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Chronic Oral Administration of Mineral Oil Compared With Corn Oil: Effects on Gut Permeability and Plasma Inflammatory and Lipid Biomarkers

Pieterman, E.J. (author), Princen, H.M.G. (author), Jarke, A. (author), Nilsson, R. (author), Cavallin, A. (author), Bergenholm, L. (author), Henricsson, M. (author), Gopaul, V.S. (author), Agrawal, R. (author), Nissen, S.E. (author), Hurt-Camejo, E. (author)

We investigated the effects of chronic oral administration of mineral oil, versus corn oil as control, on intestinal permeability, inflammatory markers, and plasma lipids in APOE*3-Leiden.CETP mice. Mice received mineral oil or corn oil 15 or 30 μL/mouse/day for 16 weeks (15 mice/group). Intestinal permeability was increased with mineral versus...

article 2021

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Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice

Pouwer, M.G. (author), Pieterman, E.J. (author), Worms, N. (author), Keijzer, N. (author), Jukema, J.W. (author), Gromada, J. (author), Gusarova, V. (author), Princen, H.M.G. (author)

Atherosclerosis-related cardiovascular disease causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab-monoclonal...

article 2020

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The AT04A vaccine against proprotein convertase subtilisin/kexin type 9 reduces total cholesterol, vascular inflammation, and atherosclerosis in APOE*3Leiden.CETP mice

Landlinger, C. (author), Pouwer, M.G. (author), Juno, C. (author), van der Hoorn, J.W.A. (author), Pieterman, E.J. (author), Jukema, J.W. (author), Staffler, G. (author), Princen, H.M.G. (author), Galabova, G. (author)

Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising therapeutic target for the treatment of hypercholesterolaemia and atherosclerosis. PCSK9 binds to the low density lipoprotein receptor and enhances its degradation, which leads to the reduced clearance of low density lipoprotein cholesterol (LDLc) and a higher...

article 2017

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The effect of the apolipoprotein E genotype on response to personalized dietary advice intervention: Findings from the Food4Me randomized controlled trial

Fallaize, R. (author), Celis-Morales, C. (author), MacReady, A.L. (author), Marsaux, C.F.M. (author), Forster, H. (author), O'Donovan, C. (author), Woolhead, C. (author), San-Cristobal, R. (author), Kolossa, S. (author), Hallmann, J. (author), Mavrogianni, C. (author), Surwillo, A. (author), Livingstone, K.M. (author), Moschonis, G. (author), Navas-Carretero, S. (author), Walsh, M.C. (author), Gibney, E.R. (author), Brennan, L. (author), Bouwman, J. (author), Grimaldi, K. (author), Manios, Y. (author), Traczyk, I. (author), Drevon, C.A. (author), Martinez, J.A. (author), Daniel, H. (author), Saris, W.H.M. (author), Gibney, M.J. (author), Mathers, J.C. (author), Lovegrove, J.A. (author)

Background: The apolipoprotein E (APOE) risk allele (e4) is associated with higher total cholesterol (TC), amplified response to saturated fatty acid (SFA) reduction, and increased cardiovascular disease. Although knowledge of gene risk may enhance dietary change, it is unclear whether e4 carriers would benefit from gene-based personalized...

article 2016

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Comment on "Hypercholesterolemia with consumption of PFOA-laced Western diets is dependent on strain and sex of mice" by Rebholz S.L. et al. Toxicol. Rep. 2016 (3) 46-54

Princen, H.M.G. (author), Pouwer, M.G. (author), Pieterman, E.J. (author)

article 2016

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Innovative pharmaceutical interventions in cardiovascular disease: Focusing on the contribution of non-HDL-C/LDL-C-lowering versus HDL-C-raisingA systematic review and meta-analysis of relevant preclinical studies and clinical trials

Kühnast, S. (author), Fiocco, M. (author), van der Hoorn, J.W.A. (author), Princen, H.M.G. (author), Jukema, J.W. (author)

Non-HDL-cholesterol is well recognised as a primary causal risk factor in cardiovascular disease. However, despite consistent epidemiological evidence for an inverse association between HDL-C and coronary heart disease, clinical trials aimed at raising HDL-C (AIM-HIGH, HPS2-THRIVE, dal-OUTCOMES) failed to meet their primary goals. This...

article 2015

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Alirocumab inhibits atherosclerosis, improves the plaque morphology, and enhances the effects of a statin

Kühnast, S. (author), van der Hoorn, J.W.A. (author), Pieterman, E.J. (author), van den Hoek, A.M. (author), Sasiela, W.J. (author), Gusarova, V. (author), Peyman, A. (author), Schäfer, H.L. (author), Schwahn, U. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition is a potential novel strategy for treatment of CVD. Alirocumab is a fully human PCSK9 monoclonal antibody in phase 3 clinical development. We evaluated the antiatherogenic potential of alirocumab in APOE∗3Leiden. CETP mice. Mice received a Western-type diet and were treated with...

article 2014

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Effects of probiotic Lactobacillus rhamnosus GG and Propionibacterium freudenreichii ssp. shermanii JS supplementation on intestinal and systemic markers of inflammation in ApoE*3Leiden mice consuming a high-fat diet

Oksaharju, A. (author), Kooistra, T. (author), Kleemann, R. (author), van Duyvenvoorde, W. (author), Miettinen, M. (author), Lappalainen, J. (author), Lindstedt, K.A. (author), Kovanen, P.T. (author), Korpela, R. (author), Kekkonen, R.A. (author)

A high-fat diet disturbs the composition and function of the gut microbiota and generates local gut-associated and also systemic responses. Intestinal mast cells, for their part, secrete mediators which play a role in the orchestration of physiological and immunological functions of the intestine. Probiotic bacteria, again, help to maintain the...

article 2013

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Aliskiren inhibits atherosclerosis development and improves plaque stability in APOE*3Leiden.CETP transgenic mice with or without treatment with atorvastatin

Kühnast, S. (author), van der Hoorn, J.W.A. (author), van den Hoek, A.M. (author), Havekes, L.M. (author), Liau, G. (author), Jukema, J.W. (author), Princen, H.M.G. (author)

Objective: Aliskiren is the first commercially available, orally active, direct renin inhibitor approved to treat hypertension. The renin-angiotensin system has been shown to be a significant contributor to the development of hypercholesterolemia-induced atherosclerosis. The aim of this study was to evaluate the antiatherosclerotic and plaque...

article 2012

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The dual PPARα/γ agonist tesaglitazar blocks progression of pre-existing atherosclerosis in APOE*3Leiden.CETP transgenic mice

van der Hoorn, J.W.A. (author), Jukema, J.W. (author), Havekes, L.M. (author), Lundholm, E. (author), Camejo, G. (author), Rensen, P.C.N. (author), Princen, H.M.G. (author), TNO Kwaliteit van Leven (author)

Background and purpose: We have evaluated the effects of a peroxisome proliferator-activated receptor (PPAR)α/γ agonist on the progression of pre-existing atherosclerotic lesions in APOE*3Leiden.cholesteryl ester transfer protein (E3L.CETP) transgenic mice. Experimental approach: E3L.CETP mice were fed a high-cholesterol diet for 11 weeks to...

article 2009

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Niacin increases HDL by reducing hepatic expression and plasma levels of cholesteryl ester transfer protein in APOE*3Leiden.CETP mice

van der Hoorn, J.W.A. (author), de Haan, W. (author), Berbée, J.P.P. (author), Havekes, L.M. (author), Jukema, J.W. (author), Rensen, P.C. (author), Princen, H.M.G. (author), TNO Kwaliteit van Leven (author)

Objective - Niacin potently decreases plasma triglycerides and LDL-cholesterol. In addition, niacin is the most potent HDL-cholesterol- increasing drug used in the clinic. In the present study, we aimed at elucidation of the mechanism underlying its HDL-raising effect. Methods and Results - InAPOE*3Leiden transgenic mice expressing the human...

article 2008

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Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis

Nieuwenhuizen, W.F. (author), Duivenvoorden, I. (author), Voshol, P.J. (author), Rensen, P.C.N. (author), van Duyvenvoorde, W. (author), Romijn, J.A. (author), Emeis, J.J. (author), Havekes, L.M. (author), TNO Kwaliteit van Leven (author)

The prevalence of dyslipidemia and obesity resulting from excess energy intake and physical inactivity is increasing. The liver plays a pivotal role in the systemic lipid homeostasis. Effective, natural dietary interventions that lower plasma lipids and promote liver health are needed. APOE*3Leiden mice were fed a Western-type diet, supplemented...

article 2007

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Olmesartan and pravastatin additively reduce development of atherosclerosis in APOE*3Leiden transgenic mice

TNO Kwaliteit van Leven (author), van der Hoorn, J.W.A. (author), Kleemann, R. (author), Havekes, L.M. (author), Kooistra, T. (author), Princen, H.M.G. (author), Jukema, J.W. (author)

AIM: This study was designed to investigate the effect of the angiotensin II receptor blocker olmesartan alone, or in combination with standard treatment with a statin, pravastatin, on atherosclerosis development in APOE*3Leiden transgenic mice. METHODS AND RESULTS: Four groups of 15 mice received an atherogenic diet alone (plasma cholesterol 17...

article 2007

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Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF)

Burger-Kentischer, A. (author), Göbel, H. (author), Kleemann, R. (author), Zernecke, A. (author), Bucala, R. (author), Leng, L. (author), Finkelmeier, D. (author), Geiger, G. (author), Schaefer, H.E. (author), Schober, A. (author), Weber, C. (author), Brunner, H. (author), Rütten, H. (author), Ihling, C. (author), Bernhagen, J. (author), TNO Kwaliteit van Leven (author)

Atherosclerosis is an inflammatory response of the arterial wall to "injury", which is prominently driven by cytokines. The inflammatory mediator macrophage migration inhibitory factor (MIF) is a unique cytokine that was recently associated with atherogenesis. Here, we have investigated whether MIF has a role in spontaneous atherosclerosis by...

article 2006

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Dietary sphingolipids lower plasma cholesterol and triacylglycerol and prevent liver steatosis in APOE*3Leiden mice

Duivenvoorden, I. (author), Voshol, P.J. (author), Rensen, P.C.N. (author), van Duyvenvoorde, W. (author), Romijn, J.A. (author), Emeis, J.J. (author), Havekes, L.M. (author), Nieuwenhuizen, W.F. (author), TNO Kwaliteit van Leven (author)

Background: The prevalence of dyslipidemia and obesity resulting from excess energy intake and physical inactivity is increasing. The liver plays a pivotal role in systemic lipid homeostasis. Effective, natural dietary interventions that lower plasma lipids and promote liver health are needed. Objective: Our goal was to determine the effect of...

article 2006

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Generation of a recombinant apolipoprotein E variant with improved biological functions: Hydrophobic residues (LEU-261, TRP-264, PHE-265, LEU-268, VAL-269) of apoE can account for the apoE-induced hypertriglyceridemia

TNO Kwaliteit van Leven (author), Kypreos, K.E. (author), van Dijk, K.W. (author), Havekes, L.M. (author), Zannis, V.I. (author)

To identify the residues in the carboxyl-terminal region 260-299 of human apolipoprotein E (apoE) that contribute to hypertriglyceridemia, two sets of conserved, hydrophobic amino acids between residues 261 and 283 were mutated to alanines, and recombinant adenoviruses expressing these apoE mutants were generated. Adenovirus-mediated gene...

article 2005

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Combined Association and Linkage Analysis Applied to the APOE Locus

Beekman, M. (author), Posthuma, D. (author), Heijmans, B.T. (author), Lakenberg, N. (author), Suchiman, H.E.D. (author), Snieder, H. (author), de Knijff, P. (author), Frants, R.R. (author), van Ommen, G.J.B. (author), Kluft, C. (author), Vogler, G.P. (author), Slagboom, P.E. (author), Boomsma, D.I. (author)

Combined association and linkage analysis is a powerful tool for pinpointing functional quantitative traits (QTLs) responsible for regions of significant linkage identified in genome-wide scans. We applied this technique to apoE plasma levels and the APOEε2/ε3/ε4 polymorphism in two Dutch twin cohorts of different age ranges. Across chromosome...

article 2004

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The development of clinical activity in relapsing-remitting MS is associated with a decrease of FasL mRNA and an increase of Fas mRNA in peripheral blood

Lopatinskaya, L. (author), Boxel van-Dezaire, A.H.H. (author), Barkhof, F. (author), Polman, C.H. (author), Lucas, C.J. (author), Nagelkerken, L. (author)

In this longitudinal study, we examined the expression of Fas, FasL, CCR3, CCR5 and CXCR3 mRNA in peripheral blood mononuclear cells (PBMCs) of secondary progressive (SP) and relapsing-remitting (RR) multiple sclerosis (MS) patients. In RR patients, FasL, CCR3 and CCR5 mRNA levels were increased prior to the exacerbations, but these decreased...

article 2003

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Binding of β-VLDL to heparan sulfate proteoglycans requires lipoprotein lipase, whereas apoE only modulates binding affinity

de Beer, F. (author), Hendriks, W.L. (author), van Vark, L.C. (author), Kamerling, S.W.A. (author), van Dijk, K.W. (author), Hofker, M.H. (author), Smelt, A.H.M. (author), Havekes, L.M. (author), Gaubius instituut TNO (author)

The binding of β-VLDL to heparan sulfate proteoglycans (HSPG) has been reported to be stimulated by both apoE and lipoprotein lipase (LPL). In the present study we investigated the effect of the isoform and the amount of apoE per particle, as well as the role of LPL on the binding of β-VLDL to HSPG. Therefore, we isolated β-VLDL from transgenic...

article 1999

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Effects of fenofibrate on hyperlipidemia and postprandial triglyceride metabolism in human apolipoprotein C1 transgenic mice

Jong, M.C. (author), Dahlmans, V.E.H. (author), Princen, H.M.G. (author), Hofker, M.H. (author), Havekes, L.M. (author), Gaubius Instituut TNO (author)

To study the in vivo role of apolipoprotein (apo) C1 in lipoprotein metabolism, we have generated transgenic mice expressing the human apo C1 gene. Apo C1 is a small 6.6 kDa protein that is primarily synthesized by the liver and is present on chylomicrons, very low density lipoproteins (VLDL) and high density lipoproteins (HDL). In recent years,...

article 1998