ReviewNew insights into the molecular actions of plant sterols and stanols in cholesterol metabolism
Introduction
Whole-body cholesterol homeostasis requires precise regulation of processes that control de novo cholesterogenesis, cholesterol absorption and cholesterol excretion. An imbalance of these processes may lead to elevated plasma cholesterol concentrations, cholesterol accumulation in different tissues and increased risk of cardiovascular diseases (CVD). Wide clinical and epidemiological evidence supports a direct link between high plasma cholesterol, particularly that of low-density lipoprotein (LDL), and atherosclerotic CVD risk [1]. The management of hypercholesterolaemia normally involves hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) [2]. However, other strategies, such as the inhibition of intestinal cholesterol absorption by ezetimibe, have been pursued [3]. Similarly, phytosterols/phytostanols have long been known to lower plasma LDL cholesterol levels by reducing intestinal cholesterol absorption, while not significantly altering high-density lipoprotein (HDL)-cholesterol or triglycerides [4], [5]. Phytosterols are plant-specific phytochemicals that are essential components of cell membranes. Phytosterols and their saturated forms (saturation of the double bond at carbon-5), termed phytostanols, are structurally related to cholesterol, although they differ in the complexity of their side chain which is attached to the steroid ring [6]. These compounds cannot be synthesised by humans and, therefore, always originate from the diet. Lipid-rich plant foods such as nuts, legumes and seeds contain a relatively high amount of phytosterols [7]. Over 40 phytosterols have been identified; of these, campesterol, stigmasterol and β-sitosterol account for more than 95% of total phytosterol dietary intake (Fig. 1). Phytostanols are not abundant in nature. Minor sterols, including brassicasterols and avenasterols, can represent a small percent of sterols in particular foods such as pistachio and ginseng oils [7], [8]. The presence of phytosterols in the Western diet is almost equal to that of cholesterol (∼400 mg/day) and increases in vegetarian diets. Phytosterols are poorly absorbed in the intestine (0.4–3.5%), while phytostanol absorption (0.02–0.3%) is even lower [9], [10]. This contrasts with intestinal cholesterol absorption that ranges from 35 to 70% [9], [11]. Sitosterolaemia is a rare autosomal recessively inherited disease caused by mutations affecting ABCG5 and ABCG8 and characterised by elevated plasma and tissue phytosterol concentrations (see Section 3) [12]. In contrast to healthy subjects in whom total plasma phytosterols are less than 1 mg/dL, patients with sitosterolaemia have plasma phytosterol levels ranging from 12 to 40 mg/dL [12]. Furthermore, phytosterol absorption and plasma phytosterol concentrations are strongly determined by genetic factors [13]. There is wide variability associated with apoE phenotypes, gender and ATP-binding cassette (ABC) transporter polymorphisms, among others [14]. Further details on the contribution of all these factors to plasma phytosterol absorption can be obtained from several recent reviews [13], [14], [15].
The cholesterol-lowering effect of phytosterols/phytostanols has been demonstrated in both humans and animals [5], [16], [17], [18], [19] and existing guidelines for cholesterol management of the National Cholesterol Education Program (NCEP) encouraged phytosterol/phytostanol consumption as a therapeutic dietary option to lower LDL cholesterol [20]. A daily intake of 2–2.5 g of this functional food results in an average reduction in LDL cholesterol of up to 14% [4], [16].
This review analyses the results of recent studies addressing the molecular mechanisms by which phytosterols/phytostanols influence cholesterol homeostasis.
Section snippets
Cholesterol-lowering mechanism of action of phytosterols/phytostanols
Competition between phytosterols/phytostanols and intestinal cholesterol for incorporation into mixed micelles has been proposed as the mechanism underlying the hypocholesterolaemic effect of these plant compounds, taking into account that phytosterols/phytostanols are more hydrophobic and have higher affinity for micelles than cholesterol [21]. However, one of the potential explanations for this competition, the cocrystallisation of cholesterol and phytosterols/phytostanols in the intestinal
Transporters for intestinal cholesterol absorption
In recent years, significant advances in the understanding of intestinal sterol absorption have provided potential molecular mechanisms to explain phytosterol/phytostanol action. Cholesterol absorption is a multistep process regulated by multiple genes at enterocyte level [26]. Since cholesterol is a water-insoluble molecule, its intestinal absorption requires emulsification, hydrolysis of the ester bond (if esterified) by a specific pancreatic esterase, micellar solubilisation, absorption in
Effect of phytosterols/phytostanols on intestinal LXR-mediated targets
LXRα is highly expressed in the liver and at lower levels in the adrenal glands, intestine, adipose tissue, macrophages, lung and kidney, whereas LXRβ is ubiquitously expressed [82]. Thus, LXRα and β are broadly expressed in the body and act as a global regulator of cholesterol homeostasis, mainly by preventing excess cholesterol accumulation in tissues [83]. These LXRs are expressed in the intestine, which suggests that these transcription factors may play a role in intestinal cholesterol
Effects of phytosterols/phytostanols on the liver
Liver cholesterol homeostasis is, like that of the intestine, altered in livers of sitosterolaemic patients [112]. Thus, a marked reduction in HMG-CoA reductase activity was found in both sitosterolaemic patients [113] and ABCG5/G8-deficient mice [55]. The use of oligonucleotide expression arrays led to the finding of 12 additional downregulated liver genes in the cholesterol-biosynthetic pathway of ABCG5/G8-deficient mice [55], presumably as a consequence of interference in SREBP2 cleavage by
Effects of phytosterols/phytostanols on steroidogenic tissues
It has recently been reported that accumulations of some phytosterols such as stigmasterol with an unsaturation within the side chain (Fig. 1), disrupt cholesterol metabolism since they are endogenous regulators of the two major cholesterol regulatory pathways, LXR and SREBP [132], [133] (Fig. 2). The use of ABCG5/G8-deficient mice, which develop features characteristic of human sitosterolaemia, has been fundamental in these studies. Interestingly, ABCG5/G8-deficient animals exhibited very low
Concluding remarks and future perspectives
To gain insight into the phytosterol/phytostanol influence on circulating cholesterol concentration via mechanisms independent of the luminal incorporation of cholesterol into mixed micelles, the effect of these plant compounds on intestinal LXR-mediated targets involved in sterol absorption has been evaluated. Conclusive studies using ABCA1- and ABCG5/G8-deficient mice demonstrated that the phytosterol-mediated inhibition of intestinal cholesterol absorption is independent of these ABC
Acknowledgements
We are grateful to Christine O’Hara for editorial assistance. This work was funded by FIS grants 05/1921 and Red FIS RD06/0015. J.C.E.-G. is an I3 researcher funded by the Ministerio de Educación y Ciencia. CIBERDEM is an ISCIII project.
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