Normocholesterolemic Subjects Research Articles

Lipoproteínas y colesterol total en adultos con colesterolemia normal y elevada en un policlínico de Lima-Perú 2022: Un estudio correlacional

Objective: To evaluate the degree of correlation between high-density, low-density, and very low-density lipoproteins and total cholesterol in patients with normal and high cholesterolemia. Methodology: Observational, analytical and cross-sectional study carried out from January to September 2022 with 207 patients over 18 years of age divided into a group with normal cholesterol and another with hypercholesterolemia. The Spearman correlation test was performed. Results: In normocholesterolemic subjects there was a low and negative correlation between high-density lipoproteins and low-density lipoproteins (-0.263) as well as between high-density lipoproteins and very low-density lipoproteins (-0.220). In hypercholesterolemic patients there was a low and positive correlation between high-density lipoproteins and total cholesterol (0.344). In both groups there was a high correlation between cholesterol and low-density lipoproteins and a low and positive correlation between cholesterol and very low-density lipoproteins. Conclusions: Lipoproteins are correlated in normocholesterolemics and high-density lipoproteins are correlated in hypercholesterolemics.

Plasma proteomics identify fibroblast growth factor 5 as a biomarker for genetically proven Familial Hypercholesterolemia

Abstract Background Subjects affected by genetically proven heterozygous Familial Hypercholesterolemia (FH) present lifelong exposure to high Low Density Lipoprotein Cholesterol ("LDL-C burden") causing premature ACVD. Nevertheless, the diagnosis of FH is still far from being optimal due to shortcomings of the clinical algorithms in detecting this form of severe ACVD since early decades of life (1) and because a significant proportion of FH present comparable LDL-C levels to that of subjects who are hypercholesterolemic but are not diagnosed as FH ("non-FH") (2). Purpose We previously demonstrated that targeted proteomics identify subjects at high Atherosclerotic Cardiovascular Diseases (ACVD) risk in the general populations beyond the known risk factors (3). Hence, we now tested whether targeted proteomics may differentiate FH subjects from the general population and from "non-FH". Methods We compared the plasma relative abundance of 264 proteins (Proximity Extension Assay; Olink) in 133 genetically proven FH with that of 586 normocholesterolemic subjects ("controls") and that of 55 non-FH (LDL-C between 190-220 mg/dL, not on statins). We trained and validated a Machine Learning (ML) boosting prediction model (4) in these cohorts to identify the protein markers representative of FH (Random Forest classifiers). Results Fibroblast Growth Factor 5 (FGF-5) resulted as the most powerful plasma protein in differentiating FH subjects from the controls, with an excellent performance (Area Under the Curve (AUC)=0.995 (0.985-1.000); sensitivity=100%; specificity=99.54%; P<0.0001). FGF-5 also emerged as the top protein in differentiating the FH subjects from non-FH (AUC= 1.000 (0.914-1.000; sensitivity=100%, specificity=100% and P<0.001). Finally, when the two groups were matched for LDL-C, FGF-5 still differentiated the FH from the non-FH subjects, (AUC=1.000 (0.914-1.000), sensitivity=100%, specificity=100%, p<0.001). Conclusions FGF-5 allows a clear-cut identification of FH versus controls and, of even more importance, from non-FH with the same LDL-C. The LDL-C burden might be responsible for our findings.

Activity of Na+/K+- and Ca2+-ATPases in human erythrocyte membranes: Protocol improvement, relation to cholesterol content, and effects of polyphenols

It is known that the activities of Na+/K+- and Ca2+-ATPases in the plasma membrane with an excess of cholesterol are compromised. Our main goal was to find out whether quercetin, resveratrol, or caffeic acid, in the nano- and low micromolar concentration ranges, can improve the ATPase activity in human erythrocyte membranes with excess cholesterol. These molecules belong to different chemical classes of polyphenols and are widely present in plant foods. Also, due to some variations in the protocol for determining the ATPase activity, we first analyzed several key parameters of the protocol to improve the accuracy of the results. The activities of Na+/K+- and Ca2+-ATPases were reduced in membranes with moderate and high cholesterol levels compared to membranes from normocholesterolemic subjects (p < 0.01). All three polyphenols affected the ATPase activity in a similar biphasic manner. Namely, the ATPase activity gradually increased with increasing polyphenol concentration up to 80–200 nM, and then gradually decreased with further increase in polyphenol concentration. Moreover, the stimulating effect of the polyphenols was highest in membranes with high cholesterol content, making ATPase activity values close/equal to those in normal cholesterol membranes. In other words, quercetin, resveratrol, and caffeic acid at nanomolar concentrations were able to improve/restore the functioning of Na+/K+- and Ca2+-ATPases in erythrocyte membranes with high cholesterol levels. This suggests a common membrane-mediated mechanism of action for these polyphenols, related to the content of membrane cholesterol.

Differences in Bacterial Small RNAs in Stool Samples from Hypercholesterolemic and Normocholesterolemic Subjects.

Cholesterol metabolism is important at the physiological level as well as in several diseases, with small RNA being an element to consider in terms of its epigenetic control. Thus, the aim of this study was to identify differences between bacterial small RNAs present at the gut level in hypercholesterolemic and normocholesterolemic individuals. Twenty stool samples were collected from hypercholesterolemic and normocholesterolemic subjects. RNA extraction and small RNA sequencing were performed, followed by bioinformatics analyses with BrumiR, Bowtie 2, BLASTn, DESeq2, and IntaRNA, after the filtering of the reads with fastp. In addition, the prediction of secondary structures was obtained with RNAfold WebServer. Most of the small RNAs were of bacterial origin and presented a greater number of readings in normocholesterolemic participants. The upregulation of small RNA ID 2909606 associated with Coprococcus eutactus (family Lachnospiraceae) was presented in hypercholesterolemic subjects. In addition, a positive correlation was established between small RNA ID 2149569 from the species Blautia wexlerae and hypercholesterolemic subjects. Other bacterial and archaeal small RNAs that interacted with the LDL receptor (LDLR) were identified. For these sequences, the prediction of secondary structures was also obtained. There were significant differences in bacterial small RNAs associated with cholesterol metabolism in hypercholesterolemic and normocholesterolemic participants.

Lower plasma PCSK9 in normocholesterolemic subjects is associated with upregulated adipose tissue surface-expression of LDLR and CD36 and NLRP3 inflammasome.

BackgroundLDL‐cholesterol lowering variants that upregulate receptor uptake of LDL, such as in PCSK9 and HMGCR, are associated with diabetes via unclear mechanisms. Activation of the NLRP3 inflammasome/interleukin‐1 beta (IL‐1β) pathway promotes white adipose tissue (WAT) dysfunction and type 2 diabetes (T2D) and is regulated by LDL receptors (LDLR and CD36). We hypothesized that: (a) normocholesterolemic subjects with lower plasma PCSK9, identifying those with higher WAT surface‐expression of LDLR and CD36, have higher activation of WAT NLRP3 inflammasome and T2D risk factors, and; (b) LDL upregulate adipocyte NLRP3 inflammasome and inhibit adipocyte function.MethodologyPost hoc analysis was conducted in 27 overweight/ obese subjects with normal plasma LDL‐C and measures of disposition index (DI during Botnia clamps) and postprandial fat metabolism. WAT was assessed for surface‐expression of LDLR and CD36 (immunohistochemistry), protein expression (immunoblot), IL‐1β secretion (AlphaLISA), and function (3H‐triolein storage).ResultsCompared to subjects with higher than median plasma PCSK9, subjects with lower PCSK9 had higher WAT surface‐expression of LDLR (+81%) and CD36 (+36%), WAT IL‐1β secretion (+284%), plasma IL‐1 receptor‐antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro‐IL‐1β protein (−66%), WAT function (−62%), and DI (−28%), without group‐differences in body composition, energy intake or expenditure. Adjusting for WAT LDLR or CD36 eliminated group‐differences in WAT function, DI, and postprandial hypertriglyceridemia. Native LDL inhibited Simpson‐Golabi Behmel‐syndrome (SGBS) adipocyte differentiation and function and increased inflammation.ConclusionNormocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface‐expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL‐induced inhibition of adipocyte function.

Genetically determined hypercholesterolaemia results into premature leucocyte telomere length shortening and reduced haematopoietic precursors

Leucocyte telomere length (LTL) shortening is a marker of cellular senescence and associates with increased risk of cardiovascular disease (CVD). A number of cardiovascular risk factors affect LTL, but the correlation between elevated LDL cholesterol (LDL-C) and shorter LTL is debated: in small cohorts including subjects with a clinical diagnosis of familial hypercholesterolaemia (FH). We assessed the relationship between LDL-C and LTL in subjects with genetic familial hypercholesterolaemia (HeFH) compared to those with clinically diagnosed, but not genetically confirmed FH (CD-FH), and normocholesterolaemic subjects. LTL was measured in mononuclear cells-derived genomic DNA from 206 hypercholesterolaemic subjects (135 HeFH and 71 CD-FH) and 272 controls. HeFH presented shorter LTL vs. controls (1.27 ± 0.07 vs. 1.59 ± 0.04, P = 0.045). In particular, we found shorter LTL in young HeFH as compared to young controls (<35 y) (1.34 ± 0.08 vs. 1.64 ± 0.08, P = 0.019); moreover, LTL was shorter in statin-naïve HeFH subjects as compared to controls (1.23 ± 0.08 vs. 1.58 ± 0.04, P = 0.001). HeFH subjects presented shorter LTL compared to LDL-C matched CD-FH (1.33 ± 0.05 vs. 1.55 ± 0.08, P = 0.029). Shorter LTL was confirmed in leucocytes of LDLR-KO vs. wild-type mice and associated with lower abundance of long-term haematopoietic stem and progenitor cells (LT-HSPCs) in the bone marrow. Accordingly, HeFH subjects presented lower circulating haematopoietic precursors (CD34 + CD45dim cells) vs. CD-FH and controls. We found (i) shorter LTL in genetically determined hypercholesterolaemia, (ii) lower circulating haematopoietic precursors in HeFH subjects, and reduced bone marrow resident LT-HSPCs in LDLR-KO mice. We support early cellular senescence and haematopoietic alterations in subjects with FH.

Effects of rosuvastatin on the immune system in healthy volunteers with normal serum cholesterol.

BACKGROUNDHMG-CoA reductase inhibitors (statins) are prescribed to millions of people. Statins are antiinflammatory independent of their cholesterol-reducing effects. To date, most reports on the immune effects of statins have assayed a narrow array of variables and have focused on cell lines, rodent models, or patient cohorts. We sought to define the effect of rosuvastatin on the "immunome" of healthy, normocholesterolemic subjects.METHODSWe conducted a prospective study of rosuvastatin (20 mg/d × 28 days) in 18 statin-naive adults with LDL cholesterol <130 mg/dL. A panel of >180 immune/biochemical/endocrinologic variables was measured at baseline and on days 14, 28, and 42 (14 days after drug withdrawal). Drug effect was evaluated using linear mixed-effects models. Potential interactions between drug and baseline high-sensitivity C-reactive protein (hsCRP) were evaluated.RESULTSA wide array of immune measures changed (nominal P < 0.05) during rosuvastatin treatment, although the changes were modest in magnitude, and few met an FDR of 0.05. Among changes noted were a concordant increase in proinflammatory cytokines (IFN-γ, IL-1β, IL-5, IL-6, and TNF-α) and peripheral blood neutrophil frequency, and a decline in activated Treg frequency. Several drug effects were significantly modified by baseline hsCRP, and some did not resolve after drug withdrawal. Among other unexpected rosuvastatin effects were changes in erythrocyte indices, glucose-regulatory hormones, CD8+ T cells, and haptoglobin.CONCLUSIONRosuvastatin induces modest changes in immunologic and metabolic measures in normocholesterolemic subjects, with several effects dependent on baseline CRP. Future, larger studies are warranted to validate these changes and their physiological significance.TRIAL REGISTRATIONClinicalTrials.gov NCT01200836.FUNDINGThis research was supported by the Intramural Research Program of the NIH, National Institute of Environmental Health Sciences (Z01 ES102005), and the trans-NIH Center for Human Immunology.

Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers – a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives.Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972).It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4.At baseline (Visit 2) and during all post-dose visits (Visits 3–4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-NG-monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers.

Higher Adipose Tissue Surface-expression of LDLR and CD36 and Risk Factors for T2D in Normocholesterolemic Subjects with Low Plasma PCSK9

Higher Adipose Tissue Surface-expression of LDLR and CD36 and Risk Factors for T2D in Normocholesterolemic Subjects with Low Plasma PCSK9

Beneficial and Adverse Effects of an LXR Agonist on Human Lipid and Lipoprotein Metabolism and Circulating Neutrophils

The development of LXR agonists for the treatment of coronary artery disease has been challenged by undesirable properties in animal models. Here we show the effects of an LXR agonist on lipid and lipoprotein metabolism and neutrophils in human subjects. BMS-852927, a novel LXRβ-selective compound, had favorable profiles in animal models with a wide therapeutic index in cynomolgus monkeys and mice. In healthy subjects and hypercholesterolemic patients, reverse cholesterol transport pathways were induced similarly to that in animal models. However, increased plasma and hepatic TG, plasma LDL-C, apoB, apoE, and CETP and decreased circulating neutrophils were also evident. Furthermore, similar increases in LDL-C were observed in normocholesterolemic subjects and statin-treated patients. The primate model markedly underestimated human lipogenic responses and did not predict human neutrophil effects. These studies demonstrate both beneficial and adverse LXR agonist clinical responses and emphasize the importance of further translational research in this area.

Atherosclerosis and the Hypercholesterolemic AGE-RAGE Axis.

Background Interaction of advanced glycation end products (AGE) with the receptor for advanced glycation end products (RAGE) has been implicated in the pathogenesis of atherosclerosis. Soluble receptors for advanced glycation end products (sRAGE) act as a decoy for AGE by competing with RAGE and suppressing developing atherosclerosis. Hypercholesterolemia and the oxidative stress are known factors involved in atherosclerosis. High-density lipoprotein cholesterol (HDL-C) is known to exert a protective effect against the development of atherosclerosis. We hypothesize that hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis. Objectives Two objectives to be determined are: (1) if hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and malondialdehyde (MDA: a marker for oxidative stress) and (2) if the protective effect of HDL-C is positively associated with serum sRAGE and negatively correlated with the levels of AGE and AGE/sRAGE. Methods Measurement of serum lipid levels from 100 patients allowed the separation into two groups (hypercholesterolemic and normocholesterolemic). Measurements of serum levels of AGE, sRAGE, and MDA were performed. Results Serum levels of sRAGE were lower, while the levels of AGE and AGE/sRAGE were higher in hypercholesterolemic subjects as compared with normocholesterolemic subjects. sRAGE levels are positively correlated with HDL, while they are negatively correlated with low-density lipoprotein, triglycerides, total cholesterol, and MDA in hypercholesterolemic subjects. Conclusions Hypercholesterolemia is positively correlated with serum AGE, AGE/sRAGE, and MDA. The effect of HDL-C may be due to increases in sRAGE and decreases in the levels of AGE and AGE/sRAGE. Hypercholesterolemia-induced atherosclerosis may be mediated through the AGE-RAGE axis; however, more research must be conducted.

Some Evidences on Effect of Intake Aguamiel (Agave sap)

Honeywater or aguamiel (Agave sap) has been consumed by Mexican population since pre-columbian times. Although, it has been claimed by folk belief that aguamiel possesses some medicinal properties, scientific studies on its effect on human health have not been well documented. The behavior of blood components in nine volunteers (two young males, three adult females and four adult males) after aguamiel consumption (250 mL every three days during a period of 35 days) was analyzed. It was found that, serum red blood cell count, serum white blood cell count, platelet count, minerals (Zn, Mg and Fe) and iron-related proteins (ferritin and transferrin) levels were not negatively affected because of all of these blood indicators ranged within normal reference values. However, this study showed that aguamiel presented a specific functional effect since hypercholesterolemic adult males showed normal levels of serum total cholesterol after aguamiel consumption, whereas total cholesterol levels were kept in normal ranges after aguamiel consumption for normocholesterolemic subjects. Furthermore, aguamiel consumption did not cause hyperglycemia in any of the tested groups.

Arginase inhibition improves endothelial function in patients with familial hypercholesterolaemia irrespective of their cholesterol levels.

Elevated LDL cholesterol is an important risk factor for atherosclerosis. Endothelial dysfunction, an early event in the development of atherosclerosis, is characterized by a reduction in nitric oxide (NO) bioavailability. Arginase has emerged as a key regulator of endothelial function through competition with NO synthase for the common substrate l-arginine. Arginase in endothelial cells is activated by oxidized LDL. The study aim was to investigate the importance of arginase for endothelial dysfunction in patients with familial hypercholesterolaemia (FH). Endothelial function was evaluated in 12 patients with heterozygous FH and 12 age-matched healthy normocholesterolaemic subjects using forearm venous occlusion plethysmography. The evaluations in FH patients occurred when they were on lipid-lowering therapy and 4 weeks after withdrawal of treatment. Endothelium-dependent vasodilatation (EDV) was assessed by intrabrachial artery infusion of serotonin, and endothelium-independent dilatation was assessed by infusion of nitroprusside before and after 120 min administration of the arginase inhibitor N (ω) -hydroxy-nor-l-arginine (nor-NOHA; 0.1 mg min(-1)). In FH patients LDL cholesterol increased from 4.3 ± 0.9 mmol L(-1) at baseline to 7.6 ± 1.9 mmol L(-1) at follow-up (P < 0.001). Arginase inhibition enhanced EDV in FH patients by a similar degree independent of lipid-lowering therapy. The improvement in EDV by arginase inhibition was significantly greater in FH patients than in the control group. Arginase inhibition results in greater improvement in endothelial function in patients with FH compared to healthy controls irrespective of their cholesterol levels. Arginase may be a promising therapeutic target for improving endothelial function in patients with hypercholesterolaemia.

Identification of Genes Selectively Regulated in Human Hepatoma Cells by Treatment With Dyslipidemic Sera and PUFAs.

Serum composition is linked to metabolic diseases not only to understand their pathogenesis but also for diagnostic purposes. Quality and quantity of nutritional intake can affect disease risk and serum composition. It is then possible that diet derived serum components directly affect pathogenetic mechanisms. To identify involved factors, we evaluated the effect on gene expression of direct addition of dyslipidemic human serum samples to cultured human hepatoma cells (HepG2). Sera were selected on the basis of cholesterol level, considering this parameter as mostly linked to dietary intake. Cells were treated with 32 sera from hypercholesterolemic and normocholesterolemic subjects to identify differentially regulated mRNAs using DNA microarray analysis. We identified several mRNAs with the highest modulations in cells treated with dyslipidemic sera versus cells treated with normal sera. Since the two serum groups had variable polyunsaturated fatty acids (PUFAs) contents, selected mRNAs were further assessed for their regulation by docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA) and arachidonic acid (AA). Four genes resulted both affected by serum composition and PUFAs: 3-hydroxy-3-methylglutaryl-CoenzymeA synthase 2 (HMGCS2), glutathione S-transferase alpha 1 (GSTA1), liver expressed antimicrobial peptide 2 (LEAP2) and apolipoprotein M (ApoM). HMGCS2 expression appears the most relevant and was also found modulated via transcription factors peroxysome proliferator activated receptor α (PPARα) and forkhead box O1 (FoxO1). Our data indicate that expression levels of the selected mRNAs, primarily of HMGCS2, could represent a reference of nutritional intake, PUFAs effects and dyslipidemic diseases pathogenesis.

Changes in bile acids, FGF-19 and sterol absorption in response to bile salt hydrolase active L. reuteri NCIMB 30242

The size and composition of the circulating bile acid (BA) pool are important factors in regulating the human gut microbiota. Disrupted regulation of BA metabolism is implicated in several chronic diseases. Bile salt hydrolase (BSH)-active Lactobacillus reuteri NCIMB 30242, previously shown to decrease LDL-cholesterol and increase circulating BA, was investigated for its dose response effect on BA profile in a pilot clinical study. Ten otherwise healthy hypercholesterolemic adults, recruited from a clinical trial site in London, ON, were randomized to consume delayed release or standard release capsules containing L. reuteri NCIMB 30242 in escalating dose over 4 weeks. In another aspect, 4 healthy normocholesterolemic subjects with LDL-C below 3.4 mmol/l received delayed release L. reuteri NCIMB 30242 at a constant dose over 4 weeks. The primary outcome measure was the change in plasma BA profile over the intervention period. Additional outcomes included circulating fibroblast growth factor (FGF)-19, plant sterols and LDL-cholesterol as well as fecal microbiota and bsh gene presence. After one week of intervention subjects receiving delayed release L. reuteri NCIMB 30242 increased total BA by 1.13 ± 0.67 μmol/l (P = 0.02), conjugated BA by 0.67 ± 0.39 μmol/l (P = 0.02) and unconjugated BA by 0.46 ± 0.43 μmol/l (P = 0.07), which represented a greater than 2-fold change relative to baseline. Increases in BA were largely maintained post-week 1 and were generally correlated with FGF-19 and inversely correlated with plant sterols. This is the first clinical support showing that a BSH-active probiotic can significantly and rapidly influence BA metabolism and may prove useful in chronic diseases beyond hypercholesterolemia.

Oxidized low density lipoprotein concentration is associated with thyrotropin levels in euthyroid normocholesterolemic subjects

Oxidized low density lipoprotein concentration is associated with thyrotropin levels in euthyroid normocholesterolemic subjects

Effects of Mangifera pajang Kostermans juice on plasma antioxidant status and liver and kidney function in normocholesterolemic subjects

The effects of a bambangan juice powder (BJP) drink on plasma vitamin and antioxidant enzyme levels and liver and kidney function were investigated. Thirty-two healthy subjects (12 male and 20 female) ages 24–28years were recruited from the Faculty of Medicine and Health Sciences of University Putra Malaysia, Malaysia. Compared with consuming the placebo, consumption of the BJP drink daily for 9weeks significantly increased the concentration of plasma β-carotene and ascorbic acid. Plasma total antioxidant status was increased, but liver and kidney functions were unaffected after consumption of the BJP drink. The consumption of a BJP drink resulted in a significant improvement in certain cardiovascular biochemical parameters and thus reduced the risk of cardiovascular disease.

Effects of legume kernel fibres and citrus fibre on putative risk factors for colorectal cancer: a randomised, double-blind, crossover human intervention trial

BackgroundIn some studies, high intake of dietary fibre has been associated with a lower risk of colorectal cancer. The present study aimed to compare physiological effects of three legume kernel fibres and citrus fibre on blood lipids (primary outcome: LDL cholesterol) and colonic health.MethodsNinety-two subjects were recruited for the double-blind, controlled crossover trial. Seventy-eight participants were randomly divided into three groups. Following run-in, half the volunteers from each group consumed 25 g/d of a legume fibre, comprising blue lupin fibre, white lupin fibre, and soya fibre for two weeks. The other half received the same amount of citrus fibre (active comparator). The intervention was crossed within each group after two weeks wash-out. At the end of run-in and intervention, a quantitative faeces collection took place and fasting blood samples were drawn. Repeated measures ANOVA with the general linear model were applied to evaluate changes following interventions.ResultsSeventy-six subjects completed the study. Dietary fibre intake during all interventions was approximately twice the fibre intake at run-in. The lupin fibre supplementations increased daily faecal dry matter and faecal weight compared to run-in, representing an increase of 1.76 g faeces/g additional dietary fibre contributed by blue lupin and of 1.64 g faeces/g by white lupin, respectively. Both lupin interventions led to a significantly enhanced formation of short-chain fatty acids, and blue lupin fibre to a decrease in faecal pH compared to run-in (0.27 units, P < 0.01). Further, blue lupin increased primary bile acids-excretion (P = 0.02). All legume fibres reduced faecal concentrations of total and secondary bile acids (blue lupin: 16%; white lupin: 24%; soya: 16%). Blood lipids were not influenced by any intervention. No serious adverse effects were observed.ConclusionsThe tested fibre preparations do not affect lipid metabolism through bile acid-binding in normocholesterolaemic subjects. However, particularly blue lupin kernel fibre improve colonic function and have beneficial effects on putative risk factors for colorectal cancer such as faecal mass, transit time, SCFA, faecal pH, and secondary bile acid concentration. Therefore, enhancing dietary fibre intake through blue lupin up to about 50 g/d can be recommended.Trial registrationNCT01036308

Lowering LDL cholesterol, but not raising LDL receptor activity, by ezetimibe

Ezetimibe, an inhibitor of intestinal cholesterol absorption, is effective in lowering serum low-density lipoprotein (LDL) cholesterol with or without coadministration of statin. Ezetimibe-plus-statin therapy enhances LDL receptor activity, but it is still unclear whether ezetimibe alone enhances LDL receptor activity, resulting in LDL cholesterol decrease. We investigated whether ezetimibe lowers serum LDL cholesterol by raising LDL receptor activity in humans. Patients with hypercholesterolemia (n= 28; age [mean ± SD], 61.6 ± 13.0 years; 57% men) were treated with ezetimibe (10 mg/d) for 4 months. Before and after the treatment, serum LDL cholesterol, apolipoprotein B (apo B), and apolipoprotein C-II (apo C-II) were measured. LDL receptor activities were estimated with the equation we reported previously as follows: LDL receptor activity (represented as a percentage of normocholesterolemic subjects)= 63.595+ apo C-II (in mg/dL) × 13.459-apo B (in mg/dL) × 0.366. By the treatment of ezetimibe, LDL cholesterol (176.8 ± 17.9 vs 138.0 ± 19.7 mg/dL) was lowered 21.9% significantly (P < .01). The estimated LDL receptor activities before and after the ezetimibe treatment were 86.8% ± 21.4% and 89.6% ± 19.7%, respectively, with no significant difference between them (P= .13). Ezetimibe lowered LDL cholesterol significantly in patients with hypercholesterolemia without raising LDL receptor activity. The enhancement of LDL receptor activity is less involved in the pharmacologic action of ezetimibe.

Abstract 9703: Lowering LDL Cholesterol, but not Raising LDL Receptor Activity, by Ezetimibe

Introduction: Ezetimibe, an inhibitor of intestinal cholesterol absorption, is effective in lowering serum low-density lipoprotein (LDL) cholesterol with or without co-administration of statin. Ezetimibe-plus-statin therapy enhances LDL receptor activity, but it is still unclear whether ezetimibe alone enhances LDL receptor activity resulting in LDL cholesterol decrease. Hypothesis: We assessed the hypothesis that ezetimibe lowers serum LDL cholesterol by raising LDL receptor activity in humans. Methods: Hypercholesterolemic patients (n = 28; age 61.3 ± 12.7 (mean ± SD); 57% male) were treated with ezetimibe (10 mg/day) for 4 months. Before and after the treatment, serum LDL cholesterol, high-density lipoprotein (HDL) cholesterol, and triglyceride were measured. Serum apolipoprotein A-I (apo A-I), B (apo B), and C-II (apo C-II) were also measured and the estimated LDL receptor activities were calculated by our previously reported methods as follows: LDL receptor activity (expressed as a percentage of normocholesterolemic subjects) = 63.6 + apo C-II (mg/dl) x 13.5 - apo B (mg/dl) x 0.37. Results: By the treatment of ezetimibe, LDL cholesterol (178.5 ± 26.2 vs. 141.1 ± 26.2 mg/dl, p &lt; 0.01) was lowered 21% significantly and HDL cholesterol (56.1 ± 12.3 vs. 59.5 ± 16.2 mg/dl, p &lt; 0.01) was increased 6% significantly. Triglyceride (184.4 ± 85.6 vs.174.8 ± 85.2 mg/dl, p = 0.60) was not changed. Serum apo B (136.2 ± 24.5 vs. 113.0 ± 23.8 mg/dl, p &lt; 0.01) was lowered 17% significantly and apo A-I (143.5 ± 28.5 vs. 150.3 ± 31.9 mg/dl, p &lt; 0.01) was increased 5% significantly. Apo C-II (5.9 ± 2.2 vs. 5.5 ± 2.2 mg/dl, p = 0.11) was not changed. The estimated LDL receptor activities before and after the ezetimibe treatment were 93.5 ± 25.1% and 96.9 ± 24.4%, respectively with no significant difference between them (p = 0.14). Conclusions: Ezetimibe lowered LDL cholesterol 21% significantly in hypercholesterolemic patients without raising LDL receptor activity. In conclusion, the enhancement of LDL receptor activity is suggested to be less involved in the pharmacological action of ezetimibe.