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Division of Endocrinology, Metabolism and Nutrition, Mayo Clinic and Foundation, Rochester, MN
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPlant Sterols and Stanols...Hypocholesterolemic Effect of...Side Effects of Plant...REFERENCES |
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KEY WORDS: • sitostanol • sitosterol • cholesterol absorption • cholesterol
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPlant Sterols and Stanols...Hypocholesterolemic Effect of...Side Effects of Plant...REFERENCES |
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). Earlier studies showed that large
amounts of sitosterol (
10 g/d) lowered serum cholesterol levels by
10–20%. The high dosage and the chalky taste of sitosterol limited
its use, especially with the advent of the more powerful,
well-tolerated, lipid-lowering 3-hydroxy-3-methylglutaryl coenzyme
A reductase inhibitors. Grundy and Mok (1976)
subsequently demonstrated that 3 g/d of sitosterol was sufficient to
lower serum cholesterol levels. They suggested that plant sterols could
be considered a form of dietary treatment rather than a drug to lower
cholesterol because plant sterols are naturally present in
plant-based foods.
The differences in the various plant sterols became apparent
when saturated derivatives of plant sterols, called plant stanols, were
shown to reduce serum cholesterol at low doses. New techniques allowed
the incorporation of plant stanols into food forms without affecting
the texture and taste. In 1995, the Finnish introduced plant stanol
esters (PSE)2
in margarine, as dietary adjuncts to lower cholesterol (Cater and Grundy 1998
).
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Plant Sterols and Stanols Structure and Function. |
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TOPABSTRACTINTRODUCTIONPlant Sterols and Stanols...Hypocholesterolemic Effect of...Side Effects of Plant...REFERENCES |
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). Cholesterol is an essential component of cell membranes in higher
species. Plant sterols play an analogous role in plants; their content
is highest in edible oils, seeds and nuts (Weihrauch and Gardner 1978
).
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). The most common dietary plant stanol,
sitostanol, is a saturated derivative of sitosterol. It occurs
naturally in wood pulp, tall oil and, in lesser amounts, in soybean
oil. The Western daily diet contains 100–300 mg plant sterols and
20–50 mg plant stanols (Czubayko et al. 1991
). Absorption and metabolism.
The addition of a methyl or ethyl group on the side chain of
cholesterol results in poor intestinal absorption of plant sterols in
humans (Subbiah 1973
). Thus, only 1.5–5% of sitosterol
is absorbed when typical amounts of sterols are consumed (240–320 mg)
(Kritchevsky 1997
). Cholesterol absorption is much more
efficient, with between 20 and 80% of dietary cholesterol absorbed.
Differential absorption rates among plant sterols are related to the
length of the side chain. The longer the side chain of the sterol, the
less is absorbed because of its increased hydrophobicity
(Heinemann et al. 1993
). Serum levels of sitosterol are
0.3–1.7 mg/dL (Glueck et al. 1991
, Salen et al. 1970
), given a dietary intake of 160–360 mg/d of plant
sterols. This wide range in a normal population suggests considerable
individual variability in the handling of various plant sterols.
Consumption of 3.24 g/d of plant sterols has been shown to increase
serum sitosterol and campesterol levels by an average of 40 and 70%,
respectively (Westrate and Meijer 1998
). Because dietary
plant sterols can initiate the development of atherosclerosis
(Bhattacharyya and Connor 1974
) and may increase the
risk of premature coronary heart disease (CHD) in hypercholesterolemic
patients (Glueck et al. 1991
), the lowest serum levels
of sterols are desirable. Thus, Lees and Lees (1976)
suggested that plant sterol preparations that contain more absorbable
sterols such as campesterol should not be recommended for therapeutic
use.
Hydrogenation of plant sterols to the corresponding stanols
renders them virtually unabsorbable (Subbiah 1973
).
Absorption of sitostanol has been estimated to be between 0 and 3%,
and serum levels are practically undetectable (Gylling et al. 1999
, Westrate and Meijer 1998
). The absorption
of the other major stanol, campestanol, is also very low, in contrast
to its unsaturated counterpart, campesterol (Xu et al. 1999
).
Mechanism of action.
Plant sterols interfere with the uptake of both dietary and
biliary cholesterol from the intestinal tract in humans
(Heinemann et al. 1991
). The reason for this is not
fully understood; however, plant sterols appear to decrease the
solubility of cholesterol in the oil and micellar phases, thus
displacing cholesterol from bile salt micelles and interfering with its
absorption (Ikeda and Sugano 1998
). In humans,
intestinal infusion of sitostanol was more efficient in reducing
cholesterol absorption than infusion of sitosterol (-85% and -50%,
respectively) (Heinemann et al. 1991
). In addition,
Becker et al. (1993)
showed that 1.5 g/d of sitostanol
increased fecal secretion of neutral and acid steroids more effectively
(88%) than did 6 g/d of sitosterol (45%).
It has been proposed that sitostanol, which is relatively
unabsorbable compared with sitosterol, remains in the intestinal lumen
where it can interfere continuously and more efficiently with micellar
solubility of cholesterol (Ikeda and Sugano 1998
).
Another important determinant of the effectiveness of these compounds
is how well they mix with intestinal contents for proper physical
presentation to the gut. When compared with the unesterified stanols,
the fatty acid esters of stanols seem to mix more easily with the oil
phase of the intestinal contents to interfere with cholesterol
absorption and decrease plasma cholesterol concentrations
(Vanhanen et al. 1993
).
In addition to reducing absorption of cholesterol, plant
stanols inhibit absorption of other plant sterols (Gylling et al. 1999
). In humans, the inhibition of intestinal cholesterol
absorption is accompanied by a compensatory increase in cholesterol
synthesis, as reflected in the increase in the serum cholesterol
precursors, lathosterol and desmosterol. However, the net effect is
still reduction in serum cholesterol.
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Hypocholesterolemic Effect of Plant Sterols and Stanols. |
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TOPABSTRACTINTRODUCTIONPlant Sterols and Stanols...Hypocholesterolemic Effect of...Side Effects of Plant...REFERENCES |
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) In
addition, Vanhanen et al. (1994)
showed that the ester
form of sitostanol is more efficient than the crystalline form. Indeed,
in the only study that showed no significant cholesterol-lowering
effect with 3g/d of sitostanol, sitostanol was given in a crystalline
form that may have limited its efficacy (Denke 1995
).
Miettinen and co-workers (1995)
esterified sitostanol into rapeseed oil fatty acids, thus allowing them
to put a large amount into margarine without affecting its texture or
taste. Table 1
summarizes the clinical studies with PSE in various populations. The
majority of the early studies on stanol ester–fortified foods were
done in Finnish population studies. PSE dosages have ranged in various
studies from 0.8 to 3.8 g/d. The data suggest that at least 1 g/d of
stanol esters must be consumed to offer a good clinical response. In
general, with consumption of 2–3 g/d of PSE, serum LDL cholesterol
(LDL-C) levels were lowered between 10 and 15%. It is difficult to
compare these studies in terms of dose response because of differences
in background diet, baseline lipid levels and duration of treatment. It
has been suggested that consumption of >3 g/d of PSE may not further
decrease the cholesterol-lowering effect (Mensink and Plat 1998
). The narrow range of dose responsiveness may be due to
the compensatory increase in cholesterol synthesis that can be observed
after consumption of higher doses of plant sterols and stanols. Indeed,
Vanhanen et al. (1994)
calculated that intake of 2 g/d
of sitostanol esters increased cholesterol synthesis by 2 mg/(d · kg
body weight), although there was still a net reduction in serum
cholesterol. This was not seen with 0.8 g/d of sitostanol esters.
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compared 1.8 and 2.6 g/d of PSE and showed a
significantly greater cholesterol-lowering effect of the higher
dose on total cholesterol (TC) (10.2% with 2.6 g/d vs. 9.3% with 1.8
g/d), although the difference was small. Nguyen et al. (1998)
showed a trend for greater efficacy of 3 g/d of PSE
(n = 20) compared with 2.1 g/d of PSE
(n = 19). There was a reduction in TC of 9.4 and
5.6%, respectively, after 8 wk, compared with placebo. More studies
are required to test the optimal intake of PSE to lower serum
cholesterol, particularly above 3.7 g/d.
Most studies comparing plant stanols with plant sterols have
shown the greater potency of plant stanols in lowering serum
cholesterol. One notable exception is a crossover, randomized study by
Westrate and Meijer (1998)
; that study showed that
soybean sterol ester margarine lowered LDL-C by 13%, as much as
the plant stanol ester margarine, Benecol. However, the daily intake of
plant sterols in the soybean preparation (3.24 g/d) was greater than
that in Benecol (2.74 g/d). The fatty acid composition of the two
differed as well. The soybean sterol ester margarine was lower in
saturated fatty acids and contained more linoleic acid than does
Benecol. It is well established that linoleic acid lowers blood
cholesterol compared with other more saturated fatty acids
(Mensink and Katan 1992
). This difference in the fatty
acid profiles of the spreads in that study may have underestimated the
hypocholesterolemic effect of Benecol compared with the soybean sterol
ester margarine by ~2% in TC and LDL-C reduction. Nevertheless,
the cholesterol-lowering efficacy of plant stanols and plant
sterols was quite comparable in that study. This may be due in part to
the fact that the plant sterols were esterified. More studies are
required to determine whether esterification can render plant sterols
as effective as esterified plant stanols in lowering cholesterol.
PSE effect on other lipids.
In contrast to lowering TC and LDL-C, PSE did not exert
a significant effect on HDL-C and TG in most studies (Jones et al. 1997
). In a study of hypercholesterolemic type-2
diabetic patients, 3 g/d of PSE decreased VLDL cholesterol (VLDL-C) by
12%, intermediate density lipoprotein cholesterol (IDL-C) by 11%,
whereas HDL-C increased by 11% (P < 0.05)
(Gylling and Miettinen 1994
). The reason for this is not
entirely understood; however, it is thought to result from an increased
removal of remnant particles by up-regulation of LDL receptor
activity.
Determinants of response to stanol esters.
Which subjects would be most responsive to PSE? Several
variables have been examined as potential predictors of response to
PSE. Vanhanen et al. (1993)
showed that the decrease in
LDL-C is greater in the apoprotein (apo) E-4 homozygote group than
that in the apo E-3 homozygote group. This can be explained
presumably by the fact that baseline cholesterol absorption is higher
in subjects with the E-4 allele. On the other hand, the LDL-C
reduction was shown to be similar for different apo E genotypes in 70
subjects consuming 3.7–3.8 g/d of PSE (Plat et al. 1998
).
PSE appear to be most effective in lowering cholesterol in
subjects with a high ability to absorb cholesterol and a lower
cholesterol synthesis rate (Gylling et al. 1999
). The
degree of reduction in LDL-C by PSE has been shown to correlate
significantly with the magnitude of the PSE effect on the efficiency of
cholesterol absorption (Miettinen et al. 1995
). In
addition, subjects with high baseline cholesterol absorption, as
reflected by high serum levels of plant sterols, had a greater
cholesterol-lowering response to PSE. On the other hand, a high
cholesterol synthesis rate at baseline predicted a smaller decrease in
cholesterol absorption with consumption of PSE. These types of patients
could potentially be identified by measuring serum levels of precursor
sterols in cholesterol synthesis and serum levels of plant sterols such
as campesterol and sitosterol. However, this is currently not a
practical approach in a clinical setting.
Early studies of plant sterols in humans suggested that the
relatively high dietary cholesterol concentrations (mean, 282–340
mg/d) may have contributed to the favorable results (Mattson et al. 1982
). It has been suggested that the weak response in one
study with crystalline sitostanol may have been explained by a low
dietary cholesterol intake (<200 mg/dL) (Denke 1995
).
Most studies with PSE have been conducted in subjects after consumption
of a diet higher in fat and cholesterol than the average American diet.
In a landmark study with plant stanol ester margarine (Miettinen et al. 1995
), the average saturated fat intake was 14% and
cholesterol intake was 340 mg/d. The question arises whether plant
stanols can be as effective during a period of more restricted dietary
saturated fat and cholesterol intake. Hallikainen and Uusitupa (1999)
recently studied subjects consuming a diet that followed
closely the National Cholesterol Education Program (NCEP) step 2 diet,
in which the mean total fat intake was 26%, saturated fat intake was
6.9% and cholesterol intake was 146 mg/d. They showed that >2 g/d of
PSE lowered mean total and LDL-C by up to 10.6 and 13.7%
respectively, compared with a control group.
Thus, PSE can reduce cholesterol even in the presence of a low dietary cholesterol intake (<200 mg/d), supporting the notion that PSE can interfere with the absorption of both dietary cholesterol and biliary cholesterol.
Hypocholesterolemic effect of PSE in combination with lipid-lowering drugs.
PSE appear to have a synergistic effect in lowering
cholesterol when combined with lipid-lowering agents that act at
other steps of lipid metabolism. The combination of 3 g/d of PSE with
10–20 mg of simvastatin reduced TC and LDL-C by an additional 11
and 16% respectively (Gylling et al. 1997
). Of clinical
significance, recent data suggest that subjects who had low cholesterol
synthesis and high cholesterol absorption capacity at baseline were
more likely to have a recurrent CHD event despite simvastatin treatment
(Miettinen et al. 1996
). It is tempting to speculate
that combination treatment with PSE in those patients would improve the
response and help prevent the recurrence of coronary events. However,
the only pertinent atherosclerosis prevention data with plant stanols
exist in animal models at present (Ikeda and Sugano 1998
).
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Side Effects of Plant Stanols and Sterols. |
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TOPABSTRACTINTRODUCTIONPlant Sterols and Stanols...Hypocholesterolemic Effect of...Side Effects of Plant...REFERENCES |
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). In addition, blood variables
remained within normal range. Hypercholesterolemic children given
sitostanol for 7 mo were also free from ill effects (Becker et al. 1993
).
At high levels of intake, the potential exists for an
estrogenic effect of plant sterols but not plant stanols. When
sitosterol was injected into male rats, testicular weight and sperm
concentration decreased (Malini and Vanithakumari 1991
).
An increase in the uterine weight of female rats (Malini and Vanithakumari 1993
) and an increase in basal luteinizing
hormone secretion in immature male and female rabbits were also
observed (Register et al. 1995
).
The clinical significance of these findings in humans is
unknown. In contrast to sitosterol, sitostanol has not been found to
have an estrogenic effect (Mellanen et al. 1996
).
Furthermore, in postmenopausal women who consumed 3 g/d of PSE
margarine for 14 wk, there was no significant change in estradiol
levels (Gylling and Miettinen 1998
).
Effect on lipophilic dietary compounds.
Studies exist that have examined the effect of plant sterol
esters and stanol esters on the absorption of lipophilic compounds such
as ß-carotene and fat-soluble vitamins. Both plant sterols and
stanols may lower serum concentrations of carotene (Gylling et al. 1996
, Westrate and Meijer 1998
); however,
this finding is not universal. Hallikainen and Uusitupa (1999)
observed no significant change in lipid standardized
ß-carotene levels with PSE consumed as part of a NCEP step 2 diet. In
other studies that have shown a significant effect on ß-carotene
levels from PSE consumption, the subjects were consuming a higher fat
intake. This suggests that increasing the intake of carotenoid-rich
foods such as fruits and vegetables as part of a low fat diet can
negate the decrease in ß-carotene levels that had been observed with
PSE.
More significantly, PSE have not been shown to have a
significant effect on the fat-soluble vitamin, retinol, for which
ß-carotene is the precursor. Nor was there an effect on 25-OH vitamin
D levels. 
-Tocopherol levels were decreased with consumption of PSE;
however, the lipid standardized -tocopherol levels were unchanged.
No effect of consumption of PSE on vitamin K–dependent hemostasis in
anticoagulated patients has been seen (Nguyen and Dale 1999
). Finally, no drug interaction with PSE has been observed
to date.
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FOOTNOTES |
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2 Abbreviations used: apo, apoprotein; CHD, coronary heart disease; HDL-C, HDL cholesterol; IDL-C,
intermediate density lipoprotein cholesterol; NCEP, National
Cholesterol Education Program; PSE, plant stanol esters; TC, total cholesterol; VLDL-C, VLDL cholesterol.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONPlant Sterols and Stanols...Hypocholesterolemic Effect of...Side Effects of Plant...REFERENCES |
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K. C. Hayes, A. Pronczuk, and D. Perlman Nonesterified Phytosterols Dissolved and Recrystallized in Oil Reduce Plasma Cholesterol in Gerbils and Humans J. Nutr., June 1, 2004; 134(6): 1395 - 1399. [Abstract] [Full Text] [PDF]
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 J. W. Anderson Diet First, Then Medication for Hypercholesterolemia JAMA, July 23, 2003; 290(4): 531 - 533. [Full Text] [PDF]
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 O. A Matvienko, D. S Lewis, M. Swanson, B. Arndt, D. L Rainwater, J. Stewart, and D L. Alekel A single daily dose of soybean phytosterols in ground beef decreases serum total cholesterol and LDL cholesterol in young, mildly hypercholesterolemic men Am. J. Clinical Nutrition, July 1, 2002; 76(1): 57 - 64. [Abstract] [Full Text] [PDF]
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H. S. Ewart, L. K. Cole, J. Kralovec, H. Layton, J. M. Curtis, J. L. C. Wright, and M. G. Murphy Fish Oil Containing Phytosterol Esters Alters Blood Lipid Profiles and Left Ventricle Generation of Thromboxane A2 in Adult Guinea Pigs J. Nutr., June 1, 2002; 132(6): 1149 - 1152. [Abstract] [Full Text] [PDF]
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T. Vaskonen, E. Mervaala, L. Krogerus, and H. Karppanen Supplementation of Plant Sterols and Minerals Benefits Obese Zucker Rats Fed an Atherogenic Diet J. Nutr., February 1, 2002; 132(2): 231 - 237. [Abstract] [Full Text] [PDF]
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D. Q-H. Wang, B. Paigen, and M. C. Carey Genetic factors at the enterocyte level account for variations in intestinal cholesterol absorption efficiency among inbred strains of mice J. Lipid Res., November 1, 2001; 42(11): 1820 - 1830. [Abstract] [Full Text] [PDF]
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 R. J. Nicolosi, T. A. Wilson, C. Lawton, and G. J. Handelman Dietary Effects on Cardiovascular Disease Risk Factors: Beyond Saturated Fatty Acids and Cholesterol J. Am. Coll. Nutr., October 1, 2001; 20(90005): 421S - 427. [Abstract] [Full Text]
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A. Tammi, T. Ronnemaa, L. Valsta, R. Seppanen, L. Rask-Nissila, T. A. Miettinen, H. Gylling, J. Viikari, M. Anttolainen, and O. Simell Dietary Plant Sterols Alter the Serum Plant Sterol Concentration but Not the Cholesterol Precursor Sterol Concentrations in Young Children (The STRIP Study) J. Nutr., July 1, 2001; 131(7): 1942 - 1945. [Abstract] [Full Text] [PDF]
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A. B. Awad and C. S. Fink Phytosterols as Anticancer Dietary Components: Evidence and Mechanism of Action J. Nutr., September 1, 2000; 130(9): 2127 - 2130. [Abstract] [Full Text]
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