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Gerald F Watts - One of the best experts on this subject based on the ideXlab platform.
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Genetic determinants of Apolipoprotein B-100 kinetics
Current opinion in lipidology, 2010Co-Authors: Esther M. M. Ooi, Gerald F Watts, Dick C. Chan, P. Hugh R. BarrettAbstract:Purpose of review We review stable isotope tracer studies of Apolipoprotein B-100 (apoB) kinetics concerning genetic polymorphisms and mutations that affect human lipoprotein metabolism. Recent findings In obese men, the allelic combination of the apoB signal peptide, SP24, and cholesteryl ester transfer protein, CETP B1B1, is independently associated with lower VLDL apoB secretion. Microsomal triglyceride transfer protein -493G/T carriers have reduced IDL apoB and LDL apoB production as compared with controls. Mutations in cholesterol transporters (ATP-binding cassette transporter G8 and Niemann-Pick C1 Like 1) are associated with reduced VLDL apoB secretion and increased LDL apoB production and catabolism. The ATP-binding cassette transporter G8 400K variant is a significant, independent predictor of VLDL apoB secretion. Mutations in lipases (lipoprotein lipase and hepatic lipase) and transfer proteins (lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein) alter their functional activity, which impact on VLDL and LDL kinetics. Summary Mutations in genes that regulate intrahepatic apoB assembly and lipid substrate availability to the liver impact on VLDL apoB secretion. Lipoprotein tracer studies can provide functional insight into the potential impact of genetic polymorphisms in regulating apoB metabolism in humans.
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plasma proprotein convertase subtilisin kexin type 9 a marker of ldl Apolipoprotein b 100 catabolism
Clinical Chemistry, 2009Co-Authors: Dick C. Chan, Esther M. M. Ooi, Gilles Lambert, Hugh P R Barrett, Kerryanne Rye, Gerald F WattsAbstract:Background: Experimental studies suggest that proprotein convertase subtilisin/kexin type 9 (PCSK9) is an important regulator of LDL metabolism because of its ability to facilitate degradation of the LDL receptor. We investigated the association between plasma PCSK9 concentration and LDL Apolipoprotein B-100 (apo B-100) metabolism in men with a wide range of body mass index values. Methods: We used GC-MS to study the kinetics of LDL apo B-100 after intravenous administration of deuterated leucine and analyzed the data by compartmental modeling. The plasma PCSK9 concentration was measured by ELISA. Results: Univariate regression analysis revealed the plasma PCSK9 concentration to be significantly and positively correlated with cholesterol ( r = 0.543; P = 0.011), LDL cholesterol ( r = 0.543; P = 0.011), apo B-100 ( r = 0.548; P = 0.010), and LDL apo B-100 concentrations ( r = 0.514; P = 0.023), and inversely correlated with the LDL apo B-100 fractional catabolic rate (FCR) ( r = −0.456; P = 0.038). The association between plasma PCSK9 concentration and the LDL apo B-100 FCR remained statistically significant after adjusting for age, obesity, plasma insulin, homeostasis model assessment score, and dietary energy; however, this association had borderline significance after adjusting for plasma lathosterol. Conclusions: In men, variation in plasma PCSK9 concentration influences the catabolism of LDL apo B-100. This finding appears to be independent of obesity, insulin resistance, energy intake, and age.
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Plasma Markers of Cholesterol Homeostasis and Apolipoprotein B‐100 Kinetics in the Metabolic Syndrome
Obesity research, 2003Co-Authors: Dick C. Chan, Gerald F Watts, P. Hugh R. Barrett, Frans H. O’neill, Gilbert R. ThompsonAbstract:CHAN, DICK C., GERALD F. WATTS, P. HUGH R. BARRETT, FRANS H. O’NEILL, AND GILBERT R. THOMPSON. Plasma markers of cholesterol homeostasis and Apolipoprotein B-100 kinetics in the metabolic syndrome. Obes Res. 2003;11:591-596. Objective: The metabolic syndrome is characterized by defective hepatic Apolipoprotein B-100 (apoB) metabolism. Hepato-intestinal cholesterol metabolism may contribute to this abnormality. Research Methods and Procedures: We examined the association of cholesterol absorption and synthesis with the kinetics of apoB in 35 obese subjects with the metabolic syndrome. Plasma ratios of campesterol and lathosterol to cholesterol were used to estimate cholesterol absorption and synthesis, respectively. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and lowdensity lipoprotein apoB kinetics were studied using stable isotopy and mass spectrometry. Kinetic parameters were derived using multicompartmental modeling. Results: Compared with controls, the obese subjects had significantly lower plasma ratios of campesterol, but higher plasma ratios of lathosterol (p 0.05 in both). This was associated with elevated VLDL-apoB secretion rate (p 0.05) and delayed fractional catabolism of IDL and lowdensity lipoprotein-apoB (p 0.01). In the obese group, plasma ratios of campesterol correlated inversely with VLDL-apoB secretion (r 0.359, p 0.05), VLDLapoB (r 0.513, p 0.01) and IDL-apoB (r 0.511, p 0.01) pool size, and plasma lathosterol ratio ( r 0.366, p 0.05). Subjects with low cholesterol absorption had significantly higher VLDL-apoB secretion, VLDLapoB and IDL-apoB pool size, and plasma lathosterol ratio (p 0.05 in both) than those with high cholesterol absorption. Discussion: Subjects with the metabolic syndrome have oversecretion of VLDL-apoB and decreased catabolism of apoB-containing particles and low absorption and high synthesis rates of cholesterol. These changes in cholesterol homeostasis may contribute to the kinetic defects in apoB metabolism in the metabolic syndrome.
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Kinetics of very-low-density lipoprotein Apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies.
Metabolism: clinical and experimental, 2000Co-Authors: Gerald F Watts, P. Moroz, P.h.r. BarrettAbstract:Abstract To further explore the physiology of very–low-density lipoprotein (VLDL) Apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P
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Genotypic associations of the hepatic secretion of VLDL Apolipoprotein B-100 in obesity
Journal of lipid research, 2000Co-Authors: Gerald F Watts, F M Riches, Stephen E. Humphries, P.j. Talmud, F.m. Van BockxmeerAbstract:We examined the effect of genetic polymorphisms of proteins regulating intrahepatic processing of Apolipoprotein B-100 (apoB) and the supply of neutral lipids to the liver on the hepatic secretion of very low density lipoprotein (VLDL) apoB in obesity. Hepatic secretion of very low density Apolipoprotein B-100 (VLDL apoB) was measured using an infusion of [1-(13)C]leucine in 29 obese men. Isotopic enrichment and turnover of VLDL apoB was determined using gas chromatography-mass spectrometry and multi-compartmental modelling, respectively. Visceral fat was measured by magnetic resonance imaging. Genotypes for the apoB signal peptide (SP27/SP24 alleles), microsomal triglyceride transfer protein promoter (MTP, -493 G/T alleles), apoE (E2, E3, E4 alleles), hepatic lipase promoter (-514 C/T alleles), and cholesteryl ester transfer protein (CETP, Taq1B B1/B2 alleles) were determined using polymerase chain reaction. Statistically significant associations were found between hepatic secretion of apoB and allelic combinations of i) apoB SP with apoE (P = 0.02), hepatic lipase (P = 0.02), and CETP (P = 0. 006) genes, ii) MTP promoter with CETP genes (P = 0.03); the association with apoBSP/MTP promoter allelic combinations just failed to reach significance (P = 0.06), however. The CETP/apoBSP allelic combination was the most significant predictor of apoB secretion, and this was independent of visceral fat, plasma lathosterol and insulin levels, and dietary fat. SP24 carriers who were homozygous for CETP B1 had 60% lower apoB secretion than B2 heterozygotes who were non-carriers of SP24 (10.5 +/- 1.74 mg/kg fat free mass/day, n = 7 vs. 26.1 +/- 3.16, n = 22). The data suggest that variation in both the apoB and CETP genes may be a major genetic determinant of the hepatic secretion of apoB in men with visceral obesity.
F M Riches - One of the best experts on this subject based on the ideXlab platform.
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Genotypic associations of the hepatic secretion of VLDL Apolipoprotein B-100 in obesity
Journal of lipid research, 2000Co-Authors: Gerald F Watts, F M Riches, Stephen E. Humphries, P.j. Talmud, F.m. Van BockxmeerAbstract:We examined the effect of genetic polymorphisms of proteins regulating intrahepatic processing of Apolipoprotein B-100 (apoB) and the supply of neutral lipids to the liver on the hepatic secretion of very low density lipoprotein (VLDL) apoB in obesity. Hepatic secretion of very low density Apolipoprotein B-100 (VLDL apoB) was measured using an infusion of [1-(13)C]leucine in 29 obese men. Isotopic enrichment and turnover of VLDL apoB was determined using gas chromatography-mass spectrometry and multi-compartmental modelling, respectively. Visceral fat was measured by magnetic resonance imaging. Genotypes for the apoB signal peptide (SP27/SP24 alleles), microsomal triglyceride transfer protein promoter (MTP, -493 G/T alleles), apoE (E2, E3, E4 alleles), hepatic lipase promoter (-514 C/T alleles), and cholesteryl ester transfer protein (CETP, Taq1B B1/B2 alleles) were determined using polymerase chain reaction. Statistically significant associations were found between hepatic secretion of apoB and allelic combinations of i) apoB SP with apoE (P = 0.02), hepatic lipase (P = 0.02), and CETP (P = 0. 006) genes, ii) MTP promoter with CETP genes (P = 0.03); the association with apoBSP/MTP promoter allelic combinations just failed to reach significance (P = 0.06), however. The CETP/apoBSP allelic combination was the most significant predictor of apoB secretion, and this was independent of visceral fat, plasma lathosterol and insulin levels, and dietary fat. SP24 carriers who were homozygous for CETP B1 had 60% lower apoB secretion than B2 heterozygotes who were non-carriers of SP24 (10.5 +/- 1.74 mg/kg fat free mass/day, n = 7 vs. 26.1 +/- 3.16, n = 22). The data suggest that variation in both the apoB and CETP genes may be a major genetic determinant of the hepatic secretion of apoB in men with visceral obesity.
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Reduction in visceral adipose tissue is associated with improvement in Apolipoprotein B-100 metabolism in obese men.
The Journal of clinical endocrinology and metabolism, 1999Co-Authors: F M Riches, Rossi P Naoumova, Gerald F Watts, J. Hua, George R. Stewart, P.h.r. BarrettAbstract:We investigated the effect of reduction in visceral obesity on the kinetics of Apolipoprotein B-100 (apoB) metabolism in a controlled dietary intervention study in 26 obese men. Hepatic secretion of very low density lipoprotein (VLDL) apoB was measured using a primed, constant, infusion of 1-[13C]leucine. In seven men receiving the reduction diet, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) apoB kinetics were also determined. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry, and SAAM-II was used to estimate the fractional turnover rates. Subcutaneous and visceral adipose tissues at the L3 vertebra were quantified by magnetic resonance imaging. With weight reduction there was a significant decrease (P < 0.05) in body mass index, waist circumference, and visceral adipose tissue. The plasma concentrations of total cholesterol, triglyceride, insulin, and lathosterol also significantly decreased (P < 0.05). Compared with weight maintenance, weight re...
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hepatic secretion of very low density lipoprotein Apolipoprotein b 100 studied with a stable isotope technique in men with visceral obesity
International Journal of Obesity, 1998Co-Authors: F M Riches, Kevin D. Croft, Rossi P Naoumova, J M Kelly, Gerald F Watts, G. R. ThompsonAbstract:Hepatic secretion of very-low-density lipoprotein Apolipoprotein B-100 studied with a stable isotope technique in men with visceral obesity
Sotirios Tsimikas - One of the best experts on this subject based on the ideXlab platform.
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Original InvestigationRelationship of Oxidized Phospholipids on Apolipoprotein B-100 to Cardiovascular Outcomes in Patients Treated With Intensive Versus Moderate Atorvastatin Therapy: The TNT Trial
Journal of the American College of Cardiology, 2015Co-Authors: Young Sup Byun, Joseph L. Witztum, Jun-hee Lee, Benoit J. Arsenault, Xiaohong Yang, Weihang Bao, David A. Demicco, Rachel Laskey, Sotirios TsimikasAbstract:Background Oxidized phospholipids on Apolipoprotein B-100 (OxPL-apoB) is a biomarker of increased risk for major adverse cardiovascular events (MACE) in community cohorts, but its role in patients with stable coronary heart disease (CHD) is unknown.
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ELEVATED LEVELS OF OXIDIZED PHOSPHOLIPIDS ON Apolipoprotein B-100 PREDICT RECURRENT CEREBROVASCULAR EVENTS: A STROKE PREVENTION BY AGGRESSIVE REDUCTION IN CHOLESTEROL LEVELS (SPARCL) SUBSTUDY
Journal of the American College of Cardiology, 2015Co-Authors: Young Sup Byun, Joseph L. Witztum, Xiaohong Yang, David A. Demicco, Rachel Laskey, Bao Weihang, Sotirios TsimikasAbstract:Biomarkers to predict recurrent stroke are lacking. Elevated levels of oxidized phospholipids on Apolipoprotein B-100 lipoprotein (OxPL/apoB) predict increased risk in patients without and with prior cardiovascular events, but have not been evaluated in patients with prior cerebrovascular events.
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Antisense Oligonucleotide Directed to Human Apolipoprotein B-100 Reduces Lipoprotein(a) Levels and Oxidized Phospholipids on Human Apolipoprotein B-100 Particles in Lipoprotein(a) Transgenic Mice
Circulation, 2008Co-Authors: Esther Merki, Mark J. Graham, Adam Mullick, Elizabeth R. Miller, Rosanne M. Crooke, Robert E. Pitas, Joseph L. Witztum, Sotirios TsimikasAbstract:Background— Lipoprotein (a) [Lp(a)] is a genetic cardiovascular risk factor that preferentially binds oxidized phospholipids (OxPL) in plasma. There is a lack of therapeutic agents that reduce plasma Lp(a) levels. Methods and Results— Transgenic mice overexpressing human Apolipoprotein B-100 (h-apoB-100 [h-apoB mice]) or h-apoB-100 plus human apo(a) to generate genuine Lp(a) particles [Lp(a) mice] were treated with the antisense oligonucleotide mipomersen directed to h-apoB-100 mRNA or control antisense oligonucleotide for 11 weeks by intraperitoneal injection. Mice were then followed up for an additional 10 weeks off therapy. Lp(a) levels [apo(a) bound to apoB-100] and apo(a) levels [“free” apo(a) plus apo(a) bound to apoB-100] were measured by chemiluminescent enzyme-linked immunoassay and commercial assays, respectively. The content of OxPL on h-apoB-100 particles (OxPL/h-apoB) was measured by capturing h-apoB-100 in microtiter wells and detecting OxPL by antibody E06. As expected, mipomersen significa...
Gunilla Nordin Fredrikson - One of the best experts on this subject based on the ideXlab platform.
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Apolipoprotein B-100 Antibody Interaction With Atherosclerotic Plaque Inflammation and Repair Processes.
Stroke, 2016Co-Authors: Giuseppe Asciutto, Gunilla Nordin Fredrikson, Ragnar Alm, Harry Björkbacka, Maria Wigren, Ingrid Yao Mattisson, Caitriona Grönberg, Nuno Dias, Andreas Edsfeldt, Isabel GonçalvesAbstract:Background and Purpose— Treatment with IgG against the malondialdehyde (MDA)-modified Apolipoprotein B-100 epitope p45 reduces atherosclerosis in experimental models. This study investigated the association between p45 IgG autoantibodies and plaque inflammation in subjects with advanced cardiovascular disease. Methods— Native and MDA-p45 IgG levels were analyzed by ELISA in 349 carotid endarterectomy patients. In a subcohort of 195 subjects, endarterectomy samples were analyzed by immunohistochemistry and ELISA to determine plaque constituents and inflammation. Peripheral blood mononuclear cells were isolated from healthy donors. Results— Patients with preoperative events of neurological ischemia had lower levels of native p45 IgG. Low levels of MDA-p45 IgG were associated with increased risk of postoperative cardiovascular death during a mean follow-up of 54 months. High plasma levels of native p45 IgG were associated with increased plaque content of collagen and smooth muscle cell growth factors, as well as with lower levels of proinflammatory cytokines. Exposure of peripheral blood mononuclear cells from healthy donors to recombinant MDA-p45 IgG in presence of oxidized low-density lipoprotein reduced the expression of tumor necrosis factor-α and stimulated release of smooth muscle cell growth factors. Conclusions— This study confirms previous experimental findings of anti-inflammatory properties of Apolipoprotein B-100 p45 antibodies and provides the first clinical evidence of associations between p45 IgG autoantibody levels and atherosclerotic plaque inflammation, plaque repair as well as prevalent and incident cardiovascular events in carotid endarterectomy patients. These findings suggest the possibility that treatment with anti-p45 antibodies may have beneficial effects in advanced cardiovascular disease.
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Low Levels of Apolipoprotein B-100 Autoantibodies Are Associated With Increased Risk of Coronary Events
Arteriosclerosis thrombosis and vascular biology, 2016Co-Authors: Harry Björkbacka, Ragnar Alm, Jan Nilsson, Margaretha Persson, Bo Hedblad, Gunilla Nordin FredriksonAbstract:Objective— Previous smaller studies have indicated inverse associations between autoantibodies to oxidized low-density lipoprotein epitopes, and cardiovascular disease. The present study investigated associations between autoantibodies against the Apolipoprotein B-100 peptides p45 and p210, respectively, and risk of incident cardiovascular disease in a large population-based cohort. Approach and Results— Apolipoprotein B-100 autoantibodies were analyzed by ELISA in a prospective study, including 5393 individuals (aged 46–68 years) belonging to the cardiovascular arm of the Malmo Diet and Cancer study with a follow-up time of >15 years. Subjects that suffered an acute coronary event during follow-up (n=382) had lower levels at baseline of IgM autoantibodies recognizing the native and malondialdehyde-modified Apolipoprotein B-100 peptides p45 and p210 and also lower IgG levels recognizing native p210, whereas no association was found with risk for stroke (n=317). Subjects in the highest compared with lowest tertile of IgM-p45 MDA (hazard ratio [95% confidence interval]: 0.72 [0.55, 0.94]; P =0.017) and IgG-p210 native (hazard ratio [95% confidence interval]: 0.73 [0.56, 0.97]; P =0.029) had lower risk for incident coronary events after adjustment for cardiovascular risk factors in Cox proportional hazard regression models. Moreover, subjects with high levels of IgG-p210 native were less likely to have carotid plaques as assessed by ultrasonography at baseline (odds ratio=0.81, 95% confidence interval 0.70–0.95, P =0.008 after adjustment for risk factors). Conclusions— This large prospective study demonstrates that subjects with high levels of Apolipoprotein B-100 autoantibodies have a lower risk of coronary events supporting a protective role of these autoantibodies in cardiovascular disease.
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Circulating Autoantibodies against the Apolipoprotein B-100 Peptides p45 and p210 in Relation to the Occurrence of Carotid Plaques in 64-Year-Old Women.
PloS one, 2015Co-Authors: Björn Fagerberg, Jan Nilsson, Ragnar Alm, Ulrica Prahl Gullberg, Gunilla Nordin FredriksonAbstract:Immune responses against oxidized low density lipoprotein (LDL) play a key role in atherosclerosis. Previous studies have indicated inverse associations between autoantibodies to epitopes in oxidized LDL and cardiovascular disease. In this study we investigated the associations between autoantibodies against the Apolipoprotein B-100 (apoB-100) peptides p45 and p210 and occurrence of carotid plaques.
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Plasma autoantibodies against Apolipoprotein B-100 peptide 210 in subclinical atherosclerosis.
Atherosclerosis, 2013Co-Authors: Olga Mcleod, Gunilla Nordin Fredrikson, Angela Silveira, Karl Gertow, Damiano Baldassarre, Fabrizio Veglia, Bengt Sennblad, Rona J. Strawbridge, Malin K. Larsson, Karin LeanderAbstract:Experimental studies have suggested that autoimmunity is involved in atherosclerosis and provided evidence that both protective and pro-atherogenic immune responses exist. This concept has received support from small clinical studies implicating autoantibodies directed against Apolipoprotein B-100 (apoB-100) in human atherosclerosis. We examined circulating autoantibodies directed against native and malondialdehyde (MDA)-modified epitope p210 of apoB-100 (IgG-p210nat and IgM-p210MDA) in relation to early atherosclerosis in a large, European longitudinal cohort study of healthy high-risk individuals.
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Associations between autoantibodies against Apolipoprotein B-100 peptides and vascular complications in patients with type 2 diabetes
Diabetologia, 2009Co-Authors: Gunilla Nordin Fredrikson, Dhakshinamurthy Vijay Anand, David Hopkins, Roger Corder, Ragnar Alm, Eva Bengtsson, Prediman K. Shah, Avijit Lahiri, Jan NilssonAbstract:Aims/hypothesis Oxidation of LDL in the arterial extracellular matrix is a key event in the development of atherosclerosis and autoantibodies against oxidised LDL antigens reflect disease severity and the risk of developing acute cardiovascular events. Since type 2 diabetes is associated with increased oxidative stress, we tested the hypothesis that autoantibodies against oxidised LDL antigens are biomarkers for vascular complications in diabetes. Methods We studied 497 patients with type 2 diabetes without clinical signs of coronary heart disease. Oxidised LDL autoantibodies were determined by ELISA detecting IgG and IgM specific for native and malondialdehyde (MDA)-modified Apolipoprotein B-100 peptides p45 and p210. The severity of coronary disease was assessed as the coronary artery calcium score. Results Patients affected by retinopathy had significantly higher levels of IgG against MDA-p45 and MDA-p210. In contrast, high levels of autoantibodies against the corresponding native peptides were associated with less coronary calcification and a lower risk of progression of coronary disease. Conclusions/interpretation Our observations suggest that LDL oxidation is involved in the pathogenesis of diabetic retinopathy and that autoantibodies against Apolipoprotein B peptides may act as biomarkers for both micro- and macrovascular complications in diabetes.
P.h.r. Barrett - One of the best experts on this subject based on the ideXlab platform.
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Kinetics of very-low-density lipoprotein Apolipoprotein B-100 in normolipidemic subjects: pooled analysis of stable-isotope studies.
Metabolism: clinical and experimental, 2000Co-Authors: Gerald F Watts, P. Moroz, P.h.r. BarrettAbstract:Abstract To further explore the physiology of very–low-density lipoprotein (VLDL) Apolipoprotein B-100 (apoB), we performed a pooled analysis of 21 reports based on the intravenous administration of stable isotope-labeled amino acids in a total of 154 healthy normolipidemic subjects. Prandial status was the most significant independent predictor (P
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Reduction in visceral adipose tissue is associated with improvement in Apolipoprotein B-100 metabolism in obese men.
The Journal of clinical endocrinology and metabolism, 1999Co-Authors: F M Riches, Rossi P Naoumova, Gerald F Watts, J. Hua, George R. Stewart, P.h.r. BarrettAbstract:We investigated the effect of reduction in visceral obesity on the kinetics of Apolipoprotein B-100 (apoB) metabolism in a controlled dietary intervention study in 26 obese men. Hepatic secretion of very low density lipoprotein (VLDL) apoB was measured using a primed, constant, infusion of 1-[13C]leucine. In seven men receiving the reduction diet, intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) apoB kinetics were also determined. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry, and SAAM-II was used to estimate the fractional turnover rates. Subcutaneous and visceral adipose tissues at the L3 vertebra were quantified by magnetic resonance imaging. With weight reduction there was a significant decrease (P < 0.05) in body mass index, waist circumference, and visceral adipose tissue. The plasma concentrations of total cholesterol, triglyceride, insulin, and lathosterol also significantly decreased (P < 0.05). Compared with weight maintenance, weight re...