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Brown fat activation reduces hypercholesterolaemia and protects from atherosclerosis development

Berbeé, J.F.P. (author), Boon, M.R. (author), Khedoe, P.P.S.J. (author), Bartelt, A. (author), Schlein, C. (author), Worthmann, A. (author), Kooijman, S. (author), Hoeke, G. (author), Mol, I.M. (author), John, C. (author), Jung, C. (author), Vazirpanah, N. (author), Brouwers, L.P.J. (author), Gordts, P.L.S.M. (author), Esko, J.D. (author), Hiemstra, P.S. (author), Havekes, L.M. (author), Scheja, L. (author), Heeren, J. (author), Rensen, P.C.N. (author)

Brown adipose tissue (BAT) combusts high amounts of fatty acids, thereby lowering plasma triglyceride levels and reducing obesity. However, the precise role of BAT in plasma cholesterol metabolism and atherosclerosis development remains unclear. Here we show that BAT activation by b3-adrenergic receptor stimulation protects from atherosclerosis...

article 2015

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No effects of atorvastatin (10 mg/d or 80 mg/d) on nitric oxide, prostacyclin, thromboxane and oxidative stress in type 2 diabetes mellitus patients of the DALI study

Tsikas, D. (author), Pham, V.V. (author), Suchy, M.T. (author), van de Ree, M.A. (author), Huisman, M.V. (author), Frölich, J.C. (author), Princen, H.M.G. (author)

The present study describes the effects of atorvastatin on whole body synthesis of nitric oxide (NO), prostacyclin (PGI2), and thromboxane A2 (TxA2), on oxidative stress and nitrite/nitrate-related renal carbonic anhydrase (CA) activity in patients with type 2 diabetes mellitus (T2DM). A double-blind, randomized, placebo-controlled parallel...

article 2015

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Differential modulation by Akkermansia muciniphila and faecalibacterium prausnitzii of host peripheral lipid metabolism and histone acetylation in mouse gut organoids

Lukovac, S. (author), Belzer, C. (author), Pellis, L. (author), Keijser, B.J. (author), de Vos, W.M. (author), Montijn, R.C. (author), Roeselers, G. (author)

The gut microbiota is essential for numerous aspects of human health. However, the underlying mechanisms of many host-microbiota interactions remain unclear. The aim of this study was to characterize effects of the microbiota on host epithelium using a novel ex vivo model based on mouse ileal organoids. We have explored the transcriptional...

article 2014

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Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B

Heemskerk, M.M. (author), van den Berg, S.A. (author), Pronk, A.C.M. (author), van Klinken, J.B. (author), Boon, M.R. (author), Havekes, L.M. (author), Rensen, P.C.N. (author), Willems van Dijk, K. (author), van Harmelen, V. (author)

The lipid-lowering effect of niacin has been attributed to the inhibition of cAMP production in adipocytes, thereby inhibiting intracellular lipolysis and release of nonesterified fatty acids (NEFA) to the circulation. However, long-term niacin treatment leads to a normalization of plasma NEFA levels and induces insulin resistance, for which the...

article 2014

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In vitro models for the prediction of in vivo performance of oral dosage forms

Kostewicz, E.S. (author), Abrahamsson, B. (author), Brewster, M. (author), Brouwers, J. (author), Butler, J. (author), Carlert, S. (author), Dickinson, P.A. (author), Dressman, J. (author), Holm, R. (author), Klein, S. (author), Mann, J. (author), McAllister, M. (author), Minekus, M. (author), Muenster, U. (author), Müllertz, A. (author), Verwei, M. (author), Vertzoni, M. (author), Weitschies, W. (author), Augustijns, P. (author)

Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection with in vivo biopharmaceutical performance has...

article 2014

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Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity

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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Lipid digestion of protein stabilized emulsions investigated in a dynamic in vitro gastro-intestinal model system

Helbig, A. (author), Silletti, E. (author), van Aken, G.A. (author), Oosterveld, A. (author), Minekus, M. (author), Hamer, R.J. (author), Gruppen, H. (author)

This study investigated the effect of gastric passage of protein stabilized emulsions, i.e., whey protein isolate (WPI) and lysozyme, under dynamic in vitro conditions on both the gastric and intestinal lipolysis. Emulsions were prepared at neutral pH to enable an opposite surface charge. Experiments were performed in a multi-compartmental...

article 2013

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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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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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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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Hepatic glucose production is more sensitive to insulin-mediated inhibition than hepatic VLDL-triglyceride production

den Boer, M.A.M. (author), Voshol, P.J. (author), Kuipers, F. (author), Romijn, J.A. (author), Havekes, L.M. (author), TNO Kwaliteit van Leven (author)

Insulin is an important inhibitor of both hepatic glucose output and hepatic VLDL-triglyceride (VLDL-TG) production. We investigated whether both processes are equally sensitive to insulin-mediated inhibition. To test this, we used euglycemic clamp studies with four increasing plasma concentrations of insulin in wild-type C57Bl/6 mice. 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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Endogenous apoC-I increases hyperlipidemia in apoE-knockout mice by stimulating VLDL production and inhibiting LPL

TNO Kwaliteit van Leven (author), Westerterp, M. (author), de Haan, W. (author), Berbée, J.F.P. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)

Previous studies have shown that overexpression of human apolipoprotein C-I (apoC-I) results in moderate hypercholesterolemia and severe hypertriglyceridemia in mice in the presence and absence of apoE. We assessed whether physiological endogenous apoC-I levels are sufficient to modulate plasma lipid levels independently of effects of apoE on...

article 2006

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Rosuvastatin reduces plasma lipids by inhibiting VLDL production and enhancing hepatobiliary lipid excretion in ApoE*3-Leiden mice

Delsing, D.J.M. (author), Post, S.M. (author), Groenendijk, M. (author), Solaas, K. (author), van der Boom, H. (author), van Duyvenvoorde, W. (author), de Wit, E.C.M. (author), Bloks, V.W. (author), Kuipers, F. (author), Havekes, L.M. (author), Princen, H.M.G. (author), TNO Kwaliteit van Leven (author)

The present study was designed to investigate the lipid-lowering properties and mechanisms of action of a new HMG-CoA reductase inhibitor, rosuvastatin, in female ApoE*3-Leiden transgenic mice. Mice received a high fat/cholesterol (HFC) diet containing either rosuvastatin (O [control], 0.00125%, 0.0025%, or 0.005% [w/w]) or 0.05% (w/w)...

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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Cholesterol 7α-Hydroxylase Deficiency in Mice on an APOE*3-Leiden Background Impairs Very-Low-Density Lipoprotein Production

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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The VLDL receptor plays a major role in chylomicron metabolism by enhancing LPL-mediated triglyceride hydrolysis

Gaubius Instituut TNO (author), Goudriaan, J.R. (author), Espirito Santo, S.M.S. (author), Voshol, P.J. (author), Teusink, B. (author), van Dijk, K.W. (author), van Vlijmen, B.J.M. (author), Romijn, J.A. (author), Havekes, L.M. (author), Rensen, P.C.N. (author)

The VLDL receptor (VLDLr) is involved in tissue delivery of VLDL-triglyceride (TG)-derived FFA by facilitating the expression of lipoprotein lipase (LPL). However, vldlr-/- mice do not show altered plasma lipoprotein levels, despite reduced LPL expression. Because LPL activity is crucial in postprandial lipid metabolism, we investigated whether...

article 2004

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Increased hepatic insulin sensitivity together with decreased hepatic triglyceride stores in hormone-sensitive lipase-deficient mice

Voshol, P.J. (author), Haemmerle, G. (author), Ouwens, D.M. (author), Zimmermann, R. (author), Zechner, R. (author), Teusink, B. (author), Maassen, J.A. (author), Havekes, L.M. (author), Romijn, J.A. (author)

Hormone-sensitive lipase (HSL) is a major enzyme for triglyceride (TG) lipolysis in adipose tissue. In HSL-knockout mice, plasma free fatty acid and TG levels are low, associated with low liver TG content. Because a decreased hepatic insulin sensitivity has been reported to be associated with high liver TG levels, our aim was to determine...

article 2003

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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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Control of bioflavour and safety in fermented sausages: First results of a European project

Demeyer, D. (author), Raemaekers, M. (author), Rizzo, A. (author), Holck, A. (author), de Smedt, A. (author), ten Brink, B. (author), Hagen, B. (author), Montel, C. (author), Zanardi, E. (author), Murbrekk, E. (author), Leroy, F. (author), Vandendriessche, F. (author), Lorentsen, K. (author), Venema, K. (author), Sunesen, L. (author), Stahnke, L. (author), de Vuyst, L. (author), Talon, R. (author), Chizzolini, R. (author), Eerola, S. (author), Centraal Instituut voor Voedingsonderzoek TNO (author)

Four types of fermented sausages were prepared: two using Northern technology (Norway and Belgium) and two using Mediterranean technology (Belgium and Italy). Mediterranean sausages showed higher pH values and highest residual amounts of myosin and actin. Free fatty acid concentrations reflected the nature of the raw material, rather than the...

article 2000