LDL cholesterol lowering by bile acid malabsorption during inhibited synthesis and absorption of cholesterol in hypercholesterolemic coronary subjects

BACKGROUND AND AIMS: Recent large-scale trials have consistently documented the fact that a 25-35% reduction in low-density lipoprotein cholesterol (LDL-C) can delay the progression of atherosclerosis. This raises the question as to how much it is possible to reduce serum cholesterol using feasible therapies. The aim of this study was to investigate the cholesterol-lowering efficacy of a triple therapy combining bile acid malabsorption with the inhibition of cholesterol synthesis and absorption. METHODS AND RESULTS: Eleven consecutive hypercholesterolemic coronary patients from Lipid Clinics on a low-fat, low-cholesterol baseline diet added simvastatin (20 mg/day) for three months, and then dietary plant stanol ester margarine (2.25 g of stanols/day) for eight weeks; finally, cholestyramine 8 g/day was added for another eight weeks. This was a before-after trial, in which the results of each period were compared with baseline and those of the previous period. Serum lipids were quantitated using commercial kits, and serum sterols by means of gas-liquid chromatography. Simvastatin lowered LDL-C by 39% (p < 0.001), and additional stanol ester margarine by a further 13% (p < 0.05). The triple treatment led to 67% reduction from baseline (p < 0.001), with all LDL-C values being < 2.6 mmol/L, and increased high-density lipoprotein cholesterol (HDL-C) by 15% (p < 0.01). It also increased the serum lathosterol/cholesterol ratio (p < 0.01), thus indicating an upregulation of cholesterol synthesis, and increased the serum sitosterol ratio (p < 0.01) despite the simultaneous consumption of plant stanols. CONCLUSIONS: The massive reduction in LDL and increase in HDL-C obtained using our triple therapy suggests that the combination of stanol ester with only moderate doses of statin and resin makes it possible to control LDL-C levels effectively in hypercholesterolemic subjects.     

Vegetable oil based versus wood based stanol ester mixtures: effects on serum lipids and hemostatic factors in non-hypercholesterolemic subjects

A pine wood based stanol ester mixture-composed of sitostanol (92%) and campestanol (8%) effectively lowers cholesterol absorption and consequently LDL-cholesterol concentrations. It has been postulated that the less absorbable plant sterols reduce cholesterol absorption more effectively. As sitostanol is absorbed less than campestanol, we decided to examine if a vegetable oil based stanol ester mixture with 68% sitostanol and 32% campestanol is less effective than the wood based stanol ester mixture. For this, 112 non-hypercholesterolemic men and women consumed for 4 weeks a rapeseed oil (LEAR) based margarine and shortening. For the next 8 weeks, 42 subjects continued with these products, while the other subjects received products with a vegetable oil (n=36) or a pine wood based stanol ester mixture (n=34). Consumption of 3.8 g vegetable oil based stanols (2.6 g sitostanol plus 1.2 g campestanol) lowered LDL cholesterol 14.6+/-8.0% (-0.37 mmol/l; vs. the control group; P<0.001; 95% CI for the difference, -0.22 to -0. 51 mmol/l). Four grams pine wood based stanols (3.7 g sitostanol plus 0.3 g campestanol) showed a comparable decrease of 12.8+/-11.2% (-0.34 mmol/l; P<0.001; 95% CI-0.18 to-0.51 mmol/l). Decreases in LDL cholesterol were not different between the two experimental groups (P=0.793), while apoE genotype did not have a major impact on this hypocholesterolemic response. Serum HDL cholesterol and triacylglycerol concentrations were not changed. The decreases in apo B in both experimental groups differed significantly (P<0.001) from changes in the control group. Coagulation and fibrinolytic parameters were not affected. We therefore conclude that vegetable oil and wood based stanol ester mixtures, with a different sitostanol/campestanol ratio, have similar LDL cholesterol lowering effects in a non-hypercholesterolemic population.     

Cholesterol reduction by different plant stanol mixtures and with variable fat intake.

Our aim was to investigate (1) whether different campestanol/sitostanol mixtures in margarine differ in reducing serum cholesterol, and (2) whether sitostanol ester in butter decreases serum cholesterol and alters cholesterol absorption and metabolism. Twenty-three postmenopausal women replaced 25 g dietary fat with (1) sitostanol ester-rich (campestanol to sitostanol ratio 1:11) and (2) campestanol ester-rich (campestanol to sitostanol ratio 1:2) rapeseed oil margarine, (3) butter, and (4) sitostanol ester-rich (campestanol to sitostanol ratio 1:13) butter. The respective scheduled stanol intake was 3.18, 3.16, and 2.43 g/d. The 6-week margarine periods and, after an 8-week washout, 5-week butter periods were double-blind and in random order. Serum cholesterol precursor sterols (indicators of cholesterol synthesis) and plant sterols (indicators of cholesterol absorption) were quantified with gas-liquid chromatography (GLC). Low-density lipoprotein (LDL) cholesterol was reduced by 8% and 10% with the sitostanol and campestanol ester-rich margarines versus baseline (P < .05 for both) and high-density lipoprotein (HDL) cholesterol was increased by 6% and 5% (P < .05), so the LDL/HDL cholesterol ratio was reduced by 15% (P < .05 for both). Sitostanol ester-rich butter decreased LDL cholesterol 12% and the LDL/HDL cholesterol ratio 11% (P < .05 for both) versus the butter period. The serum proportions of plant sterols and cholestanol were similarly reduced and those of cholesterol precursor sterols were similarly increased during all periods (P < .05 for all). Serum proportions of sitostanol and campestanol were slightly increased, indicating that their absorption related to their dietary intake. During all stanol interventions, serum vitamin D and retinol concentrations and alpha-tocopherol to cholesterol ratios were unchanged, whereas those of alpha- and beta-carotenes were significantly reduced. We conclude that varying the campestanol to sitostanol ratio from 1:13 to 1:2 in margarine and in butter similarly decreased cholesterol absorption, LDL cholesterol, and the LDL/HDL cholesterol ratio such that the serum lipids became less atherogenic.     

Baseline intestinal absorption and synthesis of cholesterol regulate its response to hypolipidaemic treatments in coronary patients

Baseline cholesterol metabolism was hypothesized to regulate responses of cholesterol synthesis and absorption, and serum cholesterol lowering to hypolipidaemic treatment. Thus, serum cholesterol and non-cholesterol sterols were measured before and during long-term simvastatin treatment (inhibition of cholesterol synthesis) and subsequent combination of statin with plant stanol ester margarine (inhibition of cholesterol absorption) consumption in subjects with low (n=15) and high (n=15) absorption of cholesterol, defined by respective low and high baseline ratios of serum cholestanol to cholesterol. Cholesterol synthesis (defined by precursors of cholesterol) was markedly reduced by the long-term statin treatment in both groups, but more extensively in the low than high absorption group (P<0.05), yet the respective serum cholesterol reductions were similar. From among the absorption markers, sitosterol and cholestanol ratios were correspondingly increased more in the low than in the high absorption group. Plant stanol ester margarine consumption, combined with chronic statin treatment, further lowered the serum cholesterol level (P<0.001) only in the high absorption group. The sum of cholesterol absorption markers was reduced more (P<0.05) in the high than in the low absorption group, while the non-significant serum cholesterol reduction of the low absorption group was associated with relatively high increase of cholesterol synthesis. Thus, stanol ester margarine combined with chronic simvastatin treatment reduces cholesterol absorption and serum cholesterol more consistently in subjects with high than low baseline absorption of cholesterol. The profile of baseline cholesterol metabolism determines the changes in synthesis and absorption of cholesterol to hypolipidaemic treatments, but affects less differently serum cholesterol level.     

Incremental reduction of serum total cholesterol and low-density lipoprotein cholesterol with the addition of plant stanol ester-containing spread to statin therapy

This study compares the effect of plant stanol ester spread with a placebo spread on cholesterol in patients taking statin therapy, but who still had elevated low-density lipoprotein (LDL) cholesterol. This was a randomized, double-blind, placebo-controlled clinical trial, with 67 women and 100 men with LDL cholesterol >/=130 mg/dl and triglycerides 相似文献   

Cholesterol metabolism and non-cholesterol sterol distribution in lipoproteins of type 1 diabetes: the effect of improved glycemic control

In type 1 diabetes, the ratios to cholesterol of serum absorption markers, e.g., cholestanol, are elevated and those of synthesis markers, e.g., lathosterol, are reduced suggesting perturbed cholesterol metabolism. We studied 17 subjects with type 1 diabetes in poor glycemic control at baseline to assess whether improvement of glycemic control affects lathosterol and cholestanol ratios to cholesterol and their distribution in lipoproteins. Cholesterol and the non-cholesterol sterols were assayed directly from serum, and free and ester fractions after thin-layer chromatographic separation of lipoprotein sterols with gas-liquid chromatography. After the 2-6 months follow-up, the mean value of HbA1(c) decreased from 10.8% to 8.6% (p=0.001). Even though the concentrations of serum and lipoprotein cholesterol remained unchanged, the serum lathosterol to cholesterol ratio increased by 28% (p<0.05) and the lathosterol/cholestanol proportion by 23% (p<0.05). The ratios of total and esterified lathosterol to cholesterol in serum, chylomicrons and LDL, and free lathosterol to cholesterol in serum and IDL, were negatively associated with HbA1(c) at baseline and after follow-up, suggesting that the better glycemic control, the higher was cholesterol synthesis. The absorption markers were less consistently associated with HbA1(c). About half of the serum lathosterol and cholestanol was carried in LDL and one-fourth to one-fifth in HDL, but the lathosterol ratios were roughly similar in all lipoproteins. In contrast, cholestanol accumulated in chylomicrons and HDL. Glycemic control did not affect the distributions of lathosterol and cholestanol. In conclusion, improvement in glycemic control increased cholesterol synthesis, but had no effect on cholesterol absorption as measured by the serum or lipoprotein cholestanol to cholesterol ratio. From a clinical point of view, the better the glycemic control, the more antiatherogenic cholesterol metabolism may be in type 1 diabetes.     

Effect of stanol ester on postabsorptive squalene and retinyl palmitate

Stanol ester dissolved in margarine inhibits cholesterol absorption in general and, despite increasing cholesterol synthesis, decreases serum total and low-density lipoprotein (LDL) cholesterol levels, but its effects on postprandial lipid metabolism are unknown. We performed fat tolerance tests in 11 men at baseline and during short-term stanol ester consumption without and with stanol esters added to the test meal also containing retinol and squalene. Cholesterol, triglycerides, retinyl palmitate, and squalene were analyzed in plasma, chylomicrons, and very-low-density lipoprotein (VLDL) at baseline and 3, 4, 6, 9, 12, and 24 hours after the test meal. Serum total and LDL cholesterol only tended to diminish after the 2-week stanol ester consumption. However, the proportion of plasma plant sterol and cholesterol-precursor sterol to cholesterol was significantly altered, suggesting that cholesterol absorption was diminished and cholesterol synthesis was increased. Postprandial peak times of squalene and retinyl palmitate in plasma, chylomicrons, and VLDL were significantly reduced by stanol esters, but their concentrations in chylomicrons were unchanged. Stanol esters reduced the VLDL squalene peak concentration by 23% (P < .05) and the incremental area under the curve (AUIC) in plasma and VLDL by 22% and 32% (P < .01 for both). Chylomicron remnant metabolism measured with triglycerides only tended to diminish. The effects of stanol esters in the diet only and both in the diet and with supplementation did not differ significantly. We conclude that dietary stanol esters reduce postprandial lipoproteins measured with dietary retinyl palmitate and especially squalene, and the reduction is observed even though serum total and LDL cholesterol are only inconsistently decreased after short-term stanol ester consumption.     

Plant sterols lower LDL cholesterol without improving endothelial function in prepubertal children with familial hypercholesterolaemia

In adults with familial hypercholesterolaemia (FH), cholesterol lowering with statins has been shown to improve the endothelial function, a hallmark of early atherogenesis. Currently, therapeutic options for treating high cholesterol levels in FH children are limited. Plant sterols safely and effectively reduce serum cholesterol concentrations by inhibiting cholesterol absorption. Therefore, we evaluated the effect of plant sterols on cholesterol and vascular function in prepubertal children with FH. We included 41 children (5–12 years old) with FH in a double-blind crossover trial using spreads containing 2.3 g of plant sterols (mainly sitosterol and campesterol) per 15 g spread and a placebo spread for a 4-week period, separated by a 6-week washout period. Lipid levels and endothelial function were assessed after both 4-week treatment periods. Endothelial function was assessed as flow-mediated dilation (FMD) of the brachial artery using a wall tracking system. Data were compared to those of 20 healthy controls. Intake of 2.3 g plant sterols per day decreased total cholesterol (-11%) and low-density cholesterol (-14%) as compared to placebo spread in FH children. FH children treated with placebo spread were characterized by an impaired FMD compared to healthy control children (7.2 %± 3.4% versus 10.1%±4.2%, p < 0.005). However, the reduction of LDL in FH children did not improve FMD (placebo: 7.2% ± 3.4% versus plant sterols: 7.7% ± 4.1%). In conclusion, the present study shows a clear reduction of LDL cholesterol by plant sterol treatment. However, short-term plant sterol treatment does not improve the endothelial function in FH children. This revised version was published online in August 2006 with corrections to the Cover Date.     

Comparison of the effects of dietary plant sterol and stanol esters on lipid metabolism

BACKGROUND AND AIM: To compare the cholesterol-lowering efficacy and other metabolic effects of plant sterol and stanol esters, both of which are commonly used in the dietary management of hypercholesterolaemia. METHODS AND RESULTS: The cholesterol-lowering efficacy of equivalent intakes of sterol and stanol esters and of different intakes of stanol esters were compared at 1 and 2 months, both in normal subjects and treated patients with familial hypercholesterolaemia. Systemic effects were assessed by measuring serum levels of plant sterols and of lathosterol and 7alpha-hydroxy-cholestenone, indices of sterol absorption and of cholesterol and bile acid synthesis respectively. There were no significant differences during the study between 1.6g daily of sterol and stanol esters in reducing total cholesterol (by 3-7%) or low density lipoprotein cholesterol (by 4-8%), nor between 1.6 and 2.6 g daily of stanol. However, the cholesterol-lowering effect of plant sterol esters was attenuated between 1 and 2 months. This was accompanied by increased serum plant sterols and decreased levels of 7alpha-hydroxy-cholestenone, especially in statin-treated hypercholesterolaemic patients not taking bile acid sequestrants. CONCLUSIONS: These findings suggest that absorption of dietary plant sterols suppressed bile acid synthesis, thereby diminishing their cholesterol-lowering efficacy. In contrast, plant stanols reduced plant sterol absorption and maintained their cholesterol-lowering efficacy.     

No changes in serum fat-soluble vitamin and carotenoid concentrations with the intake of plant sterol/stanol esters in the context of a controlled diet

Spreads enriched with plant sterol and stanol esters have been shown to possess similar cholesterol-lowering properties; however, their comparative capacity to alter circulating levels of other fat-soluble compounds has not been fully assessed. To compare actions of sterol and stanol ester consumption on serum fat-soluble vitamin and carotenoid concentrations, 15 hypercholesterolemic subjects were fed each of 3 fixed foods treatment diets over 21 days using a randomized crossover controlled design. Diets contained either (1) margarine (M), (2) margarine with sterol esters (MSE; 1.92 g/d), or (3) margarine with stanol esters (MSA; 1.76 g/d). No significant differences were found in initial or final serum fat-soluble vitamin and carotenoid concentrations among the 3 phases. Serum retinol and alpha- and gamma-tocopherol concentrations at baseline and endpoint and percentage changes relative to baseline for MSE and MSA were not significantly different from those of the M diet. After adjusting for total cholesterol reduction, no changes for alpha- and gamma-tocopherol were found. Serum vitamins D and K, lycopene, and lutein concentrations and percentage changes did not differ across diets. Serum concentrations at baseline and endpoint and percentage changes for alpha- and beta-cryptoxanthin and alpha- and gamma-carotene were not different among the diets, nor did serum alpha- and gamma-carotene concentrations to total cholesterol ratios differ. Serum lutein, beta-cryptoxanthin, and alpha-carotene concentrations increased over time. In conclusion, our results show no effect of consumption of esterified plant sterols or stanols on serum fat-soluble vitamin or carotenoid concentrations compared with a control diet.     

Endothelial function in hypercholesterolemic subjects: Effects of plant stanol and sterol esters

We investigated the effects of stanol (STAEST) and sterol esters (STEEST) on endothelial function in hypercholesterolemic subjects. In addition, associations of variables of cholesterol metabolism with endothelial function were investigated. In a double-blind randomized cross-over study (n=39) with age-matched parallel control group (n=37) the subjects consumed STAEST or STEEST spread (total plant sterols and stanols 1.93-1.98g/day) for 10 weeks each. Controls consumed the spread without sterols or stanols for 20 weeks. At baseline, brachial artery diameter was positively correlated with serum triglycerides (r=0.375, p=0.001) and glucose (r=0.420, p<0.001) and with cholesterol synthesis marker ratios to cholesterol (e.g. desmosterol r=0.540, p<0.001) and negatively with HDL cholesterol (r=-0.309, p=0.008) and absorption marker ratios (e.g. campesterol r=-0.332, p=0.004). During the intervention, LDL cholesterol was reduced by 6-9% from baseline with STAEST and STEEST spreads (p<0.05), and by 9-12%, respectively, from controls (p<0.05). Flow-mediated dilatation did not change during the investigation. Brachial artery diameter was unchanged in controls and during STAEST periods, but it was reduced during STEEST by 2.2% (p=0.012) from STAEST. In conclusion, variables of cholesterol metabolism are associated with brachial artery diameter at baseline. STEEST diminishes brachial artery diameter, but its clinical relevance remains unclear.     

Non-cholesterol sterols in serum and endarterectomized carotid arteries after a short-term plant stanol and sterol ester challenge

Background and Aims

It is not known whether dietary intake of plant stanols or sterols changes the composition of arterial sterols. Therefore, we compared serum and carotid artery cholesterol and non-cholesterol sterols after plant stanol (staest) or sterol (steest) ester feeding in endarterectomized patients.

Methods and Results

Elderly statin-treated asymptomatic patients undergoing carotid endarterectomy were randomized double-blind to consume staest (n = 11) or steest (n = 11) spread (2 g of stanol or sterol/day) for four weeks preoperatively. Non-cholesterol sterols from serum and carotid artery tissue were analysed with gas-liquid chromatography. Staest spread lowered serum total (17.2%), VLDL, and LDL cholesterol and serum triglycerides, while steest spread lowered serum total (13.8%) and LDL cholesterol levels from baseline (p < 0.05 for all). Serum cholestanol and avenasterol were decreased in both groups, but campesterol and sitosterol were decreased by staest and increased by steest from baseline (p < 0.05 from baseline and between the groups). Serum sitostanol to cholesterol ratio was increased by staest, but in arterial tissue this ratio was similar in both groups. On staest, lathosterol, campesterol, and sitosterol, and on steest sitosterol and avenasterol correlated significantly between serum and arterial tissue. Cholesterol metabolism, eg. lathosterol/campesterol, suggested that plant sterols were reduced in serum and in arterial tissue during staest.

Conclusion

The novel observations were that plant stanol ester consumption, in contrast to plant sterols, tended to reduce carotid artery plant sterols in statin-treated patients. Furthermore, despite increased serum sitostanol contents during plant stanol ester consumption, their arterial levels were unchanged suggesting that sitostanol is not taken up into the arterial wall.     

Serum sterols in patients with primary biliary cirrhosis and acute liver failure before and after liver transplantation

BACKGROUND/AIMS: Liver diseases modify sterol metabolism. Liver transplantation (LTX) provides a model to evaluate the impact of disease-affected liver on sterol metabolism. METHODS: We studied serum sterol profiles and their relationships to other biochemical markers in consecutive cholestatic patients with acute liver failure (ALF, n=39) and end-stage primary biliary cirrhosis (PBC, n=67) before and 27d after LTX. Accordingly, we determined serum levels of sterols, bilirubin and prealbumin. RESULTS: Due to weak cholesterol synthesis of ALF-patients before LTX, their serum levels of cholesterol, lathosterol/cholesterol, cholestanol/cholesterol and lathosterol/campesterol were 18%-41% lower (P<0.05 for each) than in PBC, but ratios of phytosterols to cholesterol were equal. In general, non-cholesterol sterol ratios reflected bilirubin and prealbumin concentrations. Interrelation of surrogate sterols showed that homeostasis of cholesterol metabolism prevailed in lowest cholestanol tertile of ALF-patients consistently, but not in PBC. After LTX, cholesterol levels and lathosterol ratios increased in both groups and phytosterol ratios decreased (P<0.01). Cholestanol decreased profoundly in PBC, but remained 26% higher than in ALF (P<0.05). CONCLUSIONS: Homeostasis of cholesterol metabolism was maintained only in ALF. Metabolism of phytosterols was equal in study groups. PBC- and ALF-patients have differential patterns in their serum sterols and cholesterol metabolism.     

Plant sterols in serum and in atherosclerotic plaques of patients undergoing carotid endarterectomy

OBJECTIVES: The purpose of this research was to determine whether serum plant sterol levels are associated with those in atheromatous plaque. BACKGROUND: Cholesterol of low-density lipoprotein (LDL) particles contributes to atheromatous plaque formation; LDL also contains most serum non-cholesterol sterols, including plant sterols. The role of plant sterols in atheromatous plaque formation is open. METHODS: Free, ester, and total cholesterol and the respective non-cholesterol sterols were measured by gas-liquid chromatography in serum and arterial tissue of 25 consecutive patients undergoing carotid endarterectomy. The population was ranked to triads according to tissue cholesterol concentration. RESULTS: Cholesterol concentration increased markedly in tissues but not in serum with triads. The ester percentage was lower in the third than in the first triad (47% vs. 56%; p < 0.01) and lower than in serum triads (70%; p < 0.001). Ratios to cholesterol of non-cholesterol sterols decreased in increasing tissue triads, but were unchanged in serum. A major new observation was that the higher the ratio to cholesterol of the surrogate absorption sterols (cholestanol, campesterol, sitosterol, and avenasterol) in serum, the higher was their ratio also in the carotid artery wall (e.g., r = 0.683 for campesterol). Despite undetectable differences in serum and tissue cholesterol concentrations off and on statins, an additional important novel finding was that statin treatment was associated with increased ratios of the absorption sterols in serum and also in the arterial plaque. CONCLUSIONS: The higher the absorption of cholesterol, the higher are the plant sterol contents in serum resulting also in their higher contents in atherosclerotic plaque. However, the role of dietary plant sterols in the development of atherosclerotic plaque is not known.     

Effects of plant stanol esters supplied in low-fat yoghurt on serum lipids and lipoproteins, non-cholesterol sterols and fat soluble antioxidant concentrations.

Oil-based products enriched with plant stanol esters can lower low-density lipoprotein (LDL) cholesterol concentrations by 10-14%. Effectiveness of low-fat products, however, has never been evaluated, although such products fit into a healthy diet. We therefore examined the effects of plant stanol esters emulsified into low-fat yoghurt (0.7% fat) on fasting concentrations of plasma lipids and lipid-soluble antioxidants, which may also change by plant stanol consumption. Sixty non-hypercholesterolemic subjects first consumed daily three cups (3 x 150 ml) of placebo yoghurt for 3 weeks. For the next 4 weeks, 30 subjects continued with the placebo yoghurt, while the other 30 subjects received three cups of experimental yoghurt. Each cup provided 1 g of plant stanols (0.71 g sitostanol plus 0.29 g campestanol) as its fatty acid ester. LDL cholesterol (mean+/-S.D.) increased by 0.06+/-0.21 mmol/l in the placebo group, but decreased by -0.34+/-0.30 mmol/l in the experimental group. The difference in changes between the two groups of 0.40 mmol or 13.7% was highly significant (P<0.001; 95% confidence interval for the difference, (-)0.26 -(-)0.53 mmol/l). Effects were already maximal after 1 week. HDL cholesterol and triacylglycerol concentrations did not change. Total tocopherol levels increased by 1.43 micromol/mmol LDL cholesterol (14.0%, P=0.015). beta-carotene levels, however, decreased by -0.02 micromol/mmol LDL cholesterol (-14.4%, P=0.038). Decreases in absolute beta-carotene concentrations were found in all apoB-containing lipoproteins. LDL-cholesterol standardised phytofluene levels decreased by 21.4+/-25.7% (P<0.001), while other plasma carotenoid (lutein/zeaxanthin, beta-cryptoxanthin, lycopene and alpha-carotene) levels did not change significantly. We conclude that low-fat yoghurt enriched with plant stanol esters lowers within 1 week LDL cholesterol to the same extent as oil-based products. LDL-cholesterol standardised concentrations of tocopherol increased. The observed decrease in beta-carotene levels, as found in many other studies, appears not to be limited to the LDL fraction.     

Effects of diets enriched with two different plant stanol ester mixtures on plasma ubiquinol-10 and fat-soluble antioxidant concentrations

Plant stanols lower intestinal cholesterol absorption. This causes a decrease in serum low-density lipoprotein (LDL)-cholesterol, despite a compensatory increase in cholesterol synthesis. We therefore hypothesized that plant stanols also change LDL-cholesterol-standardized concentrations of ubiquinol-10 (a side product of the cholesterol synthesis cascade) and of those fat-soluble antioxidants that are mainly carried by LDL. To examine this, 112 nonhypercholesterolemic subjects consumed low erucic acid rapeseed oil (LEAR)-based margarine and shortening for 4 weeks. For the next 8 weeks, 42 subjects consumed the same products, while the other subjects received products with vegetable oil-based stanols (2.6 g sitostanol plus 1.2 g campestanol daily, n = 36) or wood-based stanols (3.7 g sitostanol plus 0.3 g campestanol daily, n = 34). Consumption of both plant stanol ester mixtures increased cholesterol synthesis and lowered cholesterol absorption, as indicated by increased serum cholesterol-standardized lathosterol and decreased plant sterol concentrations, respectively. Compared with the control group, absolute plasma ubiquinol-10 concentrations were lowered by 12.3% +/- 18.9% (-0.14 microg/mL v. the control group; P =.004; 95% confidence interval [CI] for the difference in changes, -0.05 to -0.22 microg/mL) in the vegetable oil-based group and by 15.4% +/- 13.0% (-0.17 microg/mL v. the control group; P <.001; 95% CI for the difference, -0.08 to -0.27 microg/mL) in the wood-based group. Changes in LDL-cholesterol-standardized ubiquinol-10 concentrations were not significantly changed. The most lipophylic antioxidants, the hydrocarbon carotenoids (beta-carotene, alpha-carotene, and lycopene), decreased most, followed by the less lipophylic oxygenated carotenoids (lutein/zeaxanthin and beta-cryptoxanthin) and the tocopherols. These reductions were related to the reduction in LDL, which carry most of these antioxidants. The decrease in the hydrocarbon carotenoids, however, was also significantly associated with a decrease in cholesterol absorption. LDL-cholesterol-standardized antioxidant concentrations were not changed, except for beta-carotene, which was still, although not significantly, lowered by about 10%. We conclude that the increase in endogenous cholesterol synthesis during plant stanol ester consumption does not result in increased LDL-cholesterol-standardized concentrations of ubiquinol-10, a side product of the cholesterol synthesis cascade. Furthermore, decreases in absolute fat-soluble antioxidant concentrations are related to decreases in LDL-cholesterol. However, for the most lipophylic carotenoids, some of the reduction was also related to the decrease in cholesterol absorption.     

Dietary plant stanol esters reduce VLDL cholesterol secretion and bile saturation in apolipoprotein E*3-Leiden transgenic mice

Dietary plant stanols lower serum cholesterol levels in humans and in hyperlipidemic rodents, mainly by inhibition of the intestinal cholesterol absorption. We used female apolipoprotein E*3-Leiden transgenic mice to investigate the consequences of this effect on serum lipid levels and hepatic lipid metabolism. Five groups of 6 or 7 mice received for 9 weeks a diet containing 0.25% cholesterol and 0.0%, 0.25%, 0.5%, 0.75%, or 1.0% (wt/wt) plant stanols (sitostanol 88% [wt/wt], campestanol 10% [wt/wt]) esterified to fatty acids. Compared with the control diet, plant stanol ester treatment dose-dependently reduced serum cholesterol levels by 10% to 33% (P<0.05), mainly in very low density lipoproteins (VLDLs), intermediate density lipoproteins, and low density lipoproteins. Furthermore, 1.0% of the dietary plant stanols significantly decreased the liver contents of cholesteryl esters (-62%), free cholesterol (-31%), and triglycerides (-38%) but did not change the hepatic VLDL-triglyceride and VLDL-apolipoprotein B production rates. However, plant stanol ester feeding significantly decreased the amounts of cholesteryl esters and free cholesterol incorporated in nascent VLDLs by 72% and 30%, respectively, resulting in a net 2-fold decreased VLDL cholesterol output. Liver mRNA levels of low density lipoprotein receptors, 3-hydroxy-3-methylglutaryl coenzyme A synthase, cholesterol 7alpha-hydroxylase, and sterol 27-hydroxylase were not changed by plant stanol ester feeding. Nevertheless, the serum lathosterol-to-cholesterol ratio was significantly increased by 23%, indicating that dietary plant stanol esters increased whole-body cholesterol synthesis. Plant stanol esters also significantly decreased the cholesterol saturation index in bile by 55%. In conclusion, in apolipoprotein E*3-Leiden transgenic mice, plant stanol ester feeding dose-dependently lowered serum cholesterol levels as a result of a reduced secretion of VLDL cholesterol. This was caused by a decreased hepatic cholesterol content that also resulted in a lowered biliary cholesterol output, indicative of a reduced lithogenicity of bile in these mice.     

Cholesterol synthesis and absorption in coronary patients with lipid triad and isolated high LDL cholesterol in a 4S subgroup

We assumed that assaying serum cholesterol precursors (synthesis markers) and plant sterols and cholestanol (absorption markers of cholesterol) reveals differences in cholesterol synthesis and absorption in the Finnish 4S subgroup divided in high triglyceride-low HDL cholesterol (lipid triad=HTG) and isolated high LDL cholesterol (ILDL) groups. Serum squalene and non-cholesterol sterol ratios to cholesterol were measured with gas-liquid chromatography at baseline, 6 weeks, 1 year, and 5 years on simvastatin. Patients with HTG (n=135) exhibited features of metabolic syndrome and, in spite of similar serum total and LDL cholesterol levels, ratios of synthesis markers were higher and those of absorption markers lower than in ILDL (n=133). The latter patients accumulated to a subgroup shown earlier to be clinical non-responders to simvastatin in 4S. Serum cholesterol reduction by simvastatin only tended to be higher in HTG than ILDL. The synthesis marker ratios were markedly reduced, and more effectively in HTG than ILDL, while the absorption marker ratios were increased, and for plant sterols more in ILDL than HTG. In conclusion, HTG is associated with high synthesis and low absorption of cholesterol, these events being opposite in ILDL. Synthesis is more effectively reduced by simvastatin in HTG than ILDL in spite of similar reduction in serum cholesterol. Patients defined by highest baseline absorption marker ratios in ILDL group are poor coronary event-reducers on regular simvastatin treatment.     

Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged men

Serum cholestanol was studied in relation to fecal cholestanol excretion and cholesterol metabolism in a random middle-aged population of 61 men. The serum concentrations of cholestanol ranged from 1.6 to 10.8 mumol/L and were positively correlated with those of serum total LDL and HDL cholesterol. In terms of millimole per mole of cholesterol, these correlations disappeared; inverse associations were found with VLDL cholesterol and triglyceride levels, the P/S ratio of dietary fat, and the amount of fecal plant sterols, but not with fecal cholestanol. The serum contents of cholestanol (1) were also closely positively associated with those of serum plant sterols (campesterol and sitosterol) and fractional cholesterol absorption, (2) were inversely related to the fecal excretion of neutral sterols and cholesterol synthesis which were measured either by the sterol balance technique or serum cholesterol precursor sterols (desmosterol and lathosterol), and (3) were unrelated to bile acid synthesis. Fecal cholestanol (mean = 12.5 mg/d) was (1) clearly higher than the dietary cholestanol intake (less than 2 mg/d), (2) unrelated to serum cholestanol, and (3) positively correlated with the intestinal cholesterol (dietary plus endogenous) flux as well as fecal plant sterols, neutral sterols, and bacterial products of cholesterol. The study emphasizes that, in normal men, high serum cholestanol levels reflect high efficiency of intestinal sterol absorption and low cholesterol synthesis. Thus, the changes in the serum contents of cholestanol are parallel with those of plant sterols and opposite to those of cholesterol precursor sterols.     

Plasma levels of lathosterol and phytosterols in relation to age, sex, anthropometric parameters, plasma lipids, and apolipoprotein E phenotype, in 160 Dutch families

In this study, the relation of plasma levels of lathosterol (an indicator of whole body cholesterol synthesis) and plant sterols (indicator of cholesterol absorption) with age, sex, weight, height, plasma lipids, and lipoproteins, and with apolipoprotein (apo) E phenotype, was investigated in a group of 160 nuclear families consisting of twins living with their parents. Lathosterol was higher in fathers than in mothers, but not different between boys and girls. In each of these four groups, there was a strong correlation with plasma and low-density lipoprotein (LDL)-cholesterol and -triglyceride, as well as with body weight, but not with height or high-density lipoprotein (HDL)-cholesterol. In adults, lathosterol was inversely correlated with plant sterols. Lathosterol was higher in children with E4/3 phenotype than in those with E3/3 or E3/2; in adults, lathosterol did not differ among the various E phenotypes. The plasma levels of the two plant sterols, campesterol and beta-sitosterol, were highly correlated with each other, and also with plasma or LDL-cholesterol, in each of the four groups. Plant sterols were higher in adults or children with E4/3 phenotype as compared with those with other phenotypes. In multivariate analysis (performed separately for two groups of adults and children) plasma cholesterol, plasma plant sterols, plasma triglycerides, and weight were found to make significant contributions to the variation of lathosterol in all groups, and E phenotype and sex only in one group, while age did not contribute in any group.(ABSTRACT TRUNCATED AT 250 WORDS)