No Association Between Plasma Levels of Plant Sterols and Atherosclerosis in Mice and Men

Abstract

Objective-Sitosterolemia is characterized by elevated plasma levels of plant sterols, hypercholesterolemia and premature coronary heart disease (CHD). CHD develops in some subjects with sitosterolemia, despite having normal plasma cholesterol levels, suggesting that high circulating levels of plant sterols may be atherogenic. We tested whether elevated plasma levels of plant sterols (sitosterol and campesterol) were associated with atherosclerosis in genetically modified mice and in middle-aged men and women. Methods and Results-Wild-type and hypercholesterolemic female mice with Ͼ20-fold higher plasma levels of plant sterols because of inactivation of the ATP-binding cassette (ABC) half transporters G5 and G8 (G5G8Ϫ/Ϫmice) were fed chow or Western diets for 7 months. No significant differences in aortic lesion area were found when the sitosterolemic mice were compared with littermate controls. To determine whether plasma levels of plant sterols were associated with coronary atherosclerosis in humans, the relationship between plasma plant sterols and coronary calcium (detected by electron beam computer tomography) was examined in 2542 subjects aged 30 to 67 years. Plasma levels of cholesterol, but not sitosterol or campesterol, were significantly higher in subjects with coronary calcium. Key Words: sitosterolemia Ⅲ ATP-binding cassette transporters Ⅲ atherosclerosis Ⅲ plant sterols T he 2 major classes of dietary sterols are those derived from animals (cholesterol) and those derived from plants (phytosterols). The most abundant dietary phytosterols are sitosterol and campesterol, which differ from cholesterol by an ethyl or methyl group attached to the side chain at C24. Although animal-derived and plant-derived sterols are structurally similar, they are handled differently by mammals. Less than 5% of dietary sitosterol is absorbed by the intestine, 1,2 whereas between 30% and 80% of dietary cholesterol is incorporated into chylomicrons and delivered to the liver. 3 Moreover, the small fraction of dietary plant sterols that reaches the liver is preferentially secreted into the bile. 2 As a result of the low fractional absorption and enhanced biliary secretion of plant sterols, phytosterols comprise Ͻ1% of circulating sterols. 4 Individuals with mutations in either of 2 ATP-binding cassette (ABC) half transporters, ABCG5(G5) or ABCG8(G8), have sitosterolemia. 5,6 This autosomalrecessive disorder is characterized by a Ͼ50-fold elevation in the plasma levels of plant sterols and is frequently associated with the development of tendon and cutaneous xanthomas, as well as premature coronary atherosclerosis (coronary heart disease [CHD]). 7 Although many subjects with sitosterolemia have hypercholesterolemia, the plasma levels of cholesterol can vary dramatically in these individuals and can sometimes be within the normal range. 8 -11 The presence of coronary atherosclerosis in the absence of hypercholesterolemia in some sitosterolemic patients has led to speculation that elevated plasma levels of plant sterols promot...

Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort

“…Second, only a single measure of dietary exposure and risk factor status at baseline was available; therefore, changes in diet and other lifestyle variables that might have infl uenced CHD risk throughout the ‫ف‬ 10 year follow-up were not accounted for. Finally, it could be argued that the fi ndings are specifi c for the Mediterranean cohort studied, but the similarity of plasma noncholesterol levels with those reported in epidemiologic studies from the US ( 9,26,30 ), Finland ( 10 ), Germany ( 11,12,14 ), the UK ( 13 ), and The Netherlands ( 15 ) suggests that they may be generalized to other populations.…”

“…Other contradictory evidence has been presented recently. An investigation from the Dallas Heart Study showed no relationship between plasma phytosterols and a surrogate marker for CHD, namely, coronary calcium scores measured by electron beam computed tomography ( 26 ). Miettinen et al ( 27 ) reported an association between raised plasma phytosterol levels and increased phytosterol content of surgically removed carotid plaques, while Weingärtner et al ( 28 ) showed that consumption of phytosterol-enriched margarine correlated with increased plasma concentrations and tissue deposi- An additional factor that infl uences plasma phytosterolto-cholesterol ratios is statin treatment ( 7,36 ), a reason why statin users were excluded from the analyses.…”

Baseline plasma plant sterol concentrations do not predict changes in serum lipids, C-reactive protein (CRP) and plasma plant sterols following intake of a plant sterol-enriched food

“…Wilund et al (2004) demonstrated that plasma PS concentrations do not differ between individuals with a positive history of heart disease and case-matched controls. Baseline plasma PS concentrations did not associate with atherosclerosis based on arterial calcium scores, a marker of the degree of atherosclerosis.…”

“…PS consumption at 2 g per day modestly elevates plasma PS concentrations in hypercholesterolemic individuals (Sudhop and von Bergmann, 2004). Observational studies suggest that slightly elevated concentrations of PS are associated with an increased risk of cardiovascular events; however, this relationship has not been consistently shown (Glueck et al, 1991;Rajaratnam et al, 2000;Sudhop et al, 2002;Wilund et al, 2004;Miettinen et al, 2005;Assmann et al, 2006;Pinedo et al, 2007). As plasma PS concentrations may reflect PS absorption efficiency (Matthan and Lichtenstein, 2004;Sudhop and von Bergmann, 2004) there is a need to address whether individuals with high baseline plasma PS (HPS) hyperabsorb PS and show abnormal elevations in plasma levels which are greater than what has previously established.…”

Similar serum plant sterol responses of human subjects heterozygous for a mutation causing sitosterolemia and controls to diets enriched in plant sterols or stanols

“…On the other hand, no relationship between plasma levels of phytosterols and atherosclerosis or CHD risk was found by Wilund et al (2004), who investigated this question in both mice and humans. Also, the findings discussed above do not prove a causal relationship between CHD and serum plant sterol levels, as these associations might be explained by underlying genetic defects that affect both serum plant sterol concentrations and the risk of CHD.…”