heart disease seems to be increased even at more "normal" plant sterol levels although other studies  show no induced risk with elevated blood plant sterol concentrations.. Since statins were shown to increase serum plant sterol concentrations, a combination therapy focusing on simultaneous reduction of cholesterol synthesis and absorption should be considered, potentially with agents such as Plant stanol ester the also reduces the absorption of plant sterol concentrations. [12], [13] Plant stanol ester effectively reduces both serum cholesterol and plant sterol concentrations in subjects on statin treatment [14].

The mechanism of action of plant stanol ester has been described in several preclinical and clinical trials and can be divided into two steps.

Step 1:
Cholesterol absorption occurs via the formation of mixed micelles with bile acids. Plant stanols displace cholesterol from these mixed micelles so that less cholesterol is available for absorption. Plant stanol ester foods should be consumed as part of a meal in order to be optimally incorporated into the mixed micelles.

Step 2:
In vitro studies have shown that plant stanols activate LXR alpha, LXR beta and ABCA1 transporter proteins. It is thus hypothesised that plant stanols work within the enterocytes by activating the excretion of cholesterol back into the intestinal lumen, although the effect of plant stanols on cholesterol trafficking within the enterocytes still need to be elucidated in detail.

As a consequence of the reduced absorption of cholesterol, the absorption of fat-soluble components other than cholesterol, such as vitamins and antioxidants, may also be reduced. Like cholesterol, carotenoids and tocopherols are transported by lipoprotein particles. Since the number of LDL particles in circulation decreases after consumption of plant sterols or stanols, absolute plasma concentrations of carotenoids and tocopherols also decrease. This is why these antioxidants are often standardised to plasma lipid concentrations.

The results of randomised, placebo-controlled trials on the effects of plant sterols or stanols on fat-soluble vitamins and antioxidants were summarised in 2003 [15]. Significant reductions were only seen in clinical trials for hydrocarbon carotenoids. These reductions are probably caused by reduced absorption and lower plasma concentrations of the carrier, LDL lipoprotein. After correcting for cholesterol levels, only the reduction in the β-carotene level remained significant [7-10]. It is important, however, that carotenoid and tocopherol levels remained within normal ranges even with relatively high daily intakes (up to 9g/d) of plant stanols [16], [3]. Clinical trials also showed that when consuming plant sterol or stanol food products as part of a diet with increased consumption of vegetables and fruit, carotenoid levels did not decrease [17]. Thus the moderate decrease in β-carotene levels is not a reason to avoid consumption of plant stanol ester-containing foods as part of cholesterol-lowering diet, but the hypercholesteromic patients should have five servings of fruit and vegetables a day including one serving of vegetables having high β-carotene content, such as carrots, tomatoes, spinach, broccoli or green leafy vegetables [11]. Plasma concentrations of retinol (vitamin A), 25-hydroxyvitamin D and vitamin K are unaffected by dietary plant sterols and stanols [3],[8],[9],[18],[19]. As a conclusion, there is no data to support the claim that the decrease in β-carotene levels related to consumption of plant stanols would have adverse effects on health.

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[2] Valsta et al. Br J Nutr 2004
[3] Gylling et al. Clinical Nutrition 2010
[4] Mensink et al. Am J of Clin Nutr 2010
[5] Musa-Veloso et al. PLEFA 2011a, 2011b
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