Summary
Introduction
Throughout much of human evolution, it is likely that large amounts of plant foods were consumed (1). In addition to being rich in fiber and plant protein, the diets of our ancestors were also rich in phytosterols—plant-derived sterols that are similar in structure and function to cholesterol. There is increasing evidence that the reintroduction of plant foods providing phytosterols into the modern diet can improve serum lipid (cholesterol) profiles and reduce the risk of cardiovascular disease (2).
Although cholesterol is the predominant sterol in animals, including humans, a variety of phytosterols are found in plants (3). Nutritionists recognize two classes of phytosterols: sterols, which have a double bond in the sterol ring (Figure 1), and stanols, which lack a double bond in the sterol ring (Figure 2).The most abundant sterols in plants and the human diet are sitosterol and campesterol. Stanols are also present in plants, but they comprise only about 10% of total dietary phytosterols. Cholesterol in human blood and tissues is derived from the diet as well as endogenous cholesterol synthesis. In contrast, all phytosterols in human blood and tissues are derived from the diet because humans cannot synthesize phytosterols (4).
Definitions
Phytosterols: a collective term for plant-derived sterols and stanols.
Plant sterols or stanols: terms that are generally applied to plant-derived sterols or stanols that are added to foods or supplements.
Plant sterol or stanol esters: plant sterols or stanols that have been esterified by creating an ester bond between a fatty acid and the sterol or stanol. Esterification makes plant sterols and stanols more fat-soluble so they are easily incorporated into fat-containing foods, like margarines and salad dressings. In this article, the weights of plant sterol and stanol esters are expressed as the equivalent weights of free (unesterified) sterols and stanols.
Metabolism and Bioavailability
Absorption and Metabolism of Dietary Cholesterol
Dietary cholesterol must be incorporated into mixed micelles in order to be absorbed by the cells that line the intestine (enterocytes) (5). Mixed micelles are mixtures of bile salts, lipids (fats) and sterols formed in the small intestine after a fat-containing meal is consumed. Inside the enterocyte, cholesterol is esterified and incorporated into triglyceride-rich lipoproteins known as chylomicrons, which enter the circulation (6). As circulating chylomicrons become depleted of triglycerides, they become chylomicron remnants, which are taken up by the liver. In the liver, cholesterol from chylomicron remnants may be repackaged into other lipoproteins for transport or secreted into bile, which is released into the small intestine.
Absorption and Metabolism of Dietary Phytosterols
Although varied diets typically contain similar amounts of phytosterols and cholesterol, serum phytosterol concentrations are usually several hundred times lower than serum cholesterol concentrations in humans (7). Less than 5% of dietary phytosterols are systemically absorbed, in contrast to about 50-60% of dietary cholesterol (8). Like cholesterol, phytosterols must be incorporated into mixed micelles before they are taken up by enterocytes. Once inside the enterocyte, systemic absorption of phytosterols is inhibited by the activity of efflux transporters, consisting of a pair of ATP-binding cassette (ABC) proteins known as ABCG5 and ABCG8 (4). ABCG5 and ABCG8 each form one half of a transporter that secretes phytosterols and unesterified cholesterol from the enterocyte into the intestinal lumen. Phytosterols are secreted back into the intestine by ABCG5/G8 transporters at a much greater rate than cholesterol, resulting in much lower intestinal absorption of dietary phytosterols than cholesterol. Within the enterocyte, phytosterols are not as readily esterified as cholesterol, so they are incorporated into chylomicrons at much lower concentrations. Those phytosterols that are incorporated into chylomicrons enter the circulation and are taken up by the liver. Once inside the liver, phytosterols are rapidly secreted into bile by hepatic ABCG5/G8 transporters. Although cholesterol may also be secreted into bile, the rate of phytosterol secretion into bile is much greater than cholesterol secretion (9). Thus, the low serum concentrations of phytosterols relative to cholesterol can be explained by decreased intestinal absorption and increased excretion of phytosterols into bile.
Biological Activities
Effects on Cholesterol Absorption and Lipoprotein Metabolism
It is well-established that high intakes of plant sterols or stanols can lower serum total and LDL cholesterol concentrations in humans (see Cardiovascular Disease below) (10, 11). In the intestinal lumen, phytosterols displace cholesterol from mixed micelles and inhibit cholesterol absorption (12). In humans, the consumption of 1.5-1.8 g/d of plant sterols or stanols reduced cholesterol absorption by 30-40% (13, 14). At higher doses (2.2 g/d of plant sterols), cholesterol absorption was reduced by 60% (15). In response to decreased cholesterol absorption, tissue LDL-receptor expression is increased, resulting in increased clearance of circulating LDL (16). Decreased cholesterol absorption is also associated with increased cholesterol synthesis, and increasing phytosterol intake has been found to increase endogenous cholesterol synthesis in humans (13). Despite the increase in cholesterol synthesis induced by increasing phytosterol intake, the net result is a reduction in serum LDL cholesterol concentration.
Other Biological Activities
Experiments in cell culture and animal models suggest that phytosterols may have biological activities unrelated to cholesterol-lowering. However, their significance in humans is not yet known.
Alterations in Cell Membrane Properties
Cholesterol is an important structural component of mammalian cell membranes (17). Displacement of cholesterol with phytosterols has been found to alter the physical properties of cell membranes in vitro (18), which could potentially affect signal transduction or membrane-bound enzyme activity (19, 20). Limited evidence from an animal model of hemorrhagic stroke suggested that very high intakes of plant sterols or stanols displaced cholesterol in red blood cell membranes, resulting in decreased deformability and potentially increased fragility (21, 22). However, daily phytosterol supplementation (1 g/1000 kcal) for 4 weeks did not alter red blood cell fragility in humans (23).
Alterations in Testosterone Metabolism
Limited evidence from animal studies suggests that very high phytosterol intakes can alter testosterone metabolism by inhibiting 5-alpha-reductase, a membrane-bound enzyme that converts testosterone to dihydrotestosterone, a more potent metabolite (24, 25). It is not known whether human phytosterol consumption alters testosterone metabolism. No significant changes in free or total serum testosterone concentrations were observed in men who consumed 1.6 g/d of plant sterol esters for one year (26).
Induction of Apoptosis in Cancer Cells
Unlike normal cells, cancerous cells lose their ability to respond to death signals by undergoing apoptosis (programmed cell death). Sitosterol has been found to induce apoptosis when added to cultured prostate (27), breast (28) and colon cancer cells (29).
Anti-inflammatory Effects
Limited data from cell culture and animal studies suggest that phytosterols may attenuate the inflammatory activity of immune cells, including macrophages and neutrophils (30, 31).
Disease Prevention
Cardiovascular Disease
Foods Enriched with Plant Sterols or Stanols
LDL cholesterol: Numerous clinical trials have found that daily consumption of foods enriched with plant sterols or stanols in free or esterified forms lowers serum total and LDL cholesterol concentrations (10, 32). A meta-analysis that combined the results of 18 controlled clinical trials found that the consumption of spreads providing an average of 2 g/d of plant sterols or stanols lowered serum LDL cholesterol concentrations by 9-14% (33). More recently, a meta-analysis that combined the results of 23 controlled clinical trials found that the consumption of plant foods providing an average of 3.4 g/d of plant sterols or stanols decreased LDL cholesterol concentrations by about 11% (34). The most extensive meta-analysis published to date analyzed the results of 23 clinical trials of plant sterol-enriched foods and 27 clinical trials of plant stanol-enriched foods separately (11). At doses of at least 2 g/d, both plant sterols and stanols decreased LDL cholesterol concentrations by about 10%. Doses higher than 2 g/d did not substantially improve the cholesterol-lowering effects of plant sterols or stanols. The results of studies providing lower doses of plant sterols or stanols suggest that 0.8-1.0 g/d is the lowest dose that results in clinically significant LDL cholesterol reductions of at least 5% (35-39). In general, trials that have compared the cholesterol-lowering efficacy of plant sterols with that of stanols have found them to be equivalent (40-42). Few of these studies lasted longer than 4 weeks, but at least two studies have found that the cholesterol-lowering effects of plant sterols and stanols last for up to one year (26, 43). Recently, concerns have been raised that plant sterols are not as effective as stanols in maintaining long-term LDL-cholesterol reductions (44, 45). Long-term trials that directly compare the efficacy of plant sterols and plant stanols are needed to address these concerns (11).
Coronary Heart Disease Risk: The effect of long-term use of foods enriched with plant sterols or stanols on coronary heart disease (CHD) risk is not known. The results of numerous intervention trials suggest that a 10% reduction in LDL cholesterol induced by medication or diet modification could decrease the risk of CHD by as much as 20% (46). The National Cholesterol Education Program (NCEP) Adult Treatment Panel III has included the use of plant sterol or stanol esters (2 g/d) as a component of maximal dietary therapy for elevated LDL cholesterol (47). The addition of plant sterol- or stanol-enriched foods to a heart healthy diet that is low in saturated fat and rich in fruits and vegetables, whole grains and fiber offers the potential for additive effects in CHD risk reduction. For example, following a diet that substituted monounsaturated and polyunsaturated fats for saturated fat resulted in a 9% reduction in serum LDL cholesterol after 30 days, but the addition of 1.7 g/d of plant sterols to the same diet resulted in a 24% reduction (48). More recently, a diet that provided a portfolio of cholesterol-lowering foods, including plant sterols, soy protein, almonds and viscous fibers lowered serum LDL cholesterol concentrations by an average of 30%, a decrease that was not significantly different from that induced by statin therapy (49). The US Food and Drug Administration (FDA) has authorized the use of health claims on food labels indicating that regular consumption of foods enriched with plant sterol or stanol esters may reduce the risk of heart disease (50).
Dietary Phytosterols
The results of clinical trials indicating that the daily consumption of foods enriched with plant sterols or stanols can significantly reduce LDL cholesterol concentrations do not account for naturally occurring phytosterols in the diet (51). Relatively few studies have considered the effects of dietary phytosterol intakes on serum LDL cholesterol concentrations. Dietary phytosterol intakes have been estimated to range from about 150-450 mg/d in various populations (52). Limited evidence suggests that dietary phytosterols may play an important role in decreasing cholesterol absorption. A recent cross-sectional study in the UK found that dietary phytosterol intakes were inversely related to serum total and LDL cholesterol concentrations even after adjusting for saturated fat and fiber intake (53). In single meal tests, removal of 150 mg of phytosterols from corn oil increased cholesterol absorption by 38% (54), and removal of 328 mg of phytosterols from wheat germ increased cholesterol absorption by 43% (55). Although more research is needed, these findings suggest that dietary intakes of phytosterols from plant foods could have an important impact on cardiovascular health.
Cancer
Limited data from animal studies suggest that very high intakes of phytosterols, particularly sitosterol, may inhibit the growth of breast and prostate cancer (56-58). Only a few epidemiological studies have examined associations between dietary phytosterol intakes and cancer risk in humans because databases providing information on the phytosterol content of commonly consumed foods have only been developed recently. A series of case-control studies in Uruguay found that dietary phytosterol intakes were lower in people diagnosed with stomach, lung, or breast cancer than in cancer-free control groups (59-61). Case-control studies in the US found that women diagnosed with breast or endometrial (uterine) cancer had lower dietary phytosterol intakes than women who did not have cancer (62, 63). In contrast, another case-control study in the US found that men diagnosed with prostate cancer had higher dietary campesterol intakes than men who did not have cancer, but total phytosterol consumption was not associated with prostate cancer risk (64). Although some epidemiological studies have found that higher intakes of plant foods containing phytosterols are associated with decreased cancer risk, it is not clear whether phytosterols or other compounds in plant foods are the protective factors.
Disease Treatment
Benign Prostatic Hyperplasia
Benign prostatic hyperplasia (BPH) is the term used to describe a noncancerous enlargement of the prostate. The enlarged prostate may exert pressure on the urethra, resulting in difficulty urinating. Plant extracts that provide a mixture of phytosterols (marketed as beta-sitosterol) are often included in herbal therapies for urinary symptoms related to BPH. However, relatively few controlled studies have examined the efficacy of phytosterol supplements in men with symptomatic BPH. In a six-month study of 200 men with symptomatic BPH, 60 mg/d of a beta-sitosterol preparation improved symptom scores, increased peak urinary flow and decreased post-void residual urine volume compared to placebo (65). A follow-up study reported that these improvements were maintained for up to18 months in the 38 participants who continued beta-sitosterol treatment after the study ended (66). Similarly, in a six-month study of 177 men with symptomatic BPH, 130 mg/d of a different beta-sitosterol preparation improved urinary symptom scores, increased peak flow and decreased post-void residual volume compared to placebo (67). A systematic review that combined the results of those and two other controlled clinical trials found that beta-sitosterol extracts increased peak urinary flow by an average of 3.9 ml/second and decreased post-void residual volume by an average of 29 ml (68). Although the results of a few clinical trials suggest that relatively low doses of phytosterols can improve lower urinary tract symptoms related to BPH, further research is needed to confirm these findings (69).
Sources
Foods
Unlike the typical diet in most developed countries today, the diets of our ancestors were rich in phytosterols, likely providing as much as 1000 mg/d (1). Present-day dietary phytosterol intakes have been estimated to vary from 150-450 mg/d in different populations (3). Vegetarians, particularly vegans, generally have the highest intakes of dietary phytosterols (70). Phytosterols are found in all plant foods, but the highest concentrations are found in unrefined plant oils, including vegetable, nut and olive oils (3). Nuts, seeds, whole grains and legumes are also good dietary sources of phytosterols (5). The phytosterol contents of selected foods are presented in the table below
|
Total Phytosterol Content of Selected Foods (94-97) |
||
| Food |
Serving |
Phytosterols (mg)
|
| Wheat germ | ˝ cup (57 g) |
197
|
| Corn oil | 1 tablespoon (14 g) |
102
|
| Canola oil | 1 tablespoon (14 g) |
91
|
| Peanuts | 1 ounce (28 g) |
62
|
| Wheat bran | ˝ cup (29 g) |
58
|
| Almonds | 1 ounce (28 g) |
34
|
| Brussels sprouts | ˝ cup (78 g) |
34
|
| Rye bread | 2 slices (64 g) |
33
|
| Macadamia nuts | 1 ounce (28 g) |
33
|
| Olive oil | 1 tablespoon (14 g) |
22
|
| Take Control® spread | 1 tablespoon (14 g) |
1650 mg plant sterol esters
(1000 mg free sterols) |
| Benecol® spread | 1 tablespoon (14 g) |
850 mg plant stanol esters
(500 mg free stanols) |
Foods Enriched with Plant Sterols and Plant Stanols
The majority of clinical trials that demonstrated a cholesterol-lowering effect used plant sterol or stanol esters solubilized in fat-containing foods, such as margarine or mayonnaise (11). More recent studies indicate that low-fat or even nonfat foods can effectively deliver plant sterols or stanols if they are adequately solubilized (10, 51). Plant sterols or stanols added to low-fat yogurt (39, 71), low-fat milk (72, 73) and orange juice (74) have been reported to lower LDL cholesterol in controlled clinical trials. A variety of foods containing added plant sterols or stanols are available in Europe, Asia and the US, including margarines, mayonnaises, vegetable oils, salad dressings, yogurt, milk, soy milk, orange juice, snack bars and meats (10). Available research indicates that the maximum effective dose for lowering LDL cholesterol is about 2 g/d (11) and the minimum effective dose is 0.8-1.0 g/d (10). In the majority of clinical trials that demonstrated a cholesterol-lowering effect, the daily dose of plant sterols or stanols was divided among two or three meals. However, consumption of the daily dose of plant sterols or stanols with a single meal has been found to lower LDL cholesterol in a few clinical trials (39, 75, 76).
Supplements
Phytosterol supplements marketed as beta-sitosterol are available without a prescription in the US. Doses of 60-130 mg/d of beta-sitosterol have been found to alleviate the symptoms of BPH in a few clinical trials (see Benign Prostatic Hyperplasia above). Soft gel chews providing 0.5 g of plant stanols are being marketed for cholesterol-lowering at a recommended dose of 2 g/d. Phytosterol supplements should be taken with meals that contain fat.
Safety
In the US, plant sterols and stanols added to a variety of food products are generally recognized as safe (GRAS) by the FDA (77). Additionally, the Scientific Committee on Foods of the EU concluded that plant sterols and stanols added to various food products are safe for human use (78). However, the Committee recommended that intakes of plant sterols and stanols from food products should not exceed 3 g/d.
Adverse Effects
Few adverse effects have been associated with regular consumption of plant sterols or stanols for up to one year. People who consumed a plant sterol-enriched spread providing 1.6 g/d did not report any more adverse effects than those consuming a control spread for up to one year (26), and people consuming a plant stanol-enriched spread providing 1.8-2.6 g/d for one year did not report any adverse effects (43). Consumption of up to 8.6 g/d of phytosterols in margarine for 3-4 weeks was well-tolerated by healthy men and women, and did not adversely affect intestinal bacteria or female hormone levels (79). Although phytosterols are usually well-tolerated, nausea, indigestion, diarrhea and constipation have occasionally been reported (65, 67).
Sitosterolemia (Phytosterolemia)
Sitosterolemia, also known as phytosterolemia, is a very rare hereditary disease that results from inheriting a mutation in both copies of the ABCG5 or ABCG8 gene (80). Individuals who are homozygous for a mutation in either half transporter protein have dramatically elevated serum phytosterol concentrations due to increased intestinal absorption and decreased biliary excretion of phytosterols. Although serum cholesterol concentrations may be normal or only mildly elevated, individuals with sitosterolemia are at high risk for premature atherosclerosis. People with sitosterolemia should avoid foods or supplements with added plant sterols (10). Two studies have examined the effect of plant sterol consumption in heterozygous carriers of sitosterolemia, a more common condition. Consumption of 3 g/d of plant sterols for four weeks by two heterozygous carriers (81) and consumption of 2.2 g/d of plant sterols for 6-12 weeks by 12 heterozygous carriers did not result in abnormally elevated serum phytosterols (82).
Pregnancy and Lactation
Plant sterols or stanols added to foods or supplements are not recommended for pregnant or breastfeeding women because their safety has not been studied (10). At present, there is no evidence that high dietary intakes of naturally occurring phytosterols, such as those consumed by vegetarian women, adversely affects pregnancy or lactation.
Drug Interactions
The LDL cholesterol lowering effects of plant sterols or stanols may be additive to those of HMG-CoA reductase inhibitors (statins) (83, 84). The results of controlled clinical trials suggest that consumption of 2-3 g/d of plant sterols or stanols by individuals on statin therapy may result in an additional 7-11% reduction in LDL cholesterol, an effect comparable to doubling the statin dose (45, 85-87). Consumption of 4.5 g/d of stanol esters for eight weeks did not affect prothrombin times (INR) in patients on warfarin (Coumadin) for anticoagulation (88).
Nutrient Interactions
Fat-soluble Vitamins (vitamins A, D, E and K)
Because plant sterols and stanols decrease cholesterol absorption and serum LDL cholesterol concentrations, their effects on fat-soluble vitamin status have also been studied in clinical trials. Plasma vitamin A (retinol) concentrations were not affected by plant stanol or sterol ester consumption for up to one year (11, 26). Although the majority of studies found no changes in plasma vitamin D (25-hydroxyvitamin D3) concentrations, one study observed a small (7%) but statistically significant decrease in plasma 25-hydroxyvitamin D3 concentrations at the end of one year in those who consumed 1.6 g/d of sterol esters compared to placebo (26). There is little evidence that plant sterol or stanol consumption adversely affects vitamin K status. Consumption of 1.6 g/d of sterol esters for six months was associated with a nonsignificant 14% decrease in plasma vitamin K1 concentrations, but carboxylated osteocalcin, a functional indicator of vitamin K status, was unaffected (26). In other studies of shorter duration, consumption of plant sterol and stanol esters did not significantly change plasma concentrations of vitamin K1 (89) or vitamin K-dependent clotting factors (90). Consumption of plant sterol or stanol-enriched foods has been found to decrease plasma vitamin E (alpha-tocopherol) concentrations in a number of studies (11). However, those decreases generally do not persist when plasma alpha-tocopherol concentrations are standardized to LDL cholesterol concentrations. This suggests that observed reductions in plasma alpha-tocopherol are due in part to reductions in its carrier lipoprotein, LDL. In general, consumption of plant sterol and stanol-enriched foods at doses of 1.5 g/d or more have not been found to have adverse effects on fat-soluble vitamin status in well-nourished populations.
Carotenoids
Dietary carotenoids are fat-soluble phytochemicals that circulate in lipoproteins. A number of studies have observed 10-20% reductions in plasma carotenoids after short-term and long-term consumption of plant sterol- or stanol-enriched foods (11). Even when standardized to serum total or LDL cholesterol concentrations, decreases in alpha-carotene, beta-carotene and lycopene may persist, suggesting that phytosterols can inhibit the absorption of these carotenoids (91). It is not clear whether reductions in plasma carotenoid concentrations confer any health risks, but several studies have found that increasing intakes of carotenoid-rich fruits and vegetables can prevent phytosterol-induced decreases in plasma carotenoids (92). In one case, advice to consume five daily servings of fruits and vegetables, including one serving of carotenoid-rich vegetables, was enough to maintain plasma carotenoid levels in people consuming 2.5 g/d of plant sterol or stanol esters (93).
Written by:
Jane Higdon, Ph.D.
Linus Pauling Institute
Oregon State University
Reviewed by:
Peter Jones, Ph.D.
Professor of Nutrition
Director, Mary Emily Clinical Nutrition Research Center
School of Dietetics and Human Nutrition
McGill University
Last updated 08/11/2005 Copyright 2005 Linus Pauling Institute
Disclaimer
The Linus Pauling Institute Micronutrient Information Center provides scientific information on health aspects of micronutrients and phytochemicals for the general public. The information is made available with the understanding that the author and publisher are not providing medical, psychological, or nutritional counseling services on this site. The information should not be used in place of a consultation with a competent health care or nutrition professional.
The information on micronutrients and phytochemicals contained on this Web site does not cover all possible uses, actions, precautions, side effects, and interactions. It is not intended as medical advice for individual problems. Liability for individual actions or omissions based upon the contents of this site is expressly disclaimed.