Effects of a phytosterol-enriched dairy product on lipids, sterols and 8-isoprostane in hypercholesterolemic patients: A multicenter Italian study
Introduction
The benefits of cholesterol-lowering treatment on the risk of coronary heart disease and mortality have been clearly established in large trials involving the use of statins [1], [2], [3], [4], [5]. Statins greatly reduce LDL cholesterol levels and are currently the first choice of a cholesterol-lowering drug treatment. Phytosterols (PS) have become products of increasing importance since it was reported that the addition of sterols to a cholesterol-enriched diet prevented increases in plasma cholesterol level and significantly reduced the incidence of atherosclerotic plaque in the chick aorta [6]. More recently, the Adult Treatment Panel III of the National Cholesterol Education Program (NCEP ATP-III) [7] underlined the importance of lifestyle modifications as the initial step for cholesterol levels reduction and recommended the use of phytosterols to lower plasma LDL cholesterol levels by ∼10% [7]. It has been shown that phytosterols enhance the cholesterol lowering effect of a low saturated fat diet [8]. Thus, the use of phytosterols in addition to low fat diet may be useful in those forms of diet-responsive hypercholesterolemia. Moreover, since a statin mono-therapy may be insufficient for reducing blood cholesterol levels to target levels in clinical practice, especially in hypercholesterolemic patients with increased intestinal cholesterol absorption [9], a combination of dietary phytosterols to statin treatment may represent an additional tool to lower plasma cholesterol levels [10]. Accordingly, combined treatment with a statin and dietary phytosterols has led to significantly greater reductions in LDL cholesterol compared to statin mono-therapy [11], [12], [13].
Although a number of theories have been advanced concerning the mechanism by which phytosterols lower serum cholesterol, it is generally accepted that phytosterols mainly act by inhibition of intestinal cholesterol absorption [14]. Particularly, phytosterols reduce absorption of cholesterol in the digestive tract by interfering with the solubilisation of the cholesterol in the intestinal micelles. Moreover, phytosterols are believed to be internalized by the Niemann-Pick C1-Like 1 (NPC1L1) into the enterocytes, and to enhance a process in which cholesterol is pumped back out of enterocytes into the lumen of small intestine by ATP-Binding Cassette (ABC) transporter [14]. Phytosterols can also interfere with the absorption of carotenoids; in fact, long-term use of phytosterol-ester enriched spreads results in a reduction in the serum levels of the most lipophilic carotenoids, but at current levels of intake this is unlikely to result in reductions in carotenoids that are of biological significance [15].
The isoprostanes are a unique series of prostaglandin-like compounds formed in vivo via a non-enzymatic mechanism involving the free radical-initiated peroxidation of arachidonic acid [16]. Several studies carried out over the past decade have shown that these compounds are extremely accurate measures of oxidant injury in vivo. Experimental and clinical data suggest a role for isoprostanes in atherogenesis; these compounds, once released from cell membranes by phospholipases, may induce vasoconstriction, platelet aggregation and cell proliferation [17]. Although phytosterols may contribute to the reduction in the serum levels of lipophilic carotenoids, thus possibly suggesting a hypothetical pro-oxidative effect, the potential effects of daily phytosterol consumption on a reliable marker of in vivo oxidation like plasma isoprostanes is still unknown.
The aims of the present study were to investigate the effects of daily consumption of plant sterols-enriched low fat fermented milk on plasma lipid profile of hypercholesterolemic patients; in addition, we examined the possible effects of phytosterols intake on plasma isoprostanes levels, as a measure of global in vivo oxidative burden.
Section snippets
Study design and subjects
This is a multicentric (7 centers), randomised stratified by centre and by statin treatment, parallel, double-blind, test product vs control product study. Four weeks before the study treatment allocation (Visit 1), uniformisation of subjects' diet was obtained by the use of the NCEP-ATP III dietary recommendations [7]. During 14 consecutive days (run-in period), all subjects were to take one low fat dairy product within the main meals (lunch or dinner). During the 6 consecutive weeks
Results
The baseline clinical characteristics of 116 patients randomized to either PS-enriched or control fermented milk are reported in Table 2. Treatment randomization allowed a balanced distribution of baseline characteristics, the two groups of hypercholesterolemic patients being homogeneous for age, gender, BMI, lipid values. Also statin therapy was uniformly distributed in the two arms of treatment.
Six patients (3 in each group) were excluded from the analysis due to major protocol deviations for
Discussion
The results of the present study showed a positive effect of phytosterol daily intake on LDL cholesterol levels in subjects with moderate hypercholesterolemia, the magnitude of this effect being already evident since the 3rd week of PS consumption and still present after 6 weeks of active PS intake. Moreover, daily consumption of PS-enriched low-fat fermented milk was paralleled by a concomitant reduction of plasma 8-isoprostane levels, which have been referred as a reliable marker of global in
Acknowledgements
This study was supported by a grant from Danone Research, France. We would like to kindly thank A. Simonnet, P. Rondeau, S. Doat and B. Rumo for their contribution to this study. We also thank all the volunteers who participated.
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