ARTICLE
Auteur(s) : Elke A Trautwein, Isabelle
Demonty
Unilever Food and Health Research Institute, Unilever R&D
Vlaardingen, Olivier van Noortlaan 120 (PO Box 114), 3130 AC
Vlaardingen, The Netherlands
Introduction
Phytosterols (plant sterols and stanols) are naturally occurring
compounds that resemble cholesterol both in structure and
biological function. They are structural components of the cell
membrane, where they regulate membrane fluidity and permeability as
well as membrane-associated metabolic processes. Phytosterols are
products of the isoprenoid biosynthesis pathway and are, as
cholesterol, synthesized from acetyl coenzyme-A via squalene. The
synthesis of phytosterols involves more than 30 enzyme-catalysed
reactions all taking place in plant cell membranes [1].
The term phytosterols refers to more than 200 different
compounds which are found in various plants and marine sources [2].
They all have a steroid nucleus, a hydroxyl group at carbon 3 in
the β-position and a double bond mostly located between the C-atoms
five and six in the B-ring. Major differences are found in the
alkyl side chain, which can vary by the absence or presence of a
methyl or ethyl group on C24, saturation and position of a double
bound and geometry of the substitution at C24. Plant stanols are
the saturated forms of plant sterols, lacking the double bonds in
the steroid nucleus and the alkyl side chain.
In this review, the term phytosterols refers to both plant
sterols and their saturated counterparts, the plant stanols. The
most biologically relevant phytosterols are sitosterol,
campesterol, stigmasterol and brassicasterol. Sitostanol and
campestanol, the major plant stanols, are 5,6-saturated analogues
of sitosterol and campesterol (figure 1).
The present review will focus on the established and emerging
health benefits of phytosterols. Safety aspects have been
previously reviewed [3, 4] and will not be addressed.
Occurrence and dietary intake of phytosterols
A comprehensive review of important food sources of phytosterols
including aspects of ripening, post-harvest and processing changes
in phytosterol contents has recently been published [5].
Appreciable amounts of phytosterols are found in the lipid-rich and
fibre-rich fractions of all plant foods. In particular, vegetable
oils and products made from oils like spreads and margarine are
good sources of plant sterols [1]. Other foods which contribute to
the daily intake of plant sterols are cereal grains, cereal-based
products, nuts, legumes, vegetables and fruits [6, 7]. Plant
stanols are also found in some foods, but at much lower
concentrations. They are found in some cereals grains like rye,
corn and wheat and in non-hydrogenated vegetable oils [1]. Plant
stanols are also found in plant material from coniferous trees such
as pine and spruce.
Dietary intake of plant sterols ranges from 150 to 400 mg/day
with 65% of intake as β-sitosterol, 30% as campesterol and 5% as
stigmasterol [8, 9]. The daily intake of plant stanols is in the
magnitude of about 25 mg/day [10].
Metabolism of phytosterols and their effects on cholesterol
absorption
Despite the structural similarity between cholesterol and the major
phytosterols, their absorption by mammalian intestine is low.
Absorption rates are 0.5% for sitosterol, 1.9% for campesterol,
0.04% for sitostanol and 0.16% for campestanol, compared to a
cholesterol absorption rate of, on average, 56% [9, 11]. The low
absorption of phytosterols as compared to cholesterol is explained
by their rapid re-secretion from the intestinal cells back into the
gut lumen via the ATP-binding cassette (ABC) transporters ABC G5
and ABC G8 [12].
Phytosterols are absorbed under the same conditions that exist
for cholesterol. Like cholesterol, they are taken up in the
so-called dietary mixed micelles, which typically contain mixtures
of free cholesterol, mono- and di-glycerides, fatty acids,
phoshoplipids and bile acids. Like esterified cholesterol,
phytosterol esters ingested with the diet need to be hydrolysed by
pancreatic cholesterol esterase.
Inhibition of intestinal cholesterol absorption is the mechanism
of action responsible for the cholesterol-lowering effect of
phytosterols. As a consequence, the faecal excretion of cholesterol
and its intestinal breakdown products is increased. In several
studies, the effect of dietary phytosterol intake on intestinal
cholesterol absorption has been directly measured. Intakes of 0.7
to 9 g/day of phytosterols resulted in a reduction in
cholesterol absorption in the range of 7-69% [13]. The recommended
daily intake of 2 g of phytosterols reduces cholesterol
absorption by 30-40%, leading to a 10% lowering of LDL-cholesterol
[3, 13].
Although not all details are yet fully elucidated, several
mechanisms are thought to contribute to the overall inhibition of
intestinal cholesterol absorption by phytosterols [14]. The key
mechanism of action is displacement of cholesterol from the
micellar phase. As there is limited capacity in dietary mixed
micelles to embody sterols, the competition between phytosterols
and cholesterol reduces the cholesterol content of micelles and
hence decreases its transport towards the intestinal brush border
membrane [15]. Outside the micellar phase, cholesterol is no longer
soluble and can form co-crystals with phytosterols and is then
excreted together with the non-absorbed phytosterols.
Stimulation of bile flow prompted by food intake is a crucial
step for the formation of dietary mixed micelles. This plays an
important role in the overall mechanism of action and consequently
for the optimal cholesterol-lowering efficacy of phytosterols when
consumed with various background diets and in the form of different
enriched food formats. For instance, ingestion of a (fatty) meal
stimulates bile flow, resulting in a release of (endogenous)
cholesterol into the gut lumen, which increases the likelihood for
phytosterols to compete with cholesterol for micellisation.
There is also emerging evidence that phytosterols interfere with
transporter-mediated processes of cholesterol uptake [16]. Recent
insights into the role of so-called influx and efflux sterol
transporters in the gut, like the Niemann-Pick C1 Like 1 (NPC1L1)
protein and the ABC transporters ABCG5 and ABCG8 have shown that
phytosterols and cholesterol share the same transport processes
[17]. Figure 2
summarises the various putative mechanisms by which phytosterols
lower cholesterol absorption.
As phytosterols interfere with intestinal cholesterol
absorption, and fat-soluble vitamins and carotenoids share the same
absorption pathway as cholesterol, a potential concern relates to
the effects of phytosterols on fat-soluble vitamin and carotenoid
absorption. Several studies have shown that intakes of
phytosterol-enriched foods does not affect plasma concentrations of
retinol, vitamin D and K, but significantly lower plasma
concentrations of carotenoids and vitamin E [3, 13]. As carotenoids
and vitamin E are transported by lipoproteins, usually their
concentrations are standardised for plasma lipid concentrations.
After such lipid standardisation, plasma concentrations of
tocopherols remain normally unaltered, while the concentrations of
alpha- and beta-carotene and lycopene are up to 20% lower with
phytosterol intake. Carotenoid concentrations remain, however,
still within the normal inter-individual range and typical seasonal
variations. Moreover, the phytosterol-induced decrease in plasma
carotenoid concentrations can be counterbalanced by consuming more
fruits and vegetables [3].
Health benefits of phytosterols
Beneficial effects of phytosterols related to cholesterol
metabolism and atherosclerosis risk next to other metabolic
processes in the human body have been reviewed recently [18, 19].
Plasma cholesterol-lowering
The early findings
The most important physiological effect of phytosterols relates to
their cholesterol-lowering action. The cholesterol-lowering
properties of plant sterols were observed in humans in the early
1950s [20]. Due to the crystalline nature and poor solubility of
the pure phytosterol preparations, high doses of up to 50 g/day
were required to achieve a significant cholesterol-lowering effect
[21]. A major breakthrough occurred when it was shown in the 1980s
that the esterification of phytosterols with fatty acids from
vegetable oils could ease their incorporation into a variety of
food products.
Cholesterol-lowering efficacy of phytosterol esters
A vast number of human studies have shown that phytosterol esters,
when incorporated into various food products, significantly lower
total and LDL-cholesterol. A recent meta-analysis of 41 clinical
trials with fat-based foods like spreads, margarine, mayonnaise or
salad dressings enriched with phytosterol esters has shown a
non-linear dose-response relationship between the daily dose of
phytosterols consumed and cholesterol-lowering efficacy [3]. On
average, 2 g/day phytosterols (the equivalent dose expressed as
free sterols based on 3.3 g/day phytosterol esters) lowered
LDL-cholesterol concentrations by about 10% [3]. The effect
appeared to taper off at intakes of about 2 g/day or more,
with little additional benefit at intakes higher than
2.5 g/day (Figure
3). Phytosterol esters incorporated in low-fat food
matrices such as milk, yoghurt and once-a-day yoghurt/yoghurt
drinks have also been shown to significantly lower LDL-cholesterol,
with effects ranging from – 5 to – 16% for doses of 1.6
to 3.0 g/day [22-25].
Cholesterol-lowering efficacy of free phytosterols
In recent years, considerable effort has been spent to formulate
free phytosterols into both liquid and solid food formats.
Different formulations of free phytosterols (phospholipid –
lecithin – micelles, micro-crystallised, finely dispersed, or
dissolved and then re-crystallised in oil) have been tested in
recent human trials. Except for one study which did not show a
significant effect of low-fat and non-fat dairy beverages [26],
free phytosterols provided in multiple daily doses of fat-free or
low-fat beverages such as orange juice and milk have been shown to
lower LDL-cholesterol [27, 28] to an extent similar to that
reported for plant sterol esters in fat-based food formats [3].
Phytosterols incorporated in their free form in fat-based food
matrices (margarine, butter) [29, 30] and other fat-rich foods
(tortilla chips, chocolate, cold cuts and sausages) [31-33] were
also shown to be efficacious in lowering LDL-cholesterol. Overall,
properly formulated free phytosterols may be as effective as plant
sterol and stanol esters in lowering blood cholesterol. However,
further studies with a direct head-to head comparison of free vs.
esterified phytosterols would be useful to fully clarify this
aspect.
Impact of frequency of intake and intake occasion on the
cholesterol-lowering efficacy of phytosterol-enriched foods
From a practical point of view, an important aspect to consider is
the extent to which the frequency of intake (i.e. once daily or in
divided doses throughout the day) affects the cholesterol-lowering
efficacy of phytosterol-enriched foods. A study specifically
designed to address this question did not show a significant
difference in the effects of a phytosterol-enriched spread consumed
once a day with lunch or three times a day with breakfast, lunch
and dinner [34]. Other food formats enriched with phytosterols and
consumed once-a-day (yoghurt drink, ground meat) were also shown to
significantly lower LDL-cholesterol [25, 35].
One factor that may affect the cholesterol-lowering efficacy of
phytosterols-enriched foods is their intake occasion. Indeed,
consumption of a once-a-day yoghurt drink with lunch was shown to
lower LDL-cholesterol concentrations more markedly than consumption
on an empty stomach, 30 minutes before breakfast [25]. It may be
hypothesized that the stimulation of bile release consequent to the
presence of food in the upper part of the gut facilitates the
action of phytosterols by stimulating the formation of mixed
micelles which are crucial to the process of cholesterol
absorption. Moreover, bile contains significant amounts of
cholesterol which are less effectively reabsorbed in the presence
of phytosterols and are therefore excreted in faeces.
Combination of phytosterols with other cholesterol-lowering
approaches
The LDL-cholesterol lowering effect of phytosterol-enriched foods
appears to be additive to that of some other dietary approaches to
lower plasma cholesterol. The impact of phytosterols on
LDL-cholesterol was evaluated as part of a “heart-healthy” diet
(e.g. low or moderate intakes of total and saturated fat) in
various clinical trials. When compared with the baseline, usual
diet, the healthy diet-phytosterol combination led to decreases in
LDL-cholesterol of up to 24% for doses of phytosterols ranging from
1.5 to 2.3 g/day [3, 36]. The LDL-cholesterol lowering effect
attributed to the healthy diet in these studies was about 10% [3,
36], suggesting an additive effect of phytosterols with the healthy
diet.
A more effective way to optimise dietary-induced cholesterol
lowering is to combine phytosterols with other ingredients and
functional foods that have different cholesterol-lowering
mechanisms. A good example of such a combination is the “Portfolio
diet” which includes viscous dietary fibers such as psyllium or
beta-glucan from oats, soy protein, almonds and phytosterols. This
diet was shown to lower LDL-cholesterol in hypercholesterolemic
individuals by around 30% within one month [37]. On a longer term
(one year), the LDL-cholesterol lowering obtained in free-living
individuals was about 13% on average, but reductions in
LDL-cholesterol of more than 20% were achieved in more than 30% of
the fully compliant participants [38]. These results confirmed the
contribution of phytosterols to the beneficial effect of the
“Portfolio diet” on the long term. Phytosterol ester intake had
indeed been shown to consistently lower total and LDL-cholesterrol
in long-term efficacy studies lasting up to one year [39, 40].
Phytosterol-enriched foods may also be a useful adjunct to
specific lipid-lowering medications. Additional
cholesterol-lowering benefits have been observed with statins [41]
and fibrates [42]. In one large multi-centre clinical trial,
statins alone, a phytosterol-enriched spread alone, and the
statin-phytosterol combination lowered LDL-cholesterol by 32%, 8%
and 39%, respectively, showing that the effects of phytosterols and
statins are additive [41]. Phytosterols and ezetimibe, however,
were not shown to have additive effects [43], possibly due to the
fact that both ezetimibe and phytosterols lower cholesterol
absorption, and that a “ceiling” effect may be achieved in lowering
cholesterol absorption. Figure 4 shows the
cholesterol-lowering effects that can be expected by combining
phytosterol-enriched foods with a healthy diet and statins [3,
44].
Anti-atherogenic effects of phytosterols
So far, no long-term studies on the effect of phytosterols on
atherosclerosis and thus CHD risk reduction in humans are
available. However, animal studies have convincingly shown
beneficial, anti-atherogenic effects.
Over 30 studies have investigated the effect of phytosterols on
experimental atherosclerosis models in different animals, such as
chicken, rabbits, hamsters and more recently knockout mouse models
[4]. These studies have shown clear protective effects, such as a
reduction in arterial lipid accumulation and a reduction in the
development of atherosclerosis, e.g. lesser plaque development or
reduced lesion size, an inhibition of lesion formation and
progression and even regression of existing lesions resulting from
the cholesterol-lowering action of phytosterols [45-50]. The key
findings related to the evidence from these animal studies are
summarised in table 1.
In the more recent studies, different types of genetically
modified, so-called knockout mice were studied. In ABC G5/G8 and
LDL-receptor double knockout mice fed for 7 months a Western diet,
the size of the atherosclerotic lesions was similar to that
observed in control mice, despite greatly elevated plasma
phytosterol concentrations (> 20-fold higher than control mice)
[51]. In LDL receptor-deficient mice fed for 35 weeks an
atherogenic diet with phytosterols alone or in combination with
atorvastatin, less aortic lesion development was observed compared
to mice fed the atherogenic diet without phytosterols, despite the
4 to 11-fold increase in plasma sitosterol and campesterol
concentrations resulting from phytosterol intake [52]. Moreover,
consumption of phytosterols alone for an additional period of 12
weeks resulted in lesion regression [52]. These findings suggest
that elevated plasma sitosterol and campesterol concentrations
caused by feeding dietary phytosterols alone or in combination with
a statin have no atherogenic effects.
In vitro studies utilizing vascular smooth muscle cells (VSMC)
isolated from rats have shown that phytosterols stimulated
prostacyclin release from VSMC, suggesting that natural
phytosterols may prevent VSMC hyperproliferation, which could play
a beneficial role against atherosclerosis development [54]. Another
in-vitro study with macrophages found a reduced release of
prostaglandins, possibly offering protection from atheroma
development via affecting platelet aggregation or vasodilatation of
blood vessels [55].
Human studies have not demonstrated yet clear possible benefits
of phytosterols on other risk factors related to the development of
atherosclerosis besides the substantial reduction of total and
LDL-cholesterol. For instance, coagulation and fibrinolytic
parameters as well as endothelial markers like vascular cell
adhesion molecule 1 (VCAM) and intercellular adhesion molecule 1
(ICAM) were not significantly affected after plant sterol or stanol
intake for up to 16 weeks [56, 57]. In studies with children with
familiar hypercholesterolemia, short-term phytosterol intake did
not improve endothelial dysfunction as measured by flow-mediated
dilation (FMD) despite the clear reduction in LDL-cholesterol [58].
Besides LDL-cholesterol lowering, decreased levels of oxidized-LDL
were observed with the intake of phytosterols for 4 weeks,
suggesting a protection against LDL-oxidation [59]. Whether
phytosterols indeed have distinct antioxidant properties and
whether these have any relevance to human health awaits further
investigation. Therefore, it is still uncertain whether other
possible effects next to LDL-cholesterol lowering contribute to the
anti-atherosclerotic properties of phytosterols.
Table 1 Anti-atherosclerotic effects of dietary
phytosterols in various animal models.
|
Animal studies
|
Dose (% weight of diet)
|
Sterols or stanols
|
Source
|
Effects on atherosclerosis
developmenta
|
|
Hamsters
|
|
|
|
|
|
Nanios et al., 2003 [49]
|
0.24-2.84%
|
Pure sterols
|
Vegetable oil
|
Reduced lesion formation
|
|
Mice
|
|
|
|
|
|
Moghadasian et al., 1997 [45]
|
2%
|
Mainly sterols
|
Tall oil
|
Reduced lesion formation
|
|
Moghadasian et al., 1999 [47]
|
2%
|
Mainly sterols
|
Tall oil
|
Reduced lesion formation
|
|
Moghadasian et al., 1999 [48]
|
2%
|
Mainly sterols
|
Tall oil
|
Reduced lesion size
|
|
Volge et al., 2001 [50]
|
1%
|
Mainly sterols
|
Vegetable oil vs Wood
|
Reduced extent and severity of lesions
|
|
Plat et al., 2001 [52]
|
1-2%
|
Both sterols and Stanols
|
Tall oil
|
Inhibited lesion formation & progression regression of existing
lesions
|
|
Rabbitsb
|
0.2-3%
|
Sterols/ stanols
|
Not well describeb
|
Reduced development of lesions
|
|
Chickenb
|
1-5%
|
Sterols/ stanols
|
Not well describeb
|
Reduced lesion formation
|
aWith respect to control group (where applicable).
bAs summarised by Pollak and Kritchevsky [53].
Anti-inflammatory effects and effects on the immune system
Some evidence suggests that phytosterols, particularly
beta-sitosterol, may have anti-inflammatory activity. In vitro
studies showed an inhibition of secretion of inflammatory markers
such as interleukin-6 (IL-6) or tumor necrosis factor alpha (TNF-α)
by monocytes [60]. In ovalbumin-induced asthmatic mice, lung
inflammation related to leukocytosis and eosinophil infiltration
was reduced by intra-peritoneal injection of beta-sitosterol [61].
Oral consumption or topic application of a single dose of a
phytosterol mixture containing mainly beta-sitosterol was also
shown to decrease or even inhibit oedema in murine models of
inflammation [62]. However, results from other studies in animal
models do not support a role for beta-sitosterol in preventing or
reducing inflammation [63, 64]. In humans, data on the effects of
consumption of phytosterol-enriched foods on inflammatory markers
are scarce and conflicting. One trial showed a significant
reduction in plasma C-reactive protein (CRP) concentrations
following consumption, for 8 weeks, of 2 g/day phytosterols
incorporated in a reduced-calorie orange juice [27]. However, in a
longer term study, 16-wk consumption of 2.5 g/day phytosterols
did not affect soluble adhesion molecules, CRP and monocyte
chemotactic protein-1 concentrations [57]. These latter results
suggest that at doses consumed for cholesterol-lowering,
phytosterols may not exert noticeable effects on inflammation in
human subjects. Nevertheless, further investigations would be
useful to address this question in a more comprehensive manner.
To gain insight into the modulatory effects of phytosterols on
the immune system, Bouic et al. undertook a series of in vitro,
animal and humans studies, and published reviews on this topic [60,
65]. Beneficial effects of doses of beta-sitosterol as low as
60 mg/day in combination with negligible amounts (less than
1 mg/day) of sterolins (beta-sitosterol glucosides), were
reported to improve the immune function in subjects affected by
various pathologic processes such as pulmonary tuberculosis, HIV,
stress-induced immune suppression, allergic reactions and
rheumatoid arthritis [60, 65]. The mechanisms by which
beta-sitosterol and beta-sitosterol glucosides would improve the
immune response include increases in the proliferative response of
blood lymphocytes and in the lytic/cytotoxic activity of natural
killer cells, a modulation of the T-helper 1/T-helper 2 (Th1/Th2)
balance [60, 65], as well as effects on macrophage function [66]. A
recent study in a mouse model of acute, aseptic inflammation has
given further support for a role of dietary phytosterols (a mixture
containing 41% beta-sitosterol) in increasing the Th1/Th2 ratio
[64]. However, considering that the phytosterol dose used in human
studies (60 mg/day) [60, 65] is low compared with the dose
used in the animal trial (2% of diet weight) [64], and that the
normal dietary intake of phytosterols by humans is around 150-400
mg/day, it seems doubtful whether such low additional intakes of
phytosterols could result in distinct effects on the immune
function in human subjects. Further studies with doses of
phytosterols used for cholesterol-lowering (2.0-2.5 g/day)
would be useful to evaluate the effects of phytosterols on immune
function in humans.
Anticancer activity of phytosterols and beneficial effects on
prostatic hyperplasia
The effects of plant sterols as anticancer compounds have been
recently reviewed by Bradford and Awad [66]. Evidence for a
protective role of especially plant sterols against various types
of cancer in humans comes from epidemiological, case-control
studies. In these studies, the consumption of total phytosterols
was related, after controlling for major confounding factors, to a
lower incidence of breast, lung, and stomach cancer [66]. Dietary
intake of beta-sitosterol and stigmasterol was associated to lower
risks of esophagus [67] and ovarian [68] cancer, respectively. On
the other hand, a recent prospective cohort study failed to
demonstrate a relationship between phytosterol intake and the risk
of colon and rectal cancers [10]. Although the number of controlled
studies is limited and the existence of a statistical relationship
between phytosterol intake and a lower incidence of some cancers
does not indicate a causal link, overall, the epidemiologic
evidence suggests that phytosterols may exert a protective effect
against certain types of cancer.
Additional evidence for the potential anticancer properties of
phytosterols is provided by studies in animal models and in vitro
experiments. Various studies in rats or mice administered
carcinogenic stimuli, or injected or implanted with cancer cells
showed that consumption of beta-sitosterol or a phytosterol mixture
reduced the incidence of tumors, slowed down cell proliferation
and/or lowered the number of metastases of colon, breast or
prostate cancers [66]. Various mechanisms have been proposed to
explain the potential anticancer properties of phytosterols:
inhibition of cell cycle progression, promotion of cellular
apoptosis possibly via activation of the sphingomyelin cycle and
increased generation of ceramide, down-regulation of cholesterol
synthesis, inhibition of cell invasion, migration and adhesion, as
well as stimulation of the immune function [66, 69]. A possible
estrogenic activity of phytosterols could also be involved, but
reports are inconsistent [66] and this mechanism of action seems
less likely.
Clinical evidence is lacking for a role of phytosterols in the
management of cancers. However, supplementation with phytosterols
appears to be useful in the treatment of benign prostatic
hyperplasia (BPH). Symptomatic BPH is a common medical condition in
older men. A meta-analysis of four randomised, placebo-controlled,
double blind trials showed that oral consumption of small doses
(60-130 mg/day) of beta-sitosterol for 4 to 26 weeks improved the
clinical symptoms of BPH (flow rate and residual urinary volume)
without reducing the prostate size [70]. A subsequent study showed
that the beneficial effects of 60 mg/day beta-sitosterol were
maintained over a period of 18 months [71]. This efficacy in
improving the symptomatology of BPH is remarkable as such low doses
of beta-sitosterol are small compared with the normal dietary
intake of phytosterols estimated at 150-400 mg/day. The mechanisms
responsible for the putative beneficial effects of phytosterols on
BPH remain unclear but may be related to an altered testosterone
metabolism [72]. Moreover, data on long-term safety and ability to
prevent complications related to BHP are lacking.
Conclusion
Phytosterols are naturally occurring compounds found in plants that
include sitosterol and campesterol, and their saturated
counterparts sitostanol and campestanol. Phytosterols have been
used for the last half-century because of their
cholesterol-lowering properties. They have been shown in a vast
number of human studies to be safe and effective in lowering plasma
total and LDL-cholesterol concentrations. The underlying mechanisms
of the cholesterol-lowering action of phytosterols relate to the
inhibition of intestinal cholesterol absorption. In addition to
their well-established cholesterol-lowering effect, other potential
health benefits of phytosterols have been described. However,
evidence for such promising effects, e.g. antioxidant and
anti-inflammatory actions, as well as benefits on the immune system
and anticancer properties are still at a rudimentary stage and more
research is clearly needed to draw firm conclusions.
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