Abstract
Dietary plant sterols (PS) reduce serum total and LDL-cholesterol in hyperlipidemic animal models and in humans. This hypocholesterolemic effect is generally ascribed to inhibition of cholesterol absorption. However, whether this effect fully explains the reported strong induction of neutral sterol excretion upon plant sterol feeding is not known. Recent data demonstrate that the intestine directly mediates plasma cholesterol excretion into feces, i.e., without involvement of the hepato-biliary route.ObjectiveAim of this study was to determine whether stimulation of fecal neutral sterol loss during PS feeding is (partly) explained by increased intestinal cholesterol excretion and to assess the role of the cholesterol transporter Abcg5/Abcg8 herein.Methods and ResultsWild-type mice were fed a control diet or diets enriched with increasing amounts of PS (1%, 2%, 4% or 8%, wt/wt) for two weeks. In addition, Abcg5-/- mice were fed either control or 8% PS diet. PS feeding resulted in a dose-dependent decrease of fractional cholesterol absorption (∼2–7-fold reduction) in wild-type mice and ∼80% reduction in Abcg5-/- mice. Furthermore, PS feeding led to a strong, dose-independent induction of neutral sterol excretion (3.4-fold in wild-types and 2.7-fold in Abcg5-/- mice) without changes in biliary cholesterol secretion. It was calculated that PS feeding stimulated intestinal cholesterol excretion by ∼500% in wild-type mice and by ∼250% in Abcg5-/-.ConclusionsOur data indicate that in mice the cholesterol-lowering effects of PS are to a large extent attributable to stimulation of intestinal, non-bile derived, cholesterol excretion. The Abcg5/Abcg8 heterodimer is involved in facilitating this PS-induced flux of cholesterol.
Highlights
Addition of plant sterols to the diet reduces serum total and LDL-cholesterol concentrations in normolipidemic and hypercholesterolemic subjects without affecting serum HDL-cholesterol levels [1].The structural similarity between plant sterols and cholesterol presumably under-lies their effects on cholesterol metabolism
Reductase activity, i.e., interfering with cholesterol synthesis [8], (ii) decreasing ACAT activity, reduction of cholesterol esterfication needed for incorporation into chylomicrons [9] or (iii) interference with cholesterol trafficking within the enterocytes since plant sterols may alter expression of genes encoding proteins of the ANX family that are involved in regulation of membrane properties [10]
No differences in body weights were seen between the respective groups of animals, food intake by mice fed 8% plant sterols was higher compared to mice on control diet
Summary
Addition of plant sterols to the diet reduces serum total and LDL-cholesterol concentrations in normolipidemic and hypercholesterolemic subjects without affecting serum HDL-cholesterol levels [1].The structural similarity between plant sterols and cholesterol presumably under-lies their effects on cholesterol metabolism. Plant sterols may influence expression and/ or activity of proteins involved in cholesterol metabolism, both in enterocytes and hepatocytes [for review see [3]]. It has been proposed that plant sterols may reduce plasma cholesterol levels via LXR-independent mechanisms [3]. Proposed modes of action involve (i) reduction of HMG-CoA reductase activity, i.e., interfering with cholesterol synthesis [8], (ii) decreasing ACAT activity, reduction of cholesterol esterfication needed for incorporation into chylomicrons [9] or (iii) interference with cholesterol trafficking within the enterocytes since plant sterols may alter expression of genes encoding proteins of the ANX family that are involved in regulation of membrane properties [10]
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