gamma-sitosterol and Hypercholesterolemia

Sitosterolemia is a rare inherited disease characterized by increased levels of plant sterols, such as sitosterol. The cause of this disease is ATP-binding cassette (ABC) subfamily G member 5 or member 8 (ABCG5 or ABCG8, respectively) gene mutations. Recent advances in genetics have revealed that the prevalence of subjects with deleterious mutations in ABCG5 and/or ABCG8 genes could be more than 1 in ~200,000 individuals among the general population. Furthermore, accumulated evidence, including infantile cases exhibiting progression/regression of systemic xanthomas associated with LDL cholesterol levels, have shown that the elevation of LDL cholesterol seems to be the major cause of development of atherosclerosis and not the elevation of sitosterol. Regarding therapies, LDL apheresis, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, could be useful for sitosterolemia, in addition to ezetimibe and/or colestimide. In this study, we provide the current understanding and future perspectives of sitosterolemia, which is currently considered an extremely rare disorder but is expected to be much more prevalent in clinical settings.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Coronary Artery Disease; Heterozygote; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Mutation; Phenotype; Phytosterols; Polymorphism, Genetic; Proprotein Convertase 9; Sitosterols

Essentials Diagnosis of sitosterolemia, a rare recessive or syndromic disorder, is usually delayed. Peripheral blood smear is extremely useful for establishing the suspicion of sitosterolemia. High-throughput sequencing technology enables the molecular diagnosis of inherited thrombocytopenias. Accurate characterization of sitosterolemia helps us determine appropriate management.. Background Sitosterolemia (STSL) is a recessive inherited disorder caused by pathogenic variants in the ABCG5 and ABCG8 genes. Increased levels of plasma plant sterols (PSs) usually result in xanthomas and premature coronary atherosclerosis, although hematologic abnormalities may occasionally be present. This clinical picture is unfamiliar to many physicians, and patients may be at high risk of misdiagnosis. Objectives To report two novel ABCG5 variants causing STSL in a Spanish patient, and review the clinical and mutational landscape of STSL. Patient/Methods A 46-year-old female was referred to us with lifelong macrothrombocytopenia. She showed familial hypercholesterolemia-related xanthomas. Molecular analysis was performed with high-throughput sequencing. Plasma PS levels were evaluated with gas-liquid chromatography. The STSL landscape was reviewed with respect to specific online databases and all reports published since 1974. Results A blood smear revealed giant platelets and stomatocytes. Novel compound heterozygous variants were detected in exons 7 (c.914C>G) and 13 (c.1890delT) of ABCG5. The patient showed an increased plasma level of sitosterol. These findings support the diagnosis of STSL. In our review, we identified only 25 unrelated STLS patients who presented with hematologic abnormalities including macrothrombocytopenia. It remains unknown why only some patients develop hematologic abnormalities. Conclusions This is the first Spanish STSL patient to be reported and molecularly characterized. The early diagnosis of STLS is strongly supported by the presence of stomatocytes in blood smears. The definitive diagnosis of STSL by measurement of serum PS levels and molecular analyses prompted the use of ezetimibe therapy.

Topics: Anticholesteremic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 5; DNA Mutational Analysis; Ezetimibe; Female; Genetic Predisposition to Disease; High-Throughput Nucleotide Sequencing; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Middle Aged; Mutation; Phenotype; Phytosterols; Sitosterols; Spain; Thrombocytopenia; Xanthomatosis

The ability of plant polyisoprenoids (polyprenols and polyprenyl phosphates) to diminish the levels of serum cholesterol affecting its biosynthetic pathway are highlighted here. Possible mechanism of such process is discussed. It is also noted that polyisoprenoids can prevent toxic injuries of the liver and restore disturbed hepatic functions. The possibility of polyprenyl phosphates to reveal at the same time anti-inflammatory action suppressing lipoxygenase activity and lowering the levels of proinflammatory cytokines will be illustrated. Attention will be focused on the potential usefulness of plant polyisoprenoids in the course of prevention and treatment of hypercholesterolemia. High efficiency for combined use of polyprenyl phosphate and β-sitosterol, which leads to substantial enhancement of the ability to overcome hypercholesterolemia versus the individual constituents will be demonstrated.

Topics: Animals; Anti-Inflammatory Agents; Antineoplastic Combined Chemotherapy Protocols; Chemical and Drug Induced Liver Injury; Cholesterol; Humans; Hypercholesterolemia; Lipoxygenase; Phytotherapy; Plants; Sitosterols; Terpenes

This study examined the effect of plant sterols added, together with an emulsifying agent, to a low-fat yoghurt on the serum lipid and plant sterol values in moderately hypercholesterolaemic volunteers. Study I was a randomized double-blind, cross-over trial. For 4 weeks, 15 volunteers consumed yoghurt containing 1 g plant sterols or a placebo yoghurt. Study II was a randomized, double-blind, parallel-group study. For 8 weeks, the sterol group (n = 12) ingested daily two yoghurts (2 g/day plant sterols) and the placebo group (n = 14) ingested two yoghurts without plant sterols. Study I: compared with the placebo, the sterol yoghurt reduced serum total cholesterol by 0.15 mmol/l (2.2%, P=0.235) and low-density lipoprotein (LDL) cholesterol by 0.19 mmol/l (4.3%, P=0.082), and increased serum campesterol by 0.26 mg/100 ml (P=0.006) and sitosterol by 0.11 mg/100 ml (P=0.015). Study II: compared with the placebo, the sterol yoghurt reduced serum total cholesterol by 0.41 mmol/l (6.3%, P=0.167) and LDL cholesterol by 0.28 mmol/l (6.4%, P=0.306), and increased serum campesterol by 0.28 mg/100 ml (P=0.016) and sitosterol by 0.40 mg/100 ml (P=0.206). Meta-analysis: the pooled treatment difference was -0.34 mmol/l (5.2%, P=0.173) in total cholesterol and was -0.26 mmol/l (-5.8%, P=0.261) in LDL cholesterol, when the sterol yoghurt was compared with the placebo. A low-fat yoghurt enriched with 1-2 g/day plant sterols reduced serum cholesterol levels in moderately hypercholesterolaemic subjects. Campesterol and sitosterol serum levels increased, but their concentration remained in the range of normal values.

Topics: Adult; Analysis of Variance; Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Phytosterols; Sitosterols; Yogurt

Lowering lipid levels in the cardiovascular prevention we confine ourselves to measure the cholesterol level and care less for the background effects. Namely blood cholesterol level beyond the amount consumed with the diet highly depends on balance of intestinal absorption/secretion and synthesis. Studying the rate of absorption and synthesis has come only recently into the foreground of interest. Many observations proved that using even the strongest cholesterol lowering drug - beyond reducing the synthesis in the liver - may be associated with an up to 50 percent increase of the intestinal cholesterol absorption. When studying the effectiveness of statins in everyday practice we measure only the decrease of serum cholesterol level as the final result, and do not examine the changes in the synthesis and absorption. The amount of cholesterol synthesized or absorbed can be determined in an indirect way by measuring that of the non-cholesterol sterols (phytosterols). The absorption markers are campesterol, sitosterol, avenasterol as well as cholestanol. The biosynthesis of cholesterol correlates with the level of lathosterol, cholestanol, desmostenol. In practice the concentration of lathosterol or lathosterol/cholesterol can be considered the marker of synthesis and the campesterol or campesterol/cholesterol ratio the marker of absorption. So recent study results show that while inhibiting the cholesterol synthesis with statin the cholesterol absorption increases and the absorption inhibitor ezetimibe is associated with boost of synthesis. The increase in absorption caused by statins can be reduced or prevented by combining with ezetimibe. These data confirm that combination of statin and ezetimibe, inhibiting simultaneously both the synthesis and absorption provides the most effective cholesterol-level lowering with the least side-effects.

Topics: Anticholesteremic Agents; Azetidines; Biomarkers; Cholestanol; Cholesterol; Cholesterol, Dietary; Ezetimibe; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Intestinal Absorption; Phytosterols; Sitosterols

Topics: Cholesterol, LDL; Humans; Hypercholesterolemia; Hypolipidemic Agents; Margarine; Sitosterols

Topics: Diet; Diet Therapy; Dietary Fats; Humans; Hypercholesterolemia; Sitosterols; Sterols

Plant sterols (PS) lower plasma LDL-cholesterol through partial inhibition of intestinal cholesterol absorption. Although PS themselves are poorly absorbed, increased intakes of PS result in elevated plasma concentrations. In this paper, we report time curves of changes in plasma PS during 12 weeks of PS intake. Furthermore, the impact of cholesterol synthesis and absorption on changes in plasma PS is explored.. The study was a double-blind, randomized, placebo-controlled, parallel-group study with the main aim to investigate the effects of PS on vascular function (clinicaltrials.gov: NCT01803178). Hypercholesterolemic but otherwise healthy men and women (n = 240) consumed low-fat spreads without or with added PS (3 g/d) for 12 weeks after a 4-week run-in period. Blood sampling was performed at week 0, 4, 8 and 12. Basal cholesterol-standardized concentrations of lathosterol and sitosterol + campesterol were used as markers of cholesterol synthesis and absorption, respectively. In the PS group, plasma sitosterol and campesterol concentrations increased within the first 4 weeks of intervention by 69% (95%CI: 58; 82) starting at 7.2 μmol/L and by 28% (95%CI: 19; 39) starting at 11.4 μmol/L, respectively, and remained stable during the following 8 weeks. Placebo-corrected increases in plasma PS were not significantly different between high and low cholesterol synthesizers (P-values >0.05). Between high and low cholesterol absorbers, no significant differences were observed, except for the cholesterol-standardized sum of four major plasma PS (sitosterol, campesterol, brassicasterol and stigmasterol) showing larger increases in low absorbers (78.3% (95%CI: 51.7; 109.5)) compared to high absorbers (40.8% (95%CI: 19.9; 65.5)).. Increases in plasma PS stabilize within 4 weeks of PS intake and do not seem impacted by basal cholesterol synthesis or absorption efficiency. This study was registered at clinicaltrials.gov (NCT01803178).

Topics: Adult; Aged; Cholestadienols; Cholesterol; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hypercholesterolemia; Intestinal Absorption; Lipid Metabolism; Male; Middle Aged; Phytosterols; Prospective Studies; Sitosterols; Stigmasterol

Plant sterols (PSs) lower LDL cholesterol, an established risk factor for coronary artery disease (CAD). No direct evidence is available supporting a reduced risk of CAD for foods with added PSs. Endothelial dysfunction is seen as an early indicator of atherosclerotic damage.. This study was primarily designed to investigate the effect of a low-fat spread with added PSs on brachial artery endothelial function as measured by flow-mediated dilation (FMD). Second, effects on arterial stiffness, blood pressure, serum lipids, and plasma PS concentrations were investigated. We hypothesized that PSs would not worsen FMD but would rather modestly improve FMD.. This study had a double-blind, randomized, placebo-controlled, parallel design. After a 4-wk run-in period, 240 hypercholesterolemic but otherwise healthy men and women consumed 20 g/d of low-fat spread without (control) or with added PSs (3 g/d) during 12 wk. Pre- and postintervention, vascular function measurements and blood sampling were performed.. In total, 232 participants completed the study period. For the primary endpoint FMD, 199 participants were included in the statistical analysis. PS intake did not affect FMD (+0.01 percentage points; 95% CI: -0.73, 0.75) compared with control. Measures of arterial stiffness (pulse wave velocity and augmentation index) and blood pressure were also not significantly changed compared with control. After PS intervention, LDL cholesterol significantly decreased on average by 0.26 mmol/L (95% CI: -0.40, -0.12) or 6.7% compared with control. Plasma sitosterol and campesterol concentrations significantly increased in the PS group up to on average 11.5 μmol/L and 13.9 μmol/L (expressed as geometric means), respectively.. The intake of a low-fat spread with added PSs neither improved nor worsened FMD or other vascular function markers in hypercholesterolemic men and women. As expected, serum LDL cholesterol decreased, whereas plasma PSs increased after PS intake. This study was registered at clinicaltrials.gov as NCT01803178.

Topics: Biomarkers; Brachial Artery; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Carbohydrates; Dietary Fats; Dietary Proteins; Double-Blind Method; Endpoint Determination; Energy Intake; Female; Humans; Hypercholesterolemia; Life Style; Male; Middle Aged; Phytosterols; Pulse Wave Analysis; Sitosterols; Triglycerides

Combination therapy may help high-risk patients achieve low-density lipoprotein cholesterol (LDL-C) goals. Impact of rosuvastatin 10 or 20 mg plus ezetimibe 10 mg (RSV10/EZE10 and RSV20/EZE10) has not been fully characterized previously. GRAVITY (NCT00525824) compared efficacy, safety and effect on biomarkers of RSV10/EZE10 and RSV20/EZE10 vs. simvastatin 40 mg and 80 mg plus EZE10 (SIM40/EZE10 and SIM80/EZE10) in patients with coronary heart disease (CHD) or CHD risk equivalent.. Adult patients (n = 833) were randomized to RSV10/EZE10, RSV20/EZE10, SIM40/EZE10 or SIM80/EZE10. Following a 6-week dietary lead-in, patients received 6 weeks' statin monotherapy followed by same statin dose plus ezetimibe for 6 more weeks. Primary endpoint was LDL-C change from baseline to 12 weeks.. Significantly greater (p < 0.05) reductions in LDL-C and other atherogenic lipids were observed with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. A significantly greater proportion of patients achieved LDL-C goals of <100 mg/dl and <70 mg/dl with RSV20/EZE10 vs. SIM40/EZE10 and SIM80/EZE10 and with RSV10/EZE10 vs. SIM40/EZE10. LDL-C was reduced ∼10-14% further with combination therapy vs. monotherapy. Statin monotherapy reduced cholesterol and bile acid synthesis biomarkers, ezetimibe reduced β-sitosterol (sterol absorption marker), and combination therapy achieved additive reductions in lipoprotein-associated phospholipase A2 mass and activity, free cholesterol and 7-ketocholesterol. Safety profiles of rosuvastatin/ezetimibe and simvastatin/ezetimibe combinations were comparable.. Co-administration of rosuvastatin 10 or 20 mg plus ezetimibe achieved significant improvements in lipid profiles in high-risk patients vs. simvastatin 40 or 80 mg plus ezetimibe.

Topics: Absorption; Adult; Atherosclerosis; Azetidines; Biomarkers; Cholesterol, LDL; Coronary Disease; Drug Administration Schedule; Ezetimibe; Female; Fluorobenzenes; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipids; Lipoproteins; Male; Pyrimidines; Risk; Rosuvastatin Calcium; Simvastatin; Sitosterols; Sulfonamides; Treatment Outcome

Post-menopausal women are at higher risk of cardiovascular disease and bone demineralization. Phytosterols (PS) may be used for hypercholesterolemia in some groups and β-cryptoxanthin (β-Cx) displays a unique anabolic effect on bone. Our aim was to assess the changes in cardiovascular and bone turnover markers from the oral intake of β-Cx and PS in post-menopausal women.. A randomized, double-blind, crossover study with β-Cx (0.75 mg/day) and PS (1.5 g/day), single and combined, was performed in 38 postmenopausal women. Diet was supplemented with 1 × 250 mL milk-based fruit drink/day for 4 weeks with a wash-out period of 4-weeks in between. Serum β-Cx and PS were determined by UPLC and CG-FID respectively. Outcome variables included markers of bone turnover and cardiovascular risk. Biological effect was assessed by paired t test and generalized estimating equations analysis that included the previous treatment, the order of intervention and the interactions. The intake of beverages containing β-Cx and PS brought about a significant increase in serum levels of β-Cx, β-sitosterol and campesterol. Intervention caused changes in almost all the markers while the order, previous treatment and the interaction did not reach statistical significance. Only the intake of the beverage containing β-Cx plus PS brought about significant decreases in total cholesterol, c-HDL, c-LDL and bone turnover markers.. β-Cx improves the cholesterol-lowering effect of PS when supplied simultaneously and this combination may also be beneficial in reducing risk of osteoporosis.. ClinicalTrials.gov number NCT01074723.

Topics: Administration, Oral; Aged; Bone and Bones; Cardiovascular Diseases; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Cryptoxanthins; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Female; Healthy Volunteers; Humans; Hypercholesterolemia; Middle Aged; Phytosterols; Postmenopause; Risk Factors; Sitosterols; Treatment Outcome; Triglycerides

Non-cholesterol sterols reflect cholesterol metabolism. Statins reduce cholesterol synthesis usually with a rise in cholesterol absorption. Common hyperlipemias have shown different patterns of cholesterol metabolism. We evaluated whether cholesterol absorption and synthesis may differ after statin therapy in primary hyperlipemias.. We determined lipid profile, apoprotein B and serum sterols (lathosterol, sitosterol, campesterol by gas chromatography/mass spectrometry) before and after statins in 80 untreated hyperlipemic patients, 40 with polygenic hypercholesterolemia (PH) and 40 with familial combined hyperlipemia (FCH).. At baseline in FCH lathosterol was significantly higher while campesterol and sitosterol were significantly lower than in PH. After statins, the reduction in LDL-C did not significantly differ between the two groups; in PH there was a significant decrease of lathosterol from 96.1 to 52.6 102 μmol/mmol cholesterol (p=0.0001) with no significant modifications in campesterol and sitosterol; on the opposite, in FCH lathosterol decreased from 117 to 43 102 μmol/mmol cholesterol (p=0.0001) and campesterol and sitosterol significantly increased from 38 to 48 102 μmol/mmol cholesterol (p=0.0001), and from 75 to 86 102 μmol/mmol cholesterol, (p=0.022), respectively. After statin therapy only in FCH Δ-LDL-C showed a significant inverse correlation with Δ-sitosterol and with Δ-campesterol.. Primary hyperlipemias show different patterns of response to statins: in PH LDL reduction appears completely "synthesis inhibition" dependent, while in FCH LDL decrease appears to be synthesis dependent, partially limited by absorption increase. Studying cholesterol metabolism before and after hypolipemic therapy might be useful in identifying the best tailored treatment.

Topics: Adult; Aged; Atorvastatin; Cholesterol; Cholesterol, LDL; Female; Gas Chromatography-Mass Spectrometry; Heptanoic Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipidemia, Familial Combined; Hyperlipidemias; Lipids; Male; Middle Aged; Phytosterols; Pyrroles; Simvastatin; Sitosterols

The percentage of hypercholesterolemic individuals not reaching their LDL-cholesterol (LDL-C) goal remains high and additional therapeutic strategies should be evaluated. The objective of this study was to evaluate the cholesterol-lowering efficacy and mechanism of action of bile salt hydrolase-active Lactobacillus reuteri NCIMB 30242 capsules in hypercholesterolemic adults.. A total of 127 subjects completed a randomized, double-blind, placebo-controlled, parallel-arm, multicenter study. Subjects were randomized to consume L. reuteri NCIMB 30242 capsules or placebo capsules over a 9-week intervention period. The primary outcome was LDL-C relative to placebo at the study end point.. L. reuteri NCIMB 30242 capsules reduced LDL-C by 11.64% (P<0.001), total cholesterol by 9.14%, (P<0.001), non-HDL-cholesterol (non-HDL-C) by 11.30% (P < 0.001) and apoB-100 by 8.41% (P = 0.002) relative to placebo. The ratios of LDL-C/HDL-cholesterol (HDL-C) and apoB-100/apoA-1 were reduced by 13.39% (P = 0.006) and 9.00% (P = 0.026), respectively, relative to placebo. Triglycerides and HDL-C were unchanged. High-sensitivity C-reactive protein and fibrinogen were reduced by 1.05 mg/l (P = 0.005) and 14.25% (P = 0.004) relative to placebo, respectively. Mean plasma deconjugated bile acids were increased by 1.00 nmol/l (P=0.025) relative to placebo, whereas plasma campesterol, sitosterol and stigmasterol were decreased by 41.5%, 34.2% and 40.7%, respectively.. The present results suggest that the deconjugation of intraluminal bile acids results in reduced absorption of non-cholesterol sterols and indicate that L. reuteri NCIMB 30242 capsules may be useful as an adjunctive therapy for treating hypercholesterolemia.

Topics: Adult; Apolipoprotein A-I; Apolipoprotein B-100; Bile Acids and Salts; C-Reactive Protein; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Fibrinogen; Humans; Hypercholesterolemia; Intestinal Absorption; Limosilactobacillus reuteri; Male; Middle Aged; Phytosterols; Sitosterols; Stigmasterol

Statins inhibit cholesterol synthesis but can upregulate cholesterol absorption, with higher doses producing larger effects. Ezetimibe inhibits cholesterol absorption but also upregulates synthesis. We tested whether ezetimibe added to on-going statin therapy would be most effective in lowering LDL-cholesterol (LDL-C) in subjects on high-potency statins and whether these effects would be related to alterations in cholesterol absorption (β-sitosterol) and synthesis (lathosterol) markers.. Hypercholesterolemic subjects (n = 874) on statins received ezetimibe 10 mg/day. Plasma lipids, lathosterol, and β-sitosterol were measured at baseline and on treatment. Subjects were divided into low- (n = 133), medium- (n = 582), and high- (n = 159) statin potency groups defined by predicted LDL-C-lowering effects of each ongoing statin type and dose (reductions of ~20-30%, ~31-45%, or ~46-55%, respectively).. The high-potency group had significantly lower baseline lathosterol (1.93 vs. 2.58 vs. 3.17 μmol/l; p < 0.001) and higher baseline β-sitosterol values (6.21 vs. 4.58 vs. 4.51 μmol/l, p < 0.001) than medium-/low-potency groups. Ezetimibe treatment in the high-potency group produced significantly greater reductions from baseline in LDL-C than medium-/low-potency groups (-29.1% vs. -25.0% vs. -22.7%; p < 0.001) when evaluating unadjusted data. These effects and group differences were significantly (p < 0.05) related to greater β-sitosterol reductions and smaller lathosterol increases. However, LDL-C reduction differences between groups were no longer significant after controlling for placebo effects, due mainly to modest LDL-C lowering by placebo in the high-potency group.. Patients on high-potency statins have the lowest levels of cholesterol synthesis markers and the highest levels of cholesterol absorption markers at baseline, and the greatest reduction in absorption markers and the smallest increases in synthesis markers with ezetimibe addition. Therefore, such patients may be good candidates for ezetimibe therapy if additional LDL-C lowering is needed.

Topics: Aged; Anticholesteremic Agents; Apolipoproteins; Azetidines; Biomarkers; C-Reactive Protein; Cholesterol; Cholesterol, LDL; Double-Blind Method; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Intestinal Absorption; Male; Middle Aged; Multivariate Analysis; Sitosterols; Time Factors; Treatment Outcome; United States

As sitosterolemic patients have an increased cardiovascular risk, there is concern that reducing serum LDL-cholesterol concentrations by plant sterols enriched functional foods might adversely affect vascular function. Whether increased concentrations of plant sterols truly affect vascular function and whether these effects are exclusive to the larger vessels remains unknown. We compared the effects of long-term plant sterol and -stanol consumption on changes in retinal vessels diameter which reflex alterations in the microcirculation. Three randomized groups were studied at baseline and after 85-weeks. Group one (N=11) consumed plant sterol enriched margarine (2.5g/day), the second (N=8) plant stanol enriched margarine (2.5g/day), and the control group (N=11) non-enriched margarine (2.5g/day). Serum cholesterol-standardized campesterol and sitosterol concentrations increased by 354.84±168.22·102μmol/mmol and 84.36±48.26·102μmol/mmol (p<0.001), respectively in the sterol group, while decreasing non-significantly in the plant stanol group. Serum LDL-cholesterol concentrations decreased significantly in both the plant sterol (-0.33±0.33mmol/L, p=0.016) and -stanol groups (-0.38±0.34mmol/L, p=0.018) compared to the increase in the controls (0.29±0.34mmol/L). The mean change in venular diameters for the plant sterol group (2.3±3.1μm), plant stanol groups (-0.8±3.4μm) and control group (-0.8±5.1μm) did not reach significance but the change in cholesterol-standardized campesterol concentrations correlated positively with the change in venular diameter independent of changes in serum LDL-cholesterol concentrations (r=0.39, N=30, p=0.033). Increased serum campesterol concentration correlated positively with increased retinal venular diameter, independent from changes in serum LDL-cholesterol concentrations. This may constitute an explanation for the suggested effects of plant sterols on vascular function. However, this novel finding needs confirmation and further study.

Topics: Adolescent; Adult; Aged; Arterioles; Cholesterol; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Middle Aged; Phytosterols; Plant Extracts; Retinal Vessels; Sitosterols; Sterols; Venules

Phytosterols (PS) lower LDLc, but their effect on metabolic syndrome (MetS) remains unknown. We evaluated whether low-fat milk enriched with PS improves cardiovascular risk factors in these patients.. A randomised parallel trial employing 24 moderate-hypercholesterolaemic MetS patients and consisting of two 3-month intervention phases. After a 3-month healthy diet, patients were divided into two intervention groups: diet (n = 10) and diet + PS (n = 14) (2 g/day). A control group of 24 moderate-hypercholesterolaemic patients without MetS (matched in age and BMI) underwent the same procedure.. Neither dietary intervention nor enrichment of PS induced any improvement in the serum lipoprotein profile of MetS patients. By contrast, in the non-MetS population, a healthy diet effectively reduced TC, LDLc, non-HDLc and Apo B-100, with further decreases in TC (6.9%), LDLc (10.5%), non-HDLc (10.3%), Apo B-100 (6.2%) and Apo B-100/ApoA-I ratio (11.6%) being observed when PS were administered. No differences in LDL diameter, hsCRP or homocysteine were detected in any of the groups after consuming PS. This supplementation produced a significant increase in PS levels only in the non-MetS population.. PS therapy appears to be of little value to MetS patients, likely due to its reduced intestinal cholesterol absorption. The efficacy of PS as hypocholesterolaemic agents is thus limited.

Topics: Adult; Anticholesteremic Agents; Cardiovascular Diseases; Cholesterol; Cholesterol, Dietary; Dietary Supplements; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Intestinal Absorption; Lipoproteins; Male; Metabolic Syndrome; Middle Aged; Phytosterols; Risk Factors; Severity of Illness Index; Sitosterols; Spain

The relationship between plant sterol (PS) absorption and circulatory concentrations with cholesterol absorption and biosynthesis during PS consumption has yet to be clearly elucidated in humans. It is therefore essential to examine campesterol, β-sitosterol, and cholesterol absorption and cholesterol fractional synthesis rate (FSR) following PS consumption in individuals with high versus low basal circulatory PS concentrations.. A randomized, crossover trial was conducted in 82 hypercholesterolemic men consuming spreads with or without 2 g/d of PS for two 4-week periods, each separated by a 4-week washout. Endpoint tracer enrichments after ingestion of (2)H-labeled campesterol or β-sitosterol and (13)C-labeled cholesterol were determined by isotope ratio mass spectrometry.. For both phases of dietary intervention, the endpoint cholesterol absorption index was positively correlated with campesterol (r = 0.5864, p < 0.0001) and β-sitosterol (r = 0.4676, p < 0.0001) absorption indices; inversely, endpoint cholesterol FSR correlated negatively with the absorption indices of campesterol (r = -0.5004, p < 0.0009), β-sitosterol (r = -0.4154, p < 0.05), and cholesterol (r = -0.4056, p < 0.0001). PS intervention reduced absorption indices of campesterol, β-sitosterol, and cholesterol by 36.5% ± 2.7%, 39.3% ± 2.9%, and 34.3% ± 1.9%, respectively, but increased cholesterol FSR by 33.0% ± 3.3% relative to control. Endpoint circulatory PS levels (cholesterol adjusted) were positively associated with endpoint absorption indices of campesterol (r = 0.5586, p < 0.0001, for placebo; r = 0.6530, p < 0.0001, for PS intake) and cholesterol (r = 0.3683, p < 0.001 for placebo; r = 0.3469, p < 0.002, for PS intake) and were negatively associated with cholesterol FSR (r = -0.3551, p < 0.002, for placebo; r = -0.3643, p < 0.001, for PS intake). The cholesterol-lowering effect of PS was most pronounced among individuals falling within the 50th-75th percentiles of basal PS concentrations.. These data suggest that basal PS concentrations indicate not only sterol absorption efficiency but also the extent of PS-induced cholesterol reduction and thus might be clinically useful to predict the extent of cholesterol response to PS intervention within a given individual.

Topics: Adult; Aged; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Endpoint Determination; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols; Triglycerides

It has been demonstrated that statins can increase intestinal sterol absorption. Augments in phytosterolemia seems related to cardiovascular disease.. We examined the role of soluble fiber intake in endogenous cholesterol synthesis and in sterol absorption among subjects under highly effective lipid-lowering therapy.. In an open label, randomized, parallel-design study with blinded endpoints, subjects with primary hypercholesterolemia (n = 116) were assigned to receive during 12 weeks, a daily dose of 25 g of fiber (corresponding to 6 g of soluble fibers) plus rosuvastatin 40 mg (n = 28), rosuvastatin 40 mg alone (n = 30), sinvastatin 40 mg plus ezetimibe 10 mg plus 25 g of fiber (n = 28), or sinvastatin 40 mg plus ezetimibe 10 mg (n = 30) alone.. The four assigned therapies produced similar changes in total cholesterol, LDL-cholesterol, and triglycerides (p < 0.001 vs. baseline) and did not change HDL-cholesterol. Fiber intake decreased plasma campesterol (p < 0.001 vs. baseline), particularly among those patients receiving ezetimibe (p < 0.05 vs. other groups), and β-sitosterol (p = 0.03 vs. baseline), with a trend for lower levels in the group receiving fiber plus ezetimibe (p = 0.07). Treatment with rosuvastatin alone or combined with soluble fiber was associated with decreased levels of desmosterol (p = 0.003 vs. other groups). Compared to non-fiber supplemented individuals, those treated with fibers had weight loss (p = 0.04), reduced body mass index (p = 0.002) and blood glucose (p = 0.047).. Among subjects treated with highly effective lipid-lowering therapy, the intake of 25 g of fibers added favorable effects, mainly by reducing phytosterolemia. Additional benefits include improvement in blood glucose and anthropometric parameters.

Topics: Azetidines; Blood Glucose; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fiber; Ezetimibe; Female; Fluorobenzenes; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Middle Aged; Phytosterols; Pyrimidines; Rosuvastatin Calcium; Sitosterols; Sulfonamides; Triglycerides

The object of our study was to compare the effect of high-dose vs low-dose atorvastatin vs nonstatin-based treatment (cholestyramine plus sitosterol) on cell composition of carotid plaque.. We recruited 60 hypercholesterolemic patients (total cholesterol, 5.83-7.64 mmol/L) eligible for carotid endarterectomy. Three months before surgery, patients were randomized into 3 groups (n=20) receiving atorvastatin 10 mg/day (AT-10) or atorvastatin 80 mg/day (AT-80) or cholestyramine 8 g/day plus sitosterol 2.5 g/day. Analysis of cell composition was performed on endarterectomy specimens.. The 3 treatments resulted in a significant reduction of total cholesterol and low-density lipoprotein cholesterol (LDL-C), although the decrease in total cholesterol and LDL-C was of smaller magnitude in the cholestyramine plus sitosterol group. The 3 regimens did not influence the levels of inflammatory markers (including high-sensitivity C-reactive protein). Macrophage content was significantly lower in the AT-10 group plaques compared to the cholestyramine plus sitosterol group. It was further reduced in the AT-80 group plaques. These differences were no longer significant after adjustment for changes in LDL-C. No difference in lymphocyte number was observed among treatments, whereas the content of smooth muscle cells was higher in the AT- 80 group. An inverse association was observed between LDL-C changes in the 3 groups and macrophage content in the plaques.. Short-term treatment with high-dose statin is superior to a nonstatin lipid-lowering regimen in reducing the macrophage cell content within atherosclerotic lesions, but this effect was determined by the degree of LDL-C-lowering.

Topics: Aged; Aged, 80 and over; Anticholesteremic Agents; Atherosclerosis; Atorvastatin; Biomarkers; C-Reactive Protein; Cholesterol, LDL; Cholestyramine Resin; Endarterectomy, Carotid; Female; Heptanoic Acids; Humans; Hypercholesterolemia; Lymphocyte Count; Macrophages; Male; Pyrroles; Sitosterols

To date, there are very few clinical reports that have compared the effects of ezetimibe on lipid parameters between hypercholesterolemic patients with and without type 2 diabetes mellitus (T2DM). In this study, we recruited patients for hypercholesterolemic groups with T2DM (n = 42; men/women = 24/18; HbA1c = 6.7 ± 5.4%) and without T2DM (n = 21; men/women = 7/14; HbA1c = 5.3 ± 0.4%). Patients were prescribed ezetimibe at a dose of 10 mg/daily for the course of the 12-week study. At baseline and after 12 weeks of treatment, several lipid parameters, including serum low-density-lipoprotein cholesterol (LDL-C), non-high-density-lipoprotein cholesterol (non-HDL-C), high-sensitivity C-reactive protein (hs-CRP), and cholesterol synthesis/absorption-related markers, were measured. Compared with those at the baseline, the levels of LDL-C, non-HDL-C, campesterol, and sitosterol were significantly reduced after 12 weeks of ezetimibe treatment in both groups. After adjusting for confounding factors, such as age, gender, smoking, and BMI, the levels of LDL-C and non-HDL-C displayed significantly greater reductions in the patients with T2DM (-25.1 ± 13.6% in LDL-C, -20.5 ± 11.2% in non-HDL-C) than those without T2DM (-20.5 ± 7.8% in LDL-C, P < 0.05; -17.4 ± 7.6% in non-HDL-C, P < 0.05). The reduction of the level of cholestanol was significantly and positively correlated with those of LDL-C and non-HDL-C in the patients with T2DM. Taken together, these findings indicate that ezetimibe could reduce the levels of atherogenic lipoproteins to a greater extent in hypercholesterolemic patients with T2DM than in those without T2DM.

Topics: Aged; Azetidines; Biomarkers; Body Mass Index; C-Reactive Protein; Cardiovascular Diseases; Cholestanol; Cholesterol; Cholesterol, LDL; Diabetes Mellitus, Type 2; Ezetimibe; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Lipids; Male; Middle Aged; Phytosterols; Sitosterols

To assess safety during a diet based on low-fat foods enriched with nonesterified wood-derived plant sterols and mineral nutrients related to serum phytosterol, sex hormone and fat-soluble vitamin metabolism.. Seventy-one study participants (52 women, 19 men) with mild-to-moderate hypercholesterolemia completed the double-blind, placebo-controlled feeding trial lasting for 15 weeks. The subjects were randomly allocated to the sterol group receiving food items enriched with mineral nutrients as well as with a total of 1.25, 2.5 and 5.0 g per day of plant sterols during the first, second and third 5-week periods, respectively, or to the placebo group receiving similar food items without plant sterols. This outpatient clinical trial with free-living subjects was carried out at two hospital clinics.. Two significant findings were observed. Serum sitosterol concentrations increased from 2.84 to 5.35 mg l(-1) (P<0.004 vs placebo) but those of serum total plant sterols did not because of compensatory changes in other phytosterols. The highest plant sterol levels did not exceed 0.6% of total serum sterols. Serum alpha-tocopherol concentrations decreased in the sterol group by 10% (P<0.0002), but the between-group difference disappeared after adjusting for the change in the carrier (LDL cholesterol).. Fifteen-week consumption of natural nonesterified plant sterol-enriched food does not cause any serious adverse effects during such a period. However, serum alpha-tocopherol levels were somewhat reduced in the sterol group suggesting that long-term effects of plant sterols on serum fat-soluble vitamin concentrations should be further explored, especially in relation to very low-fat diets.

Topics: Adult; Aged; alpha-Tocopherol; Cholesterol, LDL; Diet; Double-Blind Method; Female; Finland; Food, Fortified; Gonadal Steroid Hormones; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Phytosterols; Sitosterols; Vitamins

To assess the long-term efficacy and safety profile of ezetimibe 10 mg/day in patients with homozygous sitosterolemia.. This was an extension of a multi-centre, randomised, double-blind, placebo-controlled base study in which patients with homozygous sitosterolemia and plasma sitosterol concentrations > 5 mg/dl were randomised 4 : 1 to ezetimibe 10 mg/day (n = 30) or placebo (n = 7) for 8 weeks. Patients who successfully completed the base study with > 80% compliance to study medication were eligible to enter two, successive, 1-year extension studies in which ezetimibe 10 mg/day was administered in an open-label manner. Patients remained on their current treatment regimen (e.g. bile salt-binding resins, statins and low-sterol diet) during the base and extension studies. Patients had to be off ezetimibe therapy for > or = 4 weeks prior to entering the first extension. Efficacy and safety/tolerability parameters were evaluated every 12 and 26 weeks in the first and second years respectively. The primary efficacy end-point was mean percentage change in plasma sitosterol from baseline to study end for the cohort of patients (n = 21) who successfully completed the second extension study.. Treatment with ezetimibe 10 mg/day led to significant mean percentage reductions from baseline in plasma concentrations of sitosterol (-43.9%; p < 0.001), campesterol (-50.8%; p < 0.001), low-density lipoprotein (LDL) sterols (-13.1%; p < 0.050), total sterols (-10.3%; p < 0.050) and apolipoprotein (apo) B (-10.1%; p < 0.050). No significant changes from baseline were observed for lathosterol, high-density lipoprotein sterol, triglycerides or apo A-1. Maximal reductions in sitosterol and campesterol occurred within the first 52 weeks of treatment and were sustained for the duration of the study. For LDL sterol, total sterols and apo B, maximal reductions were achieved early (by weeks 4 or 16) and waned slightly through the remainder of the study. Overall ezetimibe 10 mg was well tolerated.. In patients with homozygous sitoserolemia, long-term treatment with ezetimibe 10 mg/day for 2 years was effective in reducing plasma plant sterol concentrations with an overall favourable safety and tolerability profile.

Topics: Achilles Tendon; Adolescent; Adult; Aged; Anticholesteremic Agents; Azetidines; Child; Double-Blind Method; Ezetimibe; Female; Homozygote; Humans; Hypercholesterolemia; Male; Middle Aged; Sitosterols; Treatment Outcome; Young Adult

Consumption of plant sterol- or stanol-enriched margarines by statin users results in an additional LDL-cholesterol reduction of approximately 10 %, which may be larger than the average decrease of 3-7 % achieved by doubling the statin dose. However, whether this effect persists in the long term is not known. Therefore, we examined in patients already on stable statin treatment the effects of 85 weeks of plant sterol and stanol ester consumption on the serum lipoprotein profile, cholesterol metabolism, and bile acid synthesis. For this, a double-blind randomised trial was designed in which fifty-four patients consumed a control margarine with no added plant sterols or stanols for 5 weeks (run-in period). For the next 85 weeks, seventeen subjects continued with the control margarine and the other two groups with either a plant sterol (n 18) or plant stanol (n 19) (2.5 g/d each) ester-enriched margarine. Blood was sampled at the end of the run-in period and every 20 weeks during the intervention period. Compared with the control group, plant sterol and stanol ester consumption reduced LDL-cholesterol by 0.28 mmol/l (or 8.7 %; P = 0.08) and 0.42 mmol/l (13.1 %; P = 0.006) respectively after 85 weeks. No effects were found on plasma concentrations of oxysterols or 7 alpha-hydroxy-4-cholesten-3-one, a bile acid synthesis marker. We conclude that long-term consumption of both plant sterol and stanol esters effectively lowered LDL-cholesterol concentrations in statin users.

Topics: Analysis of Variance; Anticholesteremic Agents; Biomarkers; Cholestenones; Cholesterol; Cholesterol, LDL; Double-Blind Method; Esters; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipid Metabolism; Lipoproteins; Male; Margarine; Middle Aged; Phytosterols; Sitosterols; Stigmasterol

This study examined the effect of plant sterols added, together with an emulsifying agent, to a low-fat yoghurt on the serum lipid and plant sterol values in moderately hypercholesterolaemic volunteers. Study I was a randomized double-blind, cross-over trial. For 4 weeks, 15 volunteers consumed yoghurt containing 1 g plant sterols or a placebo yoghurt. Study II was a randomized, double-blind, parallel-group study. For 8 weeks, the sterol group (n = 12) ingested daily two yoghurts (2 g/day plant sterols) and the placebo group (n = 14) ingested two yoghurts without plant sterols. Study I: compared with the placebo, the sterol yoghurt reduced serum total cholesterol by 0.15 mmol/l (2.2%, P=0.235) and low-density lipoprotein (LDL) cholesterol by 0.19 mmol/l (4.3%, P=0.082), and increased serum campesterol by 0.26 mg/100 ml (P=0.006) and sitosterol by 0.11 mg/100 ml (P=0.015). Study II: compared with the placebo, the sterol yoghurt reduced serum total cholesterol by 0.41 mmol/l (6.3%, P=0.167) and LDL cholesterol by 0.28 mmol/l (6.4%, P=0.306), and increased serum campesterol by 0.28 mg/100 ml (P=0.016) and sitosterol by 0.40 mg/100 ml (P=0.206). Meta-analysis: the pooled treatment difference was -0.34 mmol/l (5.2%, P=0.173) in total cholesterol and was -0.26 mmol/l (-5.8%, P=0.261) in LDL cholesterol, when the sterol yoghurt was compared with the placebo. A low-fat yoghurt enriched with 1-2 g/day plant sterols reduced serum cholesterol levels in moderately hypercholesterolaemic subjects. Campesterol and sitosterol serum levels increased, but their concentration remained in the range of normal values.

Topics: Adult; Analysis of Variance; Anticholesteremic Agents; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Phytosterols; Sitosterols; Yogurt

Levels of cholesterol are regulated by its synthesis, absorption, and elimination. Plasma levels of phytosterols (e.g., sitosterol, campesterol) and ratios of these sterols to total cholesterol (TC) are reported to correlate with efficiency of intestinal cholesterol absorption, whereas levels of certain cholesterol precursor sterols (e.g., desmosterol, lathosterol) and their ratios to TC correlate with cholesterol biosynthesis. However, there is a paucity of published data concerning the effects of combined treatment using HMG-CoA reductase inhibitors (statins) and a cholesterol absorption inhibitor (ezetimibe) on these parameters.. To characterize the effects of ezetimibe co-administered with statins, compared with each treatment alone, on cholesterol precursor sterols and plasma phytosterol levels.. A post-hoc analysis was performed to determine the effects of treatment with ezetimibe 10 mg, simvastatin (10-80 mg), and atorvastatin (10-80 mg), alone or in combination, on these non-cholesterol sterols using plasma samples from two randomized controlled trials involving patients with primary hypercholesterolemia (low-density lipo protein [LDL-C] = 145-250 mg/dL; triglycerides < or = 350 mg/dL; N = 975) but without a recent (< or = 6-month) history of coronary heart disease (CHD) or either uncontrolled or newly diagnosed diabetes mellitus.. Ezetimibe monotherapy significantly reduced plasma sitosterol and campesterol concentrations from baseline compared with placebo (both p < 0.001), whereas statins significantly lowered desmo sterol and lathosterol levels (p < 0.001 vs. placebo). Co-administration of ezetimibe and statins significantly decreased plasma levels of all of these sterols (p < 0.001).. The observed effects of co-administration of ezetimibe and statins on non-cholesterol sterols are consistent with net inhibition of sterol absorption (driven by ezetimibe) in conjunction with net inhibition of cholesterol synthesis (driven by statins). The potential influence of treatment-induced changes in phytosterols on cardiovascular risk warrants further investigation in long-term, prospective, randomized controlled trials. This post-hoc study was by nature exploratory, and, because data from such analyses are not customarily adjusted for multiple comparisons, some associations may have emerged as statistically significant by chance. Future prospective randomized controlled studies may help to confirm our findings and address other research issues, such as the generalizability of our findings to patients with CHD or diabetes mellitus and possible dose:response relationships between escalating statin (or ezetimibe-statin) doses and circulating non-cholesterol levels.

Topics: Aged; Anticholesteremic Agents; Azetidines; Cholesterol; Double-Blind Method; Drug Therapy, Combination; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Placebos; Simvastatin; Sitosterols; Sterols

Plant sterol (PS)-enriched foods have been shown to reduce plasma LDL-cholesterol concentrations. In most studies, however, PSs were incorporated into food products of high fat content.. We examined the effect of daily consumption of PS-supplemented low-fat fermented milk (FM) on the plasma lipid profile and on systemic oxidative stress in hypercholesterolemic subjects.. Hypercholesterolemic subjects (LDL-cholesterol concentrations >or=130 and

Topics: Animals; C-Reactive Protein; Carotenoids; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Female; Fermentation; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Milk; Oxidative Stress; Patient Compliance; Phytosterols; Sitosterols; Treatment Outcome; Triglycerides

Hypercholesterolemia is a major risk factor for coronary artery disease. Therapeutic lifestyle changes include dietary modifications such as inclusion of phytosterols, which effectively lowers low-density lipoprotein (LDL) cholesterol in margarines and other fats. Their effectiveness in nonfat moieties is not yet established. The aim of this study was to examine if phytosterols alter the plasma lipoprotein profile when incorporated into nonfat orange juice.. After a 2-week run-in phase with orange juice, 72 mildly hypercholesterolemic healthy subjects were randomized to receive either placebo orange juice (placebo OJ) or plant sterol-fortified orange juice (sterol OJ) (2g/d) for 8 weeks. Fasting blood was obtained at baseline, after 2 weeks of OJ, and after 8 weeks of placebo/sterol-OJ supplementation. Sterol OJ supplementation significantly decreased total (7.2%), LDL (12.4%), and non-high-density lipoprotein (HDL) cholesterol (7.8%) compared with baseline and compared with placebo OJ (P<0.01). Apolipoprotein B levels were significantly decreased (9.5%) with sterol OJ. There were no significant changes in HDL cholesterol or triglycerides with the sterol OJ. While folate and B12 levels significantly increased, homocysteine levels were unchanged.. Orange juice fortified with plant sterols are effective in reducing LDL cholesterol and could easily be incorporated into the therapeutic lifestyle changes dietary regimen.

Topics: Adult; Aged; Apolipoproteins B; Beverages; Cholesterol; Cholesterol, LDL; Citrus; Double-Blind Method; Female; Folic Acid; Food, Fortified; Homocysteine; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols; Stigmasterol; Treatment Outcome; Vitamin B 12

High doses of soy protein are able to decrease plasma cholesterolemia significantly, but they unbalance daily protein intake and strongly modify nutritional habits in patients.. To evaluate the antihypercholesterolemic efficacy of a low dose soy protein product with added beta-sitosterol (rapport = 4:1) in 36 moderately hypercholesterolemic subjects.. The study was divided into 3 separate periods of 40 days each: a stabilization diet period, followed by a treatment period during which all subjects took 10 g of the test product once daily and, finally, a wash out period. The following parameters were monitored: weight, dietary habits, plasma lipid levels, glycemia, uric acid, fibrinogenemia and antibodies against oxidized LDL (ox-LDL Ab).. From the end of the stabilization diet period to the end of the supplementation with the soy protein product with added beta-sitosterol we observed a 19.64 +/- 20.32 mg/dL, 8.47 +/- 54.61 mg/dL, 1.69 +/- 10.92 mg/dL, and 7.06 +/- 16.66 mg/dL mean +/- SD decrease respectively in LDL-C (p < 0.001), TG (p = 0.358), VLDLs (p = 0.358) and apoB (p = 0.016) levels, associated with a 1.31 +/- 8.08 mg/dL and 1.03 +/- 19.09 mg/dL mean increase respectively in HDLC (p = 0.251) and apoAI (p = 0.749) plasma concentrations. The dietary supplementation did not influence Lp(a) (p = 0.984) and ox-LDL Ab (p = 0.953) plasma levels. A statistically significant correlation was observed for LDL-C plasma levels, between the end of the stabilization diet period and the end of the period of supplementation with soy proteins with added beta-sitosterols (p < 0.001).. Although further long-term clinical studies are necessary before claims can be made regarding the therapeutic effects of the tested formulation, the preliminary findings regarding its efficacy and safety as an antihypercholesterolemic agent are encouraging.

Topics: Anticholesteremic Agents; Body Weight; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dose-Response Relationship, Drug; Feeding Behavior; Female; Humans; Hypercholesterolemia; Lipid Peroxidation; Male; Middle Aged; Sitosterols; Soybean Proteins; Treatment Outcome; Triglycerides

To show whether the ratios of squalene and cholesterol precursor sterols to cholesterol and cholestanol and plant sterols to cholesterol change differently in plasma and especially in the red cells of hypercholesterolemic children during consumption of plant stanol and sterol ester spreads.. In a randomized, double-blind, crossover study, hypercholesterolemic children (n = 23) consumed low-fat plant stanol and sterol ester spreads for 5-week periods separated by a 5-week washout period. Plasma and red cell lipids, squalene, and noncholesterol sterols were measured before and at the end of each period.. The plant stanol and sterol ester spreads lowered plasma total (-9% and -6%, respectively) and low-density lipoprotein (-12% and -9%) cholesterol but had no effect on red cell cholesterol, high-density lipoprotein cholesterol, or plasma triglycerides. The ratios of plasma and red cell sitosterol and campesterol to cholesterol decreased by 32% to 36% (P <.001) with the plant stanol ester and increased by 40% to 52% (P <.001) with the sterol ester spread.. Consumption of plant sterols increases and consumption of plant stanols decreases the ratios of plant sterols to cholesterol in red cells of hypercholesterolemic children proportionately to the respective changes in plasma.

Topics: Child; Child, Preschool; Cholesterol, HDL; Cholesterol, LDL; Cross-Over Studies; Double-Blind Method; Erythrocytes; Female; Humans; Hypercholesterolemia; Male; Margarine; Phytosterols; Sitosterols; Time Factors; Triglycerides

In a randomized, double-blind, placebo-controlled trial we evaluated the effect of dietary chocolates enriched with a wood-based phytosterol-phytostanol mixture, containing 18 % (w/w) sitostanol, compared with placebo dietary chocolates in seventy subjects with primary hypercholesterolaemia (total cholesterol levels below 8 mmol/l). For 4 weeks, participants consumed three servings of the phytosterol-enriched chocolate/d that provided 1.8 g unesterified phytosterols/d or a placebo chocolate in conjunction with a low-fat, low-cholesterol diet. Plasma total and LDL-cholesterol levels were statistically significantly reduced by 6.4 % (-0.44 mmol/l) and 10.3 % (-0.49 mmol/l), respectively, after 4 weeks of phytosterol-enriched-chocolate treatment. Plasma HDL-cholesterol and triacylglycerol levels were not affected. Consumption of phytosterol-enriched chocolates significantly increased plasma lathosterol concentration (+20.7 %), reflecting an increased endogenous cholesterol synthesis in response to phytosterol-induced decreased intestinal cholesterol absorption. Furthermore, the chocolates enriched with phytosterols significantly increased both plasma sitosterol (+95.8 %) and campesterol (+64.1 %) levels, compared with the placebo chocolate group. However, the absolute values of plasma sitosterol and campesterol remained within the normal range, that is, below 10 mg/l. The chocolates with phytosterols were palatable and induced no clinical or biochemical side effects. These findings indicate that dietary chocolate enriched with tall oil-derived phytosterols (1.8 g/d) is effective in lowering blood total and LDL-cholesterol levels in subjects with mild hypercholesterolaemia and thus may be helpful in reducing the risk of CHD in these individuals.

Topics: Adult; Apolipoproteins B; Cacao; Chi-Square Distribution; Cholesterol; Cholesterol, LDL; Double-Blind Method; Female; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Phytosterols; Plant Oils; Sitosterols; Statistics, Nonparametric

Plant sterols, in various forms, have been shown to reduce total and LDL-cholesterol concentrations. Particularly controversial at present is the effect of the degree of hydrogenation of the plant sterols on cholesterol-lowering efficacy and the responsible mechanisms.. Our goal was to examine the effect of supplementation with unesterified plant sterols and stanols on plasma lipid and phytosterol concentrations and cholesterol absorption, synthesis, and turnover.. Fifteen otherwise healthy hypercholesterolemic subjects consumed each of 4 dietary treatments in a randomized crossover design. Unesterified sterols and stanols were blended into the butter component of the diet at a dosage of 1.8 g/d. The diets contained plant sterols (NS), plant stanols (SS), a 50:50 mixture of sterols and stanols (NSS), or cornstarch (control).. Plasma total cholesterol concentrations were 7.8%, 11.9%, and 13.1% lower (P < 0.01) in the NS, SS, and NSS groups, respectively, than in the control group. LDL-cholesterol concentrations were 11.3%, 13.4%, and 16.0% lower (P < 0.03) in the NS, SS, and NSS groups, respectively, than in the control group. Plasma triacylglycerols and HDL-cholesterol concentrations did not differ significantly across diets. Cholesterol absorption efficiency was 56.0%, 34.4%, and 48.9% lower (P < 0.001) in the NS, SS, and NSS groups, respectively, than in the control group. The fractional synthesis rate was higher by 45.5% (P < 0.003) in the NSS group than in the control group. Plasma campesterol and sitosterol concentrations were higher (P < 0.01) in the NS group and sitosterol concentrations were lower (P < 0.01) in the SS group than in the control group.. These data indicate that, in their free unesterified form, sterols and stanols lower plasma LDL cholesterol equivalently in hypercholesterolemic persons by suppressing cholesterol absorption.

Topics: Adult; Butter; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Diet; Double-Blind Method; Female; Humans; Hypercholesterolemia; Kinetics; Lipids; Male; Middle Aged; Phytosterols; Phytotherapy; Sitosterols

Our aim was to test the hypocholesterolemic effect of a low-dose formulation of soy proteins supplemented with isolated b-sitosterol in a ratio of 4:1 in 20 moderately hypercholesterolemic subjects. The study has been divided in three different periods of forty days each: a stabilization diet period, then a treatment period during which all subjects assumed 10 g one time a day of the tested product and, finally, a wash out period. From the end of the stabilization diet period to the end of the soy protein added in b-sitosterol supplementation we observed a 0.45 +/- 0.30 mmol/L, 0.09 +/- 0.31 mmol/L and 0.17 +/- 0.22 mmol/L mean +/- SE decrease in respectively LDL-C, TG and apoB levels, associated with a 0.12 +/- 0.25 and 0.03 +/- 0.51 mg/dL mean increase respectively in HDL-C and apoA plasma concentrations. According to this recommends, low doses of soy protein added in b-sitosterol seems to be a practical and safe alternative for patients seeking modest reductions in LDL-C (< 15%).

Topics: Apolipoproteins A; Body Weight; Cholesterol, LDL; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Linear Models; Male; Middle Aged; Sitosterols; Soybean Proteins

Consumption of phytosterol-supplemented margarine lowers total plasma cholesterol (TC) and LDL-cholesterol concentrations in older middle-aged hypercholesterolemic individuals. The effects of incorporating phytosterols into lower-fat foods on the plasma lipids of young men at increased risk of developing cardiovascular disease have not been studied.. We tested the hypothesis that a single daily dose of soybean phytosterols added to ground beef will lower plasma TC and LDL-cholesterol concentrations in mildly hypercholesterolemic young men.. In a triple-blind, 4-wk study, 34 male college students with elevated plasma TC (5.85 +/- 0.70 mmol/L), LDL cholesterol (4.02 +/- 0.60 mmol/L), and TC:HDL cholesterol (5.5 +/- 1.2) were randomly assigned to the control (ground beef alone) or treatment (ground beef with 2.7 g of phytosterols) group. The phytosterol mixture was two-thirds esterified and one-third nonesterified and consisted of beta-sitosterol (48%), campesterol (27%), and stigmasterol (21%).. Consumption of phytosterol-supplemented ground beef lowered plasma TC and LDL-cholesterol concentrations and TC:HDL cholesterol from baseline by 9.3%, 14.6%, and 9.1%, respectively (P < 0.001). The LDL particle size did not change, suggesting that the decrease was primarily of particle number. The decreases were similar in subjects with (n = 8) and without (n = 9) a family history of premature cardiovascular disease. No significant changes were found in the control group.. Phytosterol-supplemented ground beef effectively lowers plasma TC and LDL cholesterol and has the potential to become a functional food to help reduce the risk of cardiovascular disease.

Topics: Adult; Animals; Cattle; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Food, Fortified; Glycine max; Humans; Hypercholesterolemia; Male; Meat Products; Phytosterols; Sitosterols; Stigmasterol

This study was performed to investigate the difference in the serum-cholesterol- and triglyceride-lowering activities between phytosterols dissolved in diacylglycerol (PS/DG) and dispersed in triacylglycerol (PS/TG). The effects of the solvent on the concentrations of serum beta-sitosterol and campesterol were examined.. The study had a randomised crossover design.. Twelve healthy normocholesterolemic or moderately hypercholesterolemic men aged 29-50 y participated in this study.. For 2 weeks before the test period (designated as the control period), all subjects consumed control mayonnaise (PS free) daily with supper and were randomly assigned to two groups for the 2 week test period; one group was given mayonnaise containing PS (500 mg/day) dissolved in DG (10 g/day), and the other mayonnaise containing PS (500 mg/day) dispersed in TG (10 g/day). After a wash out period consuming control PS-free mayonnaise for 4 weeks, the groups were reversed for 2 weeks.. PS/TG feeding had no effect on the serum cholesterol level. In contrast, PS/DG feeding significantly reduced the total and LDL cholesterol levels from the initial value of 5.57 to 5.31 mmol/l (4.7%; P<0.05) and from 3.69 to 3.39 mmol/l (7.6%; P<0.05), respectively. Moreover, the degree of total cholesterol reduction induced by PS/DG feeding in the test period was significantly greater than that induced by PS/TG feeding (P<0.05). In addition, the serum beta-sitosterol and campesterol concentrations did not change during the PS/TG or PS/DG feeding periods.. Dissolution of PS in DG had a better serum cholesterol lowering effect than dissolution in TG.. Kao Corporation.

Topics: Adult; Cholesterol; Cholesterol, LDL; Cross-Over Studies; Diglycerides; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols; Solubility; Triglycerides

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+/-1.0 mmol/l, LDL cholesterol (LDL-C) 2.5+/-1.0 mmol/l, apolipoprotein B (apo B) 1. 3+/-0.3 g/l, triglycerides (TG) 1.7+/-0.7 mmol/l, HDL-C 1.1+/-0.2 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 3.0, 4.0, 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)+0.73(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.

Topics: Adult; Aged; Anticholesteremic Agents; Apolipoproteins B; Blood Component Removal; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Lipoprotein(a); Lipoproteins, LDL; Male; Middle Aged; Simvastatin; Sitosterols; Triglycerides

To determine the efficacy of stanol esters in lowering cholesterol in a US population.. After a run-in phase, 318 subjects were randomized to receive one of the following margarine-like spreads containing stanol ester or placebo for 8 weeks: EU 3 G: 1 g of stanol (ester form) per 8-g serving of a European formula 3 times a day; US 3 G: 1 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; US 2 G: 0.67 g of stanol (ester form) per 8-g serving of a US reformulation 3 times a day; or placebo spread.. Mean +/- SD baseline total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels were 233+/-20 and 153+21 mg+/-dL, respectively. In the US 3 G group, 3 g daily of stanol esters lowered TC and LDL-C levels by 6.4% and 10.1%, respectively. There was a dose-dependent response compared with 2 g daily (US 2 G). Triglyceride and high-density lipoprotein cholesterol levels were unchanged. The incidence of adverse effects was not different from placebo. Serum vitamin A and 25-hydroxyvitamin D levels were not affected.. Stanol esters lowered TC and LDL-C levels in a mildly hypercholesterolemic US population without evidence of adverse effects. It may be a useful dietary adjunct to lower cholesterol.

Topics: Adult; Anticholesteremic Agents; beta Carotene; Cholestanols; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats; Dose-Response Relationship, Drug; Double-Blind Method; Esters; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols; Treatment Outcome; Triglycerides; United States; Vitamin A; Vitamin D

To compare effects on plasma total-, LDL-, and HDL-cholesterol concentrations of margarines enriched with different vegetable oil sterols or sitostanol-ester.. A randomized double-blind placebo-controlled balanced incomplete Latin square design with five treatments and four periods of 3.5 weeks. Margarines enriched with sterols from soybean, sheanut or ricebran oil or with sitostanol-ester were compared to a non-enriched control margarine. Sterol intake was between 1.5-3.3 g/d. Two thirds of the soybean oil sterols were esterified to fatty acids.. Unilever Research Laboratory, Vlaardingen, The Netherlands.. One hundred healthy non-obese normocholesterolaemic and mildly hypercholesterolaemic volunteers aged 45+/-12.8 y, with plasma total cholesterol levels below 8 mmol/L at entry.. Plasma lipid, carotenoid and sterol concentrations, blood clinical chemistry and haematology, fatty acid composition of plasma cholesterylesters and food intake.. Ninety-five volunteers completed the study. None of the margarines induced adverse changes in blood clinical chemistry, serum total bile acids or haematology. Plasma total- and LDL-cholesterol concentrations were significantly reduced by 8-13% (0.37-0.44 mmol/L) compared to control for margarines enriched in soybean oil sterol-esters or sitostanol-ester. No effect on HDL-cholesterol concentrations occurred. The LDL- to HDL-cholesterol ratio was reduced by 0.37 and 0.33 units for these margarines, respectively. Effects on blood lipids did not differ between normocholesterolaemic and mildly hypercholesterolaemic subjects. Plasma sitosterol and campesterol levels were significantly higher for the soybean oil sterol margarine and significantly lower for the sitostanol-ester margarine compared to control. Dietary intake was very similar across treatments. The fatty acid composition of plasma cholesterylesters confirmed the good compliance to the treatment. All sterol enriched margarines reduced lipid-standardized plasma alpha- plus beta-carotene levels. Plasma lycopene levels were also reduced but this effect was not significant for all products.. A margarine with sterol-esters from soybean oil, mainly esters from sitosterol, campesterol and stigmasterol, is as effective as a margarine with sitostanol-ester in lowering blood total- and LDL-cholesterol levels without affecting HDL-cholesterol concentrations. Incorporation in edible fat containing products of such substances may substantially reduce the risk of cardiovascular disease in the population.

Topics: Adult; Carotenoids; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Dietary Fats, Unsaturated; Double-Blind Method; Humans; Hypercholesterolemia; Margarine; Middle Aged; Phytosterols; Placebos; Plant Oils; Sitosterols; Soybean Oil

Dietary fibre has been suggested to interfere with endogenous cholesterol synthesis in the liver. Therefore the effects of oat bran on the proportions of cholesterol synthesis precursors (squalene, delta(8-) cholesterol, desmosterol and lathosterol), cholestanol and plant sterols (campesterol and beta-sitosterol) to cholesterol were analysed in serum of 36 hypercholesterolaemic subjects.. A randomized study of eight weeks duration when beta-glucan-rich oat bran (n = 20, subjects) or wheat bran (n = 16) was used as a part of a cholesterol lowering diet. Plant sterols and cholesterol synthesis precursors were analysed from frozen samples afterward.. In the oat-bran group, but not in the wheat bran group, serum total cholesterol declined transiently. The proportions of plant sterols and cholesterol in serum, which reflect cholesterol absorption efficiency were unchanged. However, the proportions of squalene appeared to be transiently increased during the study. Subjects with apolipoprotein E 4 allele had higher serum campesterol and sitosterol levels (suggestive of efficient cholesterol absorption) than those with homozygous apolipoprotein E 3 allele.. Since the cholesterol precursors in serum reflecting endogenous cholesterol synthesis remained almost unchanged the reduction in the serum cholesterol level by oat bran treatment can not be ascribed to an inhibition of the endogenous cholesterol synthesis.

Topics: Adult; Alleles; Apolipoprotein E4; Apolipoproteins E; Avena; Cholesterol; Dietary Fiber; Female; Glucans; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols; Squalene

Effects of small amounts of sitosterol, sitostanol and sitostanol esters (< 1 g/day of free sterols) dissolved in rapeseed oil (RSO) were studied on serum lipids and cholesterol metabolism in patients with primary hypercholesterolemia and different apolipoprotein E phenotypes on an RSO diet. One of the four groups was an RSO-fed control. Serum total and LDL cholesterol reductions were small in different plant sterol-fed groups, tended to be highest in the sitostanol ester group (-7%), but were significantly reduced by about 5% in the combined plant sterol groups. The reductions were -8% in the subjects with epsilon 4 allele and insignificant in those with apo E3/3 phenotype. Cholesterol precursor sterols in serum, markers of cholesterol synthesis, were increased only in the subjects with epsilon 4 allele. Cholesterol absorption was reduced by 7%, being 31% in the subjects with epsilon 4 allele, and fecal elimination of cholesterol was increased, a finding also indicating increased cholesterol synthesis. The changes in cholesterol absorption were related to those in fecal plant sterols (change in dietary intake) and serum total and LDL cholesterol (P = 0.04, 0.01 and 0.05, respectively). Thus, small amounts of dietary plant sterols (< 1 g/day), especially sitostanol esters dissolved in dietary fats, decrease serum total and LDL cholesterol by a proportional decrease in cholesterol absorption which, in turn, is associated with a compensatory increase in cholesterol synthesis. The effects are most consistent in subjects with epsilon 4 allele, but for effective hypocholesterolemic treatment dietary amount of sitostanol ester should exceed 1 g/day.

Topics: Absorption; Adult; Apolipoproteins E; Brassica; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Double-Blind Method; Fatty Acids, Monounsaturated; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Phenotype; Plant Oils; Rapeseed Oil; Sitosterols; Triglycerides

Topics: Absorption; Animals; Arteriosclerosis; Cholesterol; Cholesterol, Dietary; Cholestyramine Resin; Clinical Trials as Topic; Food; Humans; Hypercholesterolemia; Phytosterols; Risk; Sitosterols

The present study was conducted to establish a practical method for measuring non-cholesterol sterols and reference intervals of serum levels.. Healthy subjects (109 men and 151 women), four patients with sitosterolemia, and 10 heterozygous mutation carriers of ABCG5/ABCG8 genes were investigated. Then, three non-cholesterol sterols (sitosterol, campesterol, and lathosterol) of fasting serum samples were measured via a practical and highly sensitive gas chromatography (GC) method with 0.2 µg/mL as the lower limit of quantification. The coefficient of variation (CV) values for within-run reproducibility were 3.06%, 1.89%, and 1.77% for lathosterol, campesterol, and sitosterol, respectively. The CV values for between-run reproducibility were 2.81%, 2.06%, and 2.10% for lathosterol, campesterol, and sitosterol, respectively.. The serum levels of sitosterol and campesterol were significantly higher in women than in men, whereas the serum levels of lathosterol were significantly higher in men than in women. Because of these gender difference, the determination of reference intervals of the three sterol values was performed by considering gender. The reference intervals of sitosterol, campesterol, and lathosterol were 0.99-3.88, 2.14-7.43, and 0.77-3.60 µg/mL in men and 1.03-4.45, 2.19-8.34, and 0.64-2.78 µg/mL in women, respectively. The serum levels of sitosterol and campesterol were higher in patients with sitosterolemia (94.3±47.3 and 66.3±36.6 µg/mL, respectively) than in healthy subjects.. These results demonstrate a practical and highly sensitive GC method to measure non-cholesterol sterol levels and gender-segregated reference intervals of sitosterol, campesterol, and lathosterol in Japanese healthy subjects.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cholesterol; Cholesterol, Dietary; Chromatography, Gas; Female; Humans; Hypercholesterolemia; Intestinal Diseases; Japan; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Middle Aged; Phytosterols; Reference Values; Reproducibility of Results; Sex Factors; Sitosterols

HepG2 cells were incubated with a 16.5:1.7:1 ratio of cholesterol:sitosterol:campesterol (CSC), a ratio of the major sterols observed in the plasma of phytosterolemia patients, or with cholesterol alone in combination with [

Topics: Carbon Radioisotopes; Cholesterol; Cholesterol Esters; Down-Regulation; Gene Expression Profiling; Gene Expression Regulation; Hep G2 Cells; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Models, Biological; Phytosterols; Receptors, LDL; Sitosterols

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.

Topics: Anticholesteremic Agents; ATP Binding Cassette Transporter, Subfamily G, Member 5; Cholesterol; Cholesterol, LDL; Diagnostic Errors; Ezetimibe; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Hyperlipoproteinemia Type II; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Loss of Function Mutation; Middle Aged; Phytosterols; Sitosterols; Treatment Failure

Topics: Cholestanol; Cholesterol; Gas Chromatography-Mass Spectrometry; Humans; Hypercholesterolemia; Intestinal Diseases; Limit of Detection; Lipid Metabolism, Inborn Errors; Phytosterols; Reference Standards; Sitosterols; Xanthomatosis, Cerebrotendinous

Phytosterolemia is a rare genetic disease caused by mutation of the ABCG5/8 gene. Our aim was to elucidate the natural history and homeostasis of phytosterolemia.. We analyzed a Hutterite kindred consisting of 21 homozygotes with phytosterolemia assembled over a period of two decades, all of whom carried the ABCG8 S107X mutation and were treated with ezetimibe.. Most of these subjects were asymptomatic and devoid of clinical stigmata, and this, since they were ascertained primarily by a process of cascade testing, suggests that, relative to its true prevalence, phytosterolemia is a condition of low morbidity. All subjects have responded well to treatment with ezetimibe. Initial (pre-treatment) and post-ezetimibe levels of cholesterol and sitosterol were measured and percentage changes on ezetimibe were calculated. We found initial levels to be inversely related to subjects' ages as were percentage responses to ezetimibe therapy. There was also a direct correlation between initial levels and percentage responses to ezetimibe. Hence on-treatment levels were very uniform.. This evidence of a link with age leads us to propose that an age-related change in cholesterol and sterol homeostasis occurs at puberty in phytosterolemia and that the change is due to high sterol and/or stanol levels causing feedback inhibition of sterol regulatory element-binding protein (SREBP-2) processing. This would explain the well-documented phenomenon of depressed cholesterol synthesis in phytosterolemia. It is also well-known that LDL-receptor activity is increased, and this feasibly explains reduced LDL levels and consequent reduction of plasma cholesterol and sitosterol levels. Downregulated SREBP-2 processing would be expected to also lower proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and this would explain high LDL-receptor activity. The above state could be termed disrupted homeostasis and the alternative, seen mostly in children and characterized by hypercholesterolemia and hypersterolemia, simple homeostasis.

Topics: Adolescent; Adult; Age Factors; Anticholesteremic Agents; Asymptomatic Diseases; ATP Binding Cassette Transporter, Subfamily G, Member 8; Biomarkers; Canada; Child; Child, Preschool; Cholesterol; Ezetimibe; Female; Genetic Predisposition to Disease; Homeostasis; Humans; Hypercholesterolemia; Infant; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Male; Middle Aged; Mutation; Phenotype; Phytosterols; Prevalence; Puberty; Rare Diseases; Risk Factors; Sitosterols; Time Factors; Treatment Outcome; United States; Young Adult

The contribution of extra virgin olive oil (EVOO) macro- and micro-constituents in heart oxidative and inflammatory status in a hypercholesterolemic rat model was evaluated. Fatty acid profile as well as α-tocopherol, sterol, and squalene content was identified directly in rat hearts to distinguish the effect of individual components or to enlighten the potential synergisms.. Oils and oil-products with discernible lipid and polar phenolic content were used. Wistar rats were fed a high-cholesterol diet solely, or supplemented with one of the following oils, i.e., EVOO, sunflower oil (SO), and high-oleic sunflower oil (HOSO) or oil-products, i.e., phenolics-deprived EVOO [EVOO(-)], SO enriched with the EVOO phenolics [SO(+)], and HOSO enriched with the EVOO phenolics [HOSO(+)]. Dietary treatment lasted 9 weeks; at the end of the intervention blood and heart samples were collected.. High-cholesterol-diet-induced dyslipidemia was shown by increase in serum total cholesterol, low-density lipoprotein cholesterol, and triacylglycerols. Dyslipidemia resulted in increased malondialdehyde (MDA) and tumor necrosis factor-α (TNF-α) levels, while glutathione and interleukin 6 levels remained unaffected in all intervention groups. Augmentation observed in MDA and TNF-α was attenuated in EVOO, SO(+), and HOSO(+) groups. Heart squalene and cholesterol content remained unaffected among all groups studied. Heart α-tocopherol was determined by oil α-tocopherol content. Variations were observed for heart β-sitosterol, while heterogeneity was reported with respect to heart fatty acid profile in all intervention groups.. Overall, we suggest that the EVOO-polar phenolic compounds decreased MDA and TNF-α in hearts of cholesterol-fed rats.

Topics: alpha-Tocopherol; Animals; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Diet; Diet, High-Fat; Dyslipidemias; Fatty Acids; Glutathione; Hypercholesterolemia; Inflammation; Interleukin-6; Male; Malondialdehyde; Olive Oil; Oxidative Stress; Phenols; Plant Oils; Rats; Rats, Wistar; Sitosterols; Sunflower Oil; Triglycerides; Tumor Necrosis Factor-alpha

The dynamics of cholesterol homeostasis and the development of cardiovascular disease (CVD) are complex and multifactorial, to which adds individual variability in the proportion of cholesterol from exogenous versus endogenous sources. The aim of this study was to undertake the first characterization of cholesterol absorption and synthesis profiles in Portuguese hypercholesterolemic adults through the quantification of surrogate markers, and the analysis of the predictive value of age and sex on the cholesterol homeostasis biomarkers.. Serum samples for the measurement of lipid profiles and cholesterol homeostasis markers were obtained for 100 men and 112 women, aged 30-65, with TC ≥ 5.2 mmol/L (~200mg/dL) and/or LDL-C ≥ 2.6 mmol/L (~100mg/dL), none of whom were on any lipid-lowering therapy.. Overall, sex-specific significant differences were observed in the cholesterol homeostasis markers and lipid profiles; women had lower cholesterol synthesis marker concentrations (P<0.01 for lathosterol) and lipid parameters (except for HDL-C concentrations). Age-related significant differences were also found, including higher concentrations of cholesterol absorption markers in association with increasing age.. In our study, the predictors of higher levels of cholesterol absorption markers were higher age and female gender.

Topics: Adult; Age Factors; Aged; Biomarkers; Cholestanol; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Cross-Sectional Studies; Desmosterol; Diet; Female; Homeostasis; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Portugal; Sex Factors; Sitosterols; Triglycerides

The type 1 cholecystokinin receptor (CCK1R) mediates the actions of CCK to support nutritional homeostasis, including post-cibal satiety. However, elevated levels of membrane cholesterol, such as have been observed in metabolic syndrome, interfere with CCK stimulus-activity coupling at the CCK1R, thereby disrupting this important servomechanism. We hypothesize that reversal of the negative impact of cholesterol on this receptor could be useful in the management of obesity.. We have studied the effects of β-sitosterol, a phytosterol structurally related to cholesterol, on CCK receptor function. This included CCK binding and biological activity at wild type CCK1R and CCK2R, as well as at CCK1R in a high cholesterol environment, and at a CCK1R mutant, Y140A, which mimics the behavior of wild type receptor in high cholesterol.. β-sitosterol (100 μM and 10 μM) significantly improved the defective signaling of the CCK1R present in high cholesterol (p < 0.05), without affecting CCK binding affinity. This effect was absent at the CCK1R present in a normal cholesterol environment, as well as at the structurally-related CCK2R. Furthermore, the cholesterol-insensitive Y140A mutant of CCK1R was resistant to the effects of β-sitosterol.. These data suggest that β-sitosterol affects CCK1R function in high cholesterol by competing with cholesterol at a receptor cholesterol-binding site and may shift its conformation toward normal. This phytosterol extends our understanding of the structure-activity relationships for developing a drug that can target the external surface of CCK1R. Since the concentrations of β-sitosterol shown to be effective in this study are similar to serum levels of this compound achievable during oral administration, it may be worthwhile to study possible beneficial effects of β-sitosterol in metabolic syndrome.

Topics: Animals; CHO Cells; Cricetulus; Gene Expression Regulation; Hypercholesterolemia; Hypolipidemic Agents; Receptor, Cholecystokinin A; Signal Transduction; Sitosterols

The present study (i) compared plasma cholesterol-raising activity of free cholesterol (FC) with that of cholesteryl palmitate (CP) and (ii) examined plasma cholesterol-reducing activity of β-sitosterol in FC-induced and CP-induced hypercholesterolemia. Male hamsters were divided into five groups and fed one of the five diets containing no cholesterol (NC), 2.6mmol cholesterol (C), 2.6mmol cholesterol plus 2.6mmol β-sitosterol (C+S), 2.6mmol cholesteryl palmitate (CP), and 2.6mmol CP plus 2.6mmol β-sitosterol (CP+S), respectively, for 8weeks. Hamsters fed diet C had plasma TC of 317.5mg/dl whereas hamsters fed diet CP has plasma TC of 281.3mg/dl. β-Sitosterol reduced plasma TC by 17.4% and 11.6%, respectively, in FC-induced and CP-induced hypercholesterolemia (not significant). It was concluded that plasma cholesterol-raising activity of dietary cholesterol was a function of its chemical forms in diet, and β-sitosterol could similarly suppress the hypercholesterolemia induced by both dietary FC and CP.

Topics: Animals; Cholesterol Esters; Cholesterol, Dietary; Cholesterol, HDL; Cricetinae; Feces; Hypercholesterolemia; Liver; Male; Mesocricetus; Sitosterols; Triglycerides

Cholesterol analogs can be used to treat hypercholesterolemia. The present study was to test the effects of cholesteryl 3β-ethoxy (CE) and cholesteryl 3β-methoxy (CM) on plasma total cholesterol (TC) compared with that of β-sitosterol (SI) in hamsters fed a high cholesterol diet. CM and CE are the methoxy and ethoxy analogs of cholesterol while SI is an analog of cholesterol having an additional ethyl group on the side chain. Results showed that SI at a dose of 0.1% could effectively reduce plasma TC by 18%. The analysis of sterols in the plasma and liver did not detect the presence of SI, proving that it was poorly absorbed in the intestine. In contrast, both CE and CM had no effect on plasma TC. However, CE and CM were found to accumulate in both plasma and liver, indicating that they could be well absorbed in the intestine. It was therefore concluded that analogs having different side chains possessed plasma TC-lowering activity, while analogs or derivatives on the hydroxyl group had no hypocholesterolemic activity.

Topics: Animals; Anticholesteremic Agents; Cholesterol; Cholesterol, Dietary; Cricetinae; Diet, High-Fat; Feces; Hypercholesterolemia; Liver; Male; Organ Size; Sitosterols; Sterols

The efficacy and safety of plant stanols added to food products as serum cholesterol lowering agents have been demonstrated convincingly, but their effects on cholesterol metabolism and on serum non-cholesterol sterols is less evaluated. The aim of this study was to assess the validity of serum non-cholesterol sterols and squalene as bioindices of cholesterol synthesis and absorption, and to examine how the individual serum non-cholesterol sterols respond to consumption of plant stanols.. We collected all randomized, controlled plant stanol ester (STAEST) interventions in which serum cholestanol, plant sterols campesterol and sitosterol, and at least two serum cholesterol precursors had been analysed. According to these criteria, there was a total of 13 studies (total 868 subjects without lipid-lowering medication; plant stanol doses varied from 0.8 to 8.8 g/d added in esterified form; the duration of the studies varied from 4 to 52 weeks). Serum non-cholesterol sterols were assayed with gas-liquid chromatography, cholesterol synthesis with the sterol balance technique, and fractional cholesterol absorption with the dual continuous isotope feeding method.. The results demonstrated that during the control and the STAEST periods, the serum plant sterol/cholesterol- and the cholestanol/cholesterol-ratios reflected fractional cholesterol absorption, and the precursor sterol/cholesterol-ratios reflected cholesterol synthesis. Plant sterol levels were dose-dependently reduced by STAEST so that 2 g of plant stanols reduced serum campesterol/cholesterol-ratio on average by 32%. Serum cholestanol/cholesterol-ratio was reduced less frequently than those of the plant sterols by STAEST, and the cholesterol precursor sterol ratios did not change consistently in the individual studies emphasizing the importance of monitoring more than one surrogate serum marker.. Serum non-cholesterol sterols are valid markers of cholesterol absorption and synthesis even during cholesterol absorption inhibition with STAEST. Serum plant sterol concentrations decrease dose-dependently in response to plant stanols suggesting that the higher the plant stanol dose, the more cholesterol absorption is inhibited and the greater the reduction in LDL cholesterol level is that can be achieved.. Clinical Trials Register # NCT00698256 [Eur J Nutr 2010, 49:111-117].

Topics: Adult; Aged; Cholestanol; Cholesterol; Female; Humans; Hypercholesterolemia; Hypolipidemic Agents; Male; Middle Aged; Phytosterols; Randomized Controlled Trials as Topic; Sitosterols; Sterols; Young Adult

Obesity is associated with increased systemic and airway oxidative stress, which may result from a combination of adipokine imbalance and antioxidant defenses reduction. Obesity-mediated oxidative stress plays an important role in the pathogenesis of dyslipidemia, vascular disease, and nonalcoholic hepatic steatosis. The antidyslipidemic activity of pigeon pea were evaluated by high-fat diet (HFD) hamsters model, in which the level of high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), and total triglyceride (TG) were examined. We found that pigeon pea administration promoted cholesterol converting to bile acid in HFD-induced hamsters, thereby exerting hypolipidemic activity. In the statistical results, pigeon pea significantly increased hepatic carnitine palmitoyltransferase-1 (CPT-1), LDL receptor, and cholesterol 7α-hydroxylase (also known as cytochrome P450 7A1, CYP7A1) expression to attenuate dyslipidemia in HFD-fed hamsters; and markedly elevated antioxidant enzymes in the liver of HFD-induced hamsters, further alleviating lipid peroxidation. These effects may attribute to pigeon pea contained large of unsaturated fatty acids (UFA; C18:2) and phytosterol (β-sitosterol, campesterol, and stigmasterol). Moreover, the effects of pigeon pea on dyslipidemia were greater than β-sitosterol administration (4%), suggesting that phytosterone in pigeon pea could prevent metabolic syndrome.

Topics: Animals; Antioxidants; Cajanus; Carnitine O-Palmitoyltransferase; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, HDL; Cholesterol, LDL; Chromatography, High Pressure Liquid; Cricetinae; Diet, High-Fat; Disease Models, Animal; Hypercholesterolemia; Lipid Peroxidation; Liver; Male; Obesity; Oxidative Stress; Phytosterols; Receptors, LDL; Sitosterols; Stigmasterol; Triglycerides

We investigated the behaviour of non-cholesterol sterols, surrogate markers of cholesterol absorption (campesterol and sitosterol) and synthesis (lathosterol), in primary hyperlipemias.. We studied 53 patients with polygenic hypercholesterolemia (PH), 38 patients with familial combined hyperlipemia (FCH), and 19 age- and sex-matched healthy control subjects. In all participants, plasma sitosterol, campesterol and lathosterol were determined by gas chromatography coupled to mass spectrometry. To correct for the effect of plasma lipid levels, non-cholesterol sterol concentrations were adjusted for plasma cholesterol (10² μmol/mmol cholesterol). Patients with FCH were more frequently men, and had higher body mass index (BMI), fasting glucose, insulin and HOMA-IR. Lathosterol was higher in FCH than in pH or controls (p < 0.05). Campesterol was significantly lower in FCH (p < 0.05), while no differences were found between pH and controls. Sitosterol displayed higher values in pH compared to FCH (p < 0.001) and controls (p < 0.05). Spearman's rank correlations showed positive correlations of lathosterol with BMI, waist circumference, HOMA-IR, triglycerides, apoprotein B, and a negative one with HDL-cholesterol. Sitosterol had a negative correlation with BMI, waist circumference, HOMA-IR, triglycerides, and a positive one with HDL-cholesterol and apoprotein AI. Multivariate regression analyses showed that cholesterol absorption markers predicted higher HDL-cholesterol levels, while HOMA-IR was a negative predictor of sitosterol and BMI a positive predictor of lathosterol.. Our findings suggest the occurrence of an increased cholesterol synthesis in FCH, and an increased cholesterol absorption in pH. Markers of cholesterol synthesis cluster with clinical and laboratory markers of obesity and insulin resistance.

Topics: Adult; Aged; Biomarkers; Case-Control Studies; Cholesterol; Female; Gas Chromatography-Mass Spectrometry; Humans; Hypercholesterolemia; Hyperlipidemia, Familial Combined; Intestinal Absorption; Italy; Linear Models; Male; Middle Aged; Multifactorial Inheritance; Multivariate Analysis; Phytosterols; Risk Assessment; Risk Factors; Sitosterols; Sterols; Young Adult

Phytosterolemia is a rare autosomal recessive disease of plant sterol metabolism, the pathophysiological features of which are high plasma levels of plant sterols and xanthomatosis caused by mutations of ABCG5 and ABCG8 genes, and the combination of hemolysis and macrothrombocytopenia is an unusual clinical manifestation. All the patients of the 3 unrelated phytosterolemia first presented with prominent macrothrombocytopenia and stomatocytosis. They were either homozygous or compound heterozygous for ABCG5/ABCG8 gene mutations and had significantly elevated serum plant sterols levels quantified using high-performance liquid chromatography. The in vitro study demonstrated that sitosterol can cause changes in shape and osmotic fragility of red blood cells. These findings suggest that macrothrombocytopenia and stomatocytosis could be initial and main features in some patients with phytosterolemia and that serum phytosterols and relevant genes should be analyzed in patients whose macrothrombocytopenia and/or stomatocytosis are unexplained, especially whose parents are of consanguineous marriage.

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Erythrocytes, Abnormal; Female; Heterozygote; Homozygote; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Mutation; Osmotic Fragility; Pedigree; Phytosterols; Sitosterols; Xanthomatosis

Plant sterols such as sitosterol and campesterol are frequently applied as functional food in the prevention of atherosclerosis. Recently, it became clear that plasma derived plant sterols accumulate in murine brains. We questioned whether plant sterols in the brain are associated with alterations in brain cholesterol homeostasis and subsequently with brain functions. ATP binding cassette (Abc)g5-/- mice, a phytosterolemia model, were compared to Abcg5+/+ mice for serum and brain plant sterol accumulation and behavioral and cognitive performance. Serum and brain plant sterol concentrations were respectively 35-70-fold and 5-12-fold increased in Abcg5-/- mice (P<0.001). Plant sterol accumulation resulted in decreased levels of desmosterol (P<0.01) and 24(S)-hydroxycholesterol (P<0.01) in the hippocampus, the brain region important for learning and memory functions, and increased lanosterol levels (P<0.01) in the cortex. However, Abcg5-/- and Abcg5+/+ displayed no differences in memory functions or in anxiety and mood related behavior. The swimming speed of the Abcg5-/- mice was slightly higher compared to Abcg5+/+ mice (P<0.001). In conclusion, plant sterols in the brains of Abcg5-/- mice did have consequences for brain cholesterol metabolism, but did not lead to an overt phenotype of memory or anxiety related behavior. Thus, our data provide no contra-indication for nutritional intake of plant sterol enriched nutrition.

Topics: Affect; Animals; Anxiety Disorders; Atherosclerosis; ATP-Binding Cassette Transporters; Behavior, Animal; Brain; Cholesterol; Desmosterol; Diet; Hippocampus; Homeostasis; Hydroxycholesterols; Hypercholesterolemia; Intestinal Diseases; Lanosterol; Lipid Metabolism, Inborn Errors; Male; Maze Learning; Memory; Mice; Mice, Mutant Strains; Phytosterols; Sitosterols; Stigmasterol

Whole-genome sequencing is a potentially powerful tool for the diagnosis of genetic diseases. Here, we used sequencing-by-ligation to sequence the genome of an 11-month-old breast-fed girl with xanthomas and very high plasma cholesterol levels (1023 mg/dl). Her parents had normal plasma cholesterol levels and reported no family history of hypercholesterolemia, suggesting either an autosomal recessive disorder or a de novo mutation. Known genetic causes of severe hypercholesterolemia were ruled out by sequencing the responsible genes (LDLRAP, LDLR, PCSK9, APOE and APOB), and sitosterolemia was ruled out by documenting a normal plasma sitosterol:cholesterol ratio. Sequencing revealed 3 797 207 deviations from the reference sequence, of which 9726 were nonsynonymous single-nucleotide substitutions. A total of 9027 of the nonsynonymous substitutions were present in dbSNP or in 21 additional individuals from whom complete exonic sequences were available. The 699 novel nonsynonymous substitutions were distributed among 604 genes, 23 of which were single-copy genes that each contained 2 nonsynonymous substitutions consistent with an autosomal recessive model. One gene, ABCG5, had two nonsense mutations (Q16X and R446X). This finding indicated that the infant has sitosterolemia. Thus, whole-genome sequencing led to the diagnosis of a known disease with an atypical presentation. Diagnosis was confirmed by the finding of severe sitosterolemia in a blood sample obtained after the infant had been weaned. These findings demonstrate that whole-genome (or exome) sequencing can be a valuable aid to diagnose genetic diseases, even in individual patients.

Topics: Base Sequence; Cholesterol; Female; Genome; Humans; Hypercholesterolemia; Infant; Pedigree; Sequence Analysis, DNA; Sitosterols

A newly developed high-performance liquid chromatography/mass spectrometry (HPLC/MS) method has been successfully used to analyze plasma concentrations of various phytosterols (cholestanol and beta-sitosterol) and cholesterol metabolites (desmosterol and lathosterol). This was based on an unusual solvent combination of water/methanol vs. methanol/acetone/n-hexane applied on a Purospher Star RP-18e (125 x 2 mm, 3 microm) column, which proved excellent for the separation, identification and quantification of plasma sterols. Simple solid-phase extraction preparation of plasma samples was performed, followed by the developed fast and robust HPLC separation. Results on four groups of people were compared, those with low, normal and high plasma cholesterol levels and those with high cholesterol levels on statin therapy, and the results were evaluated using linear discriminant analysis (LDA). Variable selection for LDA was achieved using backward removal selection. Highly discriminatory variables were the ratios of desmosterol to sitosterol and of lathosterol to total plasma cholesterol. The latter ratio was also excellent for distinguishing subjects on statin therapy. The success rate of classification was 100%. The present pilot study shows the potential of HPLC/MS analysis and chemometrics for studying cholesterol-related disorders and warrants future full-scale medical study.

Topics: Cholestanol; Cholesterol; Chromatography, High Pressure Liquid; Desmosterol; Discriminant Analysis; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Mass Spectrometry; Pilot Projects; Sitosterols; Sterols

The ratio of serum plant sterols to cholesterol is positively correlated with the fractional cholesterol absorption, whereas serum precursors of cholesterol synthesis are positively correlated with cholesterol synthesis. Recently, two ABC (ATP-binding cassette) transporters, ABCG5 and ABCG8, have been described as playing an important role in the absorption and excretion of sterols. In the present study, we tested the hypothesis that genetic variation in ABCG5/ABCG8 influences the levels of serum plant sterol (sitosterol) and cholesterol precursor (lathosterol) in Japanese primary hypercholesterolaemic patients (n = 100). We identified a novel mutation [859T/C (C287R)] and a novel polymorphism [1285A/G (M429V)] at the ABCG5/ABCG8 loci, as well as four polymorphisms reported previously [1810C/G (Q604E), 161G/A (C54Y), 1199C/A (T400K) and 1895C/T (A632V)]. In carriers of the novel M429V variant, the serum level of sitosterol and the sitosterol/cholesterol ratio were significantly higher than those in non-carriers (3.64 compared with 2.56 microg/ml, and 1.45 microg/mg compared with 1.00 microg/mg respectively; P < 0.01 for both), and serum lathosterol tended to be lower (1.95 microg/ml compared with 3.03 microg/ml; P = 0.08), whereas no significant difference was observed in other lipid profiles. These four polymorphisms (1810C/G, 161G/A, 1199C/A and 1285A/G) generated six haplotypes, and the C/G/C/G haplotype was significantly associated with a higher sitosterol level and sitosterol/cholesterol ratio compared with the other five haplotypes (P < 0.05 for both). We conclude that, in 8% of patients with hypercholesterolaemia, the novel ABCG8 M429V variant was associated with higher cholesterol absorption efficiency. Future studies should investigate whether these findings have implications for the optimal cholesterol-lowering drug treatment in hypercholesterolaemic patients.

Topics: Adult; Aged; Aged, 80 and over; ATP-Binding Cassette Transporters; Biomarkers; Cholesterol; Female; Genetic Markers; Heterozygote; Humans; Hypercholesterolemia; Intestinal Absorption; Japan; Male; Middle Aged; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Sitosterols

Niemann-Pick C1 Like 1 (NPC1L1) is a protein localized in jejunal enterocytes that is critical for intestinal cholesterol absorption. The uptake of intestinal phytosterols and cholesterol into absorptive enterocytes in the intestine is not fully defined on a molecular level, and the role of NPC1L1 in maintaining whole body cholesterol homeostasis is not known. NPC1L1 null mice had substantially reduced intestinal uptake of cholesterol and sitosterol, with dramatically reduced plasma phytosterol levels. The NPC1L1 null mice were completely resistant to diet-induced hypercholesterolemia, with plasma lipoprotein and hepatic cholesterol profiles similar to those of wild type mice treated with the cholesterol absorption inhibitor ezetimibe. Cholesterol/cholate feeding resulted in down-regulation of intestinal NPC1L1 mRNA expression in wild type mice. NPC1L1 deficiency resulted in up-regulation of intestinal hydroxymethylglutaryl-CoA synthase mRNA and an increase in intestinal cholesterol synthesis, down-regulation of ABCA1 mRNA, and no change in ABCG5 and ABCG8 mRNA expression. NPC1L1 is required for intestinal uptake of both cholesterol and phytosterols and plays a major role in cholesterol homeostasis. Thus, NPC1L1 may be a useful drug target for the treatment of hypercholesterolemia and sitosterolemia.

Topics: Animals; Biological Transport; Cholesterol; Cholesterol, Dietary; Homeostasis; Hypercholesterolemia; Intestinal Absorption; Intestinal Mucosa; Lipoproteins; Liver; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phytosterols; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sitosterols; Triglycerides

Because dietary fat appears to be an effective vehicle for dispensing plant sterols into the diet, a special plant-sterol-containing ingredient has recently been developed. This ingredient is a plant sterol suspension in oil in which the sterols are in microcrystalline form. The objective of the present study was to analyse the cholesterol-lowering effects and safety of two different plant sterol preparations, an orally administered microcrystalline plant sterol suspension (MPS) in rapeseed oil and a powdered plant sterol supplement, in obese Zucker rats. Dietary plant sterol supplements (0.5%, w/w) were given concurrently with a high cholesterol diet (HCD, 1% cholesterol and 18% fat, w/w). No significant changes in serum triglyceride, blood glucose, serum glutamate oxaloacetic transaminase and glutamic pyruvic transaminase values or body and liver weights were observed. The powdered plant sterol supplement lowered the serum cholesterol by 25% (P < 0.05) and the MPS diet by 35% (P < 0.001) compared with HCD by the end of the 12-week experiment. Interestingly, the plant sterol supplements also produced a marked reduction in serum ubiquinone levels, suggesting a possible effect on isoprene synthesis. Unlike the powdered plant sterol, both MPS and plain rapeseed oil decreased the serum baseline diene conjugation values, suggesting that they protect against oxidative stress-induced lipid peroxidation in rats. This lipid peroxidation diminishing effect is probably due to some antioxidative components in rapeseed oil. These findings indicate that an unesterified plant sterol, such as the microcrystalline suspension in oil, effectively prevents cholesterol absorption in obese Zucker rats.

Topics: Administration, Oral; Animals; Chemistry, Pharmaceutical; Cholesterol, Dietary; Fatty Acids, Monounsaturated; Female; Hypercholesterolemia; Hypolipidemic Agents; Intestinal Absorption; Lipid Peroxidation; Obesity; Phytosterols; Plant Oils; Powders; Rapeseed Oil; Rats; Rats, Zucker; Sitosterols

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.. 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.. 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.

Topics: Aged; Anticholesteremic Agents; Bile Acids and Salts; Cholesterol; Cholesterol, Dietary; Cholesterol, HDL; Cholesterol, LDL; Cholestyramine Resin; Coronary Artery Disease; Diet, Fat-Restricted; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Intestinal Absorption; Male; Simvastatin; Sitosterols; Treatment Outcome

Low birth weight may be associated with high levels of cholesterol in later life through genetic factors that affect both birth weight and cholesterol metabolism. Alterations in cholesterol synthesis and absorption may play an important role in this association. We examined birth weight and plasma ratios of a precursor of cholesterol, lathosterol (an estimate of cholesterol synthesis), and plant sterols, campesterol and beta-sitosterol (estimates of cholesterol absorption), to cholesterol in 53 dizygotic and 58 monozygotic adolescent twin pairs. After adjustment for current weight, birth weight was not associated with the ratios of lathosterol, campesterol, and beta-sitosterol either in the overall sample [+0.07 micro mol/mmol/kg (95% confidence interval: -0.11 to 0.25), p = 0.5; +0.02 micro mol/mmol/kg (-0.33 to 0.37), p = 0.9; and -0.04 micro mol/mmol/kg (-0.23 to 0.15), p = 0.8, respectively] or in the intrapair analysis in dizygotic twins [+0.27 micro mol/mmol/kg (-0.28 to 0.82), p = 0.3; -0.03 micro mol/mmol/kg (-1.07 to 1.01), p = 1.0; and +0.04 micro mol/mmol/kg (-0.56 to 0.64), p = 0.9, respectively] or in the intrapair analysis in monozygotic twins [+0.54 micro mol/mmol/kg (-0.09 to 1.18), p = 0.09; -0.60 micro mol/mmol/kg (-1.59 to 0.39), p = 0.2; and -0.43 micro mol/mmol/kg (-0.99 to 0.14), p = 0.14, respectively]. Plasma levels of lathosterol, campesterol, and beta-sitosterol, which are indicators of cholesterol synthesis and absorption, thus do not explain the association of low birth weight with high levels of total and LDL cholesterol. As an alternative hypothesis, we suggest that a decrease in cholesterol clearance may play an important role.

Topics: Absorption; Adolescent; Biomarkers; Birth Weight; Cholesterol; Diseases in Twins; Female; Humans; Hypercholesterolemia; Infant, Low Birth Weight; Infant, Newborn; Male; Phytosterols; Risk Factors; Sitosterols; Twins, Dizygotic; Twins, Monozygotic

This paper describes a novel method of producing a microcrystalline oral suspension containing beta-sitosterol in oil for the treatment of hypercholesterolaemia. beta-Sitosterol pseudopolymorphs with different water contents were crystallized from acetone and acetone-water solutions. Structural analyses of the crystals were performed by Karl-Fisher titration, thermogravimetric analyses, X-ray diffraction and near infrared spectroscopy. The suspensions studied were composed of different concentrations of beta-sitosterol, oil and water. Suspensions were prepared by crystallization of hot concentrated solution of beta-sitosterol in oil by cooling with simultaneous agitation and water addition. The structural analyses of the suspensions were performed by X-ray diffraction, near infrared spectroscopy and optical microscopy. The viscosity of the suspensions was analysed as a function of shear stress. beta-Sitosterol was observed to exist in three different forms: anhydrous, hemihydrated and monohydrated crystals. By changing both the beta-sitosterol and the water concentration of the suspension, the crystal size and shape could be controlled. Addition of water resulted in the formation of monohydrated needle-shaped crystals instead of platy-like anhydrous crystals. Needle-shaped particles formed structured suspensions with shear thinning behaviour. By increasing the volume fraction of solid particles in suspension by increasing the water and/or sterol concentration, the viscosity increased. A high sterol concentration resulted in high supersaturation and thus formation of small crystals.

Topics: Administration, Oral; Chemistry, Pharmaceutical; Crystallization; Hypercholesterolemia; Hypolipidemic Agents; Oils; Rheology; Sitosterols; Spectroscopy, Near-Infrared; Suspensions; Technology, Pharmaceutical; Thermogravimetry; X-Ray Diffraction

Topics: ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; ATP-Binding Cassette Transporters; Cholesterol, Dietary; Humans; Hypercholesterolemia; Lipoproteins; Mutation; Sitosterols

Topics: Alcohol Drinking; Cholesterol; Dietary Fiber; Female; Garlic; Humans; Hypercholesterolemia; Male; Nuts; Plants, Medicinal; Sitosterols; Soybean Proteins

We investigated the effect of cholesterol feeding on plasma cholesterol concentrations, hepatic activities and mRNA levels of HMG-CoA reductase and cholesterol 7 alpha-hydroxylase and hepatic LDL receptor function and mRNA levels in 23 New Zealand White (NZW) and 17 Watanabe heritable hyperlipidemic (WHHL) rabbits. Plasma cholesterol concentrations were 9.9 times greater in WHHL than NZW rabbits and rose significantly in both groups when cholesterol was fed. Baseline liver cholesterol levels were 50% higher but rose only 26% in WHHL as compared with 3.6-fold increase with the cholesterol diet in NZW rabbits. In both rabbit groups, hepatic total HMG-CoA reductase activity was similar and declined > 60% without changing enzyme mRNA levels after cholesterol was fed. In NZW rabbits, cholesterol feeding inhibited LDL receptor function but not mRNA levels. As expected, receptor-mediated LDL binding was reduced in WHHL rabbits. Hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels were 2.8 and 10.4 times greater in NZW than WHHL rabbits. Unexpectedly, cholesterol 7 alpha-hydroxylase activity was reduced 53% and mRNA levels were reduced 79% in NZW rabbits with 2% cholesterol feeding. These results demonstrate that WHHL as compared with NZW rabbits have markedly elevated plasma and higher liver cholesterol concentrations, less hepatic LDL receptor function, and very low hepatic cholesterol 7 alpha-hydroxylase activity and mRNA levels. Feeding cholesterol to NZW rabbits increased plasma and hepatic concentrations greatly, inhibited LDL receptor-mediated binding, and unexpectedly suppressed cholesterol 7 alpha-hydroxylase activity and mRNA to minimum levels similar to WHHL rabbits. Dietary cholesterol accumulates in the plasma of NZW rabbits, and WHHL rabbits are hypercholesterolemic because reduced LDL receptor function is combined with decreased catabolism of cholesterol to bile acids.

Topics: Alanine Transaminase; Alkaline Phosphatase; Animals; Bile Acids and Salts; Blotting, Northern; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Cholesterol, Dietary; Dose-Response Relationship, Drug; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Lipoproteins, LDL; Liver; Protein Binding; Rabbits; Receptors, LDL; RNA, Messenger; Sitosterols

The aim of the present study was to investigate the effect of the hydroxymethylglutaryl (HMG)-CoA reductase inhibitor lovastatin on some aspects of cholesterol metabolism in cholesterol-fed rabbits. The plasma cholesterol concentration was markedly lower in lovastatin-treated rabbits (6 mg/rabbit/day) compared to controls after 36 days of cholesterol-feeding (x +/- S.E.) (19 +/- 4 mmol/l, n = 9 versus 153 +/- 17 mmol/l, n = 7) (P < 0.00001). Intestinal absorption of cholesterol in such rabbits was reduced by 15% in lovastatin-treated rabbits (n = 21) compared to controls (n = 18) (P < 0.025). The results suggest that the hypocholesterolaemic effect of lovastatin in cholesterol-fed rabbits is associated with a decreased intestinal absorption of cholesterol.

Topics: Animals; Cholesterol; Cholesterol, Dietary; Hypercholesterolemia; Intestinal Absorption; Lovastatin; Male; Rabbits; Sitosterols

Rapeseed oil fed to 24 hypercholesterolemic patients (50 g/day) reduced serum cholesterol (-8.5%) and cholestanol concentrations but increased those of campesterol and sitosterol. Continuation of rapeseed oil alone or with added sitosterol (625 mg/day) or sitostanol (630 mg/day) had no further effect on serum cholesterol. Rapeseed oil with sitosterol increased further its own proportion to cholesterol in serum but reduced that of campesterol while rapeseed oil with sitostanol reduced the proportions of both sitosterol and campesterol proportionately to the pretreatment values. The changes in the campesterol and sitosterol proportions were negatively and positively related to each other during the sitosterol and sitostanol additions, respectively. Thus, concentrations of unsaturated plant sterols in serum reflect their dietary intakes, saturated plant sterols are virtually not absorbed, plant sterols interfere with absorption of unsaturated structurally different plant sterols and cholestanol, and plant sterol-induced reduction of sterol absorption may be positively related to absorption efficiency of sterols.

Topics: Adult; Body Weight; Brassica; Cholesterol; Dietary Fats; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Plant Oils; Sitosterols

In two inbred strains of rabbits with high or low response of plasma cholesterol to dietary saturated versus polyunsaturated fatty acids, the efficiency of intestinal cholesterol absorption was measured. The feeding of a cholesterol-free purified diet containing saturated fatty acids in the form of coconut fat, when compared with a diet containing corn oil as polyunsaturated fatty acids, did not influence the efficiency of cholesterol absorption in the two rabbit strains. Irrespective of the dietary fat source, the hyperresponsive rabbits absorbed cholesterol more efficiently. It is concluded that the hypercholesterolemic effect of dietary coconut fat versus corn oil is not exerted by influencing cholesterol absorption.

Topics: Animals; Body Weight; Cholesterol; Cholesterol, Dietary; Coconut Oil; Cocos; Corn Oil; Dietary Fats; Feeding Behavior; Hypercholesterolemia; Intestinal Absorption; Liver; Male; Plant Oils; Rabbits; Sitosterols; Species Specificity

A group of 28 patients with primary hyperlipoproteinaemia [19X lipoprotein (LP) type IIA, 8X type IIB and 1X a normolipidaemic patient with concurrent hyperapoB lipoproteinaemia] were given for a period of three weeks a dietetic preparation containing phytosterols - 12 g/day. This led to a significant drop of total cholesterol and LDL-cholesterol in plasma. The cholesterol concentration in HDL and both its fractions increased, the differences however were not significant. The triglyceride levels did not change. There was a significant drop of the apolipoprotein B (apo-B) concentration in LDL, the apo-A-I in plasma did not change. There was a significant drop of atherogenic indexes TC/HDL-C, LDL-C/HDL-C and apo-B/-A-I. During investigation of the LCAT activity the authors observed a significant rise of the fractional esterification rate associated with a highly significant drop of the free cholesterol concentration in plasma as a result of treatment. Discrimination analysis of parameters of the lipoprotein metabolism and the patients' body weight before treatment helps to assess a function by means of which it is possible in 92.3% of the subjects to predict the success of treatment before the administration of beta-sitosterol.

Topics: Female; Humans; Hypercholesterolemia; Lipids; Male; Middle Aged; Sitosterols

Platelets from rats with diet-induced or genetically determined hypercholesterolemia are hypersensitive to thrombin through a pathway that is independent of the effects of released ADP or formation of thromboxane A2. We examined production of inositol phosphates by platelets from these hypercholesterolemic rats to determine whether the enhanced responsiveness to thrombin is associated with increased production of inositol trisphosphate (IP3). The opportunity to study rats with hypercholesterolemia determined genetically or induced by diet makes it possible to determine whether any differences in inositol phosphate production are caused by hypercholesterolemia alone rather than to any other effect of the diet used to induce hypercholesterolemia. Platelets were prelabeled with [3H]inositol so that increases in inositol phosphates (IP, IP2, and IP3) upon stimulation with thrombin could be assessed by measuring the amount of label in these compounds. Platelets were preincubated with CP/CPK, to inhibit effects of released ADP, and aspirin, to inhibit formation of thromboxane A2/endoperoxides. In platelets from rats with either form of hypercholesterolemia, the percentage increase in labeling of IP3 was significantly greater 30 seconds after stimulation with low concentrations of thrombin than in platelets from control rats. Increased IP3 formation in platelets from hypercholesterolemic rats indicates that there is increased activity of a pathway(s) leading to IP3 formation and that this may be a mechanism responsible for the thrombin-induced hypersensitivity of these platelets.

Topics: Animals; Aspirin; Blood Platelets; Cholesterol, Dietary; Creatine Kinase; Hypercholesterolemia; Inositol; Inositol Phosphates; Kinetics; Male; Phosphocreatine; Platelet Aggregation; Rats; Rats, Inbred Strains; Sitosterols; Thrombin

The hypocholesterolaemic mechanism of activated charcoal was studied in seven patients with primary hypercholesterolaemia. The reduction of serum cholesterol was correlated with the serum concentrations of cholesterol precursors and of two plant sterols. Activated charcoal, 8 g t.i.d. for 4 weeks, reduced serum concentration of total cholesterol by 27% (P less than 0.01). The effect was accompanied by a moderate elevation (P less than 0.05) in serum squalene and desmosterol concentrations and by a marked increase (up to 300-700%) in serum lathosterol and delta 8 lathosterol concentrations. The levels of two plant sterols, campesterol and beta-sitosterol, were unchanged or only slightly decreased by the use of activated charcoal. The decrease of serum cholesterol concentration had significant negative correlations with serum lathosterol and delta 8 lathosterol, and significant positive correlations with serum cholestanol and beta-sitosterol. These observations suggest an increased cholesterol synthesis upon treatment with activated charcoal, probably caused by the interference with the enterohepatic circulation of bile acids.

Topics: Anticholesteremic Agents; Charcoal; Cholesterol; Desmosterol; Female; Humans; Hypercholesterolemia; Male; Middle Aged; Phytosterols; Sitosterols

Attempts were made to develop an animal model for phytosterolemia. Infusion of Intralipid containing 0.2% sitosterol in rats gave circulating levels of sitosterol of about 2.5 mmol/l, which is similar to or higher than those present in patients with untreated phytosterolemia. In addition, the infusions gave serum levels of cholesterol nearly twice those obtained in rats infused with Intralipid alone or Intralipid containing 0.2% cholesterol. The hepatic HMG-CoA reductase activity was unaffected or slightly increased by the sitosterol infusions (not statistically significant). The cholesterol 7 alpha-hydroxylase activity was slightly depressed (ca. 30%). In the case of 7 alpha-hydroxylation of endogenous cholesterol, the depression reached statistical significance (p less than 0.05). The microsomal content of sitosterol in the sitosterol-infused rats was about 30% of that of microsomal cholesterol. The effect of sitosterol on 7 alpha-hydroxylation of cholesterol was investigated by incubations of acetone powder of rat liver microsomes with mixtures of cholesterol and sitosterol. Sitosterol mixed with cholesterol to a composition similar to that found in the above microsomal fraction had a depressing effect on 7 alpha-hydroxylation of cholesterol. This degree of depression was of the same magnitude as that found in the sitosterol infusion experiments. The possibility is discussed that the hypercholesterolemia obtained in the beta-sitosterol-infused rats is due to the inhibitory effect of sitosterol on the cholesterol 7 alpha-hydroxylase.

Topics: Animals; Cholesterol; Cholesterol 7-alpha-Hydroxylase; Disease Models, Animal; Hydroxymethylglutaryl CoA Reductases; Hypercholesterolemia; Male; Microsomes, Liver; Phytosterols; Rats; Rats, Inbred Strains; Sitosterols; Steroid Hydroxylases

Platelets from rats made hypercholesterolaemic with a diet enriched with milk fat and cholesterol and containing taurocholate to promote hypercholesterolaemia aggregated more extensively to a low concentration of thrombin than platelets from rats given a milk fat-enriched diet containing sitosterol. Total and specific binding of thrombin to platelets from hypercholesterolaemic rats was significantly greater than in controls when expressed per mg platelet protein, per mumol platelet cholesterol, or per unit relative surface area. Total and specific binding of thrombin per platelet were not different between the groups. However, platelets from hypercholesterolaemic rats had less protein and cholesterol, were smaller and had less surface area than control platelets; platelet cholesterol content expressed per mg platelet protein was not different. Thus, the increase in thrombin-binding to the smaller platelets from hypercholesterolaemic rats during the first 10 s after its addition may be responsible, at least in part, for the hypersensitivity of these platelets to thrombin.

Topics: Animals; Blood Platelets; Cholesterol; Cholesterol, Dietary; Dietary Fats; Hypercholesterolemia; Male; Milk; Protein Binding; Rats; Rats, Inbred Strains; Sitosterols; Taurocholic Acid; Thrombin

Topics: Animals; Cholesterol, Dietary; Humans; Hypercholesterolemia; Sitosterols

Cholesterol absorption was measured in chronically hypercholesterolemic dogs by four methods: the fecal recovery method of Borgström (1969, J. Lipid Res. 10: 331-337), the dual isotope method of Zilversmit and Hughes (1974, J. Lipid Res. 15: 465-473), the recovery of cholesterol in thoracic duct lymph collected continuously for 16 hr after a meal, and the recovery of isotopic cholesterol from the liver and plasma 24 hr after the animals consumed an isotope-containing meal. The four methods showed excellent agreement and indicated that dogs fed a cholesterol-rich synthetic diet absorb 5.2 +/- 0.5 g (mean +/- SD) of cholesterol per day and that cholesterol absorption is reasonably constant from week to week in these animals. Separate estimates of cholesterol excretion indicated that these dogs excreted 4.7 +/- 0.5 g of cholesterol per day, and thus were at or near the steady-state with regard to cholesterol input-output. These data, taken together with a previous report (1981, J. Lipid Res. 22: 598-609), indicate that the canine liver can clear up to 300 mg of chylomicron cholesterol/hr, and support the concept that chylomicron remnants do not contribute significantly to the hypercholesterolemia in these animals.

Topics: Animals; Bile; Cholesterol; Cholesterol, Dietary; Chylomicrons; Dogs; Feces; Female; Hypercholesterolemia; Intestinal Absorption; Liver; Lymph; Male; Micelles; Sitosterols; Solubility

The contribution of dietary cholesterol to hypercholesterolemia in diabetic rats fed chow ad libitum was evaluated. Diabetes was induced with streptozotocin, and the intake, absorption, and subsequent tissue distribution of dietary cholesterol were measured. Absorption was measured as the difference between [3H]cholesterol intake and fecal 3H-labeled neutral sterol excretion, using both [14C]sitosterol (added to diet) and [14C]cholesterol (added to feces) as recovery markers. [3H]Cholesterol absorption was underestimated by 1-3% using [14C]sitosterol as a recovery standard, due to the 7-8% absorption of sitosterol. After 3 weeks of diabetes, rats were hyperphagic, thereby increasing dietary cholesterol intake 2-fold. [3H]Cholesterol absorption was significantly increased from 69% in controls to 78% in diabetics, whereas [14C]sitosterol absorption was unaffected. With increased dietary cholesterol intake and decreased whole body cholesterol synthesis (Diabetes. 1983. 32: 811-819), influx from diet equaled for exceeded influx from synthesis. The amounts of 3H-labeled neutral sterol recovered from the small intestine, periphery, and plasma were increased 3- to 4-fold in the diabetic rats. Furthermore, the degree of hypercholesterolemia in diabetic rats was directly related to the fraction of plasma cholesterol derived from the diet. We conclude that the 2.3-fold increase in absorbed dietary cholesterol resulting from hyperphagia and, to a lesser extent, from increased fractional absorption, contributes to the hypercholesterolemia of diabetic rats fed chow ad libitum.

Topics: Animals; Cholesterol; Cholesterol, Dietary; Circadian Rhythm; Diabetes Mellitus, Experimental; Eating; Feces; Hypercholesterolemia; Intestinal Absorption; Male; Rats; Rats, Inbred Strains; Reference Standards; Sitosterols; Tissue Distribution

Alterations in lipid content of microvilli membranes, affecting their physical structure, as well as in lipoproteins of rat small intestinal mucosa and of blood plasma were studied in experimental hypercholesterolemia after treatment with crystalline and liposomal preparations of beta-sitosterol. The liposomal preparation of beta-sitosterol exhibited distinctly higher hypocholesterolemic activity as compared with the crystalline sterol. Possible role of structural and functional alterations in enterocyte membranes and in intestinal lipoproteins during absorption of cholesterol as well as inhibition of the processes by means of beta-sitosterol are discussed.

Topics: Animals; Hypercholesterolemia; Intestinal Absorption; Intestinal Mucosa; Intestine, Small; Lipid Metabolism; Lipids; Liposomes; Membranes; Microvilli; Phospholipids; Rats; Sitosterols

Topics: Adult; Child; Costs and Cost Analysis; Diet; Food Analysis; Humans; Hypercholesterolemia; Infant; Male; Prostatic Hyperplasia; Sitosterols

Topics: Biochemical Phenomena; Biochemistry; Carbon Isotopes; Cholesterol; Hypercholesterolemia; Lipid Metabolism; Rats; Research; Sitosterols; Sterols

Topics: Arteriosclerosis; Cholesterol; Humans; Hypercholesterolemia; Sitosterols; Sterols

Topics: alpha-Linolenic Acid; Animals; Aorta; Arachidonic Acid; Arteriosclerosis; Cholesterol; Dogs; Estradiol; Hypercholesterolemia; Lipid Metabolism; Lipids; Sitosterols; Sterols

Topics: Animals; Arteriosclerosis; Diet; Humans; Hypercholesterolemia; Rats; Sitosterols; Steroids; Thiouracil

Topics: Cholesterol; Diet; Humans; Hypercholesterolemia; Sitosterols; Steroids

Topics: Animals; Arteries; Arteriosclerosis; Cholesterol; Diet; Fats; Humans; Hypercholesterolemia; Rats; Sitosterols; Steroids; Thiouracil

Topics: Arachidonic Acid; Cholesterol; Humans; Hypercholesterolemia; Niacin; Nicotinic Acids; Safflower Oil; Sitosterols; Sterols

Topics: Arachidonic Acid; Arteriosclerosis; Atherosclerosis; Cholesterol; Humans; Hypercholesterolemia; Safflower Oil; Sitosterols; Steroids

Topics: Amides; Anesthetics, Local; Humans; Hypercholesterolemia; Sitosterols; Steroids

Topics: Cholesterol; Humans; Hypercholesterolemia; Sitosterols; Steroids

Topics: Blood; Cholesterol; Humans; Hypercholesterolemia; Lipids; Lipoproteins; Male; Sitosterols; Steroids