Nutrition and Toxicology Research Institute Maastricht NUTRIM

Maastricht, Netherlands

Nutrition and Toxicology Research Institute Maastricht NUTRIM

Maastricht, Netherlands

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Phillips C.M.,University College Dublin | Goumidi L.,French Institute of Health and Medical Research | Bertrais S.,French Institute of Health and Medical Research | Field M.R.,Hitachi Dublin Laboratory | And 15 more authors.
Journal of Lipid Research | Year: 2010

Acetyl-CoA carboxylase β (ACC2) plays a key role in fatty acid synthesis and oxidation pathways. Disturbance of these pathways is associated with impaired insulin responsiveness and metabolic syndrome (MetS). Gene-nutrient interactions may affect MetS risk. This study determined the relationship between ACC2 polymorphisms (rs2075263, rs2268387, rs2284685, rs2284689, rs2300453, rs3742023, rs3742026, rs4766587, and rs6606697) and MetS risk, and whether dietary fatty acids modulate this in the LIPGENE-SU. VI.MAX study of MetS cases and matched controls (n = 1754). Minor A allele carriers of rs4766587 had increased MetS risk (OR 1.29 [CI 1.08, 1.58], P = 0.0064) compared with the GG homozygotes, which may in part be explained by their increased body mass index (BMI), abdominal obesity, and impaired insulin sensitivity (P < 0.05). MetS risk was modulated by dietary fat intake (P = 0.04 for gene-nutrient interaction), where risk conferred by the A allele was exacerbated among individuals with a high-fat intake (>35% energy) (OR 1.62 [CI 1.05, 2.50], P = 0.027), particularly a high intake (>5.5% energy) of n-6 polyunsaturated fat (PUFA) (OR 1.82 [CI 1.14, 2.94], P = 0.01; P = 0.05 for gene-nutrient interaction). Saturated and monounsaturated fat intake did not modulate MetS risk. Importantly, we replicated some of these findings in an independent cohort.jlr In conclusion, the ACC2 rs4766587 polymorphism influences MetS risk, which was modulated by dietary fat, suggesting novel gene-nutrient interactions.

Ferguson J.F.,University College Dublin | Phillips C.M.,University College Dublin | McMonagle J.,University College Dublin | Perez-Martinez P.,University of Cordoba, Spain | And 14 more authors.
Atherosclerosis | Year: 2010

Objective: Omega-3 polyunsaturated fatty acids (n-3 PUFA) may protect against the development of cardiovascular disease (CVD). Genotype at key genes such as nitric oxide synthase (NOS3) may determine responsiveness to fatty acids. Gene-nutrient interactions may be important in modulating the development of CVD, particularly in high-risk individuals with the metabolic syndrome (MetS). Methods: Biomarkers of CVD risk, plasma fatty acid composition, and NOS3 single nucleotide polymorphism (SNP) genotype (rs11771443, rs1800783, rs1800779, rs1799983, rs3918227, and rs743507) were determined in 450 individuals with the MetS from the LIPGENE dietary intervention cohort. The effect of dietary fat modification for 12 weeks on metabolic indices of the MetS was determined to understand potential NOS3 gene-nutrient interactions. Results: Several markers of inflammation and dyslipidaemia were significantly different between the genotype groups. A significant gene-nutrient interaction was observed between the NOS3 rs1799983 SNP and plasma n-3 PUFA status on plasma triacylglycerol (TAG) concentrations. Minor allele carriers (AC. +. AA) showed an inverse association with significantly higher plasma TAG concentrations in those with low plasma n-3 PUFA status and vice versa but the major allele homozygotes (CC) did not. Following n-3 PUFA supplementation, plasma TAG concentrations of minor allele carriers of rs1799983 were considerably more responsive to changes in plasma n-3 PUFA, than major allele homozygotes. Conclusions: Carriers of the minor allele at rs1799983 in NOS3 have plasma TAG concentrations which are more responsive to n-3 PUFA. This suggests that these individuals might show greater beneficial effects of n-3 PUFA consumption to reduce plasma TAG concentrations. © 2010 Elsevier Ireland Ltd.

Delgado-Lista J.,University of Cordoba, Spain | Perez-Martinez P.,University of Cordoba, Spain | Garcia-Rios A.,University of Cordoba, Spain | Phillips C.M.,University College Dublin | And 14 more authors.
Atherosclerosis | Year: 2011

Aims/hypothesis: Variants of the TCF7L2 gene predict the development of type 2 diabetes mellitus (T2DM). We investigated the associations between gene variants of TCF7L2 and clinical features of the metabolic syndrome (MetS) (an entity often preceeding T2DM), and their interaction with non-genetic factors, including plasma saturated fatty acids (SFA) concentration and insulin resistance (IR). Methods: Fasting lipid profiles, insulin sensitivity, insulin secretion, anthropometrics, blood pressure and 10 gene variations of the TCF7L2 gene were determined in 450 subjects with MetS. Results: Several single nucleotide polymorphisms (SNP) showed phenotypic associations independent of SFA or IR. Carriers of the rare T allele of rs7903146, and of three other SNPs in linkage disequilibrium with rs7903146, had lower blood pressure and insulin secretion. High IR and the presence of the T-allele of rs7903146 acted synergistically to define those with reduced insulin secretion. Carriers of the minor allele of rs290481 exhibited an altered lipid profile, with increased plasma levels of apolipoprotein B, non-esterified fatty acids, cholesterol and apolipoprotein B in triglyceride rich lipoproteins, and LDL cholesterol. Carriers of the minor allele of rs11196224 that had higher plasma SFA levels showed elevated procoagulant/proinflammatory biomarkers, impaired insulin secretion and increased IR, whereas carriers of the minor allele of rs17685538 with high plasma SFA levels exhibited higher blood pressure. Conclusions/interpretation: SNP in the TCF7L2 gene are associated with differences in insulin secretion, blood pressure, blood lipids and coagulation in MetS patients, and may be modulated by SFA in plasma or IR. © 2010 Elsevier Ireland Ltd.

Phillips C.M.,University College Dublin | Phillips C.M.,University College Cork | Tierney A.C.,University College Dublin | Perez-Martinez P.,University of Cordoba, Spain | And 12 more authors.
Obesity | Year: 2013

Objective: Obesity is a key factor in the development of the metabolic syndrome (MetS), which is associated with increased cardiometabolic risk. We investigated whether obesity classification by BMI and body fat percentage (BF%) influences cardiometabolic profile and dietary responsiveness in 486 MetS subjects (LIPGENE dietary intervention study). Design and Methods: Anthropometric measures, markers of inflammation and glucose metabolism, lipid profiles, adhesion molecules, and hemostatic factors were determined at baseline and after 12 weeks of four dietary interventions (high saturated fat (SFA), high monounsaturated fat (MUFA), and two low fat high complex carbohydrate (LFHCC) diets, one supplemented with long chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs)). Results: About 39 and 87% of subjects classified as normal and overweight by BMI were obese according to their BF%. Individuals classified as obese by BMI (≥30 kg/m2) and BF% (≥25% (men) and ≥35% (women)) (OO, n = 284) had larger waist and hip measurements, higher BMI and were heavier (P < 0.001) than those classified as nonobese by BMI but obese by BF% (NOO, n = 92). OO individuals displayed a more proinflammatory (higher C reactive protein (CRP) and leptin), prothrombotic (higher plasminogen activator inhibitor-1 (PAI-1)), proatherogenic (higher leptin/adiponectin ratio) and more insulin resistant (higher HOMA-IR) metabolic profile relative to the NOO group (P < 0.001). Interestingly, tumor necrosis factor-α (TNF-α) concentrations were lower post-intervention in NOO individuals compared with OO subjects (P < 0.001). Conclusions: In conclusion, assessing BF% and BMI as part of a metabotype may help to identify individuals at greater cardiometabolic risk than BMI alone.

van Summeren A.,Maastricht University | van Summeren A.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | Renes J.,Maastricht University | Bouwman F.G.,Maastricht University | And 6 more authors.
Toxicological Sciences | Year: 2011

Unexpected hepatotoxicity is one of the major reasons of drugs failing in clinical trials. This emphasizes the need for new screening methods that address toxicological hazards early in the drug discovery process. Here, proteomics techniques were used to gain further insight into the mechanistic processes of the hepatotoxic compounds. Drug-induced hepatotoxicity is mainly divided in hepatic steatosis, cholestasis, or necrosis. For each class, a compound was selected, respectively amiodarone, cyclosporin A, and acetaminophen. The changes in protein expressions in HepG2, after exposure to these test compounds, were studied using quantitative two-dimensional differential gel electrophoresis. Identification of differentially expressed proteins was performed by Maldi-TOF/TOF MS and liquid chromatography-tandem mass spectrometry. In this study, 254 differentially expressed protein spots were detected in a two-dimensional proteome map from which 86 were identified, showing that the proteome of HepG2 cells is responsive to hepatotoxic compounds, cyclosporin A treatment was responsible for most differentially expressed proteins and could be discriminated in the hierarchical clustering analysis. The identified differential proteins show that cyclosporin A may induce endoplasmic reticulum (ER) stress and disturbs the ER-Golgi transport, with an altered vesicle-mediated transport and protein secretion as result. Moreover, the differential protein pattern seen after cyclosporin A treatment can be related to cholestatic mechanisms. Therefore, our findings indicate that the HepG2 in vitro cell system has distinctive characteristics enabling the assessment of cholestatic properties of novel compounds at an early stage of drug discovery. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.

Geraedts M.C.P.,Maastricht University | Geraedts M.C.P.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | Troost F.J.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | Troost F.J.,Maastricht University | And 8 more authors.
Obesity | Year: 2012

By developing novel screening technologies to test effects of food ingredients on hormone release, which are comparable to the in vivo situation, fewer tests may have to be performed using volunteers, whereas it still provides information that can be extrapolated to the human situation. In an in vivo intervention study, 10 lean (BMI: 20-25kg/m 2) and 10 obese (BMI > 30kg/m 2) were recruited. All subjects randomly received pea protein (PP) solutions or placebo, orally and intraduodenally. Cholecystokinin (CCK) and glucagon like peptide 1 (GLP-1) release was measured over 2h. During the oral interventions, gastrointestinal (GI) fluids were retrieved. For the present ex vivo study, duodenal biopsies were taken and placed in Ussing chambers. The luminal side was exposed to PP, placebo, intraduodenal fluid after oral PP-intake and oral placebo-intake in vivo, and a commercial pea-hydrolysate for 2h. CCK and GLP-1 levels were measured at the serosal side. After intraduodenal PP administration in vivo, the area under the curve (AUC) for both CCK and GLP-1 was significantly increased in both lean and obese subjects. In the ex vivo study, exposure to PP resulted in significantly elevated levels of CCK and GLP-1 compared to all other test solutions. These results indicate that the ex vivo Ussing chamber technology is a valid alternative for in vivo studies, and may therefore serve as a suitable screening tool for studying the effects of nutritional compounds on the release of satiety hormones. © 2011 The Obesity Society.

Smerecnik C.,Maastricht University | Smerecnik C.,School for Public Health and Primary Care CAPHRI | Grispen J.E.J.,School for Public Health and Primary Care CAPHRI | Grispen J.E.J.,Maastricht University | And 3 more authors.
Tobacco Control | Year: 2012

Objective To examine whether genetic testing for smoking-related diseases benefits smoking cessation. Data sources PubMed, EMBASE, ERIC, PsycINFO, PsychArticles, CiNAHL and socINDEX databases, the search engine Google Scholar, and key-author and reference list searches. Study selection Randomised controlled smoking cessation interventions using genetic testing for smoking-related diseases. Data extraction Consistent with the Cochrane guidelines, two reviewers completed the review process (initial n=139) in three phases, title selection (n=56), abstract selection (n=28) and whole paper selection (n=9). From these nine studies, each reviewer extracted information about outcome measures and statistical and methodological quality. Data synthesis Relevant data were abstracted from included papers and were subsequently subjected to meta-analysis. Results Interest in genetic testing was relatively high with 60-80% of smokers reporting to be interested. The authors observed positive short-term effects on risk perception, motivation to quit smoking and smoking cessation, but these effects fade at longer follow-ups. Importantly, the authors did not find any evidence of adverse effect of testing negative on the risk-predisposing gene. Conclusions This systematic review does not provide solid evidence for the proposed beneficial effects of genetic testing for smoking-related diseases on smoking cessation, but does suggest the presence of an immediate motivational effect, such that genetic testing resulted in higher risk perception and more motivation to quit smoking.

Bracke K.R.,Ghent University | Dentener M.A.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | Papakonstantinou E.,Maastricht University | Vernooy J.H.J.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | And 7 more authors.
American Journal of Respiratory Cell and Molecular Biology | Year: 2010

Chronic obstructive pulmonary disease (COPD) is characterized by infiltration of inflammatory cells, destruction of lung parenchyma, and airway wall remodeling. Hyaluronan (HA) is a component of the extracellular matrix, and low-molecular-weight (LMW) HA fragments have proinflammatory capacities. We evaluated the presence of HA in alveolar and airway walls of C57BL/6 mice that were exposed to air or cigarette smoke (CS) for 4 weeks (subacute) or 24 weeks (chronic). We measured deposition of the extracellular matrix proteins collagen and fibronectin in airway walls and determined the molecular weight of HA purified from lung tissue. In addition, we studied the expression of HA-modulating genes by RT-PCR. HA staining in alveolar walls was significantly enhanced upon chronic CS exposure, whereas HA levels in the airway walls were already significantly higher upon subacute CS exposure and remained elevated upon chronic CS exposure. This differed from the deposition of collagen and fibronectin, which are only elevated at the chronic time point. In lungs of CS-exposed mice, the molecular weight of HA clearly shifted toward more LMW HA fragments. CS exposure significantly increased the mRNA expression of the HA synthase gene Has3 in total lung tissue, whereas the expression of Has1 was decreased. These in vivo studies in an experimental model of COPD show that CS exposure leads to enhanced deposition of (mostly LMW) HA in alveolar and bronchial walls by altering the expression of HA-modulating enzymes. This may contribute to airway wall remodeling and pulmonary inflammation in COPD.

Touwslager R.N.H.,Maastricht University | Houben A.J.H.M.,Maastricht University | Gielen M.,Maastricht University | Gielen M.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | And 10 more authors.
Journal of Hypertension | Year: 2012

Objective: The fetal response to an adverse intrauterine environment-reflected in low birth weight-is thought to cause an increased risk for adult hypertension. A possible mechanism by which fetal adaptive responses contribute to hypertension is an adverse effect on endothelial function. Identifying individuals with endothelial dysfunction as early as possible may assist in understanding the inverse association between birth weight and hypertension. The present study aimed to identify determinants of endothelial vasodilatation in the first week of life. Methods: One hundred and four term newborns were studied in the first week after birth with regard to maximum vasodilatation in response to acetylcholine (endothelium-dependent) and nitroprusside (endothelium-independent) in the vasculature of the forearm skin, by use of a laser-Doppler device and iontophoresis. Bivariable and multivariable linear regression with various familial, gestational and neonatal potential covariates were used for the analysis. Results: In the bivariable analysis, maximum perfusion after administration of acetylcholine was positively associated with birth weight, length, head circumference and maternal education level, but negatively associated with maternal hypertension during pregnancy. In the multivariable analysis, head circumference [b = 11.9 perfusion units/z-score, P = 0.02] and hypertension during pregnancy (b =-25.3 perfusion units from nonhypertensive to hypertensive, P = 0.02) remained significantly associated. Maximum perfusion after administration of nitroprusside was not related to any of the anthropometric measures; it was, however, related to gestational age (b =-11.1 perfusion units/week, P = 0.009). Conclusion: This study showed that body size, head circumference in particular, is positively associated with endothelial vasodilatation in newborns, whereas hypertension during pregnancy is inversely associated with endothelial vasodilatation. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Schellekens D.H.S.M.,Maastricht University | Schellekens D.H.S.M.,Nutrition and Toxicology Research Institute Maastricht NUTRIM | Grootjans J.,Slotervaartziekenhuis | Dello S.A.W.G.,Amphia Ziekenhuis | And 10 more authors.
Journal of Clinical Gastroenterology | Year: 2014

BACKGROUND AND AIM:: Intestinal fatty acid-binding protein (I-FABP) is a useful marker in the detection of intestinal ischemia. However, more insight into the test characteristics of I-FABP release is needed. This study aimed to investigate the relationship between plasma I-FABP levels and the severity of ischemic mucosal injury, and define the clinical usefulness of systemic I-FABP following ischemia. METHODS:: In a human experimental model, 6 cm of the jejunum, to be removed for surgical reasons, was selectively exposed to either 15, 30, or 60 minutes of ischemia (I) followed by 30 and 120 minutes of reperfusion (R). Blood and tissue was sampled at all time points. Arteriovenous (V-A) concentration differences of I-FABP were measured. Tissue sections were stained with hematoxylin/eosin, and villus height was measured to score epithelial damage. RESULTS:: Histologic analysis showed only minor reversible intestinal damage following 15I and 30I; however, severe irreversible epithelial damage was observed in the jejunum exposed to 60I. I-FABP V-A differences paralleled the degree of tissue damage over time [7.79 (±1.8) ng/mL, 128.6 (±44.2) ng/mL, 463.3 (±139.8) ng/mL for 15I, 30I and 60I, respectively]. A good correlation was found between histologic epithelial damage and V-A I-FABP (r=-0.82, P<0.001). Interestingly, systemic I-FABP levels were significantly increased after 60I of this short small intestinal segment. CONCLUSIONS:: This study demonstrates the relationship between the duration of ischemia and the extent of tissue damage, which is reflected by I-FABP V-A plasma levels. In addition, systemic I-FABP levels appear valuable in detecting irreversible intestinal ischemia-reperfusion damage. Copyright © 2013 by Lippincott Williams & Wilkins.

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