Plant sterol intake and sitosterolemia
Sitosterolemia is a rare autosomal recessively inherited disorder which results from absorption of high amounts of plant sterol and cholesterol for unclear reasons linked to a locus at chromosome 2p21 [142-144] leading to development of coronary heart disease at young age, and development of tendon xanthomatosis. Various candidate genes involved in cholesterol absorption have been excluded at present [145]. Sitosterolemic persons should avoid food products containing plant sterols. Hydrogenated plant sterols may be safer than non-hydrogenated plant sterols for this population because the former is less absorbed, however, this argument is speculative. A recent study found that heterozygous subjects for sitosterolemia who received sterol esters in a spread providing 3.3 g of free sterol equivalents for 4 weeks, had a 10.6% reduction in LDL cholesterol [146]. Levels of campesterol and sitosterol were increased, but the magnitude of the increase was not much greater than that observed in normal subjects consuming similar spreads. In another recent study in 12 subjects who were obligate heterozygotes for sitosterolemia, consumption of plant sterol ester for 6 weeks resulted in an additional significant reduction of 5.9% in LDL cholesterol over that provided by a Step I diet alone, but no additional significant reduction was found after consumption of plant sterol ester for 12 weeks [147]. Although plasma levels of plant sterols concentration were elevated, the increase was similar to that reported in normal and mildly hypercholesterolemic subjects who consumed plant sterol esters [147]. The increase in plasma levels of plant sterols reached a plateau, which indicates that obligate heterozygotes eliminated the plant sterols from their body in order to prevent their accumulation. For prudency, it is nevertheless recommended that persons with sitosterolemia avoid plant sterols.
Anti-atherogenicity activity
In vitro studies have shown that plant sterols are effective in preventing hyperproliferation of vascular smooth muscle cell that play a role in atherosclerosis development [148]. Animal studies have shown that plant sterols also have anti-atherogenicity activity. In rabbits, sitosatanol feeding decreased plaque accumulation in coronary arteries within the ascending aorta [149]. Feeding plant sterols to apo E-deficient mice decreased platelet counts as well as the susceptibility of red blood cells to hemolysis, decreased plasma fibrinogen [16], and decreased formation of atherosclerotic lesions [15,16,150]. In healthy subjects who consumed 4 g/d of wood based stanol ester, the activity of antithrombin-III tended to increase compared to control group [99]. Thus, plant sterols may reduce atherosclerosis development not only by reducing blood cholesterol levels but also by possessing anti-atherogenicity activity.
Anti-cancer activity
The action of plant sterols as anticancer dietary components has been recently extensively reviewed [151]. Plant sterols can suppress tumor cell growth (LNCaP and HT-29) [152,153]. Compared to cholesterol, β-sitosterol caused a 24% decrease in cell growth and a 4-fold increase in apoptosis. In the latter work, the authors were interested in the effects of β-sitosterol on the sphingomyelin cycle, and measured two keys enzymes: protein phosphatase 2A (PP 2A) and phospholipase D (PLD). A 50% increase was observed in PP 2A activity in media containing 16 μM of β-sitosterol; however, there were no changes in protein levels of PP 2A. PLD activity increased in presence of phorbol myristate and β-sitosterol. This study suggests that the sphingomyelin cycle, which increases cell apoptosis, is mediated by PLD, PP 2A, and possibly, incorporation of β-sitosterol into the membrane. Another possible mechanism by which β-sitosterol can protect against cancer is through down-regulation of cholesterol synthesis, as was found in MDA-MB-231 human breast cancer cells [14]. In an important in vivo study, SCID mice were xenografted with the human breast cancer cell line MDA-MB-231 [154]. Plant sterol-fed mice had a 33% smaller tumor size and 20% less metastases in lymph nodes and lungs than cholesterol-fed mice. This finding implied the possibility that plant sterols may retard the growth and spread of breast cancer cells. In addition to retarding the growth of breast cancer cells by plant sterols, there is some evidence that plant sterols can affect the development of prostate cancer [155]. In a meta-analysis, 519 men were studied in 4 randomized, placebo-controlled, double-blind trials. β-sitosterol improved urinary symptom scores and flow measures, suggesting that non-glucosidic forms of β-sitosterol improve urinary symptoms and flow measures. Long term effectiveness, safety, and ability to prevent benign prostatic hyperplasia complications are not known [155]. In another recent study, there was no evidence that plant sterol usage at dose of 300 mg/d, decreased risk of colon and rectal cancers [156]. A similar conclusion was reached following a rat study in which rats were given the carcinogen methyl-nitroso-urea and then monitored for tumor development [157].
Plant sterols have also been found to have a protective effect against lung cancer [158]. In this study, intake of about 144 mg/d of plant sterols was associated with reduction in risk for lung cancer even after controlling of confounding factors, i.e. tobacco smoking, vegetables, fruits, and antioxidant substances. Total dietary plant sterol intake was found to be inversely associated with breast [159]), stomach [160], and esophageal [161] cancers. It was found that women with highest quartiles of total dietary intakes of plant sterols (>122 mg/d) had reduced risk of endometrial cancer [162], and intake of more than 521 mg/d reduced risk of ovarian cancer [163]. On the other hand, in a prospective epidemiological study, high dietary intake was not associated with reduced risk of colon and rectal cancers [156]. However, the intake of plant sterol might reduce the risk of more than one type of cancer.