Cholesterol Absorption and Synthesis in Vegetarians and Omnivores.

Scope: Vegetarian diets are considered health-promoting; however, a plasma cholesterol lowering effect is not always observed. We investigate the link between vegetarian-diet-induced alterations in cholesterol metabolism.

Methods And Results: We study male and female omnivores, lacto-ovo vegetarians, lacto vegetarians, and vegans.

The value of surrogate markers to monitor cholesterol absorption, synthesis and bioconversion to bile acids under lipid lowering therapies.

Introduction: Regulation of cholesterol (Chol) homeostasis is controlled by three main fluxes, i.e. intestinal absorption, de novo synthesis (ChS) and catabolism, predominantly as bile acid synthesis (BAS).

The ABCG8 G574R variant, serum plant sterol levels, and cardiovascular disease risk in the Old Order Amish.

Objective: To determine whether long-term exposure to moderate elevations in plasma plant sterol levels increases risk for atherosclerosis.

Methods And Results: In Old Order Amish participants aged 18 to 85 years, with (n=110) and without (n=181) 1 copy of the ABCG8 G574R variant, we compared mean plasma levels of plant sterols and cholesterol precursors and carotid intima-media wall thickness. Carriers of a single 574R allele had increased plant sterol levels (eg, 35%-37% higher plasma levels of sitosterol, campesterol, and stigmasterol) and increased plant sterol/cholesterol ratios (P<0.

Lifibrol as a model compound for a novel lipid-lowering mechanism of action.

Lifibrol is a potent lipid-lowering drug with an unknown mechanism of action. We investigated its effects on lipoprotein and sterol metabolism in normocholesterolemic male participants. Seven participants were treated for 4 weeks with 600 mg/d lifibrol and 9 with 40 mg/d pravastatin in a double-blind randomized parallel-group trial.

Influence of simvastatin on apoB-100 secretion in non-obese subjects with mild hypercholesterolemia.

Statins decrease apoB-100-containing lipoproteins by increasing their fractional catabolic rates through LDL receptor-mediated uptake. Their influence on hepatic secretion of these lipoproteins is controversial. The objective of the study was to examine the influence of simvastatin on the secretion of apoB-100-containing lipoproteins in fasting non-obese subjects.

Absence of ApoE upregulates murine brain ApoD and ABCA1 levels, but does not affect brain sterol levels, while human ApoE3 and human ApoE4 upregulate brain cholesterol precursor levels.

Apolipoprotein E (apoE) is a regulator of peripheral cholesterol homeostasis, and the apoE-isoform E4 is a major risk factor for the development of Alzheimer's disease (AD). Accumulating evidence suggests a key role for aberrant cholesterol metabolism in AD. We hypothesized that apoE-deficiency in mice not only affects cholesterol homeostasis in the periphery, but also in the brain, and that this can be restored by astrocyte-specific expression of human apoE3, but not apoE4.

Changes in cholesterol absorption and cholesterol synthesis caused by ezetimibe and/or simvastatin in men.

This study evaluates changes in cholesterol balance in hypercholesterolemic subjects following treatment with an inhibitor of cholesterol absorption or cholesterol synthesis or coadministration of both agents. This was a randomized, double blind, placebo-controlled, four-period crossover study to evaluate the effects of coadministering 10 mg ezetimibe with 20 mg simvastatin (ezetimibe/simvastatin) on cholesterol absorption and synthesis relative to either drug alone or placebo in 41 subjects. Each treatment period lasted 7 weeks.

Vascular effects of diet supplementation with plant sterols.

Objectives: The purpose of this study was to evaluate vascular effects of diet supplementation with plant sterol esters (PSE).

Background: Plant sterol esters are used as food supplements to reduce cholesterol levels. Their effects on endothelial function, stroke, or atherogenesis are not known.

Increased plant sterol and stanol levels in brain of Watanabe rabbits fed rapeseed oil derived plant sterol or stanol esters.

Foods containing plant sterol or stanol esters can be beneficial in lowering LDL-cholesterol concentration, a major risk factor for CVD. The present study examined whether high dietary intake of rapeseed oil (RSO) derived plant sterol and stanol esters is associated with increased levels of these components in brain tissue of homozygous and heterozygous Watanabe rabbits, an animal model for familial hypercholesterolemia. Homozygous animals received either a standard diet, RSO stanol or RSO sterol ester while heterozygous animals were additionally fed with 2 g cholesterol/kg to the respective diet form for 120 d (n 9 for each group).

Customary use of plant sterol and plant stanol enriched margarine is associated with changes in serum plant sterol and stanol concentrations in humans.

The consumption of products enriched with plant sterol or stanol esters lowers serum total and LDL-cholesterol concentrations, thereby most likely reducing the risk of coronary heart disease. However, using plant sterol (not plant stanol) enriched products elevates serum plant sterol concentrations in humans. This may be unwanted because health effects of elevated serum plant sterol concentrations are still controversial.

Moderately elevated plant sterol levels are associated with reduced cardiovascular risk--the LASA study.

Functional foods with supplementation of plant sterols are already used by millions of people. However, at the same time it is current scientific thinking that elevation of plant sterols in the circulation causes coronary heart disease. Therefore, this study aimed to define the risk for coronary heart disease associated with moderately high plant sterol plasma levels in a cohort of elderly.

Plasma levels of plant sterols and the risk of coronary artery disease: the prospective EPIC-Norfolk Population Study.

Some studies have suggested that a modest increase of plant sterol levels is a risk factor for coronary artery disease (CAD). We studied the relationship between plant sterol levels and CAD risk in a prospective nested case-control study consisting of 373 cases and 758 controls. Sitosterol and campesterol concentrations did not differ between cases and controls [sitosterol, 0.

The lipid-lowering effect of ezetimibe in pure vegetarians.

Results of previous studies have shown that ezetimibe (10 mg/day) reduces LDL cholesterol in patients with mild hypercholesterolemia on a normal-cholesterol diet (dietary intake of 200-500 mg/day) by 16-22%. However, the LDL cholesterol-lowering effect of ezetimibe in subjects with an extremely low dietary cholesterol intake (vegetarians) has not been studied. We conducted a randomized, double-blind, placebo-controlled, two-phase crossover study in 18 healthy pure vegetarians to assess the effect of ezetimibe (10 mg/day) on plasma lipids, cholesterol absorption, and its synthesis.

Serum leptin and cytokines in whole blood in relation to clinical and nutritional status in cystic fibrosis.

Objectives: Leptin plays an important role in the energy balance and may be affected by hormonal and metabolic derangement associated with chronic disease. The aim of this study was to assess the correlation between leptin, proinflammatory cytokines and nutritional status with regard to clinical status in homozygous delta F 508 cystic fibrosis patients.

Methods: Patients with mild (Shwachman score 71-100 points, group A) disease were compared with those with moderate disease (Shwachman score 41-55 points, group B) and age-matched controls (group C, n = 22).

A complex plasma plant sterol locus on mouse chromosome 14 has at least two genes regulating intestinal sterol absorption.

We previously identified two inbred mouse strains, C57BL/6J and CASA/Rk, with different plasma plant sterol levels. An intercross between these strains revealed a broad plasma plant sterol locus on chromosome 14, which peaked at 17 centimorgan (cM) with a maximum logarithm of the odds score of 9.9.

Impact of the SLCO1B1 polymorphism on the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin.

Background And Objective: The polymorphism of SLCO1B1 (solute carrier organic anion transporter family, member 1B1), encoding the hepatic uptake transporter organic anion transporting polypeptide 1B1, has been associated with increased pravastatin concentrations in single-dose studies. We have investigated whether this polymorphism influences the pharmacokinetics and lipid-lowering efficacy of multiple-dose pravastatin.

Methods: A prospective, parallel-group study of 16 healthy volunteers, including 8 carriers of an SLCO1B1 variant haplotype and 8 control subjects, was carried out.

Dietary plant sterols accumulate in the brain.

Dietary plant sterols and cholesterol have a comparable chemical structure. It is generally assumed that cholesterol and plant sterols do not cross the blood-brain barrier, but quantitative data are lacking. Here, we report that mice deficient for ATP-binding cassette transporter G5 (Abcg5) or Abcg8, with strongly elevated serum plant sterol levels, display dramatically increased (7- to 16-fold) plant sterol levels in the brain.

Polymorphism in ABCA1 influences CSF 24S-hydroxycholesterol levels but is not a major risk factor of Alzheimer's disease.

The ATP-binding cassette transporter A1 (ABCA1) mediates reverse cholesterol transport, polymorphisms have been shown to influence the levels of cholesterol and of HDL and the risk of coronary artery disease. Since altered cholesterol metabolism is also involved in Alzheimer's disease (AD), the effects of two ABCA1 polymorphisms (G-395C promoter polymorphism (rs 2246293) and exonic R219K) on the risk of AD in 241 AD patients and 294 non-demented controls, and on CSF cholesterol and 24S-hydroxycholesterol in 74 AD patients and 42 non-demented controls were investigated. None of the investigated ABCA1 polymorphisms influenced the risk of AD.

Influence of the SLCO1B1*1b and *5 haplotypes on pravastatin's cholesterol lowering capabilities and basal sterol serum levels.

We previously showed that variant SLCO1B1 haplotype *1b (A388G) accelerates and that *5 (T521C) delays hepatocellular uptake of the HMG-CoA reductase inhibitor pravastatin [Mwinyi et al. (2004): Clin Pharmacol Ther 75:415-421]. In the present study we checked for differential effects of variant SLCO1B1 haplotypes on hepatocellular cholesterol synthesis.

Intestinal expression of P-glycoprotein (ABCB1), multidrug resistance associated protein 2 (ABCC2), and uridine diphosphate-glucuronosyltransferase 1A1 predicts the disposition and modulates the effects of the cholesterol absorption inhibitor ezetimibe in humans.

Background And Aims: Ezetimibe is an inhibitor of the cholesterol uptake transporter Niemann-Pick C1-like protein (NPC1L1). Target concentrations can be influenced by intestinal uridine diphosphate-glucuronosyltransferases (UGTs) and the efflux transporters P-glycoprotein (P-gp) (ABCB1) and multidrug resistance associated protein 2 (MRP2) (ABCC2). This study evaluates the contribution of these factors to the disposition and cholesterol-lowering effect of ezetimibe before and after induction of UGT1A1, P-gp, and MRP2 with rifampin (INN, rifampicin).

Effect of pravastatin on plasma sterols and oxysterols in men.

Objectives: The HMG-CoA reductase inhibitors, or statins, are well established in the prevention and treatment of coronary artery disease, mainly by lowering low-density lipoprotein (LDL) cholesterol levels. These compounds are structurally similar, but differ in their lipophilicity. Several studies have indicated a link between cholesterol and Alzheimer's disease (AD), and there is also epidemiological evidence that statin treatment may decrease the prevalence of dementias.

Regulation of hippocampal cholesterol metabolism by apoE and environmental stimulation.

Alzheimer's disease is associated with genetic risk factors, of which the allele E4 of apolipoprotein E (apoE4) is the most prevalent, and it is also affected by environmental factors such as early life education. We have recently shown, utilizing apoE-deficient and apoE transgenic mice, that synaptogenesis in the hippocampus following environmental stimulation is affected by apoE. In view of the pivotal role of cholesterol in synaptic plasticity, and of its suggested role in synaptogenesis, we presently examined the effects of apoE and environmental stimulation on brain cholesterol homeostasis.

Inhibition of cholesterol absorption by the combination of dietary plant sterols and ezetimibe: effects on plasma lipid levels.

Consumption of plant sterols and treatment with ezetimibe both reduce cholesterol absorption in the intestine. However, the mechanism of action differs between the two treatments, and the consequences of combination treatment are unknown. Therefore, we performed a double-blind, placebo-controlled, crossover study for the plant sterol component with open-label ezetimibe treatment.

Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR- rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR- animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg).

Genetic variant of the SREBF-1 gene is significantly related to cholesterol synthesis in man.

Sterol regulatory element binding proteins-1 and -2 (SREBPs) are transcription factors controlling lipid homeostasis in human cells. The G-allele carriers of the SREBF-1 gene C-G polymorphism in exon 18c and coding for glycine at the protein level (G952G) have shown to associate more frequently with obesity and type 2 diabetes than the C-allele carriers. However, the C-allele has suggested to be linked to dyslipidemia.