Background: Consumption of plant sterols and plant stanols reduces low-density lipoprotein cholesterol (LDL-C) concentrations. At the same time, plasma plant sterol concentrations will increase after plant sterol consumption, but decrease after plant stanol consumption. In contrast to plant stanols, plant sterols can undergo oxidation and form oxyphytosterols. Findings from in vitro and animal studies suggest that oxyphytosterols might be atherogenic. Objective: The objective was to examine whether plant sterol and stanol consumption changes fasting plasma oxyphytosterol concentrations. Design: A randomized, double blind, cross-over study was performed in which 43 healthy subjects (18e70 years) consumed for 4 weeks a plant sterol-enriched (3.0 g/d of plant sterols), a plant stanol-enriched (3.0 g/d of plant stanols), and a control margarine separated by wash-out periods of 4 weeks. Oxyphytosterol concentrations were determined in BHT-enriched plasma via GCeMS. Results: Compared to control, serum LDL-C concentrations were reduced after plant sterol (À8.1%; p < 0.001) and plant stanol consumption (À7.8%; p < 0.001). Plant sterol consumption did not change plasma oxyphytosterol concentrations. On the other hand, intake of the plant stanol margarine reduced 7b-OH-campesterol by 0.07 ng/mL (w14%; p < 0.01) and by 0.07 ng/mL (w15%; p < 0.01) compared with the control and sterol margarines, respectively. When standardized for serum cholesterol, effects on these oxyphytosterols were comparable. In addition, plant stanol intake reduced cholesterolstandardized 7-keto-campesterol levels compared with plant sterol intake (p < 0.05). Conclusions: Daily consumption of a plant sterol-enriched margarine does not increase oxyphytosterol concentrations, while plant stanol consumption may reduce the concentrations of the oxidative plant sterol metabolites 7b-OH-campesterol and 7-keto-campesterol. This trial is registered at clinicaltrials.gov as NCT01559428.

This article is available online at http://www.jlr.org stigmasterol (ethyl group at C24, ⌬ 22) ( 1, 2 ). In contrast to cholesterol, these sterols are exclusively derived from the diet and cannot be synthesized endogenously in mammals. A high plant sterol intake (2-2.5 g/day) leads to reduced total and LDL-cholesterol ( ‫ف‬ 12%) in the circulation ( 3, 4 ). Therefore, plant sterols are frequently applied as functional, nonprescription food additives to prevent atherosclerosis and cardiovascular diseases ( 5 ). However, administration of high-dose plant sterols results in increased serum plant sterol concentrations ( 6 ). Hard end-point studies showing an effect on the number of cardiovascular events or on mortality after long-term intake of high-dose plant sterols are lacking ( 7 ), as are insights into the underlying molecular mechanisms ( 8 ). Because adverse events upon plant sterol administration in animal studies are increasingly being reported to cause adverse events ( 9 ), it is a current topic of debate ( 10 ).In contrast to peripheral tissues, all cholesterol within the central nervous system is synthesized in situ because circulating cholesterol is not able to cross the blood-brain barrier (BBB) ( 11,12 ). Recently, we reported that circulating plant sterols, in contrast to cholesterol, can enter the brains of ATP binding cassette g5 (Abcg5)-defi cient mice, a model for phytosterolemia ( 13 ). ABCG5 and ABCG8 act as functional heterodimer transporters at the apical membranes of enterocytes and hepatocytes, where they excrete plant sterols into the intestinal lumen and bile, Abstract Plant sterols such as sitosterol and campesterol are frequently administered as cholesterol-lowering supplements in food. Recently, it has been shown in mice that, in contrast to the structurally related cholesterol, circulating plant sterols can enter the brain. We questioned whether the accumulation of plant sterols in murine brain is reversible. After being fed a plant sterol ester-enriched diet for 6 weeks, C57BL/6NCrl mice displayed signifi cantly increased concentrations of plant sterols in serum, liver, and brain by 2-to 3-fold. Blocking intestinal sterol uptake for the next 6 months while feeding the mice with a plant stanol ester -enriched diet resulted in strongly decreased plant sterol levels in serum and liver, without affecting brain plant sterol levels. Relative to plasma concentrations, brain levels of campesterol were higher than sitosterol, suggesting that campesterol traverses the blood-brain barrier more effi ciently. In vitro experiments with brain endothelial cell cultures showed that campesterol crossed the blood-brain barrier more effi ciently than sitosterol. We conclude that, over a 6-month period, plant sterol accumulation in murine brain is virtually irreversible. Plant sterols differ structurally from cholesterol by an additional methyl or ethyl group at C24 and/or a double bond at C22 ( ⌬ 22). The most prevalent plant sterols are campesterol (methyl group at C24), sitosterol (ethyl group at C24)...

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XGB increased serum and hepatic TG levels, and VLDL production, which were restored to normal by nicotinic acid. The results suggest that FFA flux from adipose tissue to the liver is increased in XGB mice. They support the hypothesis that the GB has a role in the regulation of hepatic TG metabolism and that XGB may favour the accumulation of fat in the liver.

Oxysterols (oxidised cholesterol) may play a role in the pathogenesis of CVD. Similar to cholesterol, plant sterols are susceptible to oxidation. However, less is known about the potential atherogenicity of oxidised plant sterols (oxyphytosterols). In the present study, the atherogenicity of a mixture of oxyphytosterols was examined by feeding female LDL receptor-deficient (LDLR þ/2 ) mice for 35 weeks a control diet (atherogenic high-fat diet; n 9), an oxysterol diet (control diet þ 0·025 % (w/w) oxysterols; n 12) or an oxyphytosterol diet (control diet þ 0·025 % (w/w) oxyphytosterols; n 12). In the LDLR þ/2 mice, serum levels of cholesterol, lipoprotein profiles, cholesterol exposure and inflammatory markers at the end of the experiment were comparable between the three diet groups. Nevertheless, the proportion of severe atherosclerotic lesions was significantly higher after oxysterol (41 %; P¼ 0·004) and oxyphytosterol (34 %; P¼0·011) diet consumption than after control diet consumption (26 %). Oxyphytosterol levels in the lesions were the highest in the oxyphytosterol group. Here, we show that not only dietary oxysterols but also dietary oxyphytosterols increase the proportion of severe atherosclerotic lesions. This suggests that plant sterols when oxidised may increase atherosclerotic lesion severity instead of lowering the size and severity of lesions when fed in their non-oxidised form. Therefore, this finding might give an indication as to where to find the answer in the current hot debate about the potential atherogenicity of plant sterols. However, to what extent these results can be extrapolated to the human situation warrants further investigation. Key words: Diets: Oxysterols: Oxyphytosterols: Lipoproteins: Atherosclerosis Several lines of evidence suggest that oxysterols (oxidised cholesterol) are atherogenic and play a role in the pathogenesis of CVD. Plant sterols are structurally related to cholesterol (1) , and the presence of one or more unsaturated bonds also makes the plant sterols susceptible to oxidation. Only small amounts of oxidised plant sterols (oxyphytosterols) can be found in the diet (2,3) . Nevertheless, relatively high concentrations of oxyphytosterols are present in the serum of sitosterolaemic patients (4) and smaller amounts in the plasma of healthy individuals (5,6) . The fact that oxyphytosterol concentrations are high in sitosterolaemic patients, who also have severely elevated plasma plant sterol concentrations, may suggest that higher plasma plant sterol concentrations translate into higher plasma oxyphytosterol concentrations. Indeed, Husche et al. (6) have recently shown that consumption of a plant sterol-enriched margarine for 4 weeks increases serum 7b-OH-campesterol concentrations in healthy individuals. Factors that are related to the oxidative behaviour of plant sterols are unknown. For cholesterol, however, it has been suggested that patients characterised by oxidative stress such as type 2 diabetics (7) and patients with stable coronary artery disease (8)...