The Experts below are selected from a list of 210 Experts worldwide ranked by ideXlab platform
John J. P. Kastelein - One of the best experts on this subject based on the ideXlab platform.
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Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low
2015Co-Authors: High-density Lipoprotein, John J. P. KasteleinAbstract:Background—Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for Familial Hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these Familial hypoalphalipopro-teinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results—In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and-independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-L-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.40.2 mmol/L; P0.05), and their forearm blood flow responses to both 5HT (maximum, 49.010.4%) and L-NMMA (maximum, 22.822.9%) were blunted compared with control subjects (both P0.005). Infusion of apoA-I/PC disks increased plasma HDL to 1.30.4 mmol/L in ABCA1 heterozygotes, which resulted in complete restoration of vasomotor responses to both 5HT and L-NMMA (both P0.001). Endothelium-independent vasodilation remained unaltered throughout the protocol. Conclusions—In ABCA1 heterozygotes, isolated low HDL is associated with endothelial dysfunction, attested to b
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Treatment of Low HDL-C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations
Lipids, 2014Co-Authors: Eric J. Niesor, John J. P. Kastelein, David Kallend, Darren Bentley, G. Kees Hovingh, Erik S.g. StroesAbstract:We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with Familial combined hyperlipidemia (FCH) or Familial Hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 ( ApoA1 ) or ATP-binding cassette transporter A1 ( ABCA1 ). Patients ( n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9 %) and FCH (+18.4, +12.1 %), both p
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Treatment of Low HDL-C Subjects with the CETP Modulator Dalcetrapib Increases Plasma Campesterol Only in Those Without ABCA1 and/or ApoA1 Mutations
Lipids, 2014Co-Authors: Eric J. Niesor, Gerard K Hovingh, John J. P. Kastelein, David Kallend, Darren Bentley, Erik S.g. StroesAbstract:We investigated the effect of dalcetrapib treatment on phytosterol levels in patients with Familial combined hyperlipidemia (FCH) or Familial Hypoalphalipoproteinemia (FHA) due to mutations in apolipoprotein A1 (ApoA1) or ATP-binding cassette transporter A1 (ABCA1). Patients (n = 40) with FCH or FHA received dalcetrapib 600 mg or placebo in this 4-week, double-blind, crossover study. Lipids, apolipoproteins, cholesteryl ester transfer protein (CETP) activity and mass, and phytosterols were assessed. Dalcetrapib increased high-density lipoprotein cholesterol (HDL-C) and ApoA1 levels to a similar extent in FHA (+22.8, +13.9 %) and FCH (+18.4, +12.1 %), both p < 0.001 vs. placebo. Changes in CETP activity and mass were comparable for FHA (−31.5, +120.9 %) and FCH (−26.6, +111.9 %), both p < 0.0001 vs. placebo. Campesterol and lathosterol were unchanged in FHA (+3.8, +3.0 %), but only campesterol was markedly increased in FCH (+25.0 %, p < 0.0001 vs. placebo). Campesterol increased with dalcetrapib treatment in FCH but not in FHA, despite comparable HDL-C and ApoA1 increases, suggesting that ApoA1 and/or ABCA1 is essential for HDL lipidation by enterocytes in humans.
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Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT☆
Biochimica et biophysica acta, 2011Co-Authors: Ian Tietjen, John J. P. Kastelein, G. Kees Hovingh, Roshni R. Singaraja, Chris Radomski, Jason Mcewen, Elden Chan, Maryanne Mattice, Annick Legendre, Michael R. HaydenAbstract:Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc 40% of Familial Hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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reduced fecal sterol excretion in subjects with Familial Hypoalphalipoproteinemia
Atherosclerosis, 2009Co-Authors: Karim El Harchaoui, Remco Franssen, Radjesh J Bisoendial, Jan Albert Kuivenhoven, Erik S.g. Stroes, John J. P. Kastelein, Folkert Kuipers, Frans Stellaard, Kees G Hovingh, Albert K. GroenAbstract:BACKGROUND: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this relationship in patients with isolated low HDL-c versus controls. RESULTS: Fecal sterol excretion was studied in 12 subjects with Familial Hypoalphalipoproteinemia (FHA) and 11 healthy controls. Compared to the controls (8.9+/-6.3mg/kg/day), neutral sterol excretion was significantly lower in the FHA group (4.0+/-2.4mg/kg/day). Fecal bile acid excretion showed a similar pattern. Across the groups, a strong positive correlation between HDL-c and fecal neutral sterol excretion was found (r=0.53; p=0.01). CONCLUSIONS: Isolated low HDL-c levels in humans are associated with reduced fecal sterol excretion suggesting that in humans HDL regulates the final step in the RCT pathway at low HDL-c levels.
Radjesh J Bisoendial - One of the best experts on this subject based on the ideXlab platform.
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reduced fecal sterol excretion in subjects with Familial Hypoalphalipoproteinemia
Atherosclerosis, 2009Co-Authors: Karim El Harchaoui, Remco Franssen, Radjesh J Bisoendial, Jan Albert Kuivenhoven, Erik S.g. Stroes, John J. P. Kastelein, Folkert Kuipers, Frans Stellaard, Kees G Hovingh, Albert K. GroenAbstract:BACKGROUND: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this relationship in patients with isolated low HDL-c versus controls. RESULTS: Fecal sterol excretion was studied in 12 subjects with Familial Hypoalphalipoproteinemia (FHA) and 11 healthy controls. Compared to the controls (8.9+/-6.3mg/kg/day), neutral sterol excretion was significantly lower in the FHA group (4.0+/-2.4mg/kg/day). Fecal bile acid excretion showed a similar pattern. Across the groups, a strong positive correlation between HDL-c and fecal neutral sterol excretion was found (r=0.53; p=0.01). CONCLUSIONS: Isolated low HDL-c levels in humans are associated with reduced fecal sterol excretion suggesting that in humans HDL regulates the final step in the RCT pathway at low HDL-c levels.
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Consequences of cholesteryl ester transfer protein inhibition in patients with Familial Hypoalphalipoproteinemia.
Arteriosclerosis thrombosis and vascular biology, 2005Co-Authors: Radjesh J Bisoendial, Karim El Harchaoui, Jan Albert Kuivenhoven, John J. P. Kastelein, Sotirios Tsimikas, Aeilko E. Zwinderman, G. Kees Hovingh, Johannes H.m. Levels, Erik S.g. StroesAbstract:To the Editor: A large proportion of clinical events cannot be prevented during statin therapy, which calls for novel drug targets to further improve cardiovascular outcome. In particular, HDL-increasing strategies hold great promise. The impact of decreased HDL-C on cardiovascular disease (CVD)-related morbidity and mortality has been sharply delineated in individuals affected by Familial Hypoalphalipoproteinemia (FHA).1 HDL exerts multiple antiatherogenic actions beyond its role in reverse cholesterol transport, comprising antiinflammatory, antioxidative, and direct vascular effects.2 Whereas current strategies to raise HDL-C are limited, novel CETP-inhibitors are capable of mediating significant HDL-C elevation.3,4 Therefore, we evaluated the effects of CETP inhibition on lipid metabolism and markers of oxidation in subjects with FHA. Subjects were recruited from a Dutch population-based study to identify genes that control HDL-C levels,1 meeting the following criteria: (1) plasma HDL-C level below 10th percentile for age and sex; (2) absence of secondary lipid disorders; and (3) high likelihood of inherited low HDL (defined as HDL-C below 10th percentile in at least one first-degree family member). Nineteen FHA patients (13 men and 6 women; mean±SD age: 42.9±13.9 years), all free of overt macrovascular disease, were enrolled in the study. In 9 of these subjects the underlying defect was defined: heterozygosity for an apolipoprotein A-I (L178P) mutation,1 whereas in the remainder this genetic defect was excluded. The study protocol was approved …
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restoration of endothelial function by increasing high density lipoprotein in subjects with isolated low high density lipoprotein
Circulation, 2003Co-Authors: Radjesh J Bisoendial, John J. P. Kastelein, Michael R. Hayden, Kees G Hovingh, Johannes H.m. Levels, Peter Lerch, Irmgard Andresen, Erik S.g. StroesAbstract:Background— Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for Familial Hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these Familial Hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results— In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-l-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4±0.2 mmol/L; P<0.05), and their forearm blood flow responses to both 5HT (maximum, 49.0±10.4%) a...
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Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein
Circulation, 2003Co-Authors: Radjesh J Bisoendial, John J. P. Kastelein, Michael R. Hayden, G. Kees Hovingh, Johannes H.m. Levels, Peter Lerch, Irmgard Andresen, Erik S.g. StroesAbstract:Background— Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for Familial Hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these Familial Hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results— In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-l-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4±0.2 mmol/L; P
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The role of the ABCA1 transporter and cholesterol efflux in Familial Hypoalphalipoproteinemia
Journal of Lipid Research, 2003Co-Authors: Gerard K Hovingh, Michel J. A. Van Wijland, Alison J. Brownlie, Radjesh J Bisoendial, John J. P. Kastelein, Michael R. Hayden, A K GroenAbstract:Defects in the gene encoding for the ATP binding cassette (ABC) transporter A1 (ABCA1) were shown to be one of the genetic causes for Familial hypoalphalipoproteine- mia (FHA). We investigated the role of ABCA1-mediated cho- lesterol efflux in Dutch subjects suffering from FHA. Eighty- eight subjects (mean HDL cholesterol levels 0.63 � 0.21 mmol/l) were enrolled. Fibroblasts were cultured and loaded with ( 3 H)cholesterol. ABCA1 and non-ABCA1-mediated ef- flux was studied by using apolipoprotein A-I (apoA-I), HDL, and methyl- � -cyclodextrin as acceptors. Efflux to apoA-I was decreased in four patients (4/88, 4.5%), and in all cases, a mutation in the ABCA1 gene was found. In the remaining 84 subjects, no correlation between efflux and apoA-I or HDL cholesterol was found. Efflux to both HDL and cyclodextrin, in contrast, did correlate with HDL cholesterol plasma levels ( r � 0.34, P � 0.01; and r � 0.27, P � 0.008, respectively). The prevalence of defects in ABCA1-dependent cholesterol efflux in Dutch FHA patients is low. The significant corre- lation between plasma HDL cholesterol levels and methyl- � -cyclodextrin-mediated efflux in the FHA patients with normal ABCA1 function suggests that non-ABCA1-mediated efflux might also be important for plasma HDL cholesterol levels in these individuals. —Kees Hovingh, G., M. J. A. van Wijland, A. Brownlie, R. J. Bisoendial, M. R. Hayden, J. J. P. Kastelein, and A. K. Groen. The role of the ABCA1 trans- porter and cholesterol efflux in Familial hypoalphalipopro- teinemia. J. Lipid Res. 2003. 44: 1251-1255. Decreased plasma levels of HDL cholesterol have con- sistently been shown to be associated with an increased risk for coronary artery disease (CAD). The atheroprotec- tive role of HDL cholesterol is in part ascribed to its capac- ity to transport cholesterol from peripheral cells (includ- ing vascular macrophages) to the liver, a mechanism known as reverse cholesterol transport (RCT) (1). A considerable number of proteins, enzymes, and recep- tors are involved in RCT, and in principle, all may play a role in the pathogenesis of atherosclerosis. Identification of novel genes and proteins in the pathway may be accom- plished by family studies and genetic analysis. By means of this strategy, a crucial rate-controlling step in RCT has been identified by performing linkage analysis and muta- tion detection in families with Familial hypoalphalipopro- teinemia (FHA) not caused by LCAT or apolipoprotein A-I (apoA-I) mutations (2-4). The culprit gene was shown to encode a 250 kDa transmembrane protein called ATP binding cassette (ABC) transporter A1 (ABCA1). ABCA1 belongs to the family of ABC proteins and is expressed ubiquitously in human tissues (5). In peripheral cells, in- cluding vascular macrophages, ABCA1 regulates energy- dependent transport of cholesterol and phospholipids to apoA-I, the major protein in HDL. Mutations in the gene encoding ABCA1 give rise to decreased cholesterol and phospholipid efflux to apoA-I (6-8). Homozygosity for mutations in the ABCA1 gene causes Tangier Disease (TD), and heterozygosity is one of the causes for FHA. TD is characterized by near absence of plasma HDL choles- terol, whereas in ABCA1 heterozygotes, HDL cholesterol levels are approximately half the normal levels for sex and age. A strong correlation exists between cholesterol ef- flux capacity from fibroblasts and plasma HDL cholesterol levels in ABCA1 homo- and heterozygous patients (9). The role of ABCA1 dysfunction in CAD risk has been the subject of debate. Before the molecular defect underlying TD was identified and the disease was diagnosed by clinical assessment, CAD was found to occur in less than half of cases over 35 years of age (10), which is a remarkably low incidence given the severity of HDL deficiency. It has been suggested that this relative protection from atherosclerosis in TD patients is caused by the low levels of atherogenic LDL cholesterol (11). Because of the small numbers of TD
Albert K. Groen - One of the best experts on this subject based on the ideXlab platform.
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reduced fecal sterol excretion in subjects with Familial Hypoalphalipoproteinemia
Atherosclerosis, 2009Co-Authors: Karim El Harchaoui, Remco Franssen, Radjesh J Bisoendial, Jan Albert Kuivenhoven, Erik S.g. Stroes, John J. P. Kastelein, Folkert Kuipers, Frans Stellaard, Kees G Hovingh, Albert K. GroenAbstract:BACKGROUND: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this relationship in patients with isolated low HDL-c versus controls. RESULTS: Fecal sterol excretion was studied in 12 subjects with Familial Hypoalphalipoproteinemia (FHA) and 11 healthy controls. Compared to the controls (8.9+/-6.3mg/kg/day), neutral sterol excretion was significantly lower in the FHA group (4.0+/-2.4mg/kg/day). Fecal bile acid excretion showed a similar pattern. Across the groups, a strong positive correlation between HDL-c and fecal neutral sterol excretion was found (r=0.53; p=0.01). CONCLUSIONS: Isolated low HDL-c levels in humans are associated with reduced fecal sterol excretion suggesting that in humans HDL regulates the final step in the RCT pathway at low HDL-c levels.
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The role of the ABCA1 transporter and cholesterol efflux in Familial Hypoalphalipoproteinemia
Journal of Lipid Research, 2003Co-Authors: G. Kees Hovingh, Michel J. A. Van Wijland, Alison J. Brownlie, Radjesh J Bisoendial, John J. P. Kastelein, Michael R. Hayden, Albert K. GroenAbstract:Defects in the gene encoding for the ATP binding cassette (ABC) transporter A1 (ABCA1) were shown to be one of the genetic causes for Familial hypoalphalipoproteine- mia (FHA). We investigated the role of ABCA1-mediated cho- lesterol efflux in Dutch subjects suffering from FHA. Eighty- eight subjects (mean HDL cholesterol levels 0.63 � 0.21 mmol/l) were enrolled. Fibroblasts were cultured and loaded with ( 3 H)cholesterol. ABCA1 and non-ABCA1-mediated ef- flux was studied by using apolipoprotein A-I (apoA-I), HDL, and methyl- � -cyclodextrin as acceptors. Efflux to apoA-I was decreased in four patients (4/88, 4.5%), and in all cases, a mutation in the ABCA1 gene was found. In the remaining 84 subjects, no correlation between efflux and apoA-I or HDL cholesterol was found. Efflux to both HDL and cyclodextrin, in contrast, did correlate with HDL cholesterol plasma levels ( r � 0.34, P � 0.01; and r � 0.27, P � 0.008, respectively). The prevalence of defects in ABCA1-dependent cholesterol efflux in Dutch FHA patients is low. The significant corre- lation between plasma HDL cholesterol levels and methyl- � -cyclodextrin-mediated efflux in the FHA patients with normal ABCA1 function suggests that non-ABCA1-mediated efflux might also be important for plasma HDL cholesterol levels in these individuals. —Kees Hovingh, G., M. J. A. van Wijland, A. Brownlie, R. J. Bisoendial, M. R. Hayden, J. J. P. Kastelein, and A. K. Groen. The role of the ABCA1 trans- porter and cholesterol efflux in Familial hypoalphalipopro- teinemia. J. Lipid Res. 2003. 44: 1251-1255. Decreased plasma levels of HDL cholesterol have con- sistently been shown to be associated with an increased risk for coronary artery disease (CAD). The atheroprotec- tive role of HDL cholesterol is in part ascribed to its capac- ity to transport cholesterol from peripheral cells (includ- ing vascular macrophages) to the liver, a mechanism known as reverse cholesterol transport (RCT) (1). A considerable number of proteins, enzymes, and recep- tors are involved in RCT, and in principle, all may play a role in the pathogenesis of atherosclerosis. Identification of novel genes and proteins in the pathway may be accom- plished by family studies and genetic analysis. By means of this strategy, a crucial rate-controlling step in RCT has been identified by performing linkage analysis and muta- tion detection in families with Familial hypoalphalipopro- teinemia (FHA) not caused by LCAT or apolipoprotein A-I (apoA-I) mutations (2-4). The culprit gene was shown to encode a 250 kDa transmembrane protein called ATP binding cassette (ABC) transporter A1 (ABCA1). ABCA1 belongs to the family of ABC proteins and is expressed ubiquitously in human tissues (5). In peripheral cells, in- cluding vascular macrophages, ABCA1 regulates energy- dependent transport of cholesterol and phospholipids to apoA-I, the major protein in HDL. Mutations in the gene encoding ABCA1 give rise to decreased cholesterol and phospholipid efflux to apoA-I (6-8). Homozygosity for mutations in the ABCA1 gene causes Tangier Disease (TD), and heterozygosity is one of the causes for FHA. TD is characterized by near absence of plasma HDL choles- terol, whereas in ABCA1 heterozygotes, HDL cholesterol levels are approximately half the normal levels for sex and age. A strong correlation exists between cholesterol ef- flux capacity from fibroblasts and plasma HDL cholesterol levels in ABCA1 homo- and heterozygous patients (9). The role of ABCA1 dysfunction in CAD risk has been the subject of debate. Before the molecular defect underlying TD was identified and the disease was diagnosed by clinical assessment, CAD was found to occur in less than half of cases over 35 years of age (10), which is a remarkably low incidence given the severity of HDL deficiency. It has been suggested that this relative protection from atherosclerosis in TD patients is caused by the low levels of atherogenic LDL cholesterol (11). Because of the small numbers of TD
Michael R. Hayden - One of the best experts on this subject based on the ideXlab platform.
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Increased risk of coronary artery disease in Caucasians with extremely low HDL cholesterol due to mutations in ABCA1, APOA1, and LCAT☆
Biochimica et biophysica acta, 2011Co-Authors: Ian Tietjen, John J. P. Kastelein, G. Kees Hovingh, Roshni R. Singaraja, Chris Radomski, Jason Mcewen, Elden Chan, Maryanne Mattice, Annick Legendre, Michael R. HaydenAbstract:Mutations in ABCA1, APOA1, and LCAT reduce HDL cholesterol (HDLc) in humans. However, the prevalence of these mutations and their relative effects on HDLc reduction and risk of coronary artery disease (CAD) are less clear. Here we searched for ABCA1, APOA1, and LCAT mutations in 178 unrelated probands with HDLc 40% of Familial Hypoalphalipoproteinemia in this cohort. Moreover, individuals with mutations and large reductions in HDLc have increased risk of CAD. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010).
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Specific Mutations in ABCA1 Have Discrete Effects on ABCA1 Function and Lipid Phenotypes Both In Vivo and In Vitro
Circulation Research, 2006Co-Authors: Roshni R. Singaraja, Henk Visscher, Erick R. James, Angeliki Chroni, Jonathan M. Coutinho, Liam R. Brunham, Martin H. Kang, Vassilis I. Zannis, Giovanna Chimini, Michael R. HaydenAbstract:Mutations in ATP-binding cassette transporter A1 ( ABCA1 ) cause Tangier disease and Familial Hypoalphalipoproteinemia, resulting in low to absent plasma high-density lipoprotein cholesterol levels. However, wide variations in clinical lipid phenotypes are observed in patients with mutations in ABCA1 . We hypothesized that the various lipid phenotypes would be the direct result of discrete and differing effects of the mutations on ABCA1 function. To determine whether there is a correlation between the mutations and the resulting phenotypes, we generated in vitro 15 missense mutations that have been described in patients with Tangier disease and Familial Hypoalphalipoproteinemia. Using localization of ABCA1, its ability to induce cell surface binding of apolipoprotein A-I, and its ability to elicit efflux of cholesterol and phospholipids to apolipoprotein A-I we determined that the phenotypes of patients correlate with the severity and nature of defects in ABCA1 function.
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efflux and atherosclerosis the clinical and biochemical impact of variations in the abca1 gene
Arteriosclerosis Thrombosis and Vascular Biology, 2003Co-Authors: Roshni R. Singaraja, John J. P. Kastelein, Henk Visscher, Liam R. Brunham, Michael R. HaydenAbstract:Approximately 50 mutations and many single nucleotide polymorphisms have been described in the ABCA1 gene, with mutations leading to Tangier disease and Familial Hypoalphalipoproteinemia. Homozygotes and heterozygotes for mutations in ABCA1 display a wide range of phenotypes. Identification of ABCA1 as the molecular defect in these diseases has allowed for ascertainment based on genetic status and determination of genotype-phenotype correlations and has permitted us to identify mutations conferring a range of severity of cellular, biochemical, and clinical phenotypes. In this study we review how genetic variation at the ABCA1 locus affects its role in the maintenance of lipid homeostasis and the natural progression of atherosclerosis.
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restoration of endothelial function by increasing high density lipoprotein in subjects with isolated low high density lipoprotein
Circulation, 2003Co-Authors: Radjesh J Bisoendial, John J. P. Kastelein, Michael R. Hayden, Kees G Hovingh, Johannes H.m. Levels, Peter Lerch, Irmgard Andresen, Erik S.g. StroesAbstract:Background— Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for Familial Hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these Familial Hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results— In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-l-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4±0.2 mmol/L; P<0.05), and their forearm blood flow responses to both 5HT (maximum, 49.0±10.4%) a...
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Restoration of Endothelial Function by Increasing High-Density Lipoprotein in Subjects With Isolated Low High-Density Lipoprotein
Circulation, 2003Co-Authors: Radjesh J Bisoendial, John J. P. Kastelein, Michael R. Hayden, G. Kees Hovingh, Johannes H.m. Levels, Peter Lerch, Irmgard Andresen, Erik S.g. StroesAbstract:Background— Loss-of-function mutations in the ATP-binding cassette (ABCA)-1 gene locus are the underlying cause for Familial Hypoalphalipoproteinemia, providing a human isolated low-HDL model. In these Familial Hypoalphalipoproteinemia subjects, we evaluated the impact of isolated low HDL on endothelial function and the vascular effects of an acute increase in HDL. Methods and Results— In 9 ABCA1 heterozygotes and 9 control subjects, vascular function was assessed by venous occlusion plethysmography. Forearm blood flow responses to the endothelium-dependent and -independent vasodilators serotonin (5HT) and sodium nitroprusside, respectively, and the inhibitor of nitric oxide synthase NG-monomethyl-l-arginine (L-NMMA) were measured. Dose-response curves were repeated after systemic infusion of apolipoprotein A-I/phosphatidylcholine (apoA-I/PC) disks. At baseline, ABCA1 heterozygotes had decreased HDL levels (0.4±0.2 mmol/L; P
Karim El Harchaoui - One of the best experts on this subject based on the ideXlab platform.
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reduced fecal sterol excretion in subjects with Familial Hypoalphalipoproteinemia
Atherosclerosis, 2009Co-Authors: Karim El Harchaoui, Remco Franssen, Radjesh J Bisoendial, Jan Albert Kuivenhoven, Erik S.g. Stroes, John J. P. Kastelein, Folkert Kuipers, Frans Stellaard, Kees G Hovingh, Albert K. GroenAbstract:BACKGROUND: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this relationship in patients with isolated low HDL-c versus controls. RESULTS: Fecal sterol excretion was studied in 12 subjects with Familial Hypoalphalipoproteinemia (FHA) and 11 healthy controls. Compared to the controls (8.9+/-6.3mg/kg/day), neutral sterol excretion was significantly lower in the FHA group (4.0+/-2.4mg/kg/day). Fecal bile acid excretion showed a similar pattern. Across the groups, a strong positive correlation between HDL-c and fecal neutral sterol excretion was found (r=0.53; p=0.01). CONCLUSIONS: Isolated low HDL-c levels in humans are associated with reduced fecal sterol excretion suggesting that in humans HDL regulates the final step in the RCT pathway at low HDL-c levels.
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Reduced fecal sterol excretion in subjects with Familial Hypoalphalipoproteinemia
2009Co-Authors: Karim El Harchaoui, Franssen Remco, Hovingh G. Kees, Bisoendial, Radjesh J., Stellaard Frans, Kuipers Folkert, Kastelein, John J. P., Kuivenhoven, Jan Albert, Stroes, Erik S. G., Groen, Albert K.Abstract:Background: Fecal bile acid and neutral sterol excretion are the obligate endpoints of the reverse cholesterol transport pathway (RCT). In studies in mice, no evidence was found for a relation between HDL-cholesterol (HDL-c) levels and fecal sterol excretion. In this study, we have evaluated this relationship in patients with isolated low HDL-c versus controls. Results: Fecal sterol excretion was studied in 12 subjects with Familial Hypoalphalipoproteinemia (FHA) and 11 healthy controls. Compared to the controls (8.9 +/- 6.3 mg/kg/day), neutral sterol excretion was significantly lower in the FHA group (4.0 +/- 2.4 mg/kg/day). Fecal bile acid excretion showed a similar pattern. Across the groups, a strong positive correlation between HDL-c and fecal neutral sterol excretion was found (r = 0.53; p = 0.01). Conclusions: Isolated low HDL-c levels in humans are associated with reduced fecal sterol excretion suggesting that in humans HDL regulates the final step in the RCT pathway at low HDL-c levels. (c) 2009 Elsevier Ireland Ltd. All rights reserve
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Consequences of cholesteryl ester transfer protein inhibition in patients with Familial Hypoalphalipoproteinemia.
Arteriosclerosis thrombosis and vascular biology, 2005Co-Authors: Radjesh J Bisoendial, Karim El Harchaoui, Jan Albert Kuivenhoven, John J. P. Kastelein, Sotirios Tsimikas, Aeilko E. Zwinderman, G. Kees Hovingh, Johannes H.m. Levels, Erik S.g. StroesAbstract:To the Editor: A large proportion of clinical events cannot be prevented during statin therapy, which calls for novel drug targets to further improve cardiovascular outcome. In particular, HDL-increasing strategies hold great promise. The impact of decreased HDL-C on cardiovascular disease (CVD)-related morbidity and mortality has been sharply delineated in individuals affected by Familial Hypoalphalipoproteinemia (FHA).1 HDL exerts multiple antiatherogenic actions beyond its role in reverse cholesterol transport, comprising antiinflammatory, antioxidative, and direct vascular effects.2 Whereas current strategies to raise HDL-C are limited, novel CETP-inhibitors are capable of mediating significant HDL-C elevation.3,4 Therefore, we evaluated the effects of CETP inhibition on lipid metabolism and markers of oxidation in subjects with FHA. Subjects were recruited from a Dutch population-based study to identify genes that control HDL-C levels,1 meeting the following criteria: (1) plasma HDL-C level below 10th percentile for age and sex; (2) absence of secondary lipid disorders; and (3) high likelihood of inherited low HDL (defined as HDL-C below 10th percentile in at least one first-degree family member). Nineteen FHA patients (13 men and 6 women; mean±SD age: 42.9±13.9 years), all free of overt macrovascular disease, were enrolled in the study. In 9 of these subjects the underlying defect was defined: heterozygosity for an apolipoprotein A-I (L178P) mutation,1 whereas in the remainder this genetic defect was excluded. The study protocol was approved …