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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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TNO Kwaliteit van Leven (author), Berbée, J.F.P. (author), van der Hoogt, C.C. (author), Sundararaman, D. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)Studies in humans and mice have shown that increased expression of apolipoprotein C-I (apoC-I) results in combined hyperlipidemia with a more pronounced effect on triglycerides (TGs) compared with total cholesterol (TC). The aim of this study was to elucidate the main reason for this effect using human apoC-I-expressing (APOC1) mice. Moderate...article 2005
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TNO Kwaliteit van Leven (author), Duivenvoorden, I. (author), Teusink, B. (author), Rensen, P.C.N. (author), Kuipers, F. (author), Romijn, J.A. (author), Havekes, L.M. (author), Voshol, P.J. (author)Hepatic VLDL and glucose production is enhanced in type 2 diabetes and associated with hepatic steatosis. Whether the derangements in hepatic metabolism are attributable to steatosis or to the increased availability of FA metabolites is not known. We used methyl palmoxirate (MP), an inhibitor of carnitine palmitoyl transferase I, to acutely...article 2005
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TNO Kwaliteit van Leven (author), Monraats, P.S. (author), Rana, J.S. (author), Nierman, M.C. (author), Pires, N.M.M. (author), Zwinderman, A.H. (author), Kastelein, J.J.P. (author), Kuivenhoven, J.A. (author), de Maat, M.P.M. (author), Rittersma, S.Z.H. (author), Schepers, A. (author), Doevendans, P.A.F. (author), de Winter, R.J. (author), Tio, R.A. (author), Frants, R.R. (author), Quax, P.H.A. (author), van der Laarse, A. (author), van der Wall, E.E. (author), Jukema, J.W. (author)OBJECTIVES: We sought to identify polymorphisms in genes that predispose to restenosis. BACKGROUND: Variations in the lipoprotein lipase (LPL) gene have been implicated in a number of pathophysiologic conditions associated with coronary heart disease. The present study examines the impact of polymorphisms in the LPL gene on restenosis (defined...article 2005
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Clish, C.B. (author), Davidov, E. (author), Oresic, M. (author), Plasterer, T.N. (author), Lavine, G. (author), Londo, T. (author), Meys, M. (author), Snell, P. (author), Stochaj, W. (author), Adourian, A. (author), Zhang, X. (author), Morel, N. (author), Neumann, E. (author), Verheij, E. (author), Vogels, J.T.W.E. (author), Havekes, L.M. (author), Afeyan, N. (author), Regnier, F. (author), van der Greef, J. (author), Naylor, S. (author), TNO Preventie en Gezondheid (author)Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalian disease model, the apolipoprotein E3-Leiden ...article 2004
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Post, S.M. (author), Groenendijk, M. (author), Solaas, K. (author), Rensen, P.C.N. (author), Princen, H.M.G. (author), TNO Preventie en Gezondheid (author)Objective-Cholesterol 7α-hydroxylase (cyp7a1) catalyzes the rate-limiting step in conversion of cholesterol to bile acids. To study the relationship between bile acid biosynthesis and triglyceride metabolism, we cross-bred mice lacking cyp7a1 on a hyperlipidemic APOE*3-Leiden background. Methods and Results-Female mice received a chow or...article 2004
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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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Orešič, M. (author), Clish, C.B. (author), Davidov, E.J. (author), Verheij, E. (author), Vogels, J. (author), Havekes, L.M. (author), Neumann, E. (author), Adourian, A. (author), Naylor, S. (author), van der Greef, J. (author), Plasterer, T. (author), TNO Preventie en Gezondheid (author)Multifactorial diseases present a significant challenge for functional genomics. Owing to their multiple compartmental effects and complex biomolecular activities, such diseases cannot be adequately characterised by changes in single components, nor can pathophysiological changes be understood by observing gene transcripts alone. Instead, a...article 2004
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Davidov, E. (author), Clish, C.B. (author), Oresic, M. (author), Meys, M. (author), Stochaj, W. (author), Snell, P. (author), Lavine, G. (author), Londo, T.R. (author), Adourian, A. (author), Zhang, X. (author), Johnston, M. (author), Morel, N. (author), Marple, E.W. (author), Plasterer, T.N. (author), Neumann, E. (author), Verheij, E. (author), Vogels, J.T.W.E. (author), Havekes, L.M. (author), van der Greef, J. (author), Naylor, S. (author), TNO Preventie en Gezondheid (author)Multitiered quantitative analysis of biological systems is rapidly becoming the desired approach to study hierarchical functional interactions between proteins and metabolites. We describe here a novel systematic approach to analyze organisms with complex metabolic regulatory networks. By using precise analytical methods to measure biochemical...article 2004
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Espirito Santo, S.M.S. (author), Pires, N.M.M. (author), Boesten, L.S.M. (author), Gerritsen, G. (author), Bovenschen, N. (author), van Dijk, K.W. (author), Jukema, J.W. (author), Princen, H.M.G. (author), Bensadoun, A. (author), Li, W.P. (author), Herz, J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author), Gaubius Instituut TNO (author)The low-density lipoprotein (LDL) receptor-related protein (LRP) has a well-established role in the hepatic removal of atherogenic apolipoprotein E (APOE)-rich remnant lipoproteins from plasma. In addition, LRP recognizes multiple distinct pro- and antiatherogenic ligands in vitro. Here, we investigated the role of hepatic LRP in atherogenesis...article 2004
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Hollestelle, S.C.G. (author), de Vries, M.R. (author), van Keulen, J.K. (author), Schoneveld, A.H. (author), Vink, A. (author), Strijder, C.F. (author), van Middelaar, B.J. (author), Pasterkamp, G. (author), Q́uax, P.H.A. (author), de Kleijn, D.P.V. (author), TNO Preventie en Gezondheid (author)Background-Toll-like receptor 4 (Tlr4) is the receptor for exogenous lipopolysaccharides (LPS). Expression of endogenous Tlr4 ligands, heat shock protein 60 (Hsp60) and extra domain A of fibronectin, has been observed in arthritic and oncological specimens in which matrix turnover is an important feature. In atherosclerosis, outward remodeling...article 2004
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Mulder, M. (author), Jansen, P.J. (author), Janssen, B.J.A. (author), van de Berg, W.D.J. (author), van der Boom, H. (author), Havekes, L.M. (author), de Kloet, R.E. (author), Ramaekers, F.C.S. (author), Blokland, A. (author), TNO Preventie en Gezondheid (author)The low-density lipoprotein receptor (LDLR) is the first described receptor for apolipoprotein E (apoE). We hypothesize that the absence of the LDLR, similar to the absence of apoE, results in impaired learning and memory processes. Six-month-old homozygous Ldlr-/- and wild-type littermates (Ldlr+/+), maintained on a standard lab chow diet, were...article 2004
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Hofman, M.K. (author), Groenendijk, M. (author), Verkuijlen, P.J.J.H. (author), Jonkers, I.J.A.M. (author), Mohrschladt, M.F. (author), Smelt, A.H.M. (author), Princen, H.M.G. (author), Gaubius Instituut TNO (author)The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of...article 2004
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Sierksma, A. (author), Vermunt, S.H.F. (author), Lankhuizen, I.M. (author), van der Gaag, M.S. (author), Scheek, L.M. (author), Grobbee, D.E. (author), van Tol, A. (author), Hendriks, H.F.J. (author), TNO Voeding (author)Background: Alcohol consumption is associated with increased high-density lipoprotein (HDL) cholesterol levels. One of the main antiatherogenic functions of HDL is reverse cholesterol transport. Three early steps of reverse cholesterol transport are (1) cellular cholesterol efflux, (2) plasma cholesterol esterification (EST), and (3) cholesteryl...article 2004
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Gaubius Instituut TNO (author), Muurling, M. (author), van den Hoek, A.M. (author), Mensink, R.P. (author), Pijl, H. (author), Romijn, J.A. (author), Havekes, L.M. (author), Voshol, P.J. (author)Obese obob mice with strong overexpression of the human apolipoprotein C1 (APOC1) exhibit excessive free fatty acid (FFA) and triglyceride (TG) levels and severely reduced body weight (due to the absence of subcutaneous adipose tissue) and skin abnormalities. To evaluate the effects of APOC1 overexpression on hepatic and peripheral insulin...article 2004
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TNO Preventie en Gezondheid (author), Gervois, P. (author), Kleemann, R. (author), Pilon, A. (author), Percevault, F. (author), Koenig, W. (author), Staels, B. (author), Kooistra, T. (author)The peroxisome proliferator-activated receptor alpha (PPARalpha), which is highly expressed in liver, plays key roles in lipid metabolism and inflammation. Interleukin-6 (IL-6) is the principal inducer of acute phase response (APR) gene expression. In the present study, we demonstrate that chronic treatment with the PPARalpha agonist fenofibrate...article 2004
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TNO Preventie en Gezondheid (author), Schaap, F.G. (author), Rensen, P.C.N. (author), Voshol, P.J. (author), Vrins, C. (author), van der Vliet, H.N. (author), Chamuleau, R.A.F.M. (author), Havekes, L.M. (author), Groen, A.K. (author), van Dijk, K.W. (author)ApoAV has been discovered recently as a novel modifier of triglyceride (TG) metabolism, but the pathways involved are currently unknown. To gain insight into the function of apoAV, adenovirus-mediated gene transfer of murine apoa5 to C57Bl/6 mice was employed. The injection of low doses of Ad-apoa5 (1-5 x 108 plaque-forming units/mouse) dose...article 2004
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TNO Voeding Centraal Instituut voor Voedingsonderzoek TNO (author), Beulens, J.W.J. (author), Sierksma, A. (author), van Tol, A. (author), Fournier, N. (author), van Gent, T. (author), Paul, J.L. (author), Hendriks, H.F.J. (author)Moderate alcohol consumption increases HDL cholesterol, which is involved in reverse cholesterol transport (RCT). The aim of this study was to investigate the effect of moderate alcohol consumption on cholesterol efflux, using J774 mouse macrophages and Fu5AH cells, and on other parameters in the RCT pathway. Twenty-three healthy men (45-65...article 2004
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Beekman, M. (author), Heijmans, B.T. (author), Martin, N.G. (author), Whitfield, J.B. (author), Pedersen, N.L. (author), de Faire, U. (author), Snieder, H. (author), Lakenberg, N. (author), Suchiman, H.E.D. (author), de Knijff, P. (author), Frants, R.R. (author), van Ommen, G.J.B. (author), Kluft, C. (author), Vogler, G.P. (author), Boomsma, D.I. (author), Slagboom, P.E. (author)The genetic basis of cardiovascular disease (CVD) with its complex etiology is still largely elusive. Plasma levels of lipids and apolipoproteins are among the major quantitative risk factors for CVD and are well-established intermediate traits that may be more accessible to genetic dissection than clinical CVD end points. Chromosome 19 harbors...article 2003
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Delsing, D.J.M. (author), Jukema, J.W. (author), van de Wiel, M.A. (author), Emeis, J.J. (author), van der Laarse, A. (author), Havekes, L.M. (author), Princen, H.M.G. (author), Gaubius Instituut TNO (author)This study was designed to investigate the potential antiatherosclerotic effects of the calcium antagonist amlodipine as compared with the HMG-CoA reductase inhibitor atorvastatin and the combination of both in ApoE*3-Leiden transgenic mice. Four groups of 15 ApoE*3-Leiden mice were put on a high-cholesterol diet. One group received 0.002% (wt...article 2003