Optimal number of servings
It has been suggested that plant sterols should be consumed at each cholesterol containing meal to achieve an optimal effect. A daily intake of 2.5 g plant stanol esters, either consumed once per day at lunch, or divided over three portions resulted in a similar decrease in serum total and LDL cholesterol levels [96]. Similar efficacy with a single larger dose sterol esters has also been demonstrated in two additional studies [73]. A single serving of yogurt, providing 1 g of pure free sterols, resulted in a placebo-adjusted reduction in LDL cholesterol of 6.3% [40]. Consumption of a single dose of 2.4 g/d plant sterols resulted in a 9.3 and 14.6 % reductions in blood total and LDL cholesterol levels, respectively, in hypercholesterolemic individuals [73]. Single doses of plant sterols may have sustained effects on cholesterol absorption via interactions with intestinal proteins (see Section 3.1.5.1 for details).
Nevertheless, as there are a plethora of studies showing the efficacy of plant sterols distributed in 2–3 meals [19,25,37,38,70,76-82,97-100], and only two studies to date demonstrating efficacy with a single larger serving [73,96], it seems prudent to remain consistent with the more established, conservative recommendation of consuming plant sterols in 2–3 doses with food, as adopted by the United States FDA.
Population under study
Plant sterol for the adult population
Typically, cholesterol lowering properties of plant sterols are similar in both men and women, although recent studies highlight that plant sterols can diminish fat soluble vitamins only in women[37]. Mixed gender studies must possess the statistical power to separate men and women as a statistical covariant, otherwise, the researcher must assume an identical response across both sexes.
The recent study of Matvienko et al. [73] demonstrates that soy sterol esters can effectively decrease LDL cholesterol in young adults of age 23, suggesting age is not a very critical variable influencing LDL cholesterol lowering properties of plant sterols, as also confirmed in studies with children [101]. In contrast, the meta-analysis of Law [60] predicted that plant sterol and stanol esters would reduce LDL cholesterol more effectively at each dose in older compared with younger people. However, it should be taken into consideration that older people had higher starting circulating lipid levels, so the percent change did not differ across age ranges. A number of studies have shown that plant sterols effectively reduce blood cholesterol in normocholesterolemic [19,22,25,37,59,76,96,102,103], hypercholesterolemic subjects [37,38,40,62,72,73,76,77,80,97,104-106], subjects with familial hypercholesterolemia [78,100], and in type II diabetic hypercholesterolemic patients [107,108]. Further, in a type II diabetic population consuming statin, plant sterols had a combined effect on lowering LDL cholesterol an additional 27%, the combined effect being 44% [108]. The reduction in LDL cholesterol seems to be greater in hypercholesterolemic individuals with type II diabetes. Plant sterols decreased LDL cholesterol in hypercholesterolemic individuals with and without type II diabetes by 14.9 % and 29.8 %, respectively (Lau et al. unpublished data).
Plant sterols are not recommended for pregnant or lactating women. However, there has not been a systematic study testing this issue. Vegetarian women habitually consume up to 500 mg of plant sterols per day. There is no evidence that such women cannot have normal pregnancies. Certain ethnic groups are known to have high levels of plant sterol intake and their pregnancy outcome could be evaluated in future studies. For example, in 372 semiacculturated Tarahumara Indians in the Sierra Madre Occidental Mountains of Mexico, the diet was found to be high in fiber and to contain less than 100 mg/day of cholesterol and over 400 mg/day of plant sterols [4]. Further, in the earlier stages of human evolution, some 5–7 million years ago, plant sterol intake in Myocene diets would have been considerably higher, up to 1 g/d [10]. Such diets were not only rich in plant sterols, but also dietary fiber, vegetable protein, and associated phytochemicals; but low in saturated and trans-fatty acids [10]. To meet the body's needs for cholesterol, genetic differences and polymorphisms were conserved by evolution, tending to raise serum cholesterol levels.
Plant sterols likely interact with ATP-binding cassette (ABC) transport proteins to direct cholesterol back into the intestinal lumen, regulating absorption of cholesterol and plant sterols [109-113]. Plat and Mensink [114] first hypothesized that plant sterols increased the expression of ABCA1. Thereafter, based on an animal study, it was suggested that plant sterols are converted into a liver X receptor (LXR) agonist, which activates the expression of ABC proteins [115]. Mutations in ABC proteins are responsible for the rare disease sitosterolemia [116]; and polymorphisms of ABC proteins may affect cholesterol absorption based on a preliminary study [117]. Polymorphism of ABCG8 gene was found to contribute to blood plant sterol levels in healthy subjects [118] suggesting ABCG8 protein regulates non-cholesterol sterol absorption.
Apolipoprotein E phenotype was originally shown to be correlated with cholesterol absorption [119]. It was shown in one study [120] but not others [37,99] to affect plant sterol cholesterol lowering efficacy in recent trials.
In addition to the above proteins, cholesterol absorption is likely controlled by additional proteins [121], as well a putative sterol transporter system [122]. In this context, the genotype of apolipoprotein A-IV, scavenger receptor-BI, 3-hydroxy-3-methyl-coenzyme A reductase, apolipoprotein E, and cholesterol ester transfer did not affect cholesterol lowering effects of plant stanol [122].