July 2006: (I)348 –354

Brief Critical Review

The Role of Dietary Supplementation with Plant Sterols and

Stanols in the Prevention of Cardiovascular Disease
Sridevi Devaraj, PhD, and Ishwarlal Jialal, MD, PhD

Several studies have shown that increased levels of the management of LDL cholesterol in clinical practice.1
low-density lipoprotein (LDL) cholesterol predict car- Maximal dietary therapy is a major component of rec-
diovascular events. The Adult Treatment Panel II ommended therapeutic lifestyle changes. The primary
(ATP II) introduced the principle of therapeutic life- aim of maximal dietary therapy is to achieve as much
style changes, including plant sterols/stanols for the LDL lowering as possible prior to the initiation of drug
management of LDL cholesterol. Plant sterols and therapy. Recommendations for such therapy are listed in
stanols in fat matrices effectively lower LDL choles- Table 1. ATP III estimated that the application of these
terol levels in hypercholesterolemic, diabetic, and recommendations can achieve a 25% lowering of LDL
healthy human volunteers. Recent studies also show cholesterol compared with levels seen with a typical US
that sterols (2 g/d) lower LDL cholesterol even when diet. This estimate has been confirmed through studies of
incorporated in nonfat matrices. In addition, they may intensive dietary therapy by Jenkins et al.2 and Kendall
reduce biomarkers of oxidative stress and inflamma-
and Jenkins.3
tion. Plant sterols and stanols exert their hypocholes-
According to ATP III, the backbone of maximal
terolemic effects possibly by interfering with the up-
dietary therapy includes reducing saturated fatty acids to
take of both dietary and biliary cholesterol from the
less than 7% of total energy, decreasing trans fatty acids
intestinal tract. Present evidence is accumulating to
promote their use for lowering LDL cholesterol levels, as much as is feasible (⬍2%), and reducing dietary
as a first line of therapy (as well as adjunctive ther- cholesterol to less than 200 mg/d. Additionally, they said
apy) in patients on statin therapy. that LDL lowering can be achieved by adding ⱖ10 g/d of
viscous fiber and 2 g/d of plant stanols/sterols. Body
Key words: LDL cholesterol, lifestyle, stanol, sterol
weight should also be reduced to the desirable range (i.e.,
a body mass index of 19 to 25). Total dietary fat should
make up about 30% of total energy, most of which should
INTRODUCTION consist of monounsaturated and polyunsaturated fatty acids.
The cholesterol-lowering effects of dietary plant
Cardiovascular disease (CAD) is the leading cause
sterols (phytosterols) have been studied since the 1950s,
of morbidity and mortality in the United States. Several
and those of plant stanols (phytostanols) were first re-
epidemiological, pathological, and clinical studies have
ported in 1986.4,5 Since then, phytosterols/stanols have
shown a significant positive correlation between in-
become well-known dietary adjuncts that effectively
creased levels of total and low-density lipoprotein (LDL)
lower cholesterol without any symptomatic side effects.
cholesterol and the incidence of cardiovascular diseases
To this end, ATP III recommends the addition of plant
(CAD) in humans. The Adult Treatment Panel (ATP III)
sterols/stanols (2 g/d) to the diet as part of the therapeutic
of the National Cholesterol Education Program (NCEP)
lifestyle changes listed in their dietary guidelines.1 The
introduced the principle of maximal dietary therapy for
US Food and Drug Administration also issued a health
claim stating that foods containing plant stanols and
Drs. Devaraj and Jialal are with the Laboratory for stanol esters may reduce the risk of CAD.6 In this brief
Atherosclerosis and Metabolic Research, Department review, we will focus on the potential effects of plant
of Medical Pathology, UC Davis Medical Center, Sac- sterols on the lipid and lipoprotein profile.
ramento, California.
Please address all correspondence to: Dr. Ishwar-
lal Jialal, Laboratory for Atherosclerosis and Metabolic PLANT STEROLS AND STANOLS STRUCTURE
Research, Department of Medical Pathology, UC AND SOURCES
Davis Medical Center, Research Bldg 1, 4635 Second
Avenue, Sacramento, CA 95817; Phone: 916-734- Plant sterols (␤-sitosterol, campesterol, and stigmas-
6590; Fax: 916-734-6593; E-mail: ijialal@[Link]. terol) and their saturated derivatives, the stanols (sitosta-

348 Nutrition Reviews姞, Vol. 64, No. 7

Table 1. Recommendations for Maximal Dietary Therapy for Low-Density Lipoprotein Cholesterol (LDL-C)
Reduction
Approximate LDL-C
Dietary Modification Recommendation Reduction (%)
Saturated fat reduction Reduce saturated fat to ⬍7% of calories 8%–10%
Dietary cholesterol reduction Reduce dietary cholesterol to ⬍200 mg/d 3%–5%
Plant stanols/sterols Add plant stanols/sterols up to 2 g/d 6%–10%
Dietary fiber Viscous fiber 5–10 g/d 3%–5%
Weight reduction 10-lb (4.5-kg) weight loss 5%–8%
All above procedures Total LDL-C lowering:
25%–30%
Reduction in trans fat consumption to ⬍2%

nol and campestanol), are the naturally occurring equiv- cholesterol and LDL cholesterol in children, healthy
alents of the mammalian sterol cholesterol.7,8 Plant normocholesterolemic adults, hypercholesterolemic
sterols differ from cholesterol only in the structure of adults, and type 2 diabetics.10 –13 Katan et al.9 performed
their side chains, whereas saturated sterols, called a meta-analysis of 41 clinical trials, and found that intake
stanols, lack the ⌬5 double bond in their B-ring (Figure of 2 g/d of stanols or sterols (added to margarine,
1). Edible oils, seeds, and nuts have a high content of mayonnaise, olive oil, or butter) reduced LDL by 10% to
plant sterols, the major ones being sitosterol, campes- 15%. The intake of foods low in saturated fat and
terol, and stigmasterol. The Western diet contains about cholesterol and high in stanols or sterols reduced LDL by
100 to 300 mg/d of plant sterols and 20 to 50 mg/d of 20%, and additive effects were reported (16%–20% ad-
plant stanols. Because of their structural similarity to ditional LDL cholesterol lowering) by combining sterol
cholesterol, plant sterols and stanols can replace choles- or stanol intake with cholesterol-lowering medications
terol in the human body. The most striking example of such as statins.
this is the displacement of cholesterol from the micelles With regard to the incorporation of plant sterols/
in the intestine, which decreases intestinal cholesterol stanols into low-fat matrices, results have been equivo-
absorption and, as a consequence, plasma LDL choles- cal. In a randomized, double-blind, crossover study of 26
terol concentration. A recent meta-analysis of random- normocholesterolemic men, Richelle et al.14 reported a
ized, double-blind dietary intervention trials concluded 60% decrease in cholesterol absorption following a
that daily intake of 2 g of plant sterols or stanols lowered 1-week supplementation of a low-fat-milk-based bever-
plasma LDL cholesterol concentrations by 9% to 14%, age with free sterol or sterol esters (2.2 g sterol equiva-
with no effects on HDL cholesterol or triglycerides.9 lents in 600 mL milk/d) compared with the control
group. Mensink et al.15 reported a 13.7% LDL choles-
PLANT STEROLS, STANOLS, AND LOWERING terol lowering using esterified stanols (3 g/d) in low-fat
OF LDL CHOLESTEROL yogurt in 60 normocholesterolemic adults. Maki et al.16
reported a 7.6% and 8.1% LDL cholesterol lowering
The addition of plant sterols/stanols to the diet with a 50% fat spread providing 1.1 and 2.2 g plant
through incorporation into fat-based foods such as mar- sterols/d, respectively.
garine, low-fat milk beverages, and yogurt, has been No difference in cholesterol concentration was ob-
associated with a significant reduction in serum total served in another trial comparing the effects of plant

Figure 1. Structure of the most common plant sterols and stanols.

Nutrition Reviews姞, Vol. 64, No. 7 349

sterols at 3 g/d in reduced fat spread compared with 6 g shown to be equally effective as statin therapy in reduc-
in a 28% fat dressing and 9 g in a reduced-fat spread and ing LDL cholesterol and C-reactive protein (CRP), a
dressing.17 The consumption of low-fat (1%) yogurt biomarker of inflammation, in hyperlipidemic adults.24
containing 1 g/d of plant sterols significantly lowered However, the active ingredient responsible for the LDL
total and LDL cholesterol concentrations; however, the cholesterol lowering was not identified in this study.
weaknesses of this study were that the placebo decreased A single report also showed that, in addition to
total and LDL cholesterol concentrations (albeit nonsig- lowering LDL cholesterol and ApoB, intake of a spread
nificantly) and comparisons with placebo were not containing a plant stanol ester (3 g/d) in healthy Japanese
made.18 Jones et al.19 failed to observe any significant volunteers significantly lowered cholesterol ester transfer
differences in total and LDL cholesterol between placebo protein mass and levels of oxidized LDL levels follow-
and the low- or nonfat beverage containing free sterols ing 8 weeks of supplementation.25 In a recent study, we
incorporated into a precisely controlled diet regimen, showed for the first time that plant sterol-fortified orange
which in itself resulted in a 5% decrease in LDL juice results in significant lowering of CRP levels, the
cholesterol concentrations. However, Clifton et al.20 prototypic marker of inflammation and a cardiovascular
showed that plant sterols (1.6 g/d for 3 weeks) in risk marker.23 Previously, Cater et al.26 had reported a
low-fat milk were 3 times more effective than plant significant reduction in CRP levels when plant stanols
sterols incorporated into bread and cereal in lowering were added to statin therapy. Thus, plant sterols/stanols
LDL cholesterol. may also decrease cardiovascular burden, as evidenced
We performed the first study examining the effect of by a decrease in biomarkers of oxidative stress and
plant sterols incorporated into a nonfat matrix: orange inflammation; however, these findings need to be con-
juice.21 In this study, we showed a significant 7.2% firmed in large, prospective trials.
decrease in total cholesterol and a 12.4% decrease in
LDL cholesterol in 72 mildly hypercholesterolemic sub- CONSUMPTION WITH MEALS
jects following an 8-week supplementation of sterol-
Because plant sterols and stanols compete with cho-
fortified orange juice (2 g sterol in 480 mL orange
lesterol for incorporation into micelles, the general belief
juice/d) compared with a placebo sterol-free orange
was that plant sterol and stanol esters need to be con-
juice. In this study, we also reported significant reduc-
sumed at each meal to achieve a maximal cholesterol-
tions in ApoB and non-HDL cholesterol. A recent study
lowering effect. However, decreases in LDL cholesterol
by Noakes et al.22 has reported a significant reduction in
were comparable when plant sterol or stanol esters were
LDL cholesterol (8%–9%) with plant sterol esters (1.8 –2
consumed at lunch and dinner only or with each
g/d) incorporated into low-fat milk or yogurt in modestly
meal.27,28 It was recently demonstrated that a daily con-
hypercholesterolemic subjects.
sumption of 2.5 g of plant stanol esters once at lunch
We have recently completed another double-blind,
resulted in a similar LDL cholesterol-lowering efficacy
placebo-controlled trial examining the efficacy of plant
compared with the consumption of 2.5 g of plant stanols
sterols on LDL cholesterol levels when incorporated into
divided over three meals (0.42 g at breakfast, 0.84 g at
a reduced-calorie orange juice that was low in carbohy-
lunch, and 1.25 g at dinner).27,28 Therefore, it is not
drate, and again reported a significant reduction in total necessary to consume plant stanol esters simultaneously
and LDL cholesterol levels.23 The strategy of supple- with dietary fat throughout the day. These results also
menting juices/beverages with plant sterols is very at- suggest that plant stanols remain in the intestinal lumen
tractive, especially because it is also an excellent source for several hours after ingestion, possibly in or associated
of other micronutrients/antioxidants, such as ascorbate (it with enterocytes. However, studies with plant sterols or
provides the recommended daily allowance), folate, and stanols in nonfat matrices appear to decrease LDL cho-
other flavonoids. Also, orange juice is often consumed at lesterol when consumed with a meal.
breakfast and does not provide an additional source of fat
as do other phytosterol products.18 PLAUSIBLE MECHANISM FOR REDUCTION IN
No significant effects of sterol/stanol supplementa- CHOLESTEROL WITH PLANT STEROLS AND
tion on high-density lipoprotein (HDL) cholesterol, tri- STANOLS
glyceride levels, or non-HDL cholesterol levels have
been reported.17,18 As a novel dietary strategy in lower- Plant stanols are structurally related to cholesterol
ing serum lipids and inflammation, both of which in- and are incorporated into mixed micelles in the intestinal
crease the risks for CAD, Jenkins et al.24 considered tract. Plant sterols and stanols exert their hypocholester-
plant sterols (1.0 g/1000 kcal) to be an integral compo- olemic effects, possibly by interfering with the uptake of
nent of the “portfolio diet.” The combination of phytos- both dietary and biliary cholesterol from the intestinal
terols, almonds, soy protein, and viscous fibers was tract in humans.29,30 In vitro and in vivo studies have

350 Nutrition Reviews姞, Vol. 64, No. 7

shown no difference between phytosterols and phy- terol homeostasis by affecting cholesterol efflux through
tostanols in reducing cholesterol incorporation into the ABC transporters.
mixed micelles, and have shown that both sterol and
stanol esters have similar cholesterol-lowering effects EFFECTS OF PLANT STEROLS AND STANOLS
through micellar competition. This results in reduced ON LIPID-SOLUBLE ANTIOXIDANTS AND
intestinal cholesterol absorption and a higher fecal ex- VITAMINS
cretion of cholesterol and its metabolites.
This proposed mechanism also implies that plant An important issue that has been raised regarding
stanol esters should be consumed with each cholesterol- the efficacy and safety of phytosterol/stanol consumption
containing meal to achieve maximal effectiveness. How- is the concomitant decrease in plasma levels of fat-
ever, the consumption of 2.5 g of plant stanol esters only soluble vitamins, particularly tocopherols and carote-
at lunch resulted in a similar LDL cholesterol reduction noids, as a result of a decrease in their lipoprotein carrier
compared with consumption of the same amount of plant molecules. A meta-analysis of 10 to 15 trials has shown
stanol esters divided over three meals.27,28 Based on this that plasma levels of vitamins A, D, and E, alpha caro-
tene, and lycopene, were not affected by stanols or
result, it is not necessary to consume plant stanols at each
sterols. Beta-carotene levels declined, but this was not
meal or simultaneously with dietary cholesterol. How-
associated with adverse health outcomes.33 In this re-
ever, with regard to plant sterols in nonfat matrices, it
gard, Noakes et al.22 have demonstrated that an increase
may be prudent to consume these in conjunction with a
in consumption (ⱖ5 servings) of high-carotenoid fruits
meal, as shown by Devaraj et al.21,23 The fact that plant
or vegetables such as carrots, pumpkins, apricots, spin-
stanol esters lower serum LDL cholesterol concentra-
ach, or broccoli could effectively prevent the decline in
tions effectively when consumed once a day suggests plasma carotenoid concentrations accompanying phytos-
that a reduced incorporation of cholesterol into mixed terol/stanol supplementation.22 In our study using a bev-
micelles is not the only mechanism for plant stanol- erage containing phytosterols (2 g/d), we failed to ob-
induced cholesterol reductions. Thus, plant stanols/ste- serve any significant reductions in vitamins E and
rols may also enter the enterocytes, thereby affecting carotenoids.21,23
intestinal lipoprotein metabolism. Vitamin K plays an important role in the coagulation
Plant stanols are easily transported from the intesti- system. Plat et al.35 therefore analyzed the effects of
nal lumen into the enterocytes. In contrast to cholesterol, plant stanol esters on coagulation factors whose synthe-
plant stanols/sterols are minimally incorporated and se- sis depends on vitamin K. No effects were found on
creted into the circulation via the chylomicrons (absorp- either coagulation or fibrinolytic parameters.35 Also, in-
tion). For efficient incorporation into chylomicrons, ste- dividuals on warfarin therapy did not experience any
rols and stanols must first be esterified. If plant stanols adverse bleeding events at a daily consumption of 4.5 g
indeed upregulate intestinal cholesterol efflux transport- of plant stanol esters for 8 weeks. These results suggest
ers, this may explain the finding that plant stanol ester that plant stanol esters do not affect vitamin K-dependent
consumption once a day lowers serum LDL cholesterol coagulation. In their dose-response study, Hendriks et
concentrations to the same extent as plant stanol ester al.36 actually measured plasma vitamin K1 concentra-
consumption three times a day. Yang et al31 showed tions, and concluded that they were not affected by the
convincingly that dietary plant sterols disrupt cholesterol spreads enriched with plant sterol esters. Also, plasma
homeostasis by affecting the ATP-binding cassette
(ABC) transporters ABCG5 and ABCG8. Recently, Plat Table 2. Summary of Cholesterol-Lowering
et al.32 also examined the mechanisms of the cholesterol- Efficacy of Plant Sterols/Stanols
lowering effects of plant sterols and stanols, illustrating • Effectively lowers low-density lipoprotein (LDL)
two distinct pathways: effects on mixed micellar com- cholesterol as primary therapy (therapeutic lifestyle
position and effects on liver X receptor (LXR) gene change) at 2 g/d
activation. The authors demonstrated an increased ex- • Exerts additive effects in combination with low-fat
pression of ABCA1 in fully differentiated Caco-2 cells, foods and/or statin therapy
which regulate cellular cholesterol levels by transporting • Is well-accepted as part of the daily diet when
cholesterol back into the intestinal lumen. The LXR- included in margarine, butter, mayonnaise, yogurt,
activating potential of various plant sterols/stanols were or orange juice
positively correlated with ABCA1 mRNA expression.32 • Is well-tolerated by all subjects (children, type 2
Thus, plant sterols and stanols appear to lower choles- diabetics, hypercholesterolemic adults)
• Reduces inflammation (i.e., high-sensitivity C-
terol concentrations by not only interfering with micellar
reactive protein) levels
absorption of cholesterol, but also by disrupting choles-

Nutrition Reviews姞, Vol. 64, No. 7 351

25-OH-vitamin D concentrations were not lowered by risk associated with serum plant sterol levels in other-
plant sterol or stanol esters, even when the daily con- wise normal individuals is much below the levels ob-
sumption was approximately 4 g (Plat and Mensink, served in patients with sitosterolemia. Even so, without
unpublished results). more evidence of safety, high intakes of plant sterols
probably should not be recommended for the general
public. Again, however, there is less concern for their use
SAFETY OF PLANT STEROL/STANOL
in high-risk patients in whom benefit should outweigh
CONSUMPTION
any potential dangers.
Generally, about 5% of dietary plant sterols found in
the normal diet are absorbed. At higher intakes, the CONCLUSIONS
percent of absorption will be reduced, but absolute ab-
sorption should be enhanced. In very rare cases, the As outlined in Table 2, plant sterols and stanols have
ability of the liver to excrete plant sterols into the bile a great potential in cardiovascular risk management, and
(and therefore out of the body) is impaired. The result is evidence is accumulating to promote their use for low-
an accumulation of plant sterols in the body, which ering LDL cholesterol levels as a first line of therapy (as
results in a condition called sitosterolemia.37,38 Complete well as adjunctive therapy) in patients needing a higher
mutations in the genes that encode for two of the ABC dose of lipid-lowering drug. Further investigations
G-family half-transporters, ABCG5 and ABCG8, also should focus on their incorporation into more commonly
known as sterolin-1 and -2, respectively, was identified consumed low-fat, nutrient-dense foodstuffs, their af-
as the genetic defect in beta-sitosterolemia.,37,38 In per- fordability by the target population, their effects on
sons with sitosterolemia, serum plant sterols become biomarkers of oxidative stress and inflammation other
extremely elevated. Several individuals with sitosterol- than plasma lipids, and their effects on cardiovascular
emia have developed premature CHD, which suggests end points.
that the presence of high serum levels of plant sterols
may be particularly atherogenic. ACKNOWLEDGEMENT
Glueck et al.39 reported a relationship between ele-
vated serum plant sterol levels and the incidence of CHD This work was supported by National Institutes of
in a large study population, but this association was not Health grant no. NIH K24 AT00596.
independent and needs to be confirmed. Recently,
Wilund et al.40 tested whether elevated plasma levels of REFERENCES
plant sterols (sitosterol and campesterol) were associated
1. Expert Panel on Detection, Evaluation, and Treat-
with atherosclerosis in genetically modified mice and in ment of High Blood Cholesterol in Adults. Executive
middle-aged men and women. Wild-type and hypercho- Summary of the Third Report of National Choles-
lesterolemic female mice with greater than 20-fold terol Education Program (NCEP) Expert Panel on
higher plasma levels of plant sterols because of inacti- Detection, Evaluation, and Treatment of High Blood
vation of the ABC half-transporters G5 and G8 (G5G8–/– Cholesterol in Adults (Adult Treatment Panel III).
JAMA. 2001;285:2486 –2497.
mice) were fed chow or Western diets for 7 months. No 2. Jenkins DJ, Kendall CW, Marchie A, et al., Effects of
significant differences in aortic lesion area were found a dietary portfolio of cholesterol-lowering foods vs
when the sitosterolemic mice were compared with litter- lovastatin on serum lipids and C-reactive protein.
mate controls. JAMA. 2003;290:502–510.
To determine whether plasma levels of plant sterols 3. Kendall CW and Jenkins DJ. A dietary portfolio
maximal reduction of low-density lipoprotein cho-
were associated with coronary atherosclerosis in humans, lesterol with diet. Curr Atheroscler Rep. 2004;6:492–
the relationship between plasma plant sterols and coro- 498.
nary calcium (detected by electron beam computer to- 4. Peterson DW. Effect of soybean sterols in the diet
mography) was examined in 2542 subjects aged 30 to 67 on plasma and liver cholesterol in chicks. Proc Soc
years.40 Plasma levels of cholesterol, but not sitosterol or Exp Biol Med. 1951;78:143–147.
5. T. Heinemann, O. Leiss and K. von Bergmann, Ef-
campesterol, were significantly higher in subjects with fect of low-dose sitostanol on serum cholesterol in
coronary calcium. The results of this study do not sup- patients with hypercholesterolemia. Atherosclero-
port an association between elevated plasma levels of sis. 1986;61:219 –223.
plant sterols and atherosclerosis. Because of growing 6. Moreau RA, Whitaker BD, Hicks KB. Phytosterols,
interest in the mechanisms underlying sitosterolemia, phytostanols, and their conjugates in foods: struc-
tural diversity, quantitative analysis, and health-pro-
some investigators have become concerned that in- moting uses. Prog Lipid Res. 2002;41:457–500.
creased absorption of plant sterols resulting from higher 7. Pollak OJ, Kritchevsky D. Sitosterol. Monogr Ath-
intakes may be dangerous. Nonetheless, the degree of eroscler. 1998;10: 1–219.

352 Nutrition Reviews姞, Vol. 64, No. 7

 8. Ling WH, Jones PJH. Dietary phytosterols: a review in maintaining plasma carotenoid concentrations.
of metabolism, benefits, and side effects. Life Sci. Am J Clin Nutr. 2002;75:79-86.
1995;57:195–206. 23. Devaraj S, Autret BC, Jialal I. Reduced calorie or-
9. Katan MB, Grundy SM, Jones P, et al; Stresa Work- ange juice beverage with plant sterols decreases
shop Participants. Efficacy and safety of plant CRP levels and improves the lipid profile in human
stanols and sterols in the management of blood volunteers. Am J Clin Nutr. 2006 (In Press).
cholesterol levels. Mayo Clin Proc. 2003;78:965– 24. Jenkins DJA, Kendall CWC, Marchie A, et al. Effects
978. of a dietary portfolio of cholesterol-lowering foods
10. Gylling H, Miettinen TA. Serum cholesterol and cho- vs lovastatin on serum lipids and C-reactive protein.
lesterol and lipoprotein metabolism in hypercholes- JAMA. 2003;290:502–510.
terolaemic NIDDM patients before and during 25. Homma Y, Ikeda I, Ishikawa T, Tateno M, Sugano
sitostanol ester-margarine treatment. Diabetologia. M, Nakamura H. Decrease in plasma low-density
1994;37:773–780. lipoprotein cholesterol, apolipoprotein B, cho-
11. Ketomäki A, Gylling H, Siimes MA, Vuorio A, Miet- lesteryl ester transfer protein, and oxidized low-
tinen TA. Squalene and noncholesterol sterols in density lipoprotein by plant stanol ester-containing
serum and lipoproteins of children with and without spread: a randomized, placebo-controlled trial. Nu-
familial hypercholesterolemia. Pediatr Res. 2003;53: trition. 2003;19:369 –374.
648 – 653. 26. Cater NB, Garcia-Garcia AB, Vega GL, Grundy SM.
12. Law M, Plant sterol and stanol margarines and Responsiveness of plasma lipids and lipoproteins to
health. BMJ. 2000;320:861– 864. plant stanol esters. Am J Cardiol. 2005;96:23D–
13. Heinemann T, Leiss O, von Bergmann K. Effect of 28D.
low-dose sitostanol on serum cholesterol in patients 27. Plat J, van Onselen EN, van Heugten MM, Mensink
with hypercholesterolemia. Atherosclerosis. 1986; RP. Effects on serum lipids, lipoproteins and fat-
61:219-223. soluble antioxidant concentrations of consumption
14. Richelle M, Enslen M, Hager C, et al. Both free and frequency of margarines and shortenings enriched
esterified plant sterols reduce cholesterol absorp- with plant stanol esters. Eur J Clin Nutr. 2000;54:
tion and the bioavailability of ␤-carotene and ␣-to- 671– 677.
copherol in normocholesterolemic humans. Am J 28. Plat J, Mensink RP. Plant stanol and sterol esters in
Clin Nutr. 2004;80:171-177.
the control of blood cholesterol levels: mechanism
15. Mensink RP, Ebbing S, Lindhout M, Plat J, van
and safety aspects. Am J Cardiol. 2005;96:15D–
Heugten MMA. Effects of plant stanol esters sup-
22D.
plied in low-fat yoghurt on serum lipids and lipopro-
29. Miettinen TA, Tilvis RS, Kesäniemi YA. Serum plant
teins, non-cholesterol sterols and fat soluble anti-
sterols and cholesterol precursors reflect choles-
oxidant concentrations. Atherosclerosis. 2002;160:
terol absorption and synthesis in volunteers of a
205-213.
randomly selected male population. Am J Epide-
16. Maki KC, Davidson MH, Umporowicz DM, et al.
miol. 1990;131:20 –31.
Lipid responses to plant-sterol-enriched reduced-
30. von Bergmann K, Sudhop T, Lutjohann D. Choles-
fat spreads incorporated into a National Cholesterol
Education Program Step I diet. Am J Clin Nutr. terol and plant sterol absorption: recent insights.
2001;74:33– 43. Am J Cardiol. 2005;96:10D–14D.
17. Davidson MH, Maki KC, Umporowicz DM, et al. 31. Yang C, Yu L, Li W, Xu F, Cohen JC, Hobbs HH.
Safety and tolerability of esterified phytosterols ad- Disruption of cholesterol homeostasis by plant ste-
ministered in reduced-fat spread and salad dress- rols. J Clin Invest. 2004;114:813– 822.
ing to healthy adult men and women. J Am Coll 32. Plat J, Nichols JA, Mensink RP. Plant sterols and
Nutr. 2001;20:307-319. stanols; effects on mixed micellar composition and
18. Volpe R, Niittynen L, Korpela R, et al. Effects of LXR (target gene) activation. J Lipid Res. 2005;46:
yoghurt enriched with plant sterols on serum lipids 2468 –2476.
in patients with moderate hypercholesterolaemia. 33. Richelle M, Enslen M, Hager C, et al. Both free and
Br J Nutr. 2001;86:233–239. esterified plant sterols reduce cholesterol absorp-
19. Jones PJH, Vanstone CA, Sarjaz MR, St-Onge MP. tion and the bioavailability of beta-carotene and
Phytosterols in low and non-fat beverages as part of alpha-tocopherol in normocholesterolemic humans.
a controlled diet fail to lower plasma lipid levels. J Am J Clin Nutr. 2004;80:171–177.
Lipid Res. 2003;44:713–719. 34. Noakes M, Clifton P, Ntanios F, Shrapnel W, Record
20. Clifton PM, Noakes M, Sullivan D, et al. Cholesterol- I, McInerney J. An increase in dietary carotenoids
lowering effects of plant sterol esters differ in milk, when consuming plant sterols or stanols is effective
yoghurt, bread and cereal. Eur J Clin Nutr. 2004;58: in maintaining plasma carotenoid concentrations.
503–509. Am J Clin Nutr. 2002;75:79 – 86.
21. Devaraj S, Jialal I, Vega-Lopez S. Plant sterol-forti- 35. Plat J, Mensink RP. Effects of diets enriched with
fied orange juice effectively lowers cholesterol lev- two different plant stanol ester mixtures on plasma
els in mildly hypercholesterolemic healthy individu- ubiquinol-10 and fat-soluble antioxidant concentra-
als. Arterioscler Thromb Vasc Biol. 2004;24:e25– tions. Metabolism. 2001;50:520 –529.
e28. 36. Hendriks HF, Brink EJ, Meijer GW, Princen HM,
22. Noakes M, Clifton P, Ntanios F, Shrapnel W, Record Ntanios FY. Safety of long-term consumption of
I, McInerney J. An increase in dietary carotenoids plant sterol esters-enriched spread. Eur J Clin Nutr.
when consuming plant sterols or stanols is effective 2003;57:681– 692.

Nutrition Reviews姞, Vol. 64, No. 7 353

37. Salen G, Patel S, Batta AK. Sitosterolemia. Cardio- terolemic subjects, and familial aggregation of phyt-
vasc Drug Rev. 2002;20:255–270. osterols, cholesterol, and premature coronary heart
38. Berge KE, Tian H, Graf GA, et al. Accumulation of disease in hyperphytosterolemic probands and their
dietary cholesterol in sitosterolemia caused by mu- first-degree relatives. Metabolism. 1991;40:842– 848.
tations in adjacent ABC transporters. Science. 40. Wilund KR, Yu L, Xu F, Vega GL, Grundy SM, Cohen
2000;290:1771–1775. JC, Hobbs HH. No association between plasma
39. Glueck CJ, Speirs J, Tracy T, Streicher P, Illig E, levels of plant sterols and atherosclerosis in mice
Vandegrift J. Relationships of serum plant sterols and men. Arterioscler Thromb Vasc Biol. 2004;24:
(phytosterols) and cholesterol in 595 hypercholes- 2326 –2332.

354 Nutrition Reviews姞, Vol. 64, No. 7