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Frank L J Visseren - One of the best experts on this subject based on the ideXlab platform.
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effect of adding bezafibrate to standard lipid lowering therapy on post fat load lipid levels in patients with Familial Dysbetalipoproteinemia a randomized placebo controlled crossover trial
Journal of Lipid Research, 2017Co-Authors: Charlotte Koopal, David A Marais, Jan Westerink, Yolanda Van Der Graaf, Frank L J VisserenAbstract:Familial Dysbetalipoproteinemia (FD) is a genetic disorder associated with impaired postprandial lipid clearance. The effect of adding bezafibrate to standard lipid-lowering therapy on postprandial and fasting lipid levels in patients with FD is unknown. In this randomized placebo-controlled double-blind crossover trial, 15 patients with FD received bezafibrate and placebo for 6 weeks in randomized order in addition to standard lipid-lowering therapy (statin, ezetimibe, and/or lifestyle). We assessed post-fat load lipids, expressed as incremental area under the curve (iAUC) and area under the curve (AUC), as well as fasting levels and safety, and found that adding bezafibrate did not reduce post-fat load non-HDL-cholesterol (non-HDL-C) iAUC (1.78 ± 4.49 mmol·h/l vs. 1.03 ± 2.13 mmol·h/l, P = 0.57), but did reduce post-fat load triglyceride (TG) iAUC (8.05 ± 3.32 mmol·h/l vs. 10.61 ± 5.92 mmol·h/l, P = 0.03) and apoB (0.64 ± 0.62 g·h/l vs. 0.93 ± 0.71 g·h/l, P = 0.01). Furthermore, bezafibrate significantly improved AUC and fasting levels of non-HDL-C, TG, total cholesterol, HDL-C, and apoB. Bezafibrate was associated with lower estimated glomerular filtration rate (78.4 ± 11.4 ml/min/1.73 m2 vs. 86.1 ± 5.85 ml/min/1.73 m2, P = 0.002). In conclusion, in patients with FD, the addition of bezafibrate to standard lipid-lowering therapy resulted in improved post-fat load and fasting plasma lipids. Combination therapy of statin/fibrate could be considered as standard lipid-lowering treatment in FD.
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Familial Dysbetalipoproteinemia : an underdiagnosed lipid disorder
Current opinion in endocrinology diabetes and obesity, 2017Co-Authors: Charlotte Koopal, A. David Marais, Frank L J VisserenAbstract:Purpose of review To review pathophysiological, epidemiological and clinical aspects of Familial Dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk. Recent findings Familial Dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most Familial Dysbetalipoproteinemia patients are homozygous for apolipoprotein e2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although Familial Dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an e2e2 genotype 15% develops Familial Dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of Familial Dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of Familial Dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in Familial Dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination. Summary Familial Dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.
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autosomal dominant Familial Dysbetalipoproteinemia a pathophysiological framework and practical approach to diagnosis and therapy
Journal of Clinical Lipidology, 2017Co-Authors: Charlotte Koopal, David A Marais, Jan Westerink, Frank L J VisserenAbstract:Familial Dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism associated with an increased risk for premature cardiovascular disease. In about 10% of the cases, FD is caused by autosomal dominant mutations in the apolipoprotein E gene (APOE). This review article provides a pathophysiological framework for autosomal dominant FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE. ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to increased remnants. Remnants are hepatically cleared by the low-density lipoprotein receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD is associated with secondary factors like insulin resistance that lead to HSPG-R degradation through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible misdiagnosis as Familial hypercholesterolemia. FD patients respond well to lifestyle changes and to combination therapy with statins and fibrates. To conclude, diagnosing ADFD is important to adequately treat patients and their family members. In patients presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered as part of the diagnostic work up.
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vascular risk factors vascular disease lipids and lipid targets in patients with Familial Dysbetalipoproteinemia a european cross sectional study
Atherosclerosis, 2015Co-Authors: Charlotte Koopal, J. De ,graaf, Kjetil Retterstol, Barbara Sjouke, G K Hovingh, Emilio Ros, Robin P F Dullaart, S Bertolini, Frank L J VisserenAbstract:Abstract Background Familial Dysbetalipoproteinemia (FD), also known as type III hyperlipoproteinemia, is a genetic dyslipidemia characterized by elevated very low density lipoprotein (VLDL) and chylomicron remnant particles that confers increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the prevalence of vascular risk factors, CVD, lipid values, treatment and lipid targets in patients with FD across Europe. Methods This cross-sectional study was performed in 305 patients with FD from seven academic hospitals in four European countries. Information was collected from clinical records. Results Patients mean (± standard deviation) age was 60.9 ± 14.4 years, 201 (66%) were male, 69 (23%) had diabetes mellitus (DM) and 87 (29%) had a prior history of CVD. Mean body mass index was 28.5 ± 5.0 kg/m 2 . Lipid-lowering medication was used by 227 (74%) patients (27% usual dose (theoretical low-density lipoprotein cholesterol (LDL-C) reduction ≤40%) and 46% intensive dose (theoretical LDL-C reduction >40%)). Non high-density lipoprotein cholesterol (non-HDL-C) levels below treatment target ( Conclusion The majority of FD patients had non-HDL-C levels above the treatment target of 3.3 mmol/L. Intensive dose lipid-lowering medication was used by only half of the patients, leaving them at increased cardiovascular risk.
Louis M. Havekes - One of the best experts on this subject based on the ideXlab platform.
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Niacin Reduces Atherosclerosis Development in APOE*3Leiden.CETP Mice Mainly by Reducing NonHDL-
2016Co-Authors: Mieke C Louwe, Louis M. Havekes, Mattijs M Heemskerk, Elsbet J Pieterman, Johannes W A Smit, Patrick C N Rensen, Jan B. Van, Hans M. G. Princen, Wouter J. JukemaAbstract:Objective: Niacin potently lowers triglycerides, mildly decreases LDL-cholesterol, and largely increases HDL-cholesterol. Despite evidence for an atheroprotective effect of niacin from previous small clinical studies, the large outcome trials, AIM-HIGH and HPS2-THRIVE did not reveal additional beneficial effects of niacin (alone or in combination with laropiprant) on top of statin treatment. We aimed to address this apparent discrepancy by investigating the effects of niacin without and with simvastatin on atherosclerosis development and determine the underlying mechanisms, in APOE*3Leiden.CETP mice, a model for Familial Dysbetalipoproteinemia (FD). Approach and Results: Mice were fed a western-type diet containing cholesterol without or with niacin (120 mg/kg/day), simvastatin (36 mg/kg/day) or their combination for 18 weeks. Similarly as in FD patients, niacin reduced total cholesterol by-39 % and triglycerides by 250%, (both P,0.001). Simvastatin and the combination reduced total cholesterol (230%; 255%, P,0.001) where the combination revealed a greater reduction compared to simvastatin (236%, P,0.001). Niacin decreased total cholesterol and triglycerides primarily by increasing VLDL clearance. Niacin increased HDL-cholesterol (+28%, P,0.01) and mildly increased reverse cholesterol transport. All treatments reduced monocyte adhesion to th
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plasma lipoproteins in Familial Dysbetalipoproteinemia associated with apolipoproteins e2 arg158 cys e3 leiden and e2 lys146 gln and effects of treatment with simvastatin
Arteriosclerosis Thrombosis and Vascular Biology, 1994Co-Authors: S P Zhao, A. Van Der Laarse, A.m.j.m. Van Den Maagdenberg, Louis M. Havekes, A H M Smelt, T F Vroom, R R Frants, J Gevers A Leuven, A Q M J Van Steijnvan Tol, F.m. Van 't HooftAbstract:Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with Familial Dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n = 6), or apoE2(Lys146-->Gln) heterozygosity (the E2-146 variant, n = 6), with average plasma cholesterol concentrations of 8.99 +/- 1.34 mmol/L, 9.29 +/- 1.55 mmol/L, and 8.46 +/- 1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90 +/- 0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70 +/- 0.26, 1.50 +/- 0.26, 1.05 +/- 0.36, and 0.47 +/- 0.14 mmol/L, respectively), LDL cholesterol concentration (1.83 +/- 0.50, 3.09 +/- 0.32, 3.79 +/- 0.76, and 3.77 +/- 0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 +/- 0.28, 0.48 +/- 0.04, 0.28 +/- 0.09, and 0.12 +/- 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin:cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of Dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.
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Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia.
The Journal of biological chemistry, 1993Co-Authors: A.m.j.m. Van Den Maagdenberg, B.j.m. Van Vlijmen, H. Van Der Boom, Louis M. Havekes, M.h. Hofker, P. J. A. Krimpenfort, I. De Bruijn, Rune R. FrantsAbstract:Abstract Apolipoprotein (apo) E3-Leiden, described in a large Dutch family, is associated with a dominantly inherited form of Familial Dysbetalipoproteinemia. To study the effect of the APOE*3-Leiden mutation in vivo, transgenic mice were generated using a genomic 27-kilobase DNA construct isolated from the APOE*3-Leiden proband. This construct carried the APOE gene, the APOC1 gene, and all known regulatory elements including an element that mediates liver expression. Three strains were generated that showed human APOE and APOC1 expression. All strains had significantly elevated levels of total plasma cholesterol and triglycerides on a regular diet. When mice of one strain were fed a semisynthetic cholesterol-rich diet, total plasma cholesterol and triglyceride levels increased dramatically. This increase was observed mainly in the very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-sized fractions. In cholesterol-fed mice, the apoE3-Leiden protein became equally distributed between the VLDL/LDL and HDL-sized fractions, while in mice kept on a regular diet, apoE3-Leiden protein was mainly associated with HDL-sized fractions. The presence of hyperlipoproteinemia in the APOE*3-Leiden-expressing transgenic mice supports our finding that the apoE3-Leiden variant behaves like a dominant trait in the expression of Familial Dysbetalipoproteinemia. ApoE3-Leiden transgenic mice may serve as a model to elucidate additional factors involved in the metabolism of apoE containing remnant lipoproteins in general and the etiology of Familial Dysbetalipoproteinemia in particular.
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rare mutations in the apoe gene associated with dominant mode of inheritance of Familial Dysbetalipoproteinemia fd
1993Co-Authors: Louis M. Havekes, A.m.j.m. Van Den Maagdenberg, P. De Knijff, Monique T Mulder, Rune R. FrantsAbstract:Apolipoprotein E (apoE) is a major constituent of chylomicron- and VLDL-remnants. It plays a major role in the clearance of these lipoproteins as it serves as a ligand for recognition by hepatic lipoprotein receptors. With isoelectric focusing (IEF) apoE can be separated into three commonly occuring isoforms e.g. E2, E3 and E4.
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Familial Dysbetalipoproteinemia a genetically heterogenous disease caused by mutations of the ligand apolipoprotein e
Journal of Investigative Dermatology, 1992Co-Authors: Bert J Vermeer, R R Frants, Louis M. HavekesAbstract:Apolipoprotein E is present on the surface of very-low-density lipoprotein (VLDL) and chylomicron-remnants and is essential for the receptor mediated endocytosis of these particles via hepatic receptors. Several types of mutations of the apoE can cause a deficiency in the clearance of these remnant particles. An accumulation of lipoprotein-remnant particles may occur and Familial Dysbetalipoproteinemia (FD) develops. Genotyping of the various apoE variants and relation of these mutations with their effect on the lipoprotein-remnant removal have provided more insight in the structure-relationship of apoE ligand-receptor interactions. It is postulated that the apoE2 (Arg158----Cys) mutation is just outside the binding domain and that its deficient binding can be stimulated by exogenous factors. This hypothesis can explain why apoE2/E2 homozygosity can only induce FD under certain circumstances. ApoE mutations that occur in the binding domain, e.g., apoE2 (Lys146----Gln) have a direct effect on the ligand-receptor binding and, in these individuals, FD is inherited in an autosomal dominant way. Finally, apoE3-Leiden has an arginine residue at 112 and has a repeat of seven extra amino acid residues just outside the binding domain. Because of this repeat, conformational changes of the binding domain can ensue. Due to the fact that in apo E3-Leiden the arginine residue is present at 112, apoE3 Leiden is predominantly present on chylomicron and VLDL remnants. In these persons FD is also inherited in an autosomal dominant way
A.m.j.m. Van Den Maagdenberg - One of the best experts on this subject based on the ideXlab platform.
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plasma lipoproteins in Familial Dysbetalipoproteinemia associated with apolipoproteins e2 arg158 cys e3 leiden and e2 lys146 gln and effects of treatment with simvastatin
Arteriosclerosis Thrombosis and Vascular Biology, 1994Co-Authors: S P Zhao, A. Van Der Laarse, A.m.j.m. Van Den Maagdenberg, Louis M. Havekes, A H M Smelt, T F Vroom, R R Frants, J Gevers A Leuven, A Q M J Van Steijnvan Tol, F.m. Van 't HooftAbstract:Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with Familial Dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n = 6), or apoE2(Lys146-->Gln) heterozygosity (the E2-146 variant, n = 6), with average plasma cholesterol concentrations of 8.99 +/- 1.34 mmol/L, 9.29 +/- 1.55 mmol/L, and 8.46 +/- 1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90 +/- 0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70 +/- 0.26, 1.50 +/- 0.26, 1.05 +/- 0.36, and 0.47 +/- 0.14 mmol/L, respectively), LDL cholesterol concentration (1.83 +/- 0.50, 3.09 +/- 0.32, 3.79 +/- 0.76, and 3.77 +/- 0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 +/- 0.28, 0.48 +/- 0.04, 0.28 +/- 0.09, and 0.12 +/- 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin:cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of Dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.
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variable expression of Familial Dysbetalipoproteinemia in apolipoprotein e 2 lys146 gln allele carriers
Journal of Clinical Investigation, 1994Co-Authors: P. De Knijff, A.m.j.m. Van Den Maagdenberg, Anton F. H. Stalenhoef, A H M Smelt, R R Frants, Dorret I Boomsma, J J P Kastelein, A D Marais, L M HavekesAbstract:Abstract Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with Familial Dysbetalipoproteinemia (FD) carrying the APOE*2 (Lys146-->Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2 (Lys146-->Gln) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89 +/- 0.37 vs 0.30 +/- 0.27 and 1.86 +/- 0.37 vs 0.68 +/- 0.27 mmol/liter, respectively) and plasma apolipoprotein (apo) E levels (28.1 +/- 1.6 vs 4.6 +/- 1.1 mg/dl), which is characteristic for FD. By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2 (Lys146-->Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lys146-->Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects.
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Transgenic mice carrying the apolipoprotein E3-Leiden gene exhibit hyperlipoproteinemia.
The Journal of biological chemistry, 1993Co-Authors: A.m.j.m. Van Den Maagdenberg, B.j.m. Van Vlijmen, H. Van Der Boom, Louis M. Havekes, M.h. Hofker, P. J. A. Krimpenfort, I. De Bruijn, Rune R. FrantsAbstract:Abstract Apolipoprotein (apo) E3-Leiden, described in a large Dutch family, is associated with a dominantly inherited form of Familial Dysbetalipoproteinemia. To study the effect of the APOE*3-Leiden mutation in vivo, transgenic mice were generated using a genomic 27-kilobase DNA construct isolated from the APOE*3-Leiden proband. This construct carried the APOE gene, the APOC1 gene, and all known regulatory elements including an element that mediates liver expression. Three strains were generated that showed human APOE and APOC1 expression. All strains had significantly elevated levels of total plasma cholesterol and triglycerides on a regular diet. When mice of one strain were fed a semisynthetic cholesterol-rich diet, total plasma cholesterol and triglyceride levels increased dramatically. This increase was observed mainly in the very low density lipoprotein (VLDL)- and low density lipoprotein (LDL)-sized fractions. In cholesterol-fed mice, the apoE3-Leiden protein became equally distributed between the VLDL/LDL and HDL-sized fractions, while in mice kept on a regular diet, apoE3-Leiden protein was mainly associated with HDL-sized fractions. The presence of hyperlipoproteinemia in the APOE*3-Leiden-expressing transgenic mice supports our finding that the apoE3-Leiden variant behaves like a dominant trait in the expression of Familial Dysbetalipoproteinemia. ApoE3-Leiden transgenic mice may serve as a model to elucidate additional factors involved in the metabolism of apoE containing remnant lipoproteins in general and the etiology of Familial Dysbetalipoproteinemia in particular.
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lipoproteins in Familial Dysbetalipoproteinemia variation of serum cholesterol level associated with vldl concentration
Arteriosclerosis Thrombosis and Vascular Biology, 1993Co-Authors: S P Zhao, A. Van Der Laarse, A.m.j.m. Van Den Maagdenberg, A H M Smelt, J A Leuven, F.m. Van 't HooftAbstract:Patients with Familial Dysbetalipoproteinemia (FD) associated with the apo E2/2 phenotype exhibit a marked interindividual variability in serum cholesterol and triglyceride concentrations. It has been proposed that this variability is due to a combination of the apo E2/2 phenotype and additional genetic factors implicated in diseases like Familial hypercholesterolemia, Familial combined hyperlipoproteinemia, and Familial hypertriglyceridemia. To further explore the nature of this variability, the lipoprotein profiles of 17 patients with FD associated with the apo E2/2 phenotype were analyzed by a density-gradient ultracentrifugation technique and by 2-16% polyacrylamide gel electrophoresis. It was found that all patients with FD were characterized by 1) markedly increased cholesterol concentrations of large very low density lipoprotein (VLDL) (VLDL1) (2.98 +/- 3.08 versus 0.08 +/- 0.03 mmol/L), small VLDL (VLDL2) (4.68 +/- 1.93 versus 0.27 +/- 0.13 mmol/L), and intermediate density lipoprotein (IDL) (2.25 +/- 0.72 versus 0.39 +/- 0.16 mmol/L); 2) decreased low density lipoprotein (LDL) cholesterol level (1.84 +/- 0.54 versus 3.36 +/- 0.53 mmol/L); and 3) altered composition (enrichment by cholesteryl ester) of VLDL1 and VLDL2 compared with normolipidemic control subjects. The cholesterol levels of IDL and LDL showed minor interindividual variabilities and were not correlated with serum cholesterol and triglyceride levels. The compositions of VLDL1 and VLDL2 were independent of the concentrations of lipids in serum. However, the cholesterol concentrations of VLDL1 and VLDL2 showed considerable interindividual variabilities and were positively correlated with the serum cholesterol concentration (r = 0.84 and r = 0.95, respectively, both p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
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rare mutations in the apoe gene associated with dominant mode of inheritance of Familial Dysbetalipoproteinemia fd
1993Co-Authors: Louis M. Havekes, A.m.j.m. Van Den Maagdenberg, P. De Knijff, Monique T Mulder, Rune R. FrantsAbstract:Apolipoprotein E (apoE) is a major constituent of chylomicron- and VLDL-remnants. It plays a major role in the clearance of these lipoproteins as it serves as a ligand for recognition by hepatic lipoprotein receptors. With isoelectric focusing (IEF) apoE can be separated into three commonly occuring isoforms e.g. E2, E3 and E4.
A H M Smelt - One of the best experts on this subject based on the ideXlab platform.
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apolipoprotein e and Familial Dysbetalipoproteinemia clinical biochemical and genetic aspects
Seminars in Vascular Medicine, 2004Co-Authors: A H M Smelt, F De BeerAbstract:In humans, apolipoprotein E (apoE) is a polymorphic protein of which three common isoforms can be distinguished, designated apoE2, apoE3, and apoE4. This genetic variation is associated with different plasma lipoprotein levels, different response to diet and lipid-lowering therapy, and a variable risk for cardiovascular disease and Alzheimer's disease. An example of an apoE-mediated, autosomal recessive, lipid disorder is Familial Dysbetalipoproteinemia (FD), caused by mutations in the apolipoprotein E gene. Homozygosity for APOE*2 (1 in 170 persons) causes FD or type III hyperlipoproteinemia in less than 20% of the adult APOE*2 homozygotes. Less common, dominant negative mutations may also cause the disorder. The patients may present with typical skin lesions and elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate-density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional gene and environmental factors are necessary for the expression of this hyperlipoproteinemia. Hyperinsulinemia and defects in genes involved in the hydrolysis of triglycerides are associated with this lipid disorder. Diet and weight reduction are effective but usually not sufficient to normalize the lipid levels. Additional therapy with statins or fibrates is necessary and effective in most patients.
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from gene to disease apolipoprotein e2 and Familial Dysbetalipoproteinemia
Nederlands Tijdschrift voor Geneeskunde, 2003Co-Authors: A H M SmeltAbstract:Familial dysbetalipoproteinaemia is an autosomal recessive, hereditary disorder of lipid metabolism caused by mutations in the apolipoprotein E gene. Homozygosity for apoE2 (1 in 170 persons) causes type III hyperlipoproteinaemia in less than 20% of the adult E2 homozygotes. The patients may present with typical skin lesions and have elevated plasma levels of cholesterol and triglycerides, mainly in very-low-density lipoprotein remnants and intermediate density lipoproteins. The disorder is associated with peripheral and coronary artery disease. Additional genetic and environmental factors are necessary for the expression of this hyperlipoproteinaemia. Hyperinsulinaemia and defects in genes involved in the hydrolysis of triglycerides are associated with this disorder.
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plasma lipoproteins in Familial Dysbetalipoproteinemia associated with apolipoproteins e2 arg158 cys e3 leiden and e2 lys146 gln and effects of treatment with simvastatin
Arteriosclerosis Thrombosis and Vascular Biology, 1994Co-Authors: S P Zhao, A. Van Der Laarse, A.m.j.m. Van Den Maagdenberg, Louis M. Havekes, A H M Smelt, T F Vroom, R R Frants, J Gevers A Leuven, A Q M J Van Steijnvan Tol, F.m. Van 't HooftAbstract:Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with Familial Dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Arg158-->Cys) homozygosity (the E2-158 variant, n = 6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n = 6), or apoE2(Lys146-->Gln) heterozygosity (the E2-146 variant, n = 6), with average plasma cholesterol concentrations of 8.99 +/- 1.34 mmol/L, 9.29 +/- 1.55 mmol/L, and 8.46 +/- 1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90 +/- 0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70 +/- 0.26, 1.50 +/- 0.26, 1.05 +/- 0.36, and 0.47 +/- 0.14 mmol/L, respectively), LDL cholesterol concentration (1.83 +/- 0.50, 3.09 +/- 0.32, 3.79 +/- 0.76, and 3.77 +/- 0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol to LDL cholesterol (0.98 +/- 0.28, 0.48 +/- 0.04, 0.28 +/- 0.09, and 0.12 +/- 0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin:cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of Dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD.
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variable expression of Familial Dysbetalipoproteinemia in apolipoprotein e 2 lys146 gln allele carriers
Journal of Clinical Investigation, 1994Co-Authors: P. De Knijff, A.m.j.m. Van Den Maagdenberg, Anton F. H. Stalenhoef, A H M Smelt, R R Frants, Dorret I Boomsma, J J P Kastelein, A D Marais, L M HavekesAbstract:Abstract Genetic and biochemical studies were carried out in 96 relatives of six independently ascertained probands with Familial Dysbetalipoproteinemia (FD) carrying the APOE*2 (Lys146-->Gln) allele. Compared to noncarriers, the 40 heterozygous APOE*2 (Lys146-->Gln) allele carriers exhibited markedly increased mean levels of cholesterol and triglyceride in the very low density lipoproteins (VLDL) (1.89 +/- 0.37 vs 0.30 +/- 0.27 and 1.86 +/- 0.37 vs 0.68 +/- 0.27 mmol/liter, respectively) and plasma apolipoprotein (apo) E levels (28.1 +/- 1.6 vs 4.6 +/- 1.1 mg/dl), which is characteristic for FD. By means of a pedigree-based maximum likelihood method we calculated that carrier-status accounted for 57% and 71%, respectively, of the total variance of the ratio (VLDL + IDL)-cholesterol/plasma triglyceride and plasma apoE levels. APOE*2 (Lys146-->Gln) and APOE*3-Leiden allele carriers were found to differ significantly in: (a) plasma apoE levels, (b) in the amounts of triglycerides in the VLDL and VLDL + IDL fraction, and (c) in the amount of cholesterol in the VLDL and VLDL + IDL fraction relative to the amount of triglyceride in these fractions. In the APOE*2 (Lys146-->Gln) allele carriers the VLDL and VLDL + IDL fraction is relatively rich in triglycerides as compared with that in APOE*3-Leiden carriers. We hypothesize that these two rare mutations of apoE both lead to dominantly inherited forms of FD along different underlying metabolic defects.
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changes of lipoprotein profile in Familial Dysbetalipoproteinemia with gemfibrozil
The American Journal of Medicine, 1994Co-Authors: S P Zhao, A H M Smelt, Jan Gevers A Leuven, T F Vroom, Arnoud Van Der Laarse, Ferdinand Vant M HooftAbstract:Abstract purpose: This prospective study was undertaken to evaluate the effects of gemfibrozil on the lipoprotein profile of patients with Familial Dysbetalipoproteinemia (type III hyperlipoproteinemia). patients and methods: Eight patients with well-defined Familial Dysbetalipoproteinemia associated with the apolipoprotein (apo) E2/2 phenotype were treated with gemfibrozil (Lopid) at a dose of 600 mg twice daily for a period of 10 months. Blood samples were taken at baseline, after 4 and 5 weeks, after 3 months, and after 10 months. The separation of serum lipoprotein (sub)fractions was performed by a recently developed density gradient ultracentrifugation technique. results: After 4 weeks of gemfibrozil therapy, the concentrations of serum total cholesterol and serum total triglyceride had decreased by 45% (from 11.87 to 6.51 mmol/L, p 1 ) (large VLDL), VLDL 2 (small VLDL), and intermediate-density lipoprotein (IDL) had decreased significantly by 73%, 74%, and 34%, respectively. The low-density lipoprotein (LDL)-cholesterol level remained unchanged, whereas the particle size of LDL showed a small but significant increase (from 24.09 nm to 24.43 nm, p conclusion: Gemfibrozil treatment in patients with Familial Dysbetalipoproteinemia resulted in a marked reduction of the concentrations of large VLDL, small VLDL, and IDL, and an increase in the levels of HDL, apo A-I, and apo A-II. These changes are considered to exert an antiatherosclerotic effect in these patients.
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effect of adding bezafibrate to standard lipid lowering therapy on post fat load lipid levels in patients with Familial Dysbetalipoproteinemia a randomized placebo controlled crossover trial
Journal of Lipid Research, 2017Co-Authors: Charlotte Koopal, David A Marais, Jan Westerink, Yolanda Van Der Graaf, Frank L J VisserenAbstract:Familial Dysbetalipoproteinemia (FD) is a genetic disorder associated with impaired postprandial lipid clearance. The effect of adding bezafibrate to standard lipid-lowering therapy on postprandial and fasting lipid levels in patients with FD is unknown. In this randomized placebo-controlled double-blind crossover trial, 15 patients with FD received bezafibrate and placebo for 6 weeks in randomized order in addition to standard lipid-lowering therapy (statin, ezetimibe, and/or lifestyle). We assessed post-fat load lipids, expressed as incremental area under the curve (iAUC) and area under the curve (AUC), as well as fasting levels and safety, and found that adding bezafibrate did not reduce post-fat load non-HDL-cholesterol (non-HDL-C) iAUC (1.78 ± 4.49 mmol·h/l vs. 1.03 ± 2.13 mmol·h/l, P = 0.57), but did reduce post-fat load triglyceride (TG) iAUC (8.05 ± 3.32 mmol·h/l vs. 10.61 ± 5.92 mmol·h/l, P = 0.03) and apoB (0.64 ± 0.62 g·h/l vs. 0.93 ± 0.71 g·h/l, P = 0.01). Furthermore, bezafibrate significantly improved AUC and fasting levels of non-HDL-C, TG, total cholesterol, HDL-C, and apoB. Bezafibrate was associated with lower estimated glomerular filtration rate (78.4 ± 11.4 ml/min/1.73 m2 vs. 86.1 ± 5.85 ml/min/1.73 m2, P = 0.002). In conclusion, in patients with FD, the addition of bezafibrate to standard lipid-lowering therapy resulted in improved post-fat load and fasting plasma lipids. Combination therapy of statin/fibrate could be considered as standard lipid-lowering treatment in FD.
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Familial Dysbetalipoproteinemia : an underdiagnosed lipid disorder
Current opinion in endocrinology diabetes and obesity, 2017Co-Authors: Charlotte Koopal, A. David Marais, Frank L J VisserenAbstract:Purpose of review To review pathophysiological, epidemiological and clinical aspects of Familial Dysbetalipoproteinemia; a model disease for remnant metabolism and remnant-associated cardiovascular risk. Recent findings Familial Dysbetalipoproteinemia is characterized by remnant accumulation caused by impaired remnant clearance, and premature cardiovascular disease. Most Familial Dysbetalipoproteinemia patients are homozygous for apolipoprotein e2, which is associated with decreased binding of apolipoprotein E to the LDL receptor. Although Familial Dysbetalipoproteinemia is an autosomal recessive disease in most cases, 10% is caused by autosomal dominant mutations. Of people with an e2e2 genotype 15% develops Familial Dysbetalipoproteinemia, which is associated with secondary risk factors, such as obesity and insulin resistance, that inhibit remnant clearance by degradation of the heparan sulfate proteoglycan receptor. The prevalence of Familial Dysbetalipoproteinemia ranges from 0.12 to 0.40% depending on the definition used. Clinical characteristics of Familial Dysbetalipoproteinemia are xanthomas and mixed hyperlipidemia (high total cholesterol and triglycerides); the primary lipid treatment goal in Familial Dysbetalipoproteinemia is non-HDL-cholesterol; and treatment consists of dietary therapy and treatment with statin and fibrate combination. Summary Familial Dysbetalipoproteinemia is a relatively common, though often not diagnosed, lipid disorder characterized by mixed hyperlipidemia, remnant accumulation and premature cardiovascular disease, which should be treated with dietary therapy and statin and fibrate combination.
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autosomal dominant Familial Dysbetalipoproteinemia a pathophysiological framework and practical approach to diagnosis and therapy
Journal of Clinical Lipidology, 2017Co-Authors: Charlotte Koopal, David A Marais, Jan Westerink, Frank L J VisserenAbstract:Familial Dysbetalipoproteinemia (FD) is a genetic disorder of lipoprotein metabolism associated with an increased risk for premature cardiovascular disease. In about 10% of the cases, FD is caused by autosomal dominant mutations in the apolipoprotein E gene (APOE). This review article provides a pathophysiological framework for autosomal dominant FD (ADFD) and discusses diagnostic challenges and therapeutic options. The clinical presentation and diagnostic work-up of ADFD are illustrated by two cases: a male with premature coronary artery disease and a p.K164Q mutation in APOE and a female with mixed hyperlipidemia and a p.R154H mutation in APOE. ADFD is characterized by a fasting and postprandial mixed hyperlipidemia due to increased remnants. Remnants are hepatically cleared by the low-density lipoprotein receptor and the heparan sulfate proteoglycan receptor (HSPG-R). Development of FD is associated with secondary factors like insulin resistance that lead to HSPG-R degradation through sulfatase 2 activation. Diagnostic challenges in ADFD are related to the clinical presentation; lipid phenotype; dominant inheritance pattern; genotyping; and possible misdiagnosis as Familial hypercholesterolemia. FD patients respond well to lifestyle changes and to combination therapy with statins and fibrates. To conclude, diagnosing ADFD is important to adequately treat patients and their family members. In patients presenting with mixed hyperlipidemia, (autosomal dominant) FD should be considered as part of the diagnostic work up.
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vascular risk factors vascular disease lipids and lipid targets in patients with Familial Dysbetalipoproteinemia a european cross sectional study
Atherosclerosis, 2015Co-Authors: Charlotte Koopal, J. De ,graaf, Kjetil Retterstol, Barbara Sjouke, G K Hovingh, Emilio Ros, Robin P F Dullaart, S Bertolini, Frank L J VisserenAbstract:Abstract Background Familial Dysbetalipoproteinemia (FD), also known as type III hyperlipoproteinemia, is a genetic dyslipidemia characterized by elevated very low density lipoprotein (VLDL) and chylomicron remnant particles that confers increased risk of cardiovascular disease (CVD). The objective of this study was to evaluate the prevalence of vascular risk factors, CVD, lipid values, treatment and lipid targets in patients with FD across Europe. Methods This cross-sectional study was performed in 305 patients with FD from seven academic hospitals in four European countries. Information was collected from clinical records. Results Patients mean (± standard deviation) age was 60.9 ± 14.4 years, 201 (66%) were male, 69 (23%) had diabetes mellitus (DM) and 87 (29%) had a prior history of CVD. Mean body mass index was 28.5 ± 5.0 kg/m 2 . Lipid-lowering medication was used by 227 (74%) patients (27% usual dose (theoretical low-density lipoprotein cholesterol (LDL-C) reduction ≤40%) and 46% intensive dose (theoretical LDL-C reduction >40%)). Non high-density lipoprotein cholesterol (non-HDL-C) levels below treatment target ( Conclusion The majority of FD patients had non-HDL-C levels above the treatment target of 3.3 mmol/L. Intensive dose lipid-lowering medication was used by only half of the patients, leaving them at increased cardiovascular risk.