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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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Intrauterine exposure to maternal atherosclerotic risk factors increases the susceptibility to atherosclerosis in adult life

TNO Kwaliteit van Leven (author), Alkemade, F.E. (author), de Gittenberger-Groot, A.C. (author), Schiel, A.E. (author), van Munsteren, J.C. (author), Hogers, B. (author), van Vliet, L.S.J. (author), Poelmann, R.E. (author), Havekes, L.M. (author), van Dijk, K.W. (author), de Ruiter, M.C. (author)

OBJECTIVE - Maternal hypercholesterolemia is associated with a higher incidence and faster progression of atherosclerotic lesions in neonatal offspring. We aimed to determine whether an in utero environment exposing a fetus to maternal hypercholesterolemia and associated risk factors can prime the murine vessel wall to accelerated development of...

article 2007

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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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Methods for the differential integrative omic analysis of plasma from a transgenic disease animal model

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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Hepatic low-density lipoprotein receptor-related protein deficiency in mice increases atherosclerosis independent of plasma cholesterol

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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Cardiovascular disease and mortality in statin-treated patients with familial hypercholesterolemia

Mohrschladt, M.F. (author), Westendorp, R.G.J. (author), Gevers Leuven, J.A. (author), Smelt, A.H.M. (author), Gaubius Instituut TNO (author)

Patients with familial hypercholesterolemia (FH) are at an increased risk of premature cardiovascular disease (CVD). The benefits of statin therapy are not well known since no placebo controlled studies have been performed in these patients. The aim of this study was to determine the CVD event and mortality risk in statin-treated patients with...

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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Expression of type III hyperlipoproteinemia in apolipoprotein E2 (Arg158→Cys) homozygotes is associated with hyperinsulinemia

de Beer, F. (author), Stalenhoef, A.F.H. (author), Hoogerbrugge, N. (author), Kastelein, J.J.P. (author), Leuven, J.A.G. (author), van Duijn, C.M. (author), Havekes, L.M. (author), Smelt, A.H.M. (author), Gaubius Instituut TNO (author)

Type III hyperlipoproteinemia (HLP) is mainly found in homozygous carriers of apolipoprotein E2 (apoE2, Arg158→Cys). Only a small percentage (<5%) of these apoE2 homozygotes develops hyperlipidemia, indicating that additional environmental and genetic factors contribute to the expression of type III HLP. In the present study, first, the...

article 2002

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C-reactive protein in patients with familial hypercholesterolemia: No effect of simvastatin therapy

Mohrschladt, M.F. (author), de Maat, M.P.M. (author), Westendorp, R.G.J. (author), Smelt, A.H.M (author), Gaubius Instituut TNO (author)

Patients with familial hypercholesterolemia (FH) are especially at risk for premature cardiovascular disease (CVD). Recent studies revealed C-reactive protein (CRP) as a strong predictor of future first or recurrent CVD events, suggesting that CRP plays an important role in the development of atherosclerosis. The aim of this study was to...

article 2001

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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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Additional risk factors influence excess mortality in heterozygous familial hypercholesterolaemia

TNO Preventie en Gezondheid (author), Sijbrands, E.J.G. (author), Westendorp, R.G.J. (author), Paola Lombardi, M. (author), Havekes, L.M. (author), Frants, R.R. (author), Kastelein, J.J.P. (author), Smelt, A.H.M. (author)

Life expectancy of patients with familial hypercholesterolaemia is decreased. Some untreated patients reach a normal life span and, therefore, additional risk factors and the type of mutation in the low-density lipoprotein (LDL) receptor gene are likely to influence the clinical outcome. We determined all cause mortality in kindreds with the...

article 2000

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Severe hyperlipidemia in apolipoprotein E2 homozygotes due to a combined effect of hyperinsulinemia and an SstI polymorphism

Sijbrands, E.J.G. (author), Hoffer, M.J.V. (author), Meinders, A.E. (author), Havekes, L.M. (author), Frants, R.R. (author), Smelt, A.H.M. (author), de Knijff, P. (author), Gaubius instituut TNO (author)

More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158→Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors,...

article 1999

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Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations

Sijbrands, E.J.G. (author), Lombardi, M.P. (author), Westendorp, R.G.J. (author), Gevers Leuven, J.A. (author), Meinders, A.E. (author), van der Laarse, A. (author), Frants, R.R. (author), Havekes, L.M. (author), Smelt, A.H.M. (author), Gaubius Instituut TNO (author)

In patients heterozygous for familial hypercholesterolemia, the low- density lipoprotein (LDL) cholesterol lowering effect of β-hydroxy-β- methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks,...

article 1998

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Identification of three new mutations of the low density lipoprotein receptor gene in dutch familial hypercholesterolemic patients

Lombardi, P. (author), Sijbrands, E.J.G. (author), Kamerling, S. (author), Smelt, A.H. (author), Havekes, L.M. (author), Gaubius Instituut TNO (author)

article 1998

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Effect of apolipoprotein E variants on lipolysis of very low density lipoproteins by heparan sulphate proteoglycan-bound lipoprotein lipase

de Man, F.H.A.F. (author), de Beer, F. (author), van der Laarse, A. (author), Smelt, A.H.M. (author), Leuven, J.A.G. (author), Havekes, L.M. (author), Gaubius Instituut TNO (author)

Lipoprotein lipase (LPL) is bound to heparan sulphate proteoglycans (HSPG) at the luminal surface of endothelium. It is the key enzyme involved in the hydrolysis of very low density lipoproteins (VLDL). Prior to lipolysis by LPL, the lipoproteins are considered to interact with vessel wall HSPG. Apolipoprotein (apo) E is thought to mediate this...

article 1998

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Opsporing familiaire hypercholesterolemie bij kinderen geindiceerd? Bij uitzondering wel [Search for familial hypercholesterolaemia in children indicated? Only exceptionally]

Gevers Leuven, J.A. (author), TNO Preventie en Gezondheid (author)

Searching for familial hypercholesterolaemia (FH) in children is useful only if efficacious treatment is to be administered shortly and if there are relatives with ischaemic heart disease at very early ages. In all other cases, the (psychological) drawbacks probably outweigh the doubtful benefit of early intervention. The search for the major...

article 1997

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Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase

Hendriks, W.L. (author), de Sman van der - Beer, F. (author), van Vlijmen, B.J.M. (author), van Vark, L.C. (author), Hofker, M.H. (author), Havekes, L.M. (author), TNO Preventie en Gezondheid (author)

Apolipoprotein (apo) E-deficient mice display marked accumulation in the plasma of VLDL deficient in both apoE and apoBl00 but containing apoB48, apoA-1, apoCs, and apoA-IV. Since apoE-deficient mice develop severe atherosclerotic lesions with lipid-laden macrophages, we reasoned that the uptake of lipoproteins by intimal macrophages can take...

article 1997

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Reduced very-low-density lipoprotein fractional catabolic rate in apolipoprotein C1-deficient mice

Jong, M.C. (author), van Ree, J.H. (author), Dahlmans, V.E.H. (author), Frants, R.R. (author), Hofker, M.H. (author), Havekes, L.M. (author), TNO Preventie en Gezondheid (author)

The function of apolipoprotein (apo) C1 in vivo is not clearly defined. Because transgenic mice overexpressing human apoC1 show elevated triacylglycerol (TG) levels, an as yet unknown role for apoC1 in TG metabolism has been suggested. Here we investigated directly the effect of the complete absence of apoC1 on very-low-density lipoprotein (VLDL...

article 1997

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Effects of gemfibrozil and ciprofibrate on plasma levels of tissue-type plasminogen activator, plasminogen activator inhibitor-1 and fibrinogen in hyperlipidaemic patients

Kockx, M. (author), de Maat, M.P.M. (author), Knipscheer, H.C. (author), Kastelein, J.P. (author), Kluft, C. (author), Princen, H.M.G. (author), Kooistra, T. (author), Gaubius Instituut TNO (author)

Evaluation of fibrate treatment in humans has focused primarily on its anti-lipidaemic effects. A potentially favourable haemostasis-modulating activity of fibrates has also been recognized but the data are not consistent. We sought to learn more about this variability by examining the effects of gemfibrozil and ciprofibrate on plasma levels of...

article 1997