Department of General Internal Medicine, University Medical Centre Nijmegen, Nijmegen, The Netherlands. A.Stalenhoef@aig.azn.nl
OBJECTIVE: Margarine with added plant sterols lowers plasma cholesterol levels. It is of importance to know whether these margarines can be used safely in carriers of a hereditary disorder with increased absorption of plant sterols. DESIGN: In an open feeding study of 8 weeks with a 2-week run-in period and 2 final weeks as a washout period on control margarine ( .3% plant sterols), two obligate heterozygous parents of a patient with classical sitosterolaemia were subjected for 4 weeks to a diet containing margarine enriched with plant sterols (8%). Fasting blood samples were taken weekly. Primary outcomes were plasma lipid and lipoprotein levels and plant sterol levels. RESULTS: Both parents were hyperlipidaemic. Total plasma cholesterol levels were decreased by 11 and 12%, respectively, after 4 weeks of the consumption of 40 g day(-1) of plant sterol-enriched margarine. This was mainly due to changes in LDL-cholesterol, whereas the other lipoproteins, including lipoprotein(a), were unaffected. Total plant sterol levels increased maximally 139% from .31 to .82% of total sterols in the father, and maximally 83% from .32 to .66% of total sterols in the mother. CONCLUSION: An intake of around 3 g day(-1) of plant sterols by subjects heterozygous for phytosterolaemia increased campesterol or sitosterol levels in blood to similar levels as found in normal subjects. In addition, plasma cholesterol levels were reduced to the same extent as in normal or hypercholesterolaemic individuals.
Mesh-terms: Adult; Cholesterol :: blood; Chromatography, Gas; Female; Heterozygote; Human; Male; Margarine; Metabolism, Inborn Errors :: blood; Metabolism, Inborn Errors :: drug therapy; Metabolism, Inborn Errors :: genetics; Middle Aged; Phytosterols :: blood; Phytosterols :: chemistry; Support, Non-U.S. Gov't;
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Biochemical Profiling, Paradigm Genetics, P.O. Box 14528, Research Triangle Park, North Carolina 27709-4528, USA. aberger@paragen.com
Plant sterols are naturally occurring molecules that humanity has evolved with. Herein, we have critically evaluated recent literature pertaining to the myriad of factors affecting efficacy and safety of plant sterols in free and esterified forms. We conclude that properly solubilized 4-desmetyl plant sterols, in ester or free form, in reasonable doses ( .8-1. g of equivalents per day) and in various vehicles including natural sources, and as part of a healthy diet and lifestyle, are important dietary components for lowering low density lipoprotein (LDL) cholesterol and maintaining good heart health. In addition to their cholesterol lowering properties, plant sterols possess anti-cancer, anti-inflammatory, anti-atherogenicity, and anti-oxidation activities, and should thus be of clinical importance, even for those individuals without elevated LDL cholesterol. The carotenoid lowering effect of plant sterols should be corrected by increasing intake of food that is rich in carotenoids. In pregnant and lactating women and children, further study is needed to verify the dose required to decrease blood cholesterol without affecting fat-soluble vitamins and carotenoid status.
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Department of Medicine, Division of General Internal Medicine, University of Nijmegen, PO Box 9101, 6500 HB Nijmegen, The Netherlands.
The role of the apo E polymorphism in the removal of remnants of very low density lipoproteins and chylomicrons was studied after a carbohydrate-rich diet in 10 healthy normolipidemic volunteers with different apo E phenotypes during 7 days. The cholesterol concentration in the heparin-sepharose bound part of the VLDL + IDL fraction (d < 1.019 g/ml) was taken as an estimate of the remnant concentration. Before and after carbohydrate-rich diet retinyl palmitate, mixed with cream, was consumed by each subject the evening before the fasting venepuncture to quantify the removal of chylomicron remnants. After the diet there was a comparable mean rise in the three groups in serum and in very low density lipoprotein triglycerides of about 30% and 50%, respectively. The concentration of remnants of very low density lipoproteins increased slightly in all subjects. The concentration of retinyl palmitate in the d < 1.019 g/ml fraction was 20% lower than before this diet in the E-2 homozygous subjects. In the other two groups, however, 25 to 80% higher retinyl palmitate levels were found. It is concluded, that after a carbohydrate-rich diet there is only a slight increase of very low density lipoprotein remnants, independent of the apo E polymorphism. The removal of chylomicron remnants, however, seems to be facilitated in E-2 homozygous subjects, in contrast to a slower removal in the groups with other apo E phenotypes.
Department of Medicine, University Medical Centre of Nijmegen, The Netherlands. S.Bredie@aig.azn.nl
OBJECTIVE: To examine whether a reduced daily glucose load by overnight application of the less-absorbed glucose polymer icodextrin would have favorable effects on lipid profiles of continuous ambulatory peritoneal dialysis (CAPD) patients. STUDY DESIGN: Randomized crossover study with two subsequent periods of 6 weeks. SETTING: Home PD unit of a secondary-care hospital. PATIENTS: Twenty-one nondiabetic CAPD patients (15 male, 6 female; mean age 50.3+/-11.8 years). INTERVENTION: Participants were randomly assigned to receive an overnight dwell with either standard glucose solution or with a 7.5% icodextrin-containing solution. MAIN OUTCOME MEASURES: Relation between reduction in the total amount of intraperitoneal infused glucose and parameters of glucose (plasma glucose, insulin, and HbA1C) and lipid metabolism [free fatty acids, plasma lipids, lipoproteins, and low density lipoprotein (LDL) subfraction profile]. RESULTS: After the icodextrin dwells, a reduction of plasma total cholesterol (from 5.43+/- .85 to 4.86+/- .70 mmol/L, p < .001) and LDL cholesterol (from 3.38+/- .87 to 2.93+/- .73 mmol/L, p = .001) was observed. Also, high density lipoprotein (HDL) cholesterol (from .95+/- .27 to .90+/- .24 mmol/L, p = .029) was reduced, but the plasma total cholesterol-to-HDL ratio remained similar. Plasma free fatty acids and triglyceride levels tended to decrease (from .16+/- .10 to .13+/- .08 mmol/L, p= .06, and from 2.14+/-1.96 to 1.92+/-1.03 mmol/L, respectively). Evaluation of LDL subfraction profiles after ultracentrifugation showed a more buoyant LDL subfraction profile with fewer dense LDL particles in 6 patients and no changes in 14 patients after icodextrin.The effects on lipids were not accompanied by a decrease in fasting plasma glucose (from 5.76+/-1.29 to 5.86+/- .80 mmol/L) or insulin levels (from 19.5+/-14.4 to 20.3+/-13. mU/L). CONCLUSION: These results suggest a beneficial effect on lipid profiles of CAPD patients with the use of an overnight dwell with icodextrin.
Department of Medicine, Division of General Internal Medicine, University Medical Center Nijmegen, Nijmegen, The Netherlands. B.vantits@aig.azn.nl
Antioxidants have been postulated to exert beneficial effects in atherosclerosis. Atherosclerosis is associated with raised plasma levels of soluble intercellular adhesion molecule-1 (sICAM-1) and autoantibodies against oxidized low-density lipoprotein (oxLDL). It is not known whether antioxidants affect these plasma factors in chronic smokers. In a randomized double-blind placebo-controlled study involving 128 male normolipidemic chronic smokers the effect of a 2-year alpha-tocopherol treatment (400 IU dL-alpha-tocopherol daily) on plasma levels of sICAM-1 and autoantibodies against oxLDL was evaluated. In addition, we monitored production of superoxide by leukocytes ex vivo. It was found that compared to nonsmokers (n = 33) plasma levels of IgG but not IgM autoantibodies against oxLDL and concentrations of sICAM-1 in smokers were significantly elevated (30 and 42%, respectively). After supplementation with alpha-tocopherol concentration of TBARS in plasma and in vitro oxidizability of LDL had decreased, but autoantibodies and sICAM-1 had not changed. Production of superoxide was not different between alpha-tocopherol- and placebo-treated smokers. It is concluded that in chronic smokers, long-term treatment with alpha-tocopherol does not normalize the raised levels of sICAM-1 and autoantibodies against oxLDL, both risk factors for initiation or progression of cardiovascular disease, despite a decrease in in vitro oxidizability of LDL.
Department of Medicine, UMC St. Radboud, Nijmegen, The Netherlands. p.demacker@aig.azn.nl
We compared in 506 members of families with familial combined hyperlipidaemia (FCH), two approaches to selecting subjects with an apparent increased risk for coronary heart disease: assay of apolipoprotein (apo) B only versus measurement of plasma lipids and lipoproteins. When comparing both criteria, there was an overlap of 81.2% at apo B levels < or = 1250 mg/l and of 86.9% at apo B levels > 1250 mg/l. At apo B < or = 1250 mg/l all subjects were normolipidemic. However, 18.8% of these subjects had sub-normal HDL-cholesterol concentrations (< .9 mmol/l) but were not considered to have an increased risk because of very low LDL-cholesterol levels (< 2.5 mmol/l). At apo B concentrations > 1250 mg/l we observed a group with normal plasma lipid levels (13.1%). In this group, defined as normolipidemic hyperapobetalipoproteinemia, and considered to have an increased risk for coronary heart disease, apo B determination was thus most informative. The selection of the subgroup with 'normolipidemic hyperapobetalipoproteinemia' on the basis of the conventional approach could be refined using a cut off limit for plasma triglycerides < 1.5 mmol/l. This limit distinguished optimally between an atherogenic very dense LDL pattern versus a dense and buoyant pattern. Thus, based on the results of our study, the determination of apo B appeared to be, if not superior, at least as effective as the conventional lipid and lipoprotein parameters in classifying subjects at increased risk for coronary heart disease.
Division of Human Nutrition and Epidemiology, Wageningen University, Wageningen, Netherlands.
BACKGROUND: Cafestol is a diterpene in unfiltered coffee that raises plasma triacylglycerol in humans. OBJECTIVE: We studied whether cafestol increases plasma triacylglycerol by increasing the production rate or by decreasing the fractional catabolic rate of VLDL(1)[Svedberg flotation unit (S(f)) 60-400] apolipoprotein (apo) B. In addition, we studied the effect of cafestol on the composition of VLDL(1) and VLDL(2)(S(f) 20-60). DESIGN: Eight healthy normolipidemic men were administered a daily dose of 75 mg cafestol for 2 wk. A bolus injection of 7 mg L-[5,5,5-(2)H(3)]leucine/kg body wt was given after a baseline period with no cafestol and again after treatment with cafestol. We derived kinetic constants to describe the metabolism of VLDL(1) apo B by using a multicompartmental model. RESULTS: Cafestol significantly increased plasma triacylglycerol by 31% or .32 mmol/L (95% CI: .03, .61); the increase was due mainly to a nonsignificant rise in VLDL(1) triacylglycerol of 57% or .23 mmol/L (95% CI:- .02, .48). Cafestol significantly increased the mean rate of VLDL(1) apo B production by 80% or 755 mg/d (95% CI: .2, 5353), whereas it did not significantly change the mean fractional catabolic rate of VLDL(1) apo B (mean increase of 3 pools/d; 95% CI:-4, 10]). Cafestol did not change the composition of VLDL(1). A significant increase in the ratio of VLDL(2) cholesteryl ester to triacylglycerol indicates that VLDL(2) became enriched with cholesteryl esters at the cost of triacylglycerol. CONCLUSION: Cafestol increases plasma triacylglycerol by increasing the production rate of VLDL(1) apo B, probably via increased assembly of VLDL(1) in the liver.
Department of Medicine, Division of General Internal Medicine, University Hospital Nijmegen, The Netherlands. F.Vandenberkmortel@aig.azn.nL
BACKGROUND: Enhanced induction of low density lipoprotein (LDL) oxidation may play a role in the increased cardiovascular risk in smokers. We determined LDL oxidisability in vitro in non-smokers, smokers and in subjects after smoking cessation. PATIENTS AND METHODS: Plasma lipids and copper induced LDL oxidation in vitro were measured in 31 persistent smokers, 47 smokers who tried to stop smoking and 25 non-smokers. In the smoking cessation group, blood was collected before then 1, 3, 6 and 12 months after smoking cessation, and in the persistent smoking and non-smoking groups at baseline and after 12 months. Plasma thiobarbituric acid reactive substances (TBARS) were measured 3 times (at baseline then after 1 and 3 months) in all subjects who refrained from smoking (controlled by urinary cotinine concentrations) for at least 3 months. RESULTS: At baseline, no differences in mean age, body mass index and lipid profiles between groups were present. Seventeen subjects of the smoking cessation group (36%) managed to quit during 12 months. Smoking cessation was associated with an increase in mean weight (P </= .001) and waist-hip ratio (P </= .001). No major differences in LDL oxidisability were found between groups. A significant transient increase in high density lipoprotein (HDL) cholesterol was seen (from 1.20 +/- .39 to 1.34 +/- .42 mmol L-1) after 1 month of smoking cessation that disappeared after 3 months. However, after 1 month of smoking cessation, plasma TBARS decreased significantly (P < .05). CONCLUSIONS: Neither the previously observed increased cardiovascular risk in smokers nor the decreased risk in those who stopped smoking seem to be mediated by permanent changes in lipid profiles or by alterations in the susceptibility to in vitro oxidation of LDL.
541 Department of Internal Medicine, University Hospital Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands. a.stalenhoef@aig.azn.nl
We evaluated in a double-blind randomized trial with a double-dummy design in 28 patients with primary hypertriglyceridemia, the effect of gemfibrozil (1200 mg/day) versus Omacor (4 g/day), a drug containing the n-3 fatty acids eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), on lipid and lipoprotein levels, low density lipoprotein (LDL) subfraction profile and LDL oxidizability. Both Omacor and gemfibrozil therapy resulted in a similar significant decrease in serum triglyceride (TG), very low density lipoprotein (VLDL) triglyceride and VLDL cholesterol concentrations and an increase in high density lipoprotein (HDL) and LDL cholesterol concentrations. The increase in LDL cholesterol was due to a significant increase in cholesterol content of the relatively buoyant LDL subfractions LDL1, LDL2 and LDL3, whereas the relative contribution of the dense LDL subfractions LDL4 and LDL5 to total LDL tended to decrease. So, both therapies resulted in a more buoyant LDL subfraction profile, reflected by a significant increase of the value of parameter K (+10.3% on Omacor vs.+26.5% on gemfibrozil therapy, gemfibrozil vs Omacor P> .05). Cu(2+)-induced oxidation of LDL was measured by continuous monitoring of conjugated dienes. After 12 weeks of Omacor treatment LDL appeared more prone to oxidative modification in vitro than LDL after gemfibrozil treatment, as measured by the significantly decreased lag time, preceding the onset of the lipid peroxidation. In both groups the rate of oxidation did not change with therapy. The amount of dienes formed during oxidation increased significantly on Omacor treatment, but not on gemfibrozil treatment. Plasma thiobarbituric acid reactive substances were higher after Omacor and lower after gemfibrozil treatment, although not significantly. We conclude that both Omacor and gemfibrozil have favorable effects on lipid and lipoprotein concentrations and the LDL subfraction profile. However, Omacor increased the susceptibility of LDL to oxidation, whereas gemfibrozil did not affect the resistance of LDL to oxidative modification in vitro. The clinical relevance of these changes remains to be established in the light of other postulated favorable effects of n-3 fatty acids on the course of cardiovascular disease.
Department of Medicine, Division of General Internal Medicine, Nijmegen, The Netherlands. b.vantits@aigazn.nl
Polymorphonuclear leukocytes (PMN) have been suggested to play a role in atherosclerosis, but intracellular signaling after stimulation with oxidized low-density lipoprotein (LDL) is unknown. We investigated mechanistic aspects of oxidized LDL-induced superoxide production by human PMN, with special emphasis on intracellular Ca(2+) concentration ([Ca(2+)](i)). Oxidized LDL, but not native LDL, evoked an early but sustained increase in [Ca(2+)](i) and a delayed production of superoxide. The increase in [Ca(2+)](i) could be reduced by fucoidan and completely prevented by U73122, suggesting involvement of the scavenger receptor and coupling to the phospholipase C signal transduction pathway. Furthermore, we provide evidence that the increase in [Ca(2+)](i) partly results from protein kinase C-dependent Ca(2+) influx. The relevance of this Ca(2+) entry for oxidized LDL-stimulated effects is illustrated by the finding that superoxide production was markedly reduced in the absence of external Ca(2+). Finally, inhibition of phagocytosis by cytochalasin B abolished oxidized LDL-stimulated superoxide production without affecting, however, the Ca(2+) mobilization. These effects of oxidized LDL on [Ca(2+)](i) and on respiratory burst of PMN may underlie the occurrence of elevated levels of [Ca(2+)](i) of resting PMN in hypercholesterolemia and represent a mechanism by which PMN can amplify processes in the early phase of atherosclerosis.
The rebound of lipoproteins after LDL-apheresis. Kinetics and estimation of mean lipoprotein levels.
Division of General Internal Medicine, Department of Medicine, 541 AIG, University Hospital Nijmegen, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.
We studied the rebound of lipoproteins in 20 hypercholesterolemic men [mean total cholesterol (TC) levels 9.6+/-1.8 mmol/l] after LDL-apheresis (LA) to determine the rate of recovery and the change in cholesterol synthesis, and to find a uniform estimation for time-averaged levels. After 10-20 months on biweekly LA using dextran sulfate cellulose columns and concomitant simvastatin administration, time-averaged levels (+/-SD) measured by integration of the area under the curve were as follows: TC 4.4+/-1. mmol/l, LDL cholesterol (LDL-C) 2.5+/-1. mmol/l, apolipoprotein B (apo B) 1. 3+/- .3 g/l, triglycerides (TG) 1.7+/- .7 mmol/l, HDL-C 1.1+/- .2 mmol/l, and lipoprotein(a)[Lp(a)] 53.7+/-49.4 mg/dl. Mean acute reductions in TC, LDL-C, apo B, Lp(a), and TG were 61, 77, 75, 76, and 62%, respectively. HDL-C levels were not influenced. Median recovery half times for TC, LDL-C, apo B, and Lp(a) were 3. , 4. , 2. 3, and 3.5 days, respectively. The rebound of Lp(a) was identical to LDL-C, in 12 and 13 days post-treatment, respectively, whereas apo B and TC returned to pre-treatment levels in 7.5 and 10 days, respectively, due to the fast rebound of VLDL particles. Notwithstanding these differences, time-averaged levels (C(AVG)) could be estimated uniformly for the four latter parameters with the formula: C(AVG)=C(MIN)+ .73(C(MAX)-C(MIN)), where C(MAX) and C(MIN) are the immediate pre- and post-treatment levels. During long-term treatment the whole-body cholesterol synthesis was increased as measured by the ratio lathosterol to cholesterol of 3.24+/-1.49 mmol/mmol, whereas no further transient increase in the recovery period after LA was found. In conclusion, long-term LA and simvastatin therapy induced acute and chronic changes in lipids and lipoproteins showing the feasibility of biweekly treatment. It was shown that time-averaged levels, as a measure for the effective plasma levels, can be accurately estimated from pre- and post-treatment levels only.
Academic Medical Center Nijmegen, The Netherlands.
BACKGROUND: All lipoproteins are able to bind to bacterial lipopolysaccharide (LPS), thereby neutralizing its deleterious effects. However, we demonstrated, recently, that in the absence of apolipoprotein E (apoE), eight-fold increased very-low-density lipoprotein levels were not sufficient to protect apoE-deficient (apoE-/-) mice against LPS. During a live Gram-negative infection, mechanisms other than LPS-neutralization may play a role in the pathogenesis of the disease. In the present study we further examined the role of apoE in Gram-negative sepsis. METHODS: Survival, bacterial outgrowth in liver, spleen, kidneys and blood, and tumour necrosis factor-alpha (TNF-alpha) production were measured in apoE-/- mice and control C57BL/6J mice, after an intravenous infection with Klebsiella pneumoniae. RESULTS: Mice that lack apoE showed higher mortality in response to K. pneumoniae than control mice (90% vs. 23% respectively after 2 weeks). ApoE-/- mice had 10-100 times more outgrowth of the bacteria in their organs than controls. Furthermore, circulating TNF-alpha concentrations 90 min after a challenge, were almost twice as high in the apoE-/- mice compared to controls (13. +/- 2.9 ng mL-1 vs. 7.6 +/- 3.8 ng mL-1). When apoE-/- and control mice were rendered neutropenic, the discrepancy in survival and outgrowth of K. pneumoniae disappeared. CONCLUSIONS: The apoE-/- mice were more susceptible than control C57BL/6 mice to a K. pneumoniae infection. The absence of apoE may render these mice more susceptible, since this protein is of importance in the detoxification of lipopolysaccharide of Gram-negative bacteria. On the other hand, the phagocytic capacity of granulocytes seems to be decreased in apoE-/- mice, resulting in increased outgrowth and mortality.
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Department of Preventive Cardiology, Ullevaal University Hospital, N-0407 Oslo, Norway.
BACKGROUND AND AIMS: Data comparing the impact of different sources of plant sterols on CVD risk factors and antioxidant levels is scarce. We evaluated the effects of plant sterols from rapeseed and tall oils on serum lipids, lipoproteins, fat-soluble vitamins and plant sterol concentrations. METHODS AND RESULTS: This was a double-blinded, randomized, crossover trial in which 59 hypercholesterolemic subjects consumed 25g/day of margarine for 4weeks separated by 1week washout periods. The two experimental margarines provided 2g/day of plant sterols from rapeseed or tall oil. The control margarine had no added plant sterols. The control margarine reduced LDL cholesterol by 4.5%(95% CI 1.4, 7.6%). The tall and rapeseed sterol margarines additionally reduced LDL cholesterol by 9. %(95% CI 5.5, 12.4%) and 8.2%(95% CI 5.2, 11.4%) and apolipoprotein B by 5.3%(95% CI 1. , 9.6%) and 6.9%(95% CI 3.6, 10.2%), respectively. Lipid-adjusted beta-carotene concentrations were reduced by both sterol margarines (P< .017). alpha-Tocopherol concentrations were reduced by the tall sterol compared to the rapeseed sterol margarine (P= .001). Campesterol concentrations increased more markedly with the rapeseed sterol versus tall sterol margarine (P< .001). The rapeseed sterol margarine increased while the tall sterol margarine decreased brassicasterol concentrations (P< .001). CONCLUSIONS: Plant sterols from tall and rapeseed oils reduce atherogenic lipids and lipoproteins similarly. The rapeseed sterol margarine may have more favorable effects on serum alpha-tocopherol concentrations.
Hospital de la Santa Creu i Sant Pau, Servei de Bioquímica, Barcelona, Spain.
A number of studies have raised the possibility of circulating plant sterols being a risk factor in the pathogenesis of atherosclerosis. Evidence in support of this hypothesis comes mainly from observations in sitosterolemic patients, who hyperabsorb plant sterols and suffer premature atherosclerosis. Accordingly, the atherogenicity of plant sterols of dietary origin is currently under debate, in view of the widespread use of cholesterol-lowering functional foods enriched with these compounds. Although some reports have suggested the vascular perils of small increases in plasma plant sterol concentrations, other prospective and large population-based studies have indicated otherwise. Further, the potential risk of plant sterol-enriched foods may be counterbalanced by the notable reduction in plasma cholesterol. This review summarizes the current evidence on the possible impact of plant sterols as a risk factor for atherosclerosis.
Shweta Khandelwal,
Isabelle Demonty,
Panniyammakal Jeemon,
Ramakrishnan Lakshmy,
Rajat Mukherjee,
Ruby Gupta,
Uma Snehi,
Devasenapathy Niveditha,
Yogendra Singh,
Henk C M van der Knaap,
Santosh J Passi,
Dorairaj Prabhakaran,
K Srinath Reddy
Centre for Chronic Disease Control (CCDC), New Delhi, India.
The present study was designed to evaluate the independent and interactive effects of a once-a-day yoghurt drink providing 2 g plant sterols/d and capsules providing 2 g fish oil n-3 long-chain (LC) PUFA/d on plasma lipids, apolipoproteins and LDL particle size. Following a 2-week run-in period, 200 mildly hypercholesterolaemic Indian adults aged 35-55 years were randomised into one of four groups of a 2 x 2 factorial, double-blind controlled trial. The 4-week treatments consisted of (1) control yoghurt drink and control capsules,(2) control yoghurt drink and fish oil capsules,(3) plant sterol-enriched yoghurt drink and control capsules, or (4) plant sterol-enriched yoghurt drink and fish oil capsules. Blood was drawn before and after the 4-week intervention. Changes in health status, lifestyle and dietary habits, and daily compliance were recorded. The main effects of plant sterols were a 4.5 % reduction in LDL-cholesterol and a 15 % reduction in TAG without a significant change in HDL-cholesterol. Overall, fish oil n-3 LC-PUFA did not significantly affect cholesterol concentrations but reduced TAG by 15 % and increased HDL-cholesterol by 5.4 %. The combination significantly lowered TAG by 15 % v. control. No significant interaction between plant sterols and n-3 LC-PUFA was observed on plasma cholesterol concentrations. In conclusion, once-a-day intake of 2 g plant sterols/d in a yoghurt drink, 2 g fish oil n-3 LC-PUFA/d in capsules, and their combination had beneficial effects on the lipid profile of mildly hypercholesterolaemic Indian adults. The potent hypotriacylglycerolaemic effect of plant sterols observed in the present study and this population warrants additional investigation.
Charles University in Prague, First Faculty of Medicine, Clinical Department of Gastroenterology and Hepatology, Prague. marvec@volny.cz
Although most of us are more or less familiar with the term "cholesterol", the world of sterols is far more complicated and interesting. Apart from cholesterol, many non-cholesterol sterols can be found in human plasma and these sterols serve many important functions in human organism. They are either derived from endogenous biosynthesis of cholesterol or they come from dietary sources (phytosterols). The sole cholesterol molecule is used for keeping our cell membranes fit, for signalization purposes as well as a precursor for bile acids and steroid hormones. The compounds prior to cholesterol in its biosynthetic pathway were identified as vitamin D3 precursor, meiosis activating sterols and nowadays it seems that they could play a role in cholesterol homeostasis. The sterols from ingested vegetable sources, the phytosterols, are expelled from enterocytes and thus indirectly help our gut in coping with abundant cholesterol in the lumen. Higher plants synthesize many phytosterols, but in marine organisms, we can find other innumerous sterol molecules. The diversity of sterol molecules produced and resistance of their tetracyclic core to enzymatic activities implies crucial importance of sterols during the ontogenesis of multicellular organisms. First oxygen appeared on the Earth app. 2.7 billion years ago and since that time, every new life form took the advantage of oxygen needed also for build-up of sterol molecules. The last decades changed our view to the sterol molecules on almost at all levels of their appearance in human body. In the gut, the absorption of sterols was proven to be protein dependent and the quest for the transporter was successful. The general concepts of intracellular homeostasis of cholesterol have been described including the covalent interaction unbelievable so far - cholesterol and a protein. The clinical importance of non-cholesterol sterols rises with the effort to discover underlying facts about the causes of atherosclerosis. The compound in question, cholesterol, seems to be involved, but it sounds not to be crucial per se. The fact that the accumulation of phytosterols in sitosterolemia enhances the probability of early atherosclerosis onset further supports the hypothesis about some sterol (or steroid) compound being responsible on the molecular level for triggering the pathobiochemical cascade of events leading to atherosclerosis. Understanding the processes taking place in the enterocyte during the absorption of sterols resulted in synthesis of selective inhibitors at the level of sterol translocation into the enterocyte, sterol esterification and chylomicron packing, which are in different phases of clinical testing. The studies in the last part of the monograph represent the clinical potential of the analyses of non-cholesterol sterols. In well-defined groups, these analytes enables us to assess the changes in the homeostasis of cholesterol, which can be reflected in the concentration of total cholesterol. Furthermore, the high concentrations of some plasma sterols could point to the inborn errors of cholesterol biosynthesis (Smith-Laemli-Opitz syndrome), transport (sitosterolemia) or metabolization (cerebrotendinous xanthomatosis). Some issues concerning the research on the non-cholesterol sterols still remain unanswered - it is not known why some of the enzymes of the cholesterol biosynthesis (seladin-1, sterol D14 reductase) have other functions, qualitative aspects of sterol absorption are not satisfactorily explained and exact reason for expulsion of phytosterols from human body is not clear. Nevertheless, the authors hope that the presented facts can broaden the reader's perspective about the area, which is usually hidden beneath the cholesterol molecule.
Oliver Weingärtner,
Dieter Lütjohann,
Shengbo Ji,
Nicole Weisshoff,
Franka List,
Thomas Sudhop,
Klaus von Bergmann,
Karen Gertz,
Jochem König,
Hans-Joachim Schäfers,
Matthias Endres,
Michael Böhm,
Ulrich Laufs
Klinik für Innere Medizin III, Kardiologie, Angiologie und Internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany.
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. +/- 1.5%). Plant sterol plasma concentration strongly correlated with increased atherosclerotic lesion formation (r = .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.
Masanori Kurokawa,
Yasunobu Masuda,
Mitsuhiro Noda,
Ranko Marushima,
Mika Usuda,
Sayaka Takeda,
Mineo Hasegawa,
Yasuhiko Homma,
Michihiro Sugano
We examined the minimal effective dose on serum cholesterol concentration and the safety of dressing containing plant sterol in humans. Exp.1: Sixty-eight healthy Japanese males (total cholesterol (TC)>/= 170 mg/dL) were randomly divided into four groups, and were given , 400, 800 or 1200 mg/day of plant sterol in 15 g dressing for 4 weeks followed by the washout period of 4 weeks. Although there were no significant differences in serum TC and low-density lipoprotein cholesterol (LDL-C) concentrations among all groups after feeding plant sterol for 4 weeks, in 36 subjects with TC >/= 220 mg/dL, serum LDL-C concentration tended to reduce when received 800 or 1200 mg of plant sterol, and the difference between and 1200 mg groups was statistically significant. The difference between and 800 mg groups was near significant (p= .053). Intake of 400 mg of plant sterol did not change serum LDL-C concentration. Exp.2: Twenty-one healthy Japanese subjects (TC >/= 180 mg/dL, 10 men, 11 women) were given 2400 mg/day of plant sterol in 45 g dressing for 4 weeks. Clinical data were all remained normal. These results indicated that minimal effective dose of the plant sterol on serum cholesterol concentration in healthy male subjects is around 800 mg/day, and intake of 2400 mg/day of plant sterol is regarded to be safe.
Background/Objectives:Plant sterol (PS) consumption lowers serum cholesterol levels, while modestly increasing plasma PS concentrations. Plasma PS concentrations may reflect sterol absorption, thus individuals with high plasma plant sterol (HPS) concentrations may show greater changes in circulating cholesterol and PS than individuals with low plasma plant sterol (LPS) concentrations. The objective of this study was to examine whether HPS and LPS concentrations are related to subsequent changes in plasma PS, serum lipid and C-reactive protein (CRP) concentrations, following dietary PS intake in otherwise healthy hypercholesterolemic men.Subjects/Methods:This single-blinded, randomized, diet-controlled study consisted of two 4-week phases, separated by a 4-week washout, where a diet with a placebo or the 2. g per day PS-enriched spread was consumed during the phases.Results:At baseline, men with HPS possessed higher (P< .01) mean serum cholesterol concentration, while those with LPS had higher (P< .05) body mass index. Following PS intake, plasma sum of campesterol plus sitosterol concentrations were elevated from 34.6+/-4.2 to 46.2+/-3.3 mumol l(-1)(mean+/-SE) and 16.5+/- .9 to 20.8+/-1.2 mumol l(-1) after PS intake in men with HPS and LPS, respectively. Changes in plasma PS concentrations, however, were not different between individuals with either HPS or LPS baseline concentrations. Total cholesterol and low-density lipoprotein cholesterol levels were decreased (P< .0001) by 6.3 and 7.8%, respectively, with PS consumption for all individuals. Changes in lipid parameters were not different between individuals with HPS or LPS baseline concentrations. No changes in CRP were apparent subsequent to PS intervention.Conclusions:Baseline plasma PS concentrations are not associated or predictive of changes in serum cholesterol or plasma PS concentrations after PS intervention. Thus, individuals with HPS show similar increases in PS concentrations as individuals with LPS following PS supplementation. Plasma PS remained in the range of previously reported concentrations.European Journal of Clinical Nutrition advance online publication, 12 December 2007; doi:10.1038/sj.ejcn.1602969.
L Mannucci,
O Guardamagna,
P Bertucci,
L Pisciotta,
L Liberatoscioli,
S Bertolini,
C Irace,
A Gnasso,
G Federici,
C Cortese
Background Sitosterolaemia is a rare autosomal recessive disorder characterised by elevated plasma levels of plant sterols and cholesterol. Sitosterolaemia is caused by gene mutations in either of two ATP-binding cassette (ABC) half transporters, ABCG5 and ABCG8. The plasma sterol profile and genetic analysis of a 10-year-old girl who had tuberous xanthomas is the subject of this report. Materials and methods Genomic DNA was isolated from white blood cells from the proband, her family and a control group of healthy people. All exons of ABCG5 and ABCG8 were sequenced. Plasma cholesterol and triglycerides were measured by routine methods. All other plasma sterols were measured by Gas Chromatography coupled to Mass Spectrometry. Results The proband was found to be homozygous for a single nucleotide mutation in exon 10 of the ABCG5 gene, consisting of a C to T transition at nucleotide 1336 of the coding sequence, which results in the premature termination of the ABCG5 protein at amino acid 446 (Arg446X). Her mother and brother were also homozygous for the same mutation and all had elevated plasma beta-sitosterol levels. The father was heterozygous and showed normal beta-sitosterol levels. This mutation was not found in healthy normolipidaemic subjects. Conclusions We describe a novel nonsense mutation in exon 10 of the ABCG5 gene in a 10-year-old girl showing clinical and biochemical features of sitosterolaemia. This family study broadens the spectrum of the ABCG5/ABCG8 mutations causing sitosterolaemia and helps highlight the correlations between such gene mutations, biochemical phenotype and the development of cardiovascular disease.
BACKGROUND: Phytosterolaemia (sitosterolaemia) is a rare autosomal recessive condition caused by mutations on the ABCG5 and ABCG8 gut transporter proteins. This leads to accumulation of plant-derived cholesterol-like molecules in blood and tissues. CASE: We describe a family of Bangladesh origin, where three siblings (two males and one female) have homozygous mutations for phytosterolaemia, and exhibit short stature and adrenal failure with the female having ovarian failure. FINDINGS: The index case (18-year-old female) and her sibling (16 years) have adrenal insufficiency with hyperpigmentation and raised levels of ACTH, at 367 and 690 ng/l respectively. The youngest child at 7 years has normal adrenal function. In addition, the index case has ovarian failure and sibling 2 has partial growth hormone deficiency. CONCLUSION: Although short stature is a recognised phenomenon, no previous association has been made between phytosterolaemia and other endocrine abnormalities. We postulate that the elevated plant sterol levels in phytosterolaemia may interfere with endocrine hormone synthesis; in particular, we present evidence that adrenal cholesterol metabolism may be preferentially affected, accounting for the adrenal insufficiency.
