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van de Pas, N.C.A. (author), Rullmann, J.A.C. (author), Woutersen, R.A. (author), van Ommen, B. (author), Rietjens, I.M.C.M. (author), de Graaf, A.A. (author)We used a previously developed physiologically based kinetic (PBK) model to analyze the effect of individual variations in metabolism and transport of cholesterol on pravastatin response. The PBK model is based on kinetic expressions for 21 reactions that interconnect eight different body cholesterol pools including plasma HDL and non-HDL...article 2014
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Boon, M.R. (author), Kooijman, S. (author), van Dam, A.D. (author), Pelgrom, L.R. (author), Berbée, J.F.P. (author), Visseren, C.A.R. (author), van Aggele, R.C. (author), van den Hoek, A.M. (author), Sips, H.C.M. (author), Lombès, M. (author), Havekes, L.M. (author), Tamsma, J.T. (author), Guigas, B. (author), Meijer, O.C. (author), Jukema, J.W. (author), Rensen, P.C.N. (author)The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis, and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintenance of weight loss and reduction of dyslipidemia in experimental and human obesity. The molecular mechanism by which CB1R blockade...article 2014
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Joosten, M.M. (author), Schrieks, I.C. (author), Hendriks, H.F.J. (author)Background: Fetuin-A, a liver-derived glycoprotein that impairs insulin-signalling, has emerged as a biomarker for diabetes risk. Although moderate alcohol consumption has been inversely associated with fetuin-A, data from clinical trials are lacking. Thus, we evaluated whether moderate alcohol consumption decreases circulating levels of fetuin...article 2014
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Ason, B. (author), van der Hoorn, J.W.A. (author), Chan, J. (author), Lee, E. (author), Pieterman, E.J. (author), Nguyen, K.K. (author), Di, M. (author), Shetterly, S. (author), Tang, J. (author), Yeh, W.C. (author), Schwarz, M. (author), Jukema, J.W. (author), Scott, R. (author), Wasserman, S.M. (author), Princen, H.M.G. (author), Jackson, S. (author)LDL cholesterol (LDL-C) contributes to coronary heart disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases LDL-C by inhibiting LDL-C clearance. The therapeutic potential for PCSK9 inhibitors is highlighted by the fact that PCSK9 loss-of-function carriers exhibit 15-30% lower circulating LDL-C and a disproportionately lower...article 2014
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Kooijman, S. (author), Boon, M.R. (author), Parlevliet, E.T. (author), Geerling, J.J. (author), van de Pol, V. (author), Romijn, J.A. (author), Havekes, L.M. (author), Meurs, I. (author), Rensen, P.C.N. (author)The melanocortin system is an important regulator of energy balance, and melanocortin 4 receptor (MC4R) deficiency is the most common monogenic cause of obesity. We investigated whether the relationship between melanocortin system activity and energy expenditure (EE) is mediated by brown adipose tissue (BAT) activity. Therefore, female APOE∗3...article 2014
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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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Gierman, L.M. (author), Kühnast, S. (author), Koudijs, A. (author), Pieterman, E.J. (author), Kloppenburg, M. (author), van Osch, G.J.V.M. (author), Stojanovic-Susulic, V. (author), Huizinga, T.W.J. (author), Princen, H.M.G. (author), Zuurmond. A.M., (author)Objective Hypercholesterolaemia, a risk factor for atherosclerosis (ATH), has been suggested to have a role in the development of osteoarthritis (OA). To test this hypothesis, the effect of cholesterol and different cholesterol-lowering treatments on OA was investigated in a mouse model resembling human lipoprotein metabolism. Methods Female...article 2014
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Zeegers, M.P. (author), Nekeman, D. (author), Khan, H.S. (author), van Dijk, B.A.C. (author), Goldbohm, R.A. (author), Schalken, J. (author), Shajahan, S. (author), Pearlman, A. (author), Oddoux, C. (author), van den Brandt, P.A. (author), Schouten, L.J. (author), Ostrer, H. (author), TNO Preventie en Gezondheid (author)Background:Prostate cancer is the most commonly diagnosed cancer in men in Europe and the United States. Numerous studies have indicated genetics to have a major role in the aetiology of this disease; as much as 42% of the risk may be explained by heritable factors. Genome-wide association studies have detected an association between prostate...article 2013
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van Diepen, J.A. (author), Berbée, J.F.P. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)Dyslipidemia and inflammation are well known causal risk factors the development of atherosclerosis. The interplay between lipid metabolism and inflammation at multiple levels in metabolic active tissues may exacerbate the development of atherosclerosis, and will be discussed in this review. Cholesterol, fatty acids and modified lipids can...article 2013
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Georgiadi, A. (author), Wang, Y. (author), Stienstra, R. (author), Tjeerdema, N. (author), Janssen, A. (author), Stalenhoef, A. (author), van der Vliet, J.A. (author), de Roos, A. (author), Tamsma, J.T. (author), Smit, J.W. (author), Tan, N.S. (author), Müller, M. (author), Rensen, P.C. (author), Kersten, S. (author)Objective: Macrophage foam cells play a crucial role in several pathologies including multiple sclerosis, glomerulosclerosis, and atherosclerosis. Angiopoietin-like protein 4 (Angptl4) was previously shown to inhibit chyle-induced foam cell formation in mesenteric lymph nodes. Here we characterized the regulation of Angptl4 expression in...article 2013
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Li, Z. (author), Wang, Y. (author), van der Sluis, R.J. (author), van der Hoorn, J.W.A. (author), Princen, H.M.G. (author), van Eck, M. (author), van Berkel, T.J.C. (author), Rensen, P.C.N. (author), Hoekstra, M. (author)The anti-dyslipidemic drug niacin has recently been shown to reduce the hepatic expression and plasma levels of CETP. Since liver macrophages contribute to hepatic CETP expression, we investigated the role of macrophages in the CETP-lowering effect of niacin in mice. In vitro studies showed that niacin does not directly attenuate CETP expression...article 2012
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Butenhoff, J.L. (author), Pieterman, E. (author), Ehresman, D.J. (author), Gorman, G.S. (author), Olsen, G.W. (author), Chang, S.C. (author), Princen, H.M. (author)Some cross-sectional epidemiological studies have reported positive associations of serum concentrations of non-high density lipoprotein cholesterol with serum perfluorooctanesulfonate (PFOS) and perfluorooctanoate (PFOA). However, the strength of the reported associations is inconsistent for exposure–response across three orders of magnitude of...article 2012
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Bijland, S. (author), Rensen, P.C.N. (author), Pieterman, E.J. (author), Maas, A.C.E. (author), van der Hoorn, J.W. (author), van Erk, M.J. (author), Havekes, L.M. (author), van Dijk, K.W. (author), Chang, S.C. (author), Ehresman, D.J. (author), Butenhoff, J.L. (author), Princen, H.M.G. (author)Perfluorobutane sulfonate (PFBS), perfluorohexane sulfonate (PFHxS), and perfluorooctane sulfonate (PFOS) are stable perfluoroalkyl sulfonate (PFAS) surfactants, and PFHxS and PFOS are frequently detected in human biomonitoring studies. Some epidemiological studies have shown modest positive correlations of serum PFOS with non-high-density...article 2011
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van de Pas, N.C.A. (author), Woutersen, R.A. (author), van Ommen, B. (author), Rietjens, I.M.C.M. (author), de Graaf, A.A. (author)The LDL cholesterol (LDL-C) and HDL cholesterol (HDL-C) concentrations are determined by the activity of a complex network of reactions in several organs. Physiologically-based kinetic (PBK) computational models can be used to describe these different reactions in an integrated, quantitative manner. A PBK model to predict plasma cholesterol...article 2011
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TNO Kwaliteit van Leven (author), Diepen, J.A.V. (author), Wong, M.C. (author), Guigas, B. (author), Bos, J. (author), Stienstra, R. (author), Hodson, L. (author), Shoelson, S.E. (author), Jimmy F. P. Berbée, (author), Rensen, P.C.N. (author), Romijn, J.A. (author), Havekes, L.M. (author), Voshol, P.J. (author)Low-grade inflammation in different tissues, including activation of the nuclear factor k B pathway in liver, is involved in metabolic disorders such as type 2 diabetes and cardiovascular diseases (CVDs). In this study, we investigated the relation between chronic hepatocyte-specifi c overexpression of IkB kinase (IKK)- beta and...article 2011
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Gaubius Instituut TNO (author), Wang, Y. (author), Berbée, J.F.P. (author), Stroes, E.S. (author), Smit, J.W.A. (author), Havekes, L.M. (author), Romijn, J.A. (author), Rensen, P.C.N. (author)Human data suggest that reconstituted HDL (rHDL) infusion can induce atherosclerosis regression. Studies in mice indicated that rHDL infusion adversely affects VLDL levels, but this effect is less apparent in humans. This discrepancy may be explained by the fact that humans, in contrast to mice, express cholesteryl ester transfer protein (CETP)....article 2011
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Gaubius Instituut TNO (author), Coomans, C.P. (author), Geerling, J.J. (author), Guigas, B. (author), van den Hoek, A.M. (author), Parlevliet, E.T. (author), Ouwens, D.M. (author), Pijl, H. (author), Voshol, P.J. (author), Rensen, P.C.N. (author), Havekes, L.M. (author), Romijn, J.A. (author)Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In wild-type mice, hyperinsulinemic-euglycemic...article 2011
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van Diepen, J.A. (author), Vroegrijk, I.O.C.M. (author), Berbée, J.F.P. (author), Shoelson, S.E. (author), Romijn, J.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Voshol, P.J. (author)Systemic inflammation is strongly involved in the pathophysiology of the metabolic syndrome, a cluster of metabolic risk factors that includes hypertriglyceridemia. Aspirin treatment lowers inflammation via inhibition of NF-?B activity but also reduces hypertriglyceridemia in humans. The aim of this study was to investigate the mechanism by...article 2011
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de Graaf, A.A. (author), van Schalkwijk, D.B. (author)At present, several measurement technologies are available for generating highly detailed concentration-size profiles of lipoproteins, offering increased diagnostic potential. Computational models are useful in aiding the interpretation of these complex datasets and making the data more accessible for clinical diagnosis. They do so by...article 2011
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van Schalkwijk, D.B. (author), van Bochove, K. (author), van Ommen, B. (author), Freidig, A.P. (author), van Someren, E.P. (author), van der Greef, J. (author), de Graaf, A.A. (author), TNO Kwaliteit van Leven (author)This article provides methodological and technical considerations to researchers starting to develop computational model-based diagnostics using clinical chemistry data.These models are of increasing importance, since novel metabolomics and proteomics measuring technologies are able to produce large amounts of data that are difficult to...article 2010