European Lipoprotein Club: report of the 26th ELC Annual Conference, Tutzing, 8-11 September 2003.
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Child↗
Biomedical subjects
P Talmud
Publications and source records attributed to P Talmud.
Binding of low density lipoproteins to lipoprotein lipase is dependent on lipids but not on apolipoprotein B.
Lipoprotein lipase (LPL) efficiently mediates the binding of lipoprotein particles to lipoprotein receptors and to proteoglycans at cell surfaces and in the extracellular matrix. It has been proposed that LPL increases the retention of atherogenic lipoproteins in the vessel wall and mediates the uptake of lipoproteins in cells, thereby promoting lipid accumulation and plaque formation. We investigated the interaction between LPL and low density lipoproteins (LDLs) with special reference to the protein-protein interaction between LPL and apolipoprotein B (apoB). Chemical modification of lysines and arginines in apoB or mutation of its main proteoglycan binding site did not abolish the interaction of LDL with LPL as shown by surface plasmon resonance (SPR) and by experiments with THP-I macrophages. Recombinant LDL with either apoB100 or apoB48 bound with similar affinity. In contrast, partial delipidation of LDL markedly decreased binding to LPL. In cell culture experiments, phosphatidylcholine-containing liposomes competed efficiently with LDL for binding to LPL. Each LDL particle bound several (up to 15) LPL dimers as determined by SPR and by experiments with THP-I macrophages. A recombinant NH(2)-terminal fragment of apoB (apoB17) bound with low affinity to LPL as shown by SPR, but this interaction was completely abolished by partial delipidation of apoB17. We conclude that the LPL-apoB interaction is not significant in bridging LDL to cell surfaces and matrix components; the main interaction is between LPL and the LDL lipids.
Animals↗
ApoE polymorphism and fish oil supplementation in subjects with an atherogenic lipoprotein phenotype.
The study assessed the efficacy of fish oil supplementation in counteracting the classic dyslipidemia of the atherogenic lipoprotein phenotype (ALP). In addition, the impact of the common apolipoprotein E (apoE) polymorphism on the fasting and postprandial lipid profile and on responsiveness to the dietary intervention was established. Fifty-five ALP males (aged 34 to 69 years, body mass index 22 to 35 kg/m(2), triglyceride [TG] levels 1.5 to 4.0 mmol/L, high density lipoprotein cholesterol [HDL-C] <1.1 mmol/l, and percent low density lipoprotein [LDL]-3 >40% total LDL) completed a randomized placebo-controlled crossover trial of fish oil (3.0 g eicosapentaenoic acid/docosahexaenoic acid per day) and placebo (olive oil) capsules with the 6-week treatment arms separated by a 12-week washout period. In addition to fasting blood samples, at the end of each intervention arm, a postprandial assessment of lipid metabolism was carried out. Fish oil supplementation resulted in a reduction in fasting TG level of 35% (P<0.001), in postprandial TG response of 26% (TG area under the curve, P<0.001), and in percent LDL-3 of 26% (P<0.05). However, no change in HDL-C levels was evident (P=0.752). ANCOVA showed that baseline HDL-C levels were significantly lower in apoE4 carriers (P=0.035). The apoE genotype also had a striking impact on lipid responses to fish oil intervention. Individuals with an apoE2 allele displayed a marked reduction in postprandial incremental TG response (TG incremental area under the curve, P=0.023) and a trend toward an increase in lipoprotein lipase activity relative to non-E2 carriers. In apoE4 individuals, a significant increase in total cholesterol and a trend toward a reduction in HDL-C relative to the common homozygous E3/E3 profile was evident. Our data demonstrate the efficacy of fish oil fatty acids in counteracting the proatherogenic lipid profile of the ALP but also that the apoE genotype influences responsiveness to this dietary treatment.
Adult↗
Relations of plasma fibrinogen level in children to measures of obesity, the (G-455-->A) mutation in the beta-fibrinogen promoter gene, and family history of ischemic heart disease: the Columbia University BioMarkers Study.
Higher plasma fibrinogen levels are associated with increased risk of myocardial infarction in adults, but little is known about factors that influence fibrinogen levels in childhood. The authors examined the associations of measures of obesity, presence of the (G-455-->A) allele in the beta-fibrinogen promoter gene, and family history of early onset of ischemic heart disease with plasma fibrinogen levels in children. Children (n = 299) were recruited during 1994-1997 from 276 families living in a racially mixed area of New York City. The mean age of the study children was 9.9 years; 79% were Hispanic. The frequency of the (G-455-->A) allele was lower in Hispanics than in non-Hispanic Whites (15.5% vs. 28.3% in children (p < 0.01) and 13.9% vs. 28.3% in parents (p < 0.001)). Graded relations of children's plasma fibrinogen levels were found with tertiles of body mass index (weight (kg)/height (m)2) and sum of skinfolds (tests for linear trend: p < 0.001). Plasma fibrinogen levels in the children were not related to race/ethnicity, presence of the (G-455-->A) allele, or family history. Multiple linear regression analyses adjusting plasma fibrinogen levels for age, sex, race/ethnicity, the (G-455-->A) allele, and family history of early onset of heart disease showed a significant association with either body mass index or sum of skinfolds (p < 0.001 for both models) but not with the other variables.
Adolescent↗
ApoCIII gene variants modulate postprandial response to both glucose and fat tolerance tests.
BACKGROUND: We investigated the relationship between variation in the apolipoprotein (apo) AI-CIII-AIV gene cluster and response to an oral glucose test (OGTT) and oral fat load test (OFTT) in the EARSII group of young, healthy male offspring whose fathers had had a myocardial infarction before the age of 55 years (cases, n=407) compared with age-matched controls (n=415). The apoCIII variations examined were C3238G (SstI) in the 3'-UTR, C1100T in exon 3, C-482T in the insulin response element (IRE), and T-2854G in the apoCIII-AIV intergenic region. METHODS AND RESULTS: The postprandial response was regulated by variation at the T-2854G and C3238G sites. After the OFTT, carriers of the rare alleles had delayed clearance of triglyceride (Tg) levels; G-2854 carriers showed the largest effect on Tg (AUC, 24% greater, P<0.002; peak, 19% greater, P<0.005), and G3238 carriers showed a smaller response (AUC, 13% greater, P<0.05; peak, 13% greater, P=0.03). However, after adjustment for fasting level of Tg, only the effect with the T-2854G remained significant. Variation at the C-482T (IRE) determined response to the OGTT, with carriers of the rare T-482 having significantly elevated glucose (28.7% AUC, P=0.013) and insulin (20.5% AUC, P<0. 01) concentrations. CONCLUSIONS: These data suggest that specific genetic variants at the apoCIII gene locus differentially affect postprandial and response to OGTT and suggest a novel mechanism for the effects of variation at this locus on risk for atherosclerosis.
Adolescent↗
Angiotensin-converting-enzyme gene insertion/deletion polymorphism and response to physical training.
BACKGROUND: The function of local renin-angiotensin systems in skeletal muscle and adipose tissue remains largely unknown. A polymorphism of the human angiotensin converting enzyme (ACE) gene has been identified in which the insertion (I) rather than deletion (D) allele is associated with lower ACE activity in body tissues and increased response to some aspects of physical training. We studied the association between the ACE gene insertion or deletion polymorphism and changes in body composition related to an intensive exercise programme, to investigate the metabolic effects of local human renin-angiotensin systems. METHODS: We used three independent methods (bioimpedance, multiple skinfold-thickness assessment of whole-body composition, magnetic resonance imaging of the mid-thigh) to study changes in body composition in young male army recruits over 10 weeks of intensive physical training. FINDINGS: Participants with the II genotype had a greater anabolic response than those with one or more D alleles for fat mass (0.55 vs -0.20 kg, p=0.04 by bioimpedance) and non-fat mass (1.31 vs -0.15 kg, p=0.01 by bioimpedance). Changes in body morphology with training measured by the other methods were also dependent on genotype. INTERPRETATION: II genotype, as a marker of low ACE activity in body tissues, may conserve a positive energy balance during rigorous training, which suggests enhanced metabolic efficiency. This finding may explain some of the survival and functional benefits of therapy with ACE inhibitors.
Adipose Tissue↗
European Lipoprotein Club: report of the 21st Annual Conference, Tutzing, September 28-October 1, 1998.
Molecular biology and genetics were the hallmarks of the conference. Attendees from 20 European countries participated in lively discussions with international speakers. The opening round table session entitled 'Genetic approach to complex diseases' was chaired by Harald Funke. Steve Humphries (London) presented association studies and Harald Funke (Munster) presented multiparameter analyses, as models of genetic epidemiological approaches to atherosclerosis. Gerd Utermann (Innsbruck) showed, through sib pair linkage analysis, how apo (a) gene polymorphism determines plasma levels of Lp(a). Klaus Lindpainter (Basel) described novel genetic strategies heading for a more targeted medicine, through the identification of genetic mechanisms of disease and therapeutic responses. Session I, chaired by Richard James (Geneva) and Guido Franceschini (Milano), on 'Basic mechanisms of action of drugs' highlighted molecular and cellular actions by which present (fibrates, statins) or future (ACAT or MTP inhibitors) drugs or hormones may modulate lipoprotein metabolism. Marten Hofker (Leiden) and Philippa Talmud (London) chaired Session II on 'Regulation of gene expression', which reported cellular regulations by nuclear receptors (PPARs), or the regulation of lipid trafficking by membrane receptors (SR-BI, Megalin, Apo-E receptor, scavenger receptors) or by intracellular (IFN gamma signalling pathways) or extracellular proteins (lipases). Beyond gene expression, Session III, 1st part, entitled 'Lipoprotein modifying enzymes' was chaired by Katriina Aalto-Setälä (Tampere). Roles of lipases (HL, LPL) and transfer proteins (CETP, PLTP), as well as structures of lipid binding molecules (LCAT, apolipoproteins), were further explored. The 'Gene interactions' session chaired by Rudolph Poledne (Prague), and 'Novelties' chaired by Hans Dieplinger (Innsbruck), reported elegant models of cross-bred, tissue specific knock-out or YAC-transgenic mice for lipoprotein metabolism, and descriptions of gene interactions in polygenic disorders or new loci for familial lipid disorders (familial combined hyperlipidemia, metabolic syndrome and Tangier disease) in humans.
Animals↗
Association of angiotensin-converting enzyme gene I/D polymorphism with change in left ventricular mass in response to physical training.
BACKGROUND: The absence (deletion allele [D]) of a 287-base pair marker in the ACE gene is associated with higher ACE levels than its presence (insertion allele [I]). If renin-angiotensin systems regulate left ventricular (LV) growth, then individuals of DD genotype might show a greater hypertrophic response than those of II genotype. We tested this hypothesis by studying exercise-induced LV hypertrophy. METHODS AND RESULTS: Echocardiographically determined LV dimensions and mass (n=140), electrocardiographically determined LV mass and frequency of LV hypertrophy (LVH) (n=121), and plasma brain natriuretic peptide (BNP) levels (n=49) were compared at the start and end of a 10-week physical training period in male Caucasian military recruits. Septal and posterior wall thicknesses increased with training, and LV mass increased by 18% (all P<.0001). Response magnitude was strongly associated with ACE genotype: mean LV mass altered by +2.0, +38.5, and +42.3 g in II, ID and DD, respectively (P<.0001). The prevalence of electrocardiographically defined LVH rose significantly only among those of DD genotype (from 6 of 24 before training to 11 of 24 after training, P<.01). Plasma brain natriuretic peptide levels rose by 56.0 and 11.5 pg/mL for DD and II, respectively (P<.001). CONCLUSIONS: Exercise-induced LV growth in young males is strongly associated with the ACE I/D polymorphism.
Adult↗
Activation of a cryptic splice-site in intron 24 leads to the formation of apolipoprotein B-27.6.
Apo B expression is confined to the intestine and liver, and its secretion from these tissues is dependent on the expression of a lipid transfer protein, microsomal triglyceride transfer protein (MTP). Previously, we reported a model system for the study of apolipoprotein (apo B) biogenesis using heterologous expression in COS cells (Patel SB, Grundy SM. J. Lipid Res. 1995;36:2090-2103). We now report the characterization of the effects of a T-->C transition in the splice-site at +2 of intron 24 previously reported by Talmud et al. (J. Lipid Res. 1994;35:468-77). Using our heterologous expression system, we show that the mutation led to aberrant processing of intron 24, but normal processing of intron 25. The resultant translation of this mutant mRNA produced a truncated apo B protein of the size of apo B-27.6. Reverse transcription, polymerase chain reaction and sequencing of the amplified products were used to show that a cryptic donor splice-site within intron 24 was utilized, resulting in the generation of a novel hydrophilic 29 amino acid carboxyl-terminal tail. Co-expression of apo B-27.6 with microsomal triglyceride transfer protein (MTP) showed that this protein could bind MTP and resulted in the secretion of a lipoprotein particle with a buoyant density in the range 1.16-1.25 g/ml. These results indicate that this splice-site mutation leads to an activation of a downstream cryptic splice-site within intron 24, causing an insertion of 40 bases of intron 24 sequences into the mature RNA. This leads to a frame-shift of translation resulting in addition of 29 new amino acids at the carboxyl-terminus, before an in-frame stop translation codon is encountered, truncating the apo B at B-27.6.
Alternative Splicing↗
The angiotensin-converting enzyme gene and the angiotensin II type I receptor gene as candidate genes for microalbuminuria. A study in nondiabetic and non-insulin-dependent diabetic subjects.
Familial clustering of microalbuminuria with cardiovascular disease suggests a possible common genetic antecedent. We have tested the hypothesis that the angiotensin-converting enzyme (ACE) DD genotype and the angiotensin II type I receptor (AT1R) gene C allele represent the common link between microalbuminuria and coronary heart disease. The frequency of polymorphisms of the ACE and AT1R genes were investigated in 509 nondiabetic white subjects and in 86 non-insulin-dependent diabetic white patients. There was no significant difference in albumin excretion rate between the genotypes in nondiabetic subjects on either a daytime or an overnight sample or in diabetic subjects expressed as a normalized albumin concentration on an untimed morning urine collection. We have found no evidence for an association between polymorphism of the ACE or AT1R genes and microalbuminuria in two groups of subjects without insulin-dependent diabetes.
Adult↗
The amino terminus of apolipoprotein B is necessary but not sufficient for microsomal triglyceride transfer protein responsiveness.
Human apolipoprotein (apo) B mediates the formation of neutral lipid-containing lipoproteins in the liver and intestine. The association of apoB with lipid is thought to be promoted by the microsomal triglyceride transfer protein complex. We have reconstituted lipoprotein assembly in an insect cell line that normally does not support this process. Expression of human microsomal triglyceride transfer protein (MTP) and apolipoprotein B48 (apoB48) together enabled Sf-21 insect cells to secrete approximately 60-fold more lipoprotein-associated triacylglycerol than control cells. This dramatic effect demonstrates that effective partitioning of triacylglycerol into the secretory pathway requires an endoplasmic reticulum-associated neutral lipid transporter (provided by MTP) and an apolipoprotein to shuttle the lipid through the pathway. Expression of the human apoB48 gene in insect cells resulted in secretion of the protein product. Including both MTP subunits with apoB48 and oleic acid specifically increased apoB48 secretion 8-fold over individual subunits alone. To assess whether specific regions of apoB are necessary for MTP responsiveness, nine apoB segments were expressed. These included NH2-terminal segments as well as internal and COOH-terminal regions of apoB fused with a heterologous signal sequence. ApoB segments containing the NH2-terminal 17% of the protein were secreted and responded to MTP activity; however, a segment containing only the NH2-terminal 17% of the protein was not significantly responsive to MTP. Segments lacking the NH2 terminus were not MTP-responsive, and five of six of these proteins were trapped intracellularly but, in certain cases, could be rescued by fusion to apoB17. These results suggest that the NH2 terminus of apoB is necessary but not sufficient for MTP responsiveness.
Animals↗
Prediction of signal peptide functional properties: a study of the orientation and angle of insertion of yeast invertase mutants and human apolipoprotein B signal peptide variants.
A number of studies have introduced mutations into the yeast invertase signal peptide, using it as a model system to elucidate features for targeting, translocation and intracellular transport. Using molecular modelling of the invertase signal peptide we have analysed the hydrophobicity potential and the change in dielectric constant of the energy transfer, when the molecule moves from a hydrophobic to a hydrophilic phase at the simulated hydrophobic-hydrophilic interface. This modelling has been carried out on wild type and mutant invertase signal peptides of altered function, previously reported in the literature. While the predicted angle of insertion correlates with the measured extent of invertase secretion, with an optimum angle of 45 degrees, mutations that change the angle of orientation reduce the extent of invertase secretion. We have applied these same molecular modelling principles to the naturally occurring variants of the human apolipo-protein B (apoB) signal peptide, that confer a secretion defective phenotype when fused to yeast invertase and expressed in yeast. Our modelling thus identifies a strong correlation between the predicted angle of insertion of the signal peptide into the membrane and its ability to direct secretion.
Amino Acid Sequence↗
Lipoprotein lipase gene mutations D9N and N291S in four pedigrees with familial combined hyperlipidaemia.
The role of the lipoprotein lipase (LPL) gene in familial combined hyperlipidaemia (FCH) is unclear at present. We screened a group of 28 probands with familial combined hyperlipidaemia and a group of 91 population controls for two LPL gene mutations, D9N and N291S. LPL-D9N was found in two probands and one normolipidaemic population control. LPL-N291S was found in four probands and four population controls. Subsequently, two pedigrees from probands with the D9N mutation and two pedigrees from probands with the N291S mutation were studied, representing a total of 24 subjects. Both LPL gene mutations were associated with a significant effect on plasma lipids and apolipoproteins. Presence of the D9N mutation (n = 7) was associated with hypertriglyceridaemia [2.69 +/- 1.43 (SD) mmol L-1] and reduced plasma high-density lipoprotein cholesterol (HDL-C) concentrations (0.92 +/- 0.21 mmol L-1) compared with 11 non-carriers (triglyceride 1.75 +/- 0.64 mmol L-1; HDL-C 1.23 +/- 0.30 mmol L-1, P = 0.03 and P = 0.025 respectively). LPL-D9N carriers had higher diastolic blood pressures than non-carriers. LPL-N291S carriers (n = 6) showed significantly higher (26%) apo B plasma concentrations (174 +/- 26 mg dL-1) than non-carriers (138 +/- 26 mg dL-1; P = 0.023), with normal post-heparin plasma LPL activities. Linkage analysis revealed no significant relationship between the D9N or N291S LPL gene mutations and the FCH phenotype (hypertriglyceridaemia, hypercholesterolaemia or increased apo B concentrations). It is concluded that the LPL gene did not represent the major single gene causing familial combined hyperlipidaemia in the four pedigrees studied, but that the LPL-D9N and LPL-N291S mutations had significant additional effects on lipid and apolipoprotein phenotype.
Adult↗
Reduced cholesteryl ester transfer in plasma of patients with lipoprotein lipase deficiency.
The net mass transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to the apolipoprotein (apo) B-containing lipoproteins, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) in plasma (cholesteryl ester transfer (CET)) from three patients lacking lipoprotein lipase (LpL) activity was significantly lower (P < 0.001) than in plasma from fasting control subjects with comparable triglyceride levels. Chylomicrons isolated from LpL-deficient fasting plasma showed the same low level of CET activity as observed in the intact plasma when combined with HDL and cholesteryl ester transfer protein (CETP)-containing d 1.063 g/ml bottom fractions from control subjects. Preincubation of chylomicrons and large triglyceride-rich lipoproteins (Sf > 400) from LpL-deficient plasma with milk LpL, however, stimulated the capacity to engage in CET 4- to 5-fold to the same level as chylomicrons and VLDL from control subjects after a fat load. Consistent with these measurements of CET activity in plasma, chylomicrons obtained from the LpL-deficient subjects after a 14-h fast had higher TG/CE ratios than chylomicrons from controls 3 h after ingesting a fat load (LpL-deficient 26.3 +/- 9.0 vs. controls 6.9 +/- 2.1; mean +/- SD). The mass of CETP did not differ in LpL-deficient and control subjects (LpL-deficient 1.03 +/- 0.22 micrograms/ml vs. controls 1.58 +/- 0.58 micrograms/ml). These studies are consistent with earlier in vitro studies showing that the actions of lipoprotein lipase and its lipolytic products are essential, for maximal cholesteryl ester transfer protein activity.
Cholesterol Esters↗
The insertion allele of the ACE gene I/D polymorphism. A candidate gene for insulin resistance?
BACKGROUND: The insertion/deletion (ID) polymorphism of the angiotensin-converting enzyme (ACE) gene has been associated with increased coronary heart disease (CHD), although the mechanism of this association is not apparent. We tested the hypothesis that the deletion allele of the ACE gene is associated with insulin resistance. METHODS AND RESULTS: We related ACE genotype to components of the insulin-resistance syndrome in 103 non-insulin-dependent diabetic (NIDDM) and 533 nondiabetic white subjects. NIDDM subjects with the DD genotype had significantly lower levels of specific insulin (DD 38.6, ID 57.1, and II 87.4 pmol.L-1 by ANOVA, P = .011). Non-insulin-treated subjects with the DD genotype had increased insulin sensitivity by HOMA % (DD 56.4%, II 29.4%, P = .027) and lower levels of des 31,32 proinsulin (DD 3.3, II 7.6 pmol.L-1, P = .012) compared with II subjects. There were no differences in prevalence of CHD or levels of blood pressure, serum lipids, or plasminogen activator inhibitor-1 (PAI-1) activity between the three ACE genotypes. In nondiabetic subjects there were no differences in insulin sensitivity, levels of insulin-like molecules, blood pressure, PAI-1, serum lipids, or CHD prevalence between the three ACE genotypes. CONCLUSIONS: We conclude that increased cardiovascular risk of the DD genotype is not mediated through insulin resistance or abnormalities in fibrinolysis. Conversely, we report an increased sensitivity in NIDDM subjects with the ACE DD genotype.
Alleles↗
Bimonthly update in lipidology: Genetics and molecular biology.
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Animals↗
European Atherosclerosis Research Study: genotype at the fibrinogen locus (G-455-A beta-gene) is associated with differences in plasma fibrinogen levels in young men and women from different regions in Europe. Evidence for gender-genotype-environment interaction.
The European Atherosclerosis Research Study (EARS) compares genetic and environmental factors in the offspring of fathers with myocardial infarction before the age of 55 years (designated cases) and control subjects from five different regions of Europe. Genotype was determined for a G-A polymorphism 455 bp upstream from the start of transcription of the beta-fibrinogen gene. In 585 cases and 1106 control subjects, the relative frequency of the A allele was similar (0.223 and 0.217, respectively), with small and nonsignificant differences in frequency observed among the five regions. Because of evidence for an interaction between a number of factors and genotype in the determination of plasma fibrinogen levels (in particular among female cases who reported use of oral contraceptives), the data were analyzed without adjusting for covariates except for age and region, and analyses were carried out excluding women taking oral contraceptives (n = 297). In agreement with previous reports, in all regions the A allele was associated with elevated plasma fibrinogen levels, with the strongest and most consistent effects being seen in men. In nonsmokers, after adjusting for the effects of age and region, male cases and control subjects with genotype A/A had mean fibrinogen levels 0.49 and 0.33 g/L higher, respectively, than those with genotype G/G, whereas those with genotype G/A had intermediate levels (P < .01). In female nonsmokers there was a similar but smaller and nonsignificant effect (A/A levels higher than G/G by 0.12 and 0.07 g/L, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Three new polymorphisms of the ApoAI-CIII-AIV gene cluster.
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Apolipoprotein A-I↗