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Phytosterols as functional food ingredients: linkages to
cardiovascular disease and cancer
Peter J.H. Jones
a
and Suhad S. AbuMweis
b
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
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 ina 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
a
Richardson Centre for Functional Foods and
Nutraceuticals, University of Manitoba, Smartpark,
Winnipeg, Manitoba, Canada and
b
Department 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: peter_jones@umanitoba.ca
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
ß2009 Wolters Kluwer Health | Lippincott Williams & Wilkins
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80% other phytosterols (primarily sitosterol and campes-
terol) 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 concen-
trations were statistically significantly reduced by 3.8 and
6%, respectively, for the spread enriched with free soy-
bean 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]. Deuter-
ated cholesterol was included in the meal and the plasma
enrichment was measured several days later. Cholesterol
tracer in plasma following a test meal containing sterol-
free oil was 38% (10%) higher than that observed using
native corn oil. Phytosterols were the principal nontrigly-
ceride 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 hyper-
cholesterolemic persons showed that 1.8 g/day of free
sterols, free stanols, or a free stanol/sterol mixture incor-
porated 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]. Hypercholester-
olemic 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 phytos-
terols (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 crys-
tals 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% confi-
dence 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, bev-
erages, 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 nor-
mocholesterolemic 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 2.2g 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 hypercholes-
terolemic 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]. Partici-
pants were fed five different dietary sterols including
148 Lipid metabolism and therapy
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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%, respect-
ively. 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 choles-
terol 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 beta-
sitosterol 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. Sitos-
terol has increased affinity for biliary micelles compared
with cholesterol, so sitosterol uptake by micelles is
energetically favored. Further evidence of the import-
ance of micellar solubility is the finding that the absorb-
ability 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 mech-
anisms of action for phytosterols. For example, some
unsaturated vegetable oils increase hepatic LDL recep-
tor activity, decrease LDL production, and increase LDL
clearance. These actions correspond to what is anticip-
ated 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
Phytosterols as functional food ingredients Jones and AbuMweis 149
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 choles-
terol excretion back into the intestinal lumen through the adenosine
triphosphate binding cassette G 5 (ABCG5) and G 8 (ABCG8) trans-
porters. Phytosterols could also prevent esterification of the free cho-
lesterol into cholesterol esters and thus its assembling into the
chylomicrons. As a result of reducing cholesterol absorption by phytos-
terols, the cholesterol synthesis rate increase, but the net effect is a
reduction in LDL-cholesterol levels.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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 phytos-
terols 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 effec-
tively inhibited by beta-sitosterol as compared to cho-
lesterol 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 choles-
terol. 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 apop-
tosis 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 hyper-
plasia is treated clinically with beta-sitosterol-containing
products.
The exact mechanism by which phytosterols offer pro-
tection 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 alpha-
carotene by 10%, and concentrations of vitamin E by
8% [35]. However, an important point in the interpret-
ation 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 caroten-
oids 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, sta-
nols and sterols did not significantly lower blood concen-
tration 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 supple-
ments 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 phytosterol-
fish 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 atten-
tion 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 provo-
catively exhibit anticancer properties. These data pro-
vide 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).
1
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Phytosterols as functional food ingredients Jones and AbuMweis 151