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Phytosterols as functional food ingredients: Linkages to cardiovascular disease and cancer Article · April 2009 DOI: 10.1097/MCO.0b013e328326770f · Source: PubMed

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Phytosterols as functional food ingredients: linkages to cardiovascular disease and cancer Peter J.H. Jonesa and Suhad S. AbuMweisb a

Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Smartpark, Winnipeg, Manitoba, Canada and bDepartment of Clinical Nutrition and Dietetics, Faculty of Allied Health Sciences, The Hashemite University, Zarqa, Jordan Correspondence to Peter J.H. Jones, PhD, Richardson Centre for Functional Foods and Nutraceuticals, University of Manitoba, Smartpark, 196 Innovation Drive, Winnipeg, MB, Canada R3T 6C5 Tel: +1 204 474 8883; fax: +1 204 474 7552; e-mail: [email protected] Current Opinion in Clinical Nutrition and Metabolic Care 2009, 12:147–151

Purpose of review To examine experimental evidence that has examined association of phytosterols and the reduction of the risk of cardiovascular disease and cancer. Recent findings Phytosterols exist as naturally occurring plant sterols that are present in the nonsaponifiable fraction of plant oils. Phytosterols are plant components that have a chemical structure similar to cholesterol except for the addition of an extra methyl or ethyl group; however, phytosterol absorption in humans is considerably less than that of cholesterol. In fact, phytosterols reduce cholesterol absorption, although the exact mechanism is not known, and thus reduce circulating levels of cholesterol. The efficacy of phytosterols as cholesterol-lowering agents have been shown when incorporated into fat spreads as well as other food matrices. In addition, phytosterols have been combined with other beneficial dietary components including fish and olive oils, psyllium and beta-glucan to enhance their effect on risk factors of cardiovascular disease. Phytosterols appear not only to play an important role in the regulation of cardiovascular disease but also to exhibit anticancer properties. A side effect associated with the consumption of phytosterols is that they reduce the blood levels of carotenoid. Nevertheless, it has been suggested that compensation for this impact on serum carotenoid levels can occur either by increasing the intake of carotenoid-rich foods or by taking supplements containing these carotenoids. Summary Dietary phytosterols appear to play an important role in the regulation of serum cholesterol and to exhibit anticancer properties. Keywords cancer, cholesterol, phytosterols Curr Opin Clin Nutr Metab Care 12:147–151 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins 1363-1950

Introduction Phytosterols exist as naturally occurring plant sterols that are present in the nonsaponifiable fraction of plant oils. Structurally, phytosterols are similar to cholesterol except for substitutions on the sterol side chain at the C24 position. Phytosterols are not synthesized in humans, are poorly absorbed, and are excreted faster from the liver than cholesterol, which explains their low abundance in human tissues. The primary phytosterols in the diet are sitosterol, stigmasterol, and campesterol. Typical consumption of plant sterols is approximately 200–400 mg/day. The most abundant phytosterol in western diets is beta-sitosterol, but these materials are found in the tissues and plasma of healthy individuals at concentrations 800–1000 times lower than that of endogenous cholesterol. Epidemiological evidence indicates a reduced incidence of various types of cancer, cardiovascular disease, and other chronic conditions in populations consuming 1363-1950 ß 2009 Wolters Kluwer Health | Lippincott Williams & Wilkins

diets rich in vegetables and fruits. Although many studies have concentrated on the protective effects of minerals, trace elements and vitamins, it is only in recent years that the phytosterol content of the foods has been taken into account and yielded positive correlations in terms of chronic disease risk reduction. The purpose of this review is to examine experimental evidence of such associations. Reduction of serum cholesterol levels

Phytosterols have been shown to inhibit the uptake of both dietary and endogenously produced (biliary) cholesterol from intestinal cells. Such inhibition results in a decrease in serum total and LDL-cholesterol (LDL-C) levels [1]. Levels of HDL-cholesterol and triglycerides do not appear to be affected by dietary phytosterol consumption.

Human studies For example, a 30-day trial [2] has shown that a 1.7 g/day dose of oil phytosterols containing 20% sitostanol and DOI:10.1097/MCO.0b013e328326770f

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148 Lipid metabolism and therapy

80% other phytosterols (primarily sitosterol and campesterol) reduced LDL-C by 24.4% in hypercholesterolemic men compared with 8.9% with the control diet. Moreover, a 9-week double-blind, crossover study was designed to assess the cholesterol-lowering effect of two table spreads fortified with free (nonesterified) vegetable oil sterols (mainly from soybean oil) or with sheanut oil sterols [3]. Plasma total cholesterol and LDL-C concentrations were statistically significantly reduced by 3.8 and 6%, respectively, for the spread enriched with free soybean oil sterols compared with the control spread. Other studies have determined the effect of whole corn oil and purified phytosterol-free corn oil triglyceride on cholesterol absorption in single-meal tests [4]. Deuterated cholesterol was included in the meal and the plasma enrichment was measured several days later. Cholesterol tracer in plasma following a test meal containing sterolfree oil was 38% (10%) higher than that observed using native corn oil. Phytosterols were the principal nontriglyceride component of commercial corn oil and readdition of corn oil sterols to sterol-free oil restored cholesterol absorption to the original value. Amounts of corn oil sterols as small as 150 mg reduced cholesterol absorption significantly. These data show a prominent effect of corn oil phytosterols on cholesterol absorption at doses much lower than those used in commercial supplements. More recently, a clinical study [5] involving 15 hypercholesterolemic persons showed that 1.8 g/day of free sterols, free stanols, or a free stanol/sterol mixture incorporated into a dairy fat spread gave statistically similar reductions in LDL-C in the range of 10–15%.

Factors affecting efficacy of phytosterols The physical state of plant sterols may have an impact on their cholesterol-lowering effect. For example, in a double-blind randomized, placebo-controlled study, a crystallizing method was used to add plant sterols into dietary fats and oils homogeneously [6]. Hypercholesterolemic participants consuming 1.5 or 3.0 g/day of free unesterified plant sterols in this ‘microcrystalline’ form experienced a 7.5–11.6% reduction in LDL-C levels. However, conflicting data raise some doubts about the biologic activity of the microcrystalline phytosterols. During single-meal tests in humans, crystalline phytosterols (1000 mg) did not reduce absorption of labeled cholesterol consistently, whereas 300 mg of phytosterols complexed with lecithin reduced cholesterol absorption by 34% [7]. Despite the increased sterol purity, it has been suggested that the extremely stable state of the crystalline structure requires both energy and time to disrupt. Crystalline phytosterols took several days to reach an equilibrium state during solubilization in

solutions of bile salts [8]. There is almost no transfer of crystalline phytosterols from the solid state to the micelles of artificial bile solutions over periods of a few hours at physiologic temperature [7]. These in-vitro findings suggest that it is unlikely that phytosterol crystals are biologically active. Phytosterols have been added to food matrices other than fat spread including low-fat milk [9], bakery products [10], orange juice [11], cereal bars [12], low-fat and nonfat beverages [13], and chocolate bars [14]. A recent analysis [1] of these trials showed that compared with control, LDL levels were reduced by 0.33 mmol/l [95% confidence interval (CI) 0.38 to 0.28], 0.32 mmol/l (95% CI 0.40 to 0.25), 0.34 mmol/l (95% CI 0.40 to 0.28), and 0.20 mmol/l (95% CI 0.28 to 0.11) in the fat spreads, mayonnaise and salad dressing, milk and yoghurt drinks, and other food products, respectively. Other food products subgroup included studies testing the efficacy of plant sterols incorporated in chocolate and cereal bars, beverages, juices, meat and croissants, and muffins. Therefore, the matrix to which phytosterols are added can influence their efficacy as cholesterol-lowering agents. It is also relevant to compare the cholesterol-lowering activity of vegetable oil-based table spreads enriched in plant sterol esters for normocholesterolemic with mildly hypercholesterolemic participants. This was done in two studies [15,16] in which consumption of margarine or spreads enriched with plant sterols effectively lowered plasma total and LDL-C concentrations. However, the effects on blood lipids did not differ between normocholesterolemic and mildly hypercholesterolemic participants. These effects can also be seen even for those individuals who are already on a low-cholesterol diet. For example, a study chose to work with people following a National Cholesterol Education Program Step I diet. Participants consuming 1.1 and 2.2 g of sterols per day had total cholesterol values that were 5.2 and 6.6% lower, LDL-C values that were 7.6 and 8.1% lower, respectively, than values for the control group [17]. In another clinical trial, a combination of low-fat margarine and milk enriched with plant sterols reduced LDL-C by 7.7% and apolipoprotein B by 4.6%, compared to placebo, in mildly hypercholesterolemic participants [18]. So plant sterols can offer an additional, significant reduction in serum cholesterol concentrations to that obtained with a low-fat diet alone.

Phytosterols in combination with other agents A recent set of studies compared the cholesterol-lowering efficacy of different esters of plant sterols [19,20]. Participants were fed five different dietary sterols including


Phytosterols as functional food ingredients Jones and AbuMweis 149

olive oil, fish oil, and fatty acid plant sterol esters of sunflower oil, as well as olive oil, and fish oil at level of 1.7 g/day for 28 days, each separated by washout periods. Diets were controlled precisely so that participants ate meals provided from a central metabolic kitchen to maintain weight balance. Plant sterol-fish oil ester reduced fasting and postprandial plasma triacylglycerol levels compared with plant sterol-sunflower oil ester by 39 and 40%, respectively. Compared with an olive oil diet, plant sterol-fish oil ester and plant sterol-sunflower oil ester lowered LDL-C levels by 3 and 6%, respectively. HDL-cholesterol levels were not affected by any of the treatments. Fish oil and sunflower oil plant sterols resulted in a lower total cholesterol : HDL-cholesterol ratio and lower apolipoprotein B levels than olive oil and fish oil. Phytosterols are also effective when combined with other dietary factors including psyllium [21], fish oil [22], beta-glucan [23], or statin drugs [24,25] and could be useful in secondary prevention of heart disease when greater targeted reductions in LDL-C are needed.

Mechanism of action of phytosterols The exact mechanism by which phytosterols decrease serum cholesterol levels is not completely understood, but several theories have been proposed [26]. One of them suggests that cholesterol in the intestine, already marginally soluble, is precipitated into a nonabsorbable state in the presence of added phytosterols and stanols. Another theory is based on the fact that cholesterol must enter bile-salt and phospholipid-containing ‘mixed micelles’ in order to pass through intestinal cells and to be absorbed into the bloodstream. Moreover, phytosterols may modulate the action of key transporters involved in cholesterol absorption (Fig. 1). Cholesterol absorption is a very important physiological mechanism that regulates cholesterol metabolism. A recent trial showed that efficacy of phytosterols is not influenced by dietary cholesterol intake in hypercholesterolemic individuals [27]. Both dietary cholesterol (300 mg/day) and recirculating biliary cholesterol (1000 mg/day) mix in the intestine and are partially absorbed. Failure to reabsorb intestinal cholesterol is the principal means of cholesterol elimination from the body. Some studies show that phytosterols compete with and displace cholesterol from bile salt/phospholipid micelles, the form from which cholesterol absorption occurs. During one trial, nine adults were fed a meal containing 500 mg of cholesterol and 1 g beta-sitosterol or 2 g beta-sitosteryl oleate [28]. The addition of betasitosterol resulted in a 42% decrease in cholesterol absorption, and the beta-sitosteryl oleate caused a 33% reduction compared to the control group, which resulted in a consequent decrease in plasma cholesterol. Sitosterol has increased affinity for biliary micelles compared

Figure 1 Mechanism of action of phytosterols

Phytosterols may reduce cholesterol absorption by competing with cholesterol for incorporation into the bile salts micelles, or for uptaking of cholesterol by enterocytes through Niemann Pick C1 Like 1 (NPC1L1) transporter. In addition, phytosterols may enhance cholesterol excretion back into the intestinal lumen through the adenosine triphosphate binding cassette G 5 (ABCG5) and G 8 (ABCG8) transporters. Phytosterols could also prevent esterification of the free cholesterol into cholesterol esters and thus its assembling into the chylomicrons. As a result of reducing cholesterol absorption by phytosterols, the cholesterol synthesis rate increase, but the net effect is a reduction in LDL-cholesterol levels.

with cholesterol, so sitosterol uptake by micelles is energetically favored. Further evidence of the importance of micellar solubility is the finding that the absorbability of different sterols is directly related to their equilibrium micellar concentration [8]. Unlike cholesterol, phytosterols, and to a greater extent, phytostanols, are poorly absorbed and the small amount that is absorbed is actively re-excreted in bile. This results in low serum levels of these sterol molecules. The inhibition of cholesterol absorption is thought to produce a state of relative cholesterol deficiency that is followed by upregulation of cholesterol biosynthesis and LDL receptor activity [29]. Although the exact effect on serum lipoprotein levels is not yet known, it is interesting to notice that some of the known effects of vegetable fats on lipid metabolism are compatible with known mechanisms of action for phytosterols. For example, some unsaturated vegetable oils increase hepatic LDL receptor activity, decrease LDL production, and increase LDL clearance. These actions correspond to what is anticipated from the known effect of phytosterols to reduce delivery of dietary and biliary cholesterol to the liver. Reduction of cancer risk

Several studies suggest a protective role of phytosterols, especially beta-sitosterol, from colon, prostate, and breast cancer. Animal studies have investigated the effect of


150 Lipid metabolism and therapy

dietary phytosterols on human breast cancer cell line xenografted in mice [30]. After 8 weeks, the tumor size in animals fed phytosterols was 33% smaller and they had 20% fewer metastases to lymph nodes and lungs than the control group (cholesterol-fed). The tumor weight of the animals fed the phytosterol diet was also less than that of the cholesterol group. It is concluded that dietary phytosterols retard the growth and spread of breast cancer cells. An in-vitro study [31] showed that tumor growth of HT-29 cells (a human colon cancer cell line) was effectively inhibited by beta-sitosterol as compared to cholesterol or to the control (no sterol supplementation). After supplementation with 16 mmol/l beta-sitosterol for 9 days, cell growth was only one-third that of cells supplemented with equimolar concentration of cholesterol. Similar results to those obtained in HT-29 cells, but at a lower extent, in LNCaP, a human prostate cancer cell line [32]. Compared with cholesterol, beta-sitosterol (16 mmol/l) decreased growth by 24% and induced apoptosis four-fold. More whole animal and clinical research is required, however, before we can place too much emphasis on the results of in-vitro work. Dietary supplementation of beta-sitosterol at 60 mg/day for 6 months has been shown to improve significantly the clinical symptoms of prostatic hyperplasia in humans [33]. This disorder, which is benign and does not lead to prostate cancer, is common among older men and results in restricted urinary flow and polyuria due to the enlargement of the gland. In Europe, prostatic hyperplasia is treated clinically with beta-sitosterol-containing products. The exact mechanism by which phytosterols offer protection from cancer is not known. However, several theories have been reviewed [34]: they are incorporated in the cell membrane, altering membrane fluidity and the activity of membrane-bound enzymes. They can alter signal transduction in pathways leading to tumor growth and stimulate apoptosis in tumor cell lines. They have been shown to enhance in-vitro human peripheral blood lymphocyte and T-cell proliferation in vitro, which suggests a possible stimulation of the immune system function. Finally, by altering the level of fecal sterols resulting from the conversion of cholesterol and primary bile acids to coprostanol and secondary bile acids by bacterial action in the large intestine, plant sterols may play a role in the prevention of colon cancer. Effects on the absorption of fat soluble vitamins and antioxidants

The most important concern about plant sterols is that they reduce the absorption of some fat-soluble vitamins. A review of some of these randomized trials showed that plant sterols and stanols lower blood concentrations of

beta-carotene by about 25%, concentrations of alphacarotene by 10%, and concentrations of vitamin E by 8% [35]. However, an important point in the interpretation of these results is that a key role for these vitamins may be to protect LDL-C from oxidation. Sterols appear to reduce the amount of LDL-C, and lipophilic carotenoids and tocopherols are known to be associated with LDL particles. Thus, it may be appropriate to adjust, or correct, blood concentrations of these vitamins for the lower LDL-C concentrations. With this adjustment, stanols and sterols did not significantly lower blood concentration of vitamin E, but concentrations of beta-carotene were reduced by 8–19%. It has been suggested that compensation for this impact on serum carotenoid levels can occur either by increasing the intake of carotenoid-rich foods or by taking supplements containing these carotenoids. This has been attempted in one clinical study, which indicated that an increase in dietary carotenoids when consuming plant sterols or stanols was effective in maintaining plasma carotenoid levels [36]. A recent study showed that consumption of phytosterolfish oil ester resulted in higher beta-carotene and retinol levels than other phytosterol esters [37]. Finally, it has been noted that administration of free phytosterols and phytostanols may not induce malabsorption of fat-soluble vitamins and antioxidants as much as that caused from consumption of the fatty acid ester forms [38]. If this is verified in more studies, it might bring even more attention to the use of the free phytosterols and phytostanols in functional foods.

Conclusion Dietary phytosterols appear to play an important role in the regulation of serum cholesterol and appear to provocatively exhibit anticancer properties. These data provide a strong rationale for their use in functional foods.

References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: of special interest of outstanding interest Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 211–212). AbuMweis SS, Barake R, Jones P. Plant sterols/stanols as cholesterol lowering agents: a meta-analysis of randomized controlled trials. Food Nutr Res 2008; 52. doi: 10.3402/fnr.v52i0.1811. This paper precisely quantifies the effect of plant sterols on LDL-C concentrations in humans and looks into factors that affect plant sterols efficacy.

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Ostlund RE, Racette SB, Okeke A, Stenson WF. Phytosterols that are naturally present in commercial corn oil significantly reduce cholesterol absorption in humans. Am J Clin Nutr 2002; 75:1000–1004.

21 Shrestha S, Volek JS, Udani J, et al. A combination therapy including psyllium and plant sterols lowers LDL cholesterol by modifying lipoprotein metabolism in hypercholesterolemic individuals. J Nutr 2006; 136:2492–2497.

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Vanstone CA, Raeini-Sarjaz M, Parsons WE, Jones PJ. Unesterified plant sterols and stanols lower LDL-cholesterol concentrations equivalently in hypercholesterolemic persons. Am J Clin Nutr 2002; 76:1272– 1278.

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