Amiodarone disrupts cholesterol biosynthesis pathway and causes accumulation of circulating desmosterol by inhibiting 24-dehydrocholesterol reductase.

BACKGROUND: We have earlier reported that amiodarone, a potent and commonly used antiarrhythmic drug increases serum desmosterol, the last precursor of cholesterol, in 20 cardiac patients by an unknown mechanism. OBJECTIVE: Here, we extended our study to a large number of cardiac patients of heterogeneous diagnoses, evaluated the effects of combining amiodarone and statins (inhibitors of cholesterol synthesis at the rate-limiting step of hydroxy-methyl-glutaryl CoA reductase) on desmosterol levels and investigated the mechanism(s) by which amiodarone interferes with the metabolism of desmosterol using in vitro studies. METHODS AND RESULTS: We report in a clinical case-control setting of 236 cardiac patients (126 with and 110 without amiodarone treatment) that amiodarone medication is accompanied by a robust increase in serum desmosterol levels independently of gender, age, body mass index, cardiac and other diseases, and the use of statins. Lipid analyses in patient samples taken before and after initiation of amiodarone therapy showed a systematic increase of desmosterol upon drug administration, strongly arguing for a direct causal link between amiodarone and desmosterol accumulation. Mechanistically, we found that amiodarone resulted in desmosterol accumulation in cultured human cells and that the compound directly inhibited the 24-dehydrocholesterol reductase (DHCR24) enzyme activity. CONCLUSION: These novel findings demonstrate that amiodarone blocks the cholesterol synthesis pathway by inhibiting DHCR24, causing a robust accumulation of cellular desmosterol in cells and in the sera of amiodarone-treated patients. It is conceivable that the antiarrhythmic potential and side effects of amiodarone may in part result from inhibition of the cholesterol synthesis pathway.

Desmosterol accumulation in users of amiodarone.

BACKGROUND: Amiodarone is an effective and widely used antiarrhythmic drug with many possible adverse effects including hypercholesterolaemia and hepatotoxicity. OBJECTIVE: Our aim was to evaluate how long-term amiodarone treatment affects cholesterol metabolism. METHODS: The study population consisted of 56 cardiac patients, of whom 20 were on amiodarone (amiodarone + group) and 36 did not use the drug (amiodarone - group). We also studied a control group of 124 individuals selected randomly from the population. Cholesterol metabolism was evaluated by analysis of serum noncholesterol sterols by gas-liquid chromatography and gas chromatography-mass spectrometry. RESULTS: Comparisons of serum lipids and noncholesterol sterols across the three groups showed increased serum triglyceride in users of amiodarone but no statistically significant group differences in total, LDL or HDL cholesterol or serum proprotein convertase subtilisin/kexin type 9 concentrations. Nor did the groups differ in the ratios of cholestanol or plant sterols to cholesterol in serum, suggesting that cholesterol absorption was unaltered. However, all users of amiodarone had very markedly elevated serum desmosterol concentrations: the desmosterol-to-cholesterol ratio (102 × µmol mmol-1 ) averaged 1030.7 ± 115.7 (mean ± SE) in the amiodarone + group versus 82.7 ± 3.4 and 75.9 ± 1.4 in the amiodarone - and the population control groups (P < 0.001), respectively. CONCLUSION: Use of amiodarone was associated with on average 12-fold serum desmosterol concentrations compared with the control groups. This observation is fully novel and suggests that amiodarone interferes with the conversion of desmosterol to cholesterol in the cholesterol synthesis pathway. Whether accumulation of desmosterol plays a role in amiodarone-induced hepatotoxicity deserves to be studied in the future.

Physical function and properties of quadriceps femoris muscle after bariatric surgery and subsequent weight loss.

OBJECTIVES: To investigate the effects of bariatric surgery-induced weight loss on physical function, the properties of quadriceps femoris muscle (QFM), and the subjective disabilities of the subjects with excessive weight. METHODS: Thirteen female and three male subjects were studied before and 8.8 months after Roux-en-Y gastric bypass (RYGP) operation. The health-related quality of life (RAND-36) and the self-reported disease-specific joint symptoms (WOMAC) were estimated. The objective physical function was evaluated with sock, repeated sit-to-stand, 6-minute walk, stair ascending and descending and timed up and go tests and the properties of the QFM were measured with ultrasound. RESULTS: The average weight loss was 27.3 kg. Objectively measured physical function improved after RYGP operation. Physical functioning, physical role functioning and general health domain scores of the RAND-36 were significantly improved. The stiffness and function scores were lower after RYGP operation in knee OA subjects. The subcutaneous fat thickness and the absolute muscle thickness of QFM decreased, but the ratio of muscle cross sectional area/total body weight did not change. The fat and connective tissue proportion in the QFM muscle were significantly increased. CONCLUSIONS: The RYPG-surgery-induced weight loss exerts a positive impact on physical function but a negative impact on a muscle structure.

Cholesterol metabolism altered and FGF21 levels high after pediatric liver transplantation despite normal serum lipids.

Liver transplantation (LT) predisposes to metabolic derangements and increases the risk for cardiovascular disease. We conducted a national cross-sectional study of all pediatric recipients who underwent LT between 1987 and 2007. We measured serum levels of noncholesterol sterols (surrogate markers of cholesterol synthesis and intestinal absorption) and fibroblast growth factor 21 (FGF21) in 49 patients (74% of survivors) at a median of 10 years posttransplant and in 93 controls matched for age and gender. Although serum cholesterol levels were similar in patients and controls, patients displayed increased whole-body synthesis and decreased intestinal absorption of cholesterol compared with controls (lathosterol to cholesterol ratio 129 ± 55 vs. 96 ± 41, respectively, p < 0.001; campesterol to cholesterol ratio 233 ± 91 vs. 316 ± 107, respectively; p < 0.001). Azathioprine (r =-0.383, p = 0.007) and low-dose methylpredisolone (r =-0.492, p < 0.001) were negatively associated with lathosterol/sitosterol ratio reflecting a favorable effect on cholesterol metabolism. FGF21 levels were higher in patients than in controls (248 pg/mL vs. 77 pg/mL, p < 0.001). In healthy controls, FGF21 was associated with cholesterol metabolism, an association missing in LT recipients. Normal serum lipids are achievable in long-term survivors of pediatric LT, but changes in cholesterol metabolism and increased FGF21 levels may explicate later cardiovascular risk.

Serum and lipoprotein sitostanol and non-cholesterol sterols after an acute dose of plant stanol ester on its long-term consumption.

PURPOSE: Chronic inhibition of cholesterol absorption with large doses of plant stanol esters (staest) alters profoundly cholesterol metabolism, but it is unknown how an acute inhibition with a large staest dose alters the postprandial serum and lipoprotein cholesterol precursor, plant sterol, and sitostanol contents. METHODS: Hypercholesterolemic subjects, randomly and double-blind divided into control (n = 18) and intervention groups (n = 20), consumed experimental diet without and with staest (plant stanols 8.8 g/day) for 10 weeks. Next morning after a fasting blood sample (0 h), the subjects had a breakfast without or with staest (4.5 g of plant stanols). Blood sampling was repeated 4 h later. Lipoproteins were separated with ultracentrifugation, and sterols were measured with gas-liquid chromatography. RESULTS: In 0-h chylomicrons and VLDL, plant sterols were lower in staest than in controls. Postprandially, cholestenol (cholesterol synthesis marker) was reduced in chylomicrons in staest compared with controls (-0.13 ± 0.04 µg/dL vs. 0.01 ± 0.08 µg/dL, P < 0.05). Staest decreased postprandially avenasterol in chylomicrons (P < 0.05 from 0 h). Sitostanol was high at 0 h by chronic staest in serum and VLDL but not in chylomicrons. Postprandial sitostanol was increased by staest in VLDL only. CONCLUSIONS: Chronic cholesterol absorption inhibition with large amount of plant stanol esters decreases plant sterols in triglyceride-rich lipoproteins. Acute plant stanol ester consumption increases sitostanol content in triglyceride-rich lipoproteins but suggests to decrease the risk of plant sterol and plant stanol accumulation into vascular wall by chylomicrons.

Effect of weight loss on inflammation in patients with mild obstructive sleep apnea.

BACKGROUND AND AIMS: Inflammation may be one mediating mechanism for cardiovascular diseases in obstructive sleep apnea (OSA). However, little is known about subclinical inflammation or the effect of lifestyle intervention on inflammation in early stages of OSA. The aim of this substudy of an existing randomized controlled trial, with post hoc analyses, was to determine the impact of lifestyle changes aimed at weight reduction on inflammatory biomarkers in overweight patients with mild OSA. METHODS AND RESULTS: Patients were randomized to supervised intensive lifestyle intervention group (N=28) or to control group (N=31), which received routine lifestyle advices. Circulating concentrations of pro- and anti-inflammatory mediators were measured before and after the 1-year intervention. The concentrations of two pro-inflammatory mediators, high-sensitivity C-reactive protein (hsCRP) and interleukin (IL)-6, decreased significantly in both groups. Although the changes in inflammatory biomarkers favored the supervised lifestyle intervention, the only significant reduction observed between the groups was for the anti-inflammatory IL-1 receptor antagonist (IL-1RA). The change in hsCRP was associated with apnea-hypopnea index, and improving night-time oxygen saturation was related to tumor necrosis factor alpha. IL-1RA and IL-6 were associated with insulin metabolism. CONCLUSION: Weight loss resulted in reductions in concentrations of some pro- and anti-inflammatory mediators in overweight patients with mild OSA, overall favoring the supervised lifestyle intervention. These findings suggest that more intensive treatment of obesity in OSA patients might be well-justified.

The role of serum non-cholesterol sterols as surrogate markers of absolute cholesterol synthesis and absorption.

AIMS: To study the whole-body cholesterol metabolism in man, cholesterol synthesis and absorption need to be measured. Because of the complicated methods of the measurements, new approaches were developed including the analysis of serum non-cholesterol sterols. In current lipidologic papers and even in intervention studies, serum non-cholesterol sterols are frequently used as surrogate markers of cholesterol metabolism without any validation to the absolute metabolic variables. The present review compares serum non-cholesterol sterols with absolute measurements of cholesterol synthesis and absorption in published papers to find out whether the serum markers are valid indicators of cholesterol metabolism in various conditions. DATA SYNTHESIS: During statin treatment, during interventions of dietary fat, and in type 2 diabetes the relative and absolute variables of cholesterol synthesis and absorption were frequently but not constantly correlated with each other. In some occasions, especially in subjects with apolipoprotein E3/4 and E4/4 phenotypes, the relative metabolic markers were even more sensitive than the absolute ones to reflect changes in cholesterol metabolism during dietary interventions. Even in general population at very high absorption the homeostasis of cholesterol metabolism is disturbed damaging the validity of the serum markers. CONCLUSIONS: It is worth using several instead of only one precursor and absorption sterol marker for making conclusions of altered synthesis or absorption of cholesterol, and even then the presence of at least some absolute measurement is valuable. During consumption of plant sterol-enriched diets and in situations of interfered cholesterol homeostasis the relative markers do not adequately reflect cholesterol metabolism. Accordingly, the validity of the relative markers of cholesterol metabolism should not be considered as self-evident.

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

BACKGROUND AND AIMS: It is not known whether dietary intake of plant stanols or sterols changes the composition of arterial sterols. Therefore, we compared serum and carotid artery cholesterol and non-cholesterol sterols after plant stanol (staest) or sterol (steest) ester feeding in endarterectomized patients. METHODS AND RESULTS: Elderly statin-treated asymptomatic patients undergoing carotid endarterectomy were randomized double-blind to consume staest (n=11) or steest (n=11) spread (2 g of stanol or sterol/day) for four weeks preoperatively. Non-cholesterol sterols from serum and carotid artery tissue were analysed with gas-liquid chromatography. Staest spread lowered serum total (17.2%), VLDL, and LDL cholesterol and serum triglycerides, while steest spread lowered serum total (13.8%) and LDL cholesterol levels from baseline (p<0.05 for all). Serum cholestanol and avenasterol were decreased in both groups, but campesterol and sitosterol were decreased by staest and increased by steest from baseline (p<0.05 from baseline and between the groups). Serum sitostanol to cholesterol ratio was increased by staest, but in arterial tissue this ratio was similar in both groups. On staest, lathosterol, campesterol, and sitosterol, and on steest sitosterol and avenasterol correlated significantly between serum and arterial tissue. Cholesterol metabolism, eg. lathosterol/campesterol, suggested that plant sterols were reduced in serum and in arterial tissue during staest. CONCLUSION: The novel observations were that plant stanol ester consumption, in contrast to plant sterols, tended to reduce carotid artery plant sterols in statin-treated patients. Furthermore, despite increased serum sitostanol contents during plant stanol ester consumption, their arterial levels were unchanged suggesting that sitostanol is not taken up into the arterial wall.

Association of the FTO gene variant (rs9939609) with cardiovascular disease in men with abnormal glucose metabolism--the Finnish Diabetes Prevention Study.

BACKGROUND AND AIM: The common single nucleotide polymorphism (SNP) in the FTO (fat mass and obesity associated) gene has been consistently associated with an increased risk of obesity. We investigated whether the SNP rs9939609 (T/A) of the FTO is associated with risk factors of cardiovascular diseases (CVD), including serum levels of C - reactive protein (CRP), the chemokine RANTES (Regulated on Activation, Normal T Cell Expressed and Secreted; CCL5), and serum and lipoprotein lipids in the Finnish Diabetes Prevention Study (DPS). Furthermore, we examined whether the rs9939609 increased the CVD risk in the DPS and if these results could be replicated in a larger cross-sectional population-based random sample of Finnish men (the METSIM). METHODS AND RESULTS: In the DPS, altogether 490 (BMI≥25kg/m(2)) subjects with impaired glucose tolerance were genotyped for rs9939609. Cardiovascular morbidity and mortality data were collected during the median follow-up of 10.2 years. The replication study was a population-based cross-sectional study of 6214 men. In the DPS, the AA genotype of rs9939609 was associated, independently of BMI, with increased RANTES (p=0.002) and decreased HDL cholesterol concentrations (p=0.007) in men. During the follow-up, the AA genotype was associated with an adjusted 2.09-fold risk (95% CI 1.17-3.73, p=0.013) of CVD in men. In the METSIM Study, the association with a history of myocardial infarction was replicated in the subgroup of men with type 2 diabetes. CONCLUSION: We suggest that the variation in the FTO gene may contribute to the development of CVD in men with an abnormal glucose metabolism.

Applicability of non-cholesterol sterols in predicting response in cholesterol metabolism to simvastatin and fluvastatin treatment among hypercholesterolemic men.

BACKGROUND AND AIMS: We hypothesized that (I) certain features in cholesterol metabolism at baseline could predict a response to statins, (II) good and poor responders to statins have a differential profile of serum and fecal sterols and (III) serum non-cholesterol sterols reflect cholesterol metabolism on statins. METHODS AND RESULTS: We examined serum lipids, serum and fecal cholesterol, cholesterol precursors, cholestanol and phytosterols and cholesterol metabolism among 20 hypercholesterolemic men at baseline and on 16-wk simvastatin/fluvastatin treatment. At baseline, the mean of serum cholestanol/cholesterol was 11% lower but those of lathosterol/cholesterol, lathosterol/cholestanol, desmosterol/cholesterol, desmosterol/cholestanol were 36-65% higher among good than poor responders (p<0.05 for each). On statins, reductions in ratios of serum precursor sterols and increases of absorption sterols were 1.8-2.9 times higher among good than poor responders (p<0.05 for each). In the whole study group, changes from baseline values of lathosterol/cholestanol were related to those of cholesterol and LDL-C in serum (r=+0.513 and +0.451, p=0.021 and 0.046, respectively). Serum lathosterol ratios to cholesterol, cholestanol and sitosterol consistently reflected a ratio of cholesterol synthesis (mg/d/kg)/fractional cholesterol absorption (%) (r-range +0.456 to +0.727, p<0.05 for each). CONCLUSIONS: Low serum baseline ratios to cholesterol of lathosterol, cholestenol and desmosterol, but a high ratio of cholestanol predicted a poor response to statins. Good responders were characterized by more profound reductions of serum and fecal (lathosterol) precursor sterols and increases of serum absorption marker sterol ratios on statins. Serum surrogate sterol markers of cholesterol metabolism were applicable in evaluating cholesterol absorption and synthesis also on statins.

Dietary carbohydrate modification alters serum metabolic profiles in individuals with the metabolic syndrome.

BACKGROUND AND AIMS: Whole-grain cereals and diets with a low glycemic index may protect against the development of type 2 diabetes and heart disease, but the mechanisms are poorly understood. We studied the effect of carbohydrate modification on serum metabolic profiles, including lipids and branched chain amino acids, and dependencies between these and specific gene expression pathways in adipose tissue. METHODS AND RESULTS: Twenty subjects with metabolic syndrome were selected from the larger FUNGENUT study population, randomized either to a diet high in oat and wheat bread and potato (OWP) or rye bread and pasta (RP). Serum metabolomics analyses were performed using ultra-performance liquid chromatography coupled to electrospray ionization mass spectrometry (UPLC/MS), gas chromatography (GC) and UPLC. In the OWP group multiple proinflammatory lysophosphatidylcholines increased, while in the RP group docosahexaenoic acid (DHA 22:6n-3) increased and isoleucine decreased. mRNA expression of stress reactions- and adipose tissue differentiation-related genes were up-regulated in adipose tissue in the OWP group. In the RP group, however, pathways related to stress reactions and insulin signaling and energy metabolism were down-regulated. The lipid profiles had the strongest association with the changes in the adipose tissue differentiation pathway when using the elastic net regression model of the lipidomic profiles on selected pathways. CONCLUSION: Our results suggest that the dietary carbohydrate modification alters the serum metabolic profile, especially in lysoPC species, and may, thus, contribute to proinflammatory processes which in turn promote adverse changes in insulin and glucose metabolism.

Pandemic influenza: human rights, ethics and duty to treat.

The 2009 influenza A/H1N1 pandemic seems to be only moderately severe. In the future, a pandemic influenza with high lethality, such as the Spanish influenza in 1918-1919 or even worse, may emerge. In this kind of scenario, lethality rates ranging roughly from 2% to 30% have been proposed. Legal and ethical issues should be discussed before the incident. This article aims to highlight the legal, ethical and professional aspects that might be relevant to anaesthesiologists in the case of a high-lethality infectious disease such as a severe pandemic influenza. The epidemiology, the role of anaesthesiologists and possible threats to the profession and colleagueship within medical specialties relevant to anaesthesiologists are reviewed. During historical plague epidemics, some doctors have behaved like 'deserters'. However, during the Spanish influenza, physicians remained at their jobs, although many perished. In surveys, more than half of the health-care workers have reported their willingness to work in the case of severe pandemics. Physicians have the same human rights as all citizens: they have to be effectively protected against infectious disease. However, they have a duty to treat. Fair and responsible colleagueship among the diverse medical specialties should be promoted. Until disaster threatens humanity, volunteering to work during a pandemic might be the best way to ensure that physicians and other health-care workers stay at their workplace. Broad discussion in society is needed.

Plant stanol ester spreads as components of a balanced diet for pregnant and breast-feeding women: evaluation of clinical safety.

Clinical safety of consuming plant stanol ester spreads during pregnancy and lactation, the impact on maternal and infant serum and breast-milk cholesterol and the ratios (micromol/mmol of cholesterol) of synthesis and absorption markers were evaluated. Pregnant women (n 21) were randomised to control and dietary intervention groups, the intervention including advice to follow a balanced diet and to consume spreads enriched with plant stanol esters. Participants were followed during and after pregnancy and their infants up to 1 year of age. A mean 1.1 (sd 0.4) g consumption of plant stanols during pregnancy and 1.4 (sd 0.9) g 1 month post-partum increased sitostanol and the markers for cholesterol synthesis, lathosterol, lathosterol/campesterol and lathosterol/sitosterol, and reduced a marker for cholesterol absorption, campesterol, in maternal serum. In breast milk, desmosterol was lower in the intervention group, while no differences were detected between the groups in infants' serum. Plant stanol ester spread consumption had no impact on the length of gestation, infants' growth or serum beta-carotene concentration at 1 and 6 months of age, but the cholesterol-adjusted serum beta-carotene concentration was lowered at 1 month in the intervention group. Plant stanol ester spread consumption appeared safe in the clinical setting, except for potential lowering of infants' serum beta-carotene concentration, and was reflected in the markers of cholesterol synthesis and absorption in mothers' serum, encouraging further studies in larger settings.

Twenty-one year tracking of serum non-cholesterol sterols. The Cardiovascular Risk in Young Finns study.

BACKGROUND AND AIM: To show tracking of cholesterol metabolism, the ratios to cholesterol of e.g. serum cholestenol, desmosterol, and lathosterol, reflecting cholesterol synthesis, and cholestanol, campesterol, avenasterol and sitosterol, reflecting cholesterol absorption, were measured 21 years apart. METHODS AND RESULTS: In random population samples initially comprising 12- (n=162), 15- (n=158), and 18-year-old (n=148) males participating in the Cardiovascular Risk in Young Finns Study, serum sterols and squalene were measured with gas-liquid chromatography in 1980 and 2001. Quartiles of cholestanol, indicating low to high cholesterol absorption, were defined from the cholestanol values in 1980. Serum cholesterol increased in the oldest age group only, but synthesis markers (except desmosterol) increased in all age groups after the follow-up (e.g. lathosterol, total population +47.3+/-2.6% (SE), P<0.001). Campesterol (+69.0+/-3.0%, P<0.001) and sitosterol increased, avenasterol was unchanged, and cholestanol decreased (-6.2+/-0.7%, P<0.001), respectively. The 1980 synthesis and absorption markers were interrelated with respective values 21 years later in all age groups and quartiles (e.g. lathosterol, total population 1980 vs. 2001 r=0.460, cholestanol 1980 vs. 2001 r=0.593, P<0.001 for both). Synthesis markers were highest in the first and lowest in the fourth quartile both in 1980 and 2001 (e.g. 2001, desmosterol, quartile 1, 99+/-9, quartile 4, 83+/-2 microg/mg of cholesterol, P<0.05). CONCLUSIONS: Cholesterol metabolism is significantly tracked in adolescent males over the follow-up of 21 years. Thus, high cholesterol synthesis and low absorption characterize subjects with the lowest cholestanol quartile, while those with the highest quartile have low synthesis and high absorption in both adolescence and later in young adult life.

Weight reduction modulates expression of genes involved in extracellular matrix and cell death: the GENOBIN study.

OBJECTIVE: Lifestyle and genetic factors interact in the development of obesity and the metabolic syndrome. The molecular mechanisms underlying the beneficial dietary modifications are, however, unclear. We aimed to examine the effect of the long-term moderate weight reduction on gene expression in adipose tissue (AT) and to identify genes and gene clusters responsive to treatment and thereby likely contributing to the development of the metabolic syndrome. DESIGN: Randomized controlled and individualized weight reduction intervention. SUBJECTS: Forty-six subjects with impaired fasting glycemia or impaired glucose tolerance and features of metabolic syndrome, aged 60+/-7 years were randomized either to a weight reduction (WR) (n=28) or a control (n=18) group lasting for 33 weeks. MEASUREMENTS: Oral and intravenous glucose tolerance tests and subcutaneous AT biopsies were performed before and after the intervention. Gene expression of AT was studied using microarray technology in subgroups of WR (with weight reduction > or =5%, n=9) and control group (n=10). The results were confirmed using quantitative PCR. RESULTS: In the WR group, glucose metabolism improved. Moreover, an inverse correlation between the change in S (I) and the change in body weight was found (r=-0.44, P=0.026). Downregulation of gene expression (P<0.01) involving gene ontology groups of extracellular matrix and cell death was seen. Such changes did not occur in the control group. The tenomodulin-gene was one of the most downregulated genes (-39+/-16%, P<0.0001). Moreover, its expression correlated with insulin sensitivity (r=-0.34, P=0.005) before the intervention and with body adiposity both before (r=0.42, P=0.007) and after (r=0.30, P=0.056) the intervention. CONCLUSION: Genes regulating the extracellular matrix and cell death showed a strong downregulation after long-term weight reduction. This likely reflects a new stable state at the molecular level in AT. Further studies are warranted to elucidate the mechanisms of these genetic factors.

SREBP-1c gene polymorphism is associated with increased inhibition of cholesterol-absorption in response to ezetimibe treatment.

OBJECTIVE: Sterol regulatory binding proteins 1 and 2 (SREBPs) are transcription factors regulating lipid metabolism. A recent study has associated the CC genotype of the SREBP-1c polymorphism G952G with increased cholesterol synthesis. Further evidence suggests that SREBPs play a role in cholesterol absorption and that SREBP polymorphisms modulate the response to statin therapy. The present study examines whether the G952G polymorphism alters cholesterol synthesis and/or absorption and whether it modulates the response to widely used lipid-lowering drugs such as inhibitors of cholesterol synthesis (simvastatin) or absorption (ezetimibe). METHODS: Seventy-two healthy male subjects with LDL cholesterol <190 mg/dL participated in the study. Twenty four subjects were treated with ezetimibe (10 mg), simvastatin (40 mg) or their combination, respectively, for two weeks. Blood was drawn before and after the 2-week treatment period. RESULTS: Eleven CC homozygous carriers of the gene were found (15%). There were no differences in cholesterol synthesis or absorption between the CC homozygotes and the G allele-carriers, as measured by the ratios to cholesterol of serum lathosterol, desmosterol and cholestenol (synthesis markers) and cholestanol, sitosterol and campesterol (absorption markers). Ezetimibe had a significantly more potent effect in blocking cholesterol absorption in the CC homozygotes compared to the G-carriers ( P=0.002). CONCLUSIONS: The G/C (G952G) polymorphism of the SREBP-1 gene is not associated with cholesterol synthesis or absorption in a German male population. The CC homozygotes have a significantly increased response to the effects of ezetimibe on cholesterol absorption compared to the G allele-carriers, suggesting that SREBP-1 may be implicated in ezetimibe's mechanism of action.

Moderate increase in dietary sucrose does not influence fasting or postprandial serum lipids regardless of the presence of apolipoprotein E2 allele in healthy subjects.

OBJECTIVE: To investigate whether a moderate increase in dietary sucrose intake induces different serum lipid responses in normolipidemic subjects with the epsilon 2 allele compared with subjects without the epsilon 2 allele. DESIGN: Controlled, parallel study. SUBJECTS: There were 15 subjects with the apolipoprotein E (APOE)3/2 genotype and 19 subjects with the APOE 3/3 or 3/4 genotype, whose mean+/-s.d. age was 48+/-14 and 35+/-10 years, respectively. All subjects had normal glucose metabolism. INTERVENTIONS: The subjects were instructed to increase their sucrose intake by 40 g/day for 8 weeks and to decrease the intake of saturated and unsaturated fat to maintain energy balance. Dietary adherence was monitored using food records and the actual increase in sucrose intake was 39.8+/-18.4 g/day. Sixteen subjects (nine with APOE 3/2 genotype, seven with APOE 3/3 or 3/4 genotypes) participated also in an 8 h oral fat tolerance test at the beginning and at the end of the intervention. RESULTS: Body weight remained stable during the intervention. Sucrose intake did not have a significant effect on fasting concentrations of serum total and lipoprotein lipids, plasma glucose, serum insulin, squalene and non-cholesterol sterols in either genotype group. Neither were there any changes in postprandial lipid or insulin responses. CONCLUSIONS: Moderate increase in sucrose intake does not affect fasting or postprandial serum lipid responses in healthy subjects with or without the epsilon 2 allele.

Ester percentages of plant sterols and cholesterol in chylomicrons and VLDL of humans with low and high sterol absorption.

Ester percentages of cholesterol and non-cholesterol sterols were measured in chylomicrons and very low density lipoproteins (VLDL) in 15 subjects. Our hypothesis was that in humans, in contrast to animal experiments, plant sterols in chylomicrons are esterified similarly to cholesterol. In fact, the mean ester percentage of chylomicron sitosterol (approximately 40%), but not of campesterol ( approximately 51%), was lower than that of cholesterol (approximately 54%) in the whole study population. In high cholesterol absorbers (high serum total campesterol, > or = 2.8 mmol/mol of cholesterol), the ester percentages of sitosterol and other non-cholesterol sterols were similar to that of cholesterol in chylomicrons, and the percentages tended to be higher than those in low absorbers. In contrast to chylomicrons, the ester percentages of sterols in VLDL tended to be lower in the high than low absorbers. In conclusion, percentages of plant sterol esters are not consistently lower than those of cholesterol in chylomicrons.

Postprandial behavior of plasma squalene and non-cholesterol sterols in men with varying cholesterol absorption.

BACKGROUND: The purpose of this study was to investigate, whether low vs. high absorption of cholesterol affects the postprandial lipid clearance (squalene as the surrogate marker) and postprandial cholesterol metabolism evaluated with plasma levels of cholesterol absorption (cholestanol and plant sterols) and synthesis markers (desmosterol and lathosterol). METHODS: Fifteen normo- or mildly hypercholesterolemic men were divided into low or high cholesterol absorbers on the basis of plasma cholestanol to cholesterol ratio and they volunteered to an oral fat load test containing fat 35 g/m(2) body surface. RESULTS: Plasma squalene to cholesterol ratio did not differ between the groups throughout the postprandial follow-up of 8 h. The level differences in the plasma absorption and synthesis markers seen at baseline remained between the groups, so that in high absorbers the absorption markers remained high and synthesis markers low throughout the postprandial follow-up. The postprandial response curves of desmosterol (p<0.05) and lathosterol (p=0.052) to cholestanol decreased linearly in the low, but not in the high absorbers. CONCLUSIONS: Low vs. high absorption of cholesterol does not affect the first 8-h postprandial lipid clearance. The metabolic profile of cholesterol is maintained postprandially. The postprandial decrease in cholesterol synthesis differs in low vs. high absorbers especially through the desmosterol pathway.

Plant stanol and sterol esters in prevention of cardiovascular diseases: a review.

Plant sterol and stanol esters have been introduced as an additional dietary means to lower serum total and LDL cholesterol concentration. In short-term studies they lower LDL cholesterol by 10%, and according to a meta-analysis by Malcolm Law the incidence of coronary heart disease is considered to be reduced by over 20% in long-term use of these products. Plant stanol and sterol esters are not identical sterols; they have different metabolic effects and their long-term efficacy seems to be different. The present review deals with the differences of the sterols and discusses what is known of their role in preventing the cardiovascular diseases.