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Mechanism-Based Biomarker Prediction for Low-Grade Inflammation in Liver and Adipose Tissue

van Bilsen, J.H.M. (author), van den Brink, W. (author), van den Hoek, A.M. (author), Dulos, R. (author), Caspers, M.P.M. (author), Kleeman, R. (author), Wopereis, S. (author), Verschuren, L. (author)

Metabolic disorders, such as obesity and type 2 diabetes have a large impact on global health, especially in industrialized countries. Tissue-specific chronic low-grade inflammation is a key contributor to complications in metabolic disorders. To support therapeutic approaches to these complications, it is crucial to gain a deeper understanding...

article 2021

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Sympathetic nervous system control of triglyceride metabolism: Novel concepts derived from recent studies

Geerling, J.J. (author), Boon, M.R. (author), Kooijman, S. (author), Parlevliet, E.T. (author), Havekes, L.M. (author), Romijn, J.A. (author), Meurs, I.M. (author), Rensen, P.C.N. (author)

Abstract Important players in triglyceride (TG) metabolism include the liver (production), white adipose tissue (WAT) (storage), heart and skeletal muscle (combustion to generate ATP), and brown adipose tissue (BAT) (combustion toward heat), the collective action of which determine plasma TG levels. Interestingly, recent evidence points to a...

article 2014

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Aspirin reduces hypertriglyceridemia by lowering VLDL-triglyceride production in mice fed a high-fat diet

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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The expression of type III hyperlipoproteinemia: Involvement of lipolysis genes

Henneman, P. (author), van der Sman-de Beer, F. (author), Moghaddam, P.H. (author), Huijts, P. (author), Stalenhoef, A.F.H. (author), Kastelein, J.J.P. (author), van Duijn, C.M. (author), Havekes, L.M. (author), Frants, R.R. (author), van Dijk, K.W. (author), Smelt, A.H.M. (author), TNO Kwaliteit van Leven (author)

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous apolipoprotein (APO) E2 (R158C) carriers. Genetic factors contributing to the expression of type III HLP were investigated in 113 hyper- and 52 normolipidemic E2/2 subjects, by testing for polymorphisms in APOC3, APOA5, HL (hepatic lipase) and LPL (lipoprotein lipase) genes. In...

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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ApoE2-associated hypertriglyceridemia is ameliorated by increased levels of apoA-V but unaffected by apoC-III deficiency

TNO Kwaliteit van Leven (author), Gerritsen, G. (author), van der Hoogt, C.C. (author), Schaap, F.G. (author), Voshol, P.J. (author), Kypreos, K.E. (author), Maeda, N. (author), Groen, A.K. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), van Dijk, K.W. (author)

Apolipoprotein E2 (apoE2)-associated hyperlipidemia is characterized by a disturbed clearance of apoE2-enriched VLDL remnants. Because excess apoE2 inhibits LPL-mediated triglyceride (TG) hydrolysis in vitro, we in vestigated whether direct or indirect stimulation of LPL activity in vivo reduces the apoE2-associated hypertriglyc-eridemia. Here,...

article 2008

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Plasma apoAV levels are markedly elevated in severe hypertriglyceridemia and positively correlated with the APOA5 S19W polymorphism

Henneman, P. (author), Schaap, F.G. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Frants, R.R. (author), van Tol, A. (author), Hattori, H. (author), Smelt, A.H.M. (author), van Dijk, K.W. (author), TNO Kwaliteit van Leven (author)

Objective: The recently discovered apoAV is hypothesized to affect triglyceride metabolism by stimulating the lipolysis of triglycerides in VLDL and chylomicrons. We set out to determine the association between increased serum TG levels, plasma apoAV levels, and polymorphism of the APOA5 gene, with specific emphasis on the APOA5 S19W variation....

article 2007

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The Hyplip2 locus causes hypertriglyceridemia by decreased clearance of triglycerides

TNO Kwaliteit van Leven (author), Moen, C.J.A. (author), Tholens, A.P. (author), Voshol, P.J. (author), de Haan, W. (author), Havekes, L.M. (author), Gargalovic, P. (author), Lusis, A.J. (author), van Dyk, K.W. (author), Frants, R.R. (author), Hofker, M.H. (author), Rensen, P.C.N. (author)

The Hyplip2 congenic mouse strain contains part of chromosome 15 from MRL/MpJ on the BALB/cJ background. Hyplip2 mice show increased plasma levels of cholesterol and predominantly triglycerides (TGs) and are susceptible to diet-induced atherosclerosis. This study aimed at elucidation of the mechanism(s) explaining the hypertriglyceridemia....

article 2007

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Ritonavir impairs lipoprotein lipase-mediated lipolysis and decreases uptake of fatty acids in adipose tissue

den Boer, M.A.M. (author), Berbée, J.F.P. (author), Reiss, P. (author), van der Valk, M. (author), Voshol, P.J. (author), Kuipers, F. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Romijn, J.A. (author), Gaubius Instituut TNO (author)

Objective - The use of the HIV protease inhibitor ritonavir (RTV) is frequently associated with hypertriglyceridemia and lipodystrophy. The aim of our study was to determine the mechanism underlying the observed hypertriglyceridemia. Methods and Results - Feeding female APOE*3-Leiden transgenic mice a Western-type diet supplemented with RTV (35...

article 2006

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Apolipoprotein AV: Low concentration, high impact

Rensen, P.C.N. (author), van Dijk, K.W. (author), Havekes, L.M. (author), TNO Kwaliteit van Leven (author)

Chemicals / CAS: lipoprotein lipase, 83137-80-8, 9004-02-8; APOA5 protein, human; Apolipoproteins A; Apolipoproteins; Triglycerides

article 2005

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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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Severe hypertriglyceridemia in human APOC1 transgenic mice is caused by apoC-I-induced inhibition of LPL

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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Modulating effect of the A-278C promoter polymorphism in the cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals

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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ApoAV reduces plasma triglycerides by inhibiting very low density lipoprotein-triglycerides (VLDL-TG) production and stimulating lipoprotein lipase-mediated VLDL-TG hydrolysis

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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Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride-rich very low density lipoprotein particles

Gaubius Instituut TNO (author), Grefhorst, A. (author), Elzinga, B.M. (author), Voshol, P.J. (author), Plösch, T. (author), Kok, T. (author), Bloks, V.W. (author), van der Sluijs, F.H. (author), Havekes, L.M. (author), Romijn, J.A. (author), Verkade, H.J. (author), Kuipers, F. (author)

The oxysterol-activated liver X receptor (LXR) provides a link between sterol and fatty acid metabolism; activation of LXR induces transcription of lipogenic genes. This study shows that induction of the lipogenic genes Srebp-1c, Fas, and Acc1 upon administration of the synthetic LXR agonist T0901317 to C57BL/6J mice (10 mg/kg/day, 4 days) is...

article 2002

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Apolipoprotein E2 (Lys146→Gln) causes hypertriglyceridemia due to an apolipoprotein E variant-specific inhibition of lipolysis of very low density lipoproteins-triglycerides

de Beer, F. (author), van Dijk, K.W. (author), Jong, M.C. (author), van Vark, L.C. (author), van der Zee, A. (author), Hofker, M.H. (author), Fallaux, F.J. (author), Hoeben, R.C. (author), Smelt, A.H.M. (author), Havekes, L.M. (author), Gaubius Instituut TNO (author)

The apolipoprotein E2 (Lys146→Gln) variant is associated with a dominant form of familial dysbetalipoproteinemia. Heterozygous carriers of this variant have elevated levels of plasma triglycerides, cholesterol, and apolipoprotein E (apoE). It was hypothesized that the high amounts of triglycerides in the very low density lipoprotein (VLDL)...

article 2000

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Normal oxidative stress and enhanced lipoprotein resistance to in vitro oxidation in hypertriglyceridemia Effects of bezafibrate therapy

TNO Preventie en Gezondheid (author), de Man, F.H.A.F. (author), Jonkers, I.J.A.M. (author), Schwedhelm, E. (author), Smelt, A.H.M. (author), Onkenhout, W. (author), van Duyvenvoorde, W. (author), Buytenhek, R. (author), Leuven, J.A.G. (author), Troost, R. (author), van der Laarse, A. (author), Princen, H.M.G. (author)

Although there is evidence that hyperlipidemia and predominance of small dense low density lipoproteins (LDLs) are associated with increased oxidative stress, the oxidation status in patients with hypertriglyceridemia (HTG) has not been studied in detail. Therefore, we studied urinary levels of F2-isoprostanes (8-isoprostaglandin F(2α) and 2,3...

article 2000

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Hyperlipidemia of ApoE2(Arg158-Cys) and ApoE3-Leiden transgenic mice is modulated predominantly by LDL receptor expression

van Dijk, K.W. (author), van Vlijmen, B.J.M. (author), de Winther, M.P.J. (author), van 't Hof, B. (author), van der Zee, A. (author), van der Boom, H. (author), Havekes, L.M. (author), Hofker, M.H. (author), Gaubius instituut TNO (author)

To investigate the relative roles of the LDL receptor- and non-LDL receptor-mediated pathways in the clearance of apolipoprotein E (apoE) variants in vivo, we have generated apoE2(Arg158-Cys) (apoE2) and apoE3- Leiden transgenic mice deficient for the endogenous mouse Apoe and Ldl receptor genes (Apoe-/-.Ldlr-/- mice). Unexpectedly, on the Apoe-...

article 1999

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In LDL receptor-deficient mice, catabolism of remnant lipoproteins requires a high level of apoE but is inhibited by excess apoE

TNO Preventie en Gezondheid (author), van Dijk, K.W. (author), van Vlijmen, B.J.M. (author), van 't Hof, H.B. (author), van der Zee, A. (author), Santamarina-Fojo, S. (author), van Berkel, T.J.C. (author), Havekes, L.M. (author), Hofker, M.H. (author)

To investigate the quantitative requirement for apolipoprotein (apo) E in the clearance of lipoproteins via the non-low density lipoprotein (LDL) receptor mediated pathway, human APOE was overexpressed at various levels in the livers of mice deficient for both the endogenous Apoe and Ldlr genes (Apoe-/- · Ldlr-/-) using adenovirus-mediated gene...

article 1999

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Hyperlipidemia and cutaneous abnormalities in transgenic mice overexpressing human apolipoprotein C1

Jong, M.C. (author), Gijbels, M.J.J. (author), Dahlmans, V.E.H. (author), van Gorp, P.J.J. (author), Koopman, S.-J. (author), Ponec, M. (author), Hofker, M.H. (author), Havekes, L.M. (author), Gaubius instituut TNO (author)

Transgenic mice were generated with different levels of human apolipoprotein C1 (APOC1) expression in liver and skin. At 2 mo of age, serum levels of cholesterol, triglycerides (TG), and FFA were strongly elevated in APOC1 transgenic mice compared with wild-type mice. These elevated levels of serum cholesterol and TG were due mainly to an...

article 1998