Vascular effects of diet supplementation with plant sterols.

OBJECTIVES: The purpose of this study was to evaluate vascular effects of diet supplementation with plant sterol esters (PSE). BACKGROUND: Plant sterol esters are used as food supplements to reduce cholesterol levels. Their effects on endothelial function, stroke, or atherogenesis are not known. METHODS: In mice, plasma sterol concentrations were correlated with endothelial function, cerebral lesion size, and atherosclerosis. Plasma and tissue sterol concentrations were measured by gas-liquid chromatography-mass spectrometry in 82 consecutive patients with aortic stenosis. RESULTS: Compared with those fed with normal chow (NC), wild-type mice fed with NC supplemented with 2% PSE showed increased plant sterol but equal cholesterol plasma concentrations. The PSE supplementation impaired endothelium-dependent vasorelaxation and increased cerebral lesion size after middle cerebral artery occlusion. To test the effects of cholesterol-lowering by PSE, apolipoprotein E (ApoE)-/- mice were randomized to Western-type diet (WTD) with the addition of PSE or ezetimibe (EZE). Compared with WTD, both interventions reduced plaque sizes; however, WTD + PSE showed larger plaques compared with WTD + EZE (20.4 +/- 2.1% vs. 10.0 +/- 1.5%). Plant sterol plasma concentration strongly correlated with increased atherosclerotic lesion formation (r = 0.50). Furthermore, we examined plasma and aortic valve concentrations of plant sterol in 82 consecutive patients with aortic stenosis. Patients eating PSE-supplemented margarine (n = 10) showed increased plasma concentrations and 5-fold higher sterol concentrations in aortic valve tissue. CONCLUSIONS: Food supplementation with PSE impairs endothelial function, aggravates ischemic brain injury, effects atherogenesis in mice, and leads to increased tissue sterol concentrations in humans. Therefore, prospective studies are warranted that evaluate not only effects on cholesterol reduction, but also on clinical endpoints.

Increased plant sterol and stanol levels in brain of Watanabe rabbits fed rapeseed oil derived plant sterol or stanol esters.

Foods containing plant sterol or stanol esters can be beneficial in lowering LDL-cholesterol concentration, a major risk factor for CVD. The present study examined whether high dietary intake of rapeseed oil (RSO) derived plant sterol and stanol esters is associated with increased levels of these components in brain tissue of homozygous and heterozygous Watanabe rabbits, an animal model for familial hypercholesterolemia. Homozygous animals received either a standard diet, RSO stanol or RSO sterol ester while heterozygous animals were additionally fed with 2 g cholesterol/kg to the respective diet form for 120 d (n 9 for each group). Concentrations of cholesterol, its precursor lathosterol, plant sterols and stanols in brain and additionally in liver and plasma were determined by highly sensitive GC-MS. High-dose intake of RSO derived plant sterols and stanols resulted in increased levels of these components in plasma and liver. In brain a limited uptake of plant sterols and stanols was proven, indicating that these compounds passed the blood-brain barrier and may be retained in the brain tissue of Watanabe rabbits. Plant stanol ester feeding lowered plant sterol levels in brain, liver, and plasma. Cholesterol synthesis in brain, indicated by lathosterol, a local surrogate cholesterol synthesis marker, does not seem to be affected by plant sterol or stanol ester feeding. We conclude that high dose intake of plant sterol and stanol esters in Watanabe rabbits results in elevated concentrations of these components not only in the periphery but also in the central nervous system.

High-dose statins and skeletal muscle metabolism in humans: a randomized, controlled trial.

BACKGROUND: Myopathy, probably caused by 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibition in skeletal muscle, rarely occurs in patients taking statins. This study was designed to assess the effect of high-dose statin treatment on cholesterol and ubiquinone metabolism and mitochondrial function in human skeletal muscle. METHODS: Forty-eight patients with hypercholesterolemia (33 men and 15 women) were randomly assigned to receive 80 mg/d of simvastatin (n = 16), 40 mg/d of atorvastatin (n = 16), or placebo (n = 16) for 8 weeks. Plasma samples and muscle biopsy specimens were obtained at baseline and at the end of the follow-up. RESULTS: The ratio of plasma lathosterol to cholesterol, a marker of endogenous cholesterol synthesis, decreased significantly by 66% in both statin groups. Muscle campesterol concentrations increased from 21.1 +/- 7.1 nmol/g to 41.2 +/- 27.0 nmol/g in the simvastatin group and from 22.6 +/- 8.6 nmol/g to 40.0 +/- 18.7 nmol/g in the atorvastatin group (P = .005, repeated-measurements ANOVA). The muscle ubiquinone concentration was reduced significantly from 39.7 +/- 13.6 nmol/g to 26.4 +/- 7.9 nmol/g (P = .031, repeated-measurements ANOVA) in the simvastatin group, but no reduction was observed in the atorvastatin or placebo group. Respiratory chain enzyme activities were assessed in 6 patients taking simvastatin with markedly reduced muscle ubiquinone and in matched subjects selected from the atorvastatin (n = 6) and placebo (n = 6) groups. Respiratory chain enzyme and citrate synthase activities were reduced in the patients taking simvastatin. CONCLUSIONS: High-dose statin treatment leads to changes in the skeletal muscle sterol metabolism. Furthermore, aggressive statin treatment may affect mitochondrial volume.

Comparison of the intestinal uptake of cholesterol, plant sterols, and stanols in mice.

The recent identification of the aberrant transport proteins ABCG5 and ABCG8 resulting in sitosterolemia suggests that intestinal uptake of cholesterol is an unselective process, and that discrimination between cholesterol and plant sterols takes place at the level of sterol efflux from the enterocyte. Although plant sterols are structurally very similar to cholesterol, differing only in their side chain length, they are absorbed from the intestine to a markedly lower extent. In order to further evaluate the process of discrimination, three different sterols (cholesterol, campesterol, sitosterol) and their corresponding 5 alpha-stanols (cholestanol, campestanol, sitostanol) were compared concerning their concentration in the proximal small intestine, in serum, and in bile after a single oral dose of deuterated compounds. The data obtained support the hypothesis that i) the uptake of sterols and stanols is an extremely rapid process, ii) discrimination probably takes place on the level of reverse transport back into the gut lumen, iii) plant stanols are taken up, but not absorbed to a measurable extent, and iv) the process of discrimination probably also exists at the level of biliary excretion. The range of structural alterations that decrease intestinal absorption and increase biliary excretion is: 1) campesterol, 2) cholestanol-sitosterol, and 3) campestanol-sitostanol.