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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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Cholesterol 7α-hydroxylase deficiency in mice on an APOE*3-Leiden background increases hepatic ABCA1 mRNA expression and HDL-cholesterol

Post, S.M. (author), Groenendijk, M. (author), van der Hoogt, C.C. (author), Fievet, C. (author), Luc, G. (author), Hoekstra, M. (author), Princen, H.M.G. (author), Staels, B. (author), Rensen, P.C.N. (author), TNO Kwaliteit van Leven (author)

OBJECTIVE - High-density lipoprotein (HDL) plays a key role in protection against development of atherosclerosis by reducing inflammation, protecting against LDL oxidation, and promoting reverse cholesterol transport from peripheral tissues to the liver for secretion into bile. Cholesterol 7α-hydroxylase (Cyp7a1) catalyzes the rate-limiting step...

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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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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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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Apolipoproteins modulate the inflammatory response to lipopolysaccharide

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

An increasing body of evidence demonstrates a close interplay between lipoprotein metabolism and sepsis. Sepsis results in an increase of plasma triglycerides within VLDL as a consequence of an enhanced hepatic VLDL production and/or inhibited peripheral and hepatic VLDL clearance. In contrast, sepsis decreases plasma cholesterol within LDL and...

article 2005

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Acute hepatic steatosis in mice by blocking β-oxidation does not reduce insulin sensitivity of very-low-density lipoprotein production

TNO Kwaliteit van Leven (author), Grefhorst, A. (author), Hoekstra, J. (author), Derks, T.G.J. (author), Ouwens, D.M. (author), Baller, J.F.W. (author), Havinga, R. (author), Havekes, L.M. (author), Romijn, J.A. (author), Kuipers, F. (author)

Accumulation of triglycerides (TG) in the liver is generally associated with hepatic insulin resistance. We questioned whether acute hepatic steatosis induced by pharmacological blockade of β-oxidation affects hepatic insulin sensitivity, i.e., insulin-mediated suppression of VLDL production and insulin-induced activation of phosphatidylinositol...

article 2005

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Metabolomics in the context of systems biology: Bridging Traditional Chinese Medicine and molecular pharmacology

Wang, M. (author), Lamers, R.J.A.N. (author), Korthout, H.A.A.J. (author), van Nesselrooij, J.H.J. (author), Witkamp, R.F. (author), van der Heijden, R. (author), Voshol, P.J. (author), Havekes, L.M. (author), Verpoorte, R. (author), van der Greef, J. (author), TNO Kwaliteit van Leven (author)

The introduction of the concept of systems biology, enabling the study of living systems from a holistic perspective based on the profiling of a multitude of biochemical components, opens up a unique and novel opportunity to reinvestigate natural products. In the study of their bioactivity, the necessary reductionistic approach on single active...

article 2005

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ApoC-III deficiency prevents hyperlipidemia induced by apoE overexpression

TNO Kwaliteit van Leven (author), Gerritsen, G. (author), Rensen, P.C.N. (author), Kypreos, K.E. (author), Zannis, V.I. (author), Havekes, L.M. (author), van Dijk, K.W. (author)

Adenovirus-mediated overexpression of human apolipoprotein E (apoE) induces hyperlipidemia by stimulating the VLDL-triglyceride (TG) production rate and inhibiting the LPL-mediated VLDL-TG hydrolysis rate. Because apoC-III is a strong inhibitor of TG hydrolysis, we questioned whether Apoc3 deficiency might prevent the hyperlipidemia induced by...

article 2005

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Triglyceride-rich lipoprotein metabolism in unique VLDL receptor, LDL receptor, and LRP triple-deficient mice

TNO Kwaliteit van Leven (author), Espirito Santo, S.M.S. (author), Rensen, P.C.N. (author), Goudriaan, J.R. (author), Bensadoun, A. (author), Bovenschen, N. (author), Voshol, P.J. (author), Havekes, L.M. (author), van Vlijmen, B.J.M. (author)

The very low density lipoprotein receptor (VLDLR), low density lipoprotein receptor (LDLR), and low density lipoprotein receptor-related protein (LRP) are the three main apolipoprotein E-recognizing endocytic receptors involved in the clearance of triglyceride (TG)-rich lipoproteins from plasma. Whereas LDLR deficiency in mice results in the...

article 2005

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CD36 deficiency in mice impairs lipoprotein lipase-mediated triglyceride clearance

TNO Kwaliteit van Leven (author), Goudriaan, J.R. (author), den oer, M.A.M. (author), Rensen, P.C.N. (author), Febbraio, M. (author), Kuipers, F. (author), Romijn, J.A. (author), Havekes, L.M. (author), Voshol, P.J. (author)

CD36 is involved in high-affinity peripheral FFA uptake. CD36-deficient (cd36-/-) mice exhibit increased plasma FFA and triglyceride (TG) levels. The aim of the present study was to elucidate the cause of the increased plasma TG levels in cd36-/- mice. cd36-/- mice showed no differences in hepatic VLDL-TG production or intestinal [3H]TG uptake...

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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Acute inhibition of hepatic beta-oxidation in APOE*3Leiden mice does not affect hepatic VLDL secretion or insulin sensitivity

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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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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Clearance of coagulation factor VIII in very low-density lipoprotein receptor knockout mice

Bovenschen, N. (author), van Dijk, K.W. (author), Havekes, L.M. (author), Mertens, K. (author), van Vlijmen, B.J.M. (author), Gaubius Instituut TNO (author)

Low-density lipoprotein receptor-related protein (LRP) contributes to factor VIII (FVIII) catabolism in vivo. Besides LRP, FVIII also interacts with very low-density lipoprotein receptor (VLDLR) in vitro. We investigated the physiological role of VLDLR in FVIII catabolism, using knockout mouse models for VLDLR and LRP, alone and in combination....

article 2004

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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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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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Differential effects of amlodipine and atorvastatin treatment and their combination on atherosclerosis in ApoE*3-Leiden transgenic mice

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