Lipoprotein Phenotype Research Articles

Measurement and meaning of apolipoprotein AI and apolipoprotein B plasma levels

Apolipoproteins AI and B are structural components of lipoprotein particles, and also determinants of the metabolic fate of the encapsulated lipid, cholesterol and triglyceride. Development of accurate assays for these apolipoproteins has opened the way for their use as predictors of coronary heart disease risk. Interpretation of AI and apo B levels is best undertaken with background knowledge of the metabolic status of an individual, especially the lipolytic capacity as reflected in the triglyceride concentration. Those with raised triglyceride, in general, not only have an elevated apo B/apo AI ratio, but also apo B-containing lipoproteins with a prolonged residence time and hence ample opportunity for modification and damage. Assessment of apolipoprotein levels is an aid to risk prediction and can be useful in tailoring treatment.

Accuracy of the Ratio of Triglycerides to High-Density Lipoprotein Cholesterol for Predicting Low-Density Lipoprotein Cholesterol Particle Sizes, Phenotype B, and Particle Concentrations Among Asian Indians

Asian Indians have unusually high rates of coronary artery disease. Small low-density lipoprotein (LDL) particle predominance (phenotype B) is associated with a fourfold atherogenic risk. This study examined the accuracy of a triglyceride/high-density lipoprotein cholesterol (HDL) ratio of > or =3.8 (determined from the Adult Treatment Panel III guidelines, normal triglycerides <150 mg/dl and HDL >40 mg/dl) for predicting phenotype B in Asian Indians. Fasting blood samples were collected from 150 healthy Asian Indians. LDL size analysis was performed by nuclear magnetic resonance spectroscopy. The triglyceride/HDL cholesterol ratio correlated inversely with the LDL size and positively with the particle concentration. A triglyceride/HDL cholesterol ratio of > or =3.8 had 76% sensitivity, 93% specificity, and 83% positive and 89% negative predictive values for predicting phenotype B.

Lessons learnt from the 4D trial

Renal dysfunction alters the pathogenesis of cardiovascular disease (CVD) profoundly conferring a very high-risk to the patients. Currently strategies are developed to combat CVD and clinical studies test a number of hypothesis. In this setting the results of the 4D study, comparing atorvastatin with placebo on cardiovascular outcomes in 1255 type 2 diabetic patients on maintenance hemodialysis, came as a great and unsuspected surprise. After a median follow-up of 4 years atorvastatin (20 mg/d) decreased the relative risk by 8% (95% confidence interval, 0.77–1.10; P = 0.37) despite a high number of cardiovascular events and an overall 24% cardiovascular mortality. This indicates, that the risk in type 2 diabetic patients on hemodialysis origins from factors other than an atherogenic lipoprotein phenotype alone. Due to non-significant effects of atorvastatin on the primary endpoint and the different quality of such endpoints in dialysis patients as well as an unexplained higher rate of fatal strokes in atorvastatin treated patients we do not recommend to initiate statin treatment in patients with type 2 diabetes mellitus undergoing hemodialysis therapy at the present time. Statin therapy should be implemented earlier during the course of progressive vascular damage.

We-P14:382 The effects of weight loss on LP-PLA2 activity and low density lipoprotein (LDL) phenotype in obese women

We-P14:382 The effects of weight loss on LP-PLA2 activity and low density lipoprotein (LDL) phenotype in obese women

Apolipoprotein E Polymorphism Influences Lipid Phenotypes in Chinese Families With Familial Combined Hyperlipidemia

Apolipoprotein E (apoE) polymorphism is associated with changes in the lipoprotein profile of individuals with familial combined hyperlipidemia (FCHL), but its effects on the lipoprotein profiles of members of Chinese families with FCHL remain uncertain. 43 FCHL families (n=449) and 9 normolipidemic families (n=73) were recruited to assess the influence of apoE polymorphism on plasma lipids. The relative frequency of the epsilon4 allele in affected and unaffected FCHL relatives, spouses and normolipidemic members was 13.8%, 5.3%, 9.1% and 6.8%, respectively, with a significantly higher frequency in affected FCHL relatives, compared with unaffected FCHL relatives or normolipidemic members (p=0.0002 or p=0.029). In FCHL relatives, the apoE4 subset (E4/4 and E4/3) exhibited significantly higher levels of apoB, total cholesterol and low-density lipoprotein-cholesterol (LDL-C) than did the apoE3 (E3/3) subset, especially in women (all p<0.05), and there was significant elevation of LDL-C concentrations in men only (p<0.05). In men, the apoE2 (E3/2) subset indicated a decreased level of apoB and increased apoA1 compared with those in the apoE3 subset (p<0.05). ApoE polymorphism appears to be associated with variance of the lipoprotein phenotype in Chinese families with FCHL.

Effects of fenofibrate on apolipoprotein kinetics in patients with coexisting dysbetalipoproteinemia and heterozygous familial hypercholesterolemia

Dysbetalipoproteinemia (dysb) and familial hypercholesterolemia (FH) are two genetic disorders giving rise to severe disturbances of lipid homeostasis and premature atherosclerosis. The co-occurrence of both metabolic abnormalities is very rare and is estimated to affect 1 individual per 2,500,000 in the general population. However, the relative contribution of these two dyslipidemias to the combined lipoprotein phenotype is unknown. The two objectives of this study were (1) to compare the in vivo kinetics of triglyceride-rich lipoprotein (TRL) apolipoprotein (apo) B48, VLDL, IDL and LDL apo B100 as well as plasma apo A-l labelled with a stable isotope ( l-(5,5,5-D 3) leucine) in two subjects presenting both heterozygous FH and dysbetalipoproteinemia (FH+/dysb+), in six FH heterozygotes and in five normolipidemic controls, and (2) to examine the impact of a 6-week treatment with micronized fenofibrate 200 mg/d on apolipoprotein kinetics in FH+/dysb+. As compared with FH heterozygotes and controls, the two FH+/dysb+ subjects showed elevated TRL apo B48 and VLDL, IDL apo B100 pool sizes (PS) mainly due to lower fractional catabolic rates (FCR). Moreover, as compared with FH heterozygotes, FH+/dysb+ subjects presented lower LDL apo B100 PS due to a higher FCR. Pool size, FCR and production rate (PR) of apo A-l were higher in FH+/dysb+ subjects than in FH heterozygotes. In FH+/dysb+ subjects, fenofibrate treatment was associated with a decreased TRL apo B48 PS (−52 and −61%), VLDL apo B100 (−61 and −63%) and IDL apo B100 (−37 and −16%) and an increased FCR of TRL apo B48 (10 and 67%), VLDL apo B100 (123 and 57%) and IDL apo B100 (29 and 10%). Fenofibrate also increased LDL apo B100 PS (3 and 57%) due to an increase in PR (80 and 26%) but had divergent effects on LDL apo B100 FCR. These results indicate that the coexistence of dysbetalipoproteinemia and heterozygous FH results in a mixed lipoprotein phenotype that is intermediate between the two pure phenotypes and that fenofibrate treatment partially reverses lipoprotein abnormalities, mostly through changes in PR and FCR of apo B48- and B100-containing lipoproteins.

Familial combined hyperlipidemia in a North Indian kindred

Familial combined hyperlipidemia is the most common genetic hyperlipidemia and is responsible for premature coronary artery disease. It is genetically heterogenous and no single diagnostic marker exists. The authors report an affected North Indian kindred spanning three successive generations with a possible autosomal dominant pattern of inheritance and all of them had combined dyslipidemia [elevated total cholesterol, predominantly the low density lipoprotein (LDL) fraction and elevated triglycerides]. The proband, a 4-month-old male baby, was incidentally discovered to have a lipaemic serum and so further evaluated. Both the index case and his maternal grandmother, a non-obese diabetic (type 2) with hypertension, had an atherogenic lipoprotein phenotype. Lipaemia retinalis was documented in this baby but xanthomas and coronary artery disease were not noted in the kindred. The present case report highlights the failure of dietary therapy in the proband and explores new options.

Modelling Lipid Metabolism to Improve Healthy Ageing

Lipid metabolism has a key role in human longevity and healthy ageing. This has been demonstrated by a recent genetic study examining the lipoprotein phenotype in individuals with exceptional longevity, in a population of Ashkenazi Jews [1]. It is highly probable such subjects with exceptional longevity, have avoided cardiovascular disease (CVD). CVD is the primary cause of mortality in developed countries. Among the risk factors for CVD, elevated plasma cholesterol has consistently stood out. In response, the pharmaceutical industry has produced a wide range of agents for lowering plasma cholesterol. These work well, but are generally expensive and may pose further health problems. It is therefore important that novel, effective and risk-free ways are developed to control elevated plasma cholesterol. The goal of our work, is to use mathematical modelling to infer nutrition-based interventions, which may help to prevent the dysregulation of lipid metabolism that leads to CVD. Furthermore we are aiming to gain a better understanding of how disease-free ageing can be extended. To do this we are developing a model of cholesterol homeostasis. With the model we can monitor changes in the state of key variables, such as LDL-cholesterol. The model definition is being developed using Systems Biology Markup Language (SBML).

Common hepatic lipase gene promoter variant predicts the degree of neointima formation after carotid endarterectomy: Impact of plaque composition and lipoprotein phenotype

Background The common −514 C-T promoter polymorphism of the hepatic lipase gene (LIPC) and the cholesteryl ester transfer protein (CETP) gene TaqIB polymorphism affect atherogenesis. We investigated the potential relationship between these polymorphisms and the maximum-intima-media thickness (M-IMT) after carotid endarterectomy. Methods The LIPC and CETP genotypes were determined by PCR in 68 patients undergoing endarterectomy. Plaque specimens were analysed for cell composition by immunocytochemistry. Six month after surgery the M-IMT of the revascularized vessel was assessed by B-mode ultrasonography. Results The CC carriers had denser LDL particles ( p < 0.0005), an abundance of macrophages ( p < 0.0005), fewer SMCs in the carotid plaque ( p < 0.0005), and higher prevalence of cerebrovascular events (72% versus 28%, p = 0.002) compared to CT/TT carriers. After endarterectomy, CC carriers showed a lower M-IMT than the CT/TT group (1.36 mm versus 1.76 mm, p = 0.04). No association between the CETP polymorphism and either carotid plaque cellular composition or M-IMT was observed. In a multivariate analysis, M-IMT was associated with plaque cell composition (macrophages, r = −0.39; SMC, r = 0.44; p < 0.005 for both) but not with pre-operative LDL-C, HDL-C, triglycerides, or LDL density. Conclusions The LIPC promoter −514 C-T polymorphism is associated with a significantly reduced development of neointima after surgery. This effect seems to be mediated by scarcity of SMC in the plaque of CC carriers who display an excess prevalence of cerebrovascular events prior endarterectomy but are at low risk for restenosis. The pre-operative lipid phenotype plays a marginal role in the neointima formation.

W16-P-080 The effect of omega-3 fatty acids on the atherogenic lipoprotein phenotype in patients with nephrotic range proteinuria

W16-P-080 The effect of omega-3 fatty acids on the atherogenic lipoprotein phenotype in patients with nephrotic range proteinuria

Physiological importance of SR-BI in the in vivo metabolism of human HDL and LDL in male and female mice

The physiological role of murine scavenger receptor class B type I (SR-BI) was evaluated by in vivo clearances of human HDL3 and LDL in normal and SR-BI knockout (KO) mice. In normal mice, cholesteryl esters (CEs) were removed faster than proteins, indicating a selective uptake process from both HDL3 and LDL. SR-BI KO mice showed 80% losses of HDL-CE selective uptake and the complete loss of LDL-CE selective uptake in the first phase of clearance. However, the second phase was characterized by an acceleration of CE disappearance in SR-BI KO mice. Thus, SR-BI is the only murine receptor mediating HDL-CE selective uptake, whereas a SR-BI-independent pathway specific to LDL can rescue SR-BI deficiency. The analysis of LDL recovered 3 h after injection in mice from different genotypes revealed that LDLs are significantly depleted in CE (reduction from 19% to 50% of the CE/protein ratios). A smaller LDL size in comparison with that of noninjected LDL was also detectable but was more evident for LDL recovered from normal mice. All LDL preparations migrate faster than noninjected LDL on agarose-barbital gels. Thus, both SR-BI-dependent and -independent pathways lead to substantial changes in LDL.

Adiponectin and Coronary Heart Disease: The Strong Heart Study

To the Editor: The adipocyte secreted protein, adiponectin, is of particular interest in metabolic and vascular disease because of its close associations with insulin sensitivity and obesity.1 Lower levels of adiponectin are associated with later development of type 2 diabetes.2 Recent observations from the Health Professionals Follow-Up Study3 suggest that lower adiponectin concentrations might also be associated with incident myocardial infarction, findings in keeping with prior observations in patients with end-stage renal failure.4 We examined prospective relationships of adiponectin to vascular disease in a case–control series selected from the Strong Heart Study (SHS). The SHS is the largest study of cardiovascular disease in American Indians, a group at particular risk of obesity and type 2 diabetes and in whom an increasing incidence of coronary heart disease (CHD) is seen.5 Cases and controls were selected from the SHS cohort.6 The SHS recruited 4549 volunteers of American Indian heritage from 3 geographic areas (Arizona, North and South Dakota, and Oklahoma).6 Volunteers (59% female) were invited to a study examination on three occasions (SH1, 1988 to 1992; SH2, 1993 to 1995; SH3, 1997 to 1999) and remained under continued surveillance for development of vascular disease as described previously.7,8 Because of availability of plasma samples, baseline data for this study were taken from the second examination (SH2), and participants with prevalent cardiovascular disease at SH2 (definite CHD and stroke), …

Influence of α-linolenic acid and fish-oil on markers of cardiovascular risk in subjects with an atherogenic lipoprotein phenotype

We tested the hypothesis that dietary α-linolenic acid (ALA) can exert effects on markers of cardiovascular risk similar to that produced by its longer chain counterparts in fish-oil. A dietary intervention study was undertaken to examine the effects of an ALA-enriched diet in 57 men expressing an atherogenic lipoprotein phenotype (ALP). Subjects were randomly assigned to one of three diets enriched either with flaxseed oil (FXO: high ALA, n = 21), sunflower oil (SO: high linoleic acid, n = 17), or SO with fish-oil (SOF n = 19) for 12 weeks, resulting in dietary intake ratios of n-6: n-3 PUFA of 0.5, 27.9 and 5.2, respectively. The relative abundance of ALA and EPA in erythrocyte membranes increased on the FXO diet ( p < 0.001), whereas both EPA and DHA increased after fish-oil ( p < 0.001). There were significant decreases in total plasma cholesterol within (FXO −12.3%, p = 0.001; SOF −7.6%, p = 0.014; SO −7.3%, p = 0.033) and between diets ( p = 0.019), and decreases within diets after 12 weeks for HDL cholesterol on flaxseed oil (FXO −10%, p = 0.009), plasma TG (−23%, p < 0.001) and small, dense LDL (−22% p = 0.003) in fish-oil. Membrane DHA levels were inversely associated with the changes in plasma TG ( p = 0.001) and small, dense LDL ( p < 0.05) after fish-oil. In conclusion, fish-oil produced predictable changes in plasma lipids and small, dense LDL (sdLDL) that were not reproduced by the ALA-enriched diet. Membrane DHA levels appeared to be an important determinant of these fish-oil-induced effects.

Long-chain conversion of [13C]linoleic acid and α-linolenic acid in response to marked changes in their dietary intake in men

We studied the long-chain conversion of [U-13C]alpha-linolenic acid (ALA) and linoleic acid (LA) and responses of erythrocyte phospholipid composition to variation in the dietary ratios of 18:3n-3 (ALA) and 18:2n-6 (LA) for 12 weeks in 38 moderately hyperlipidemic men. Diets were enriched with either flaxseed oil (FXO; 17 g/day ALA, n=21) or sunflower oil (SO; 17 g/day LA, n=17). The FXO diet induced increases in phospholipid ALA (>3-fold), 20:5n-3 [eicosapentaenoic acid (EPA), >2-fold], and 22:5n-3 [docosapentaenoic acid (DPA), 50%] but no change in 22:6n-3 [docosahexanoic acid (DHA)], LA, or 20:4n-6 [arachidonic acid (AA)]. The increases in EPA and DPA but not DHA were similar to those in subjects given the SO diet enriched with 3 g of EPA plus DHA from fish oil (n=19). The SO diet induced a small increase in LA but no change in AA. Long-chain conversion of [U-13C]ALA and [U-13C]LA, calculated from peak plasma 13C concentrations after simple modeling for tracer dilution in subsets from the FXO (n=6) and SO (n=5) diets, was similar but low for the two tracers (i.e., AA, 0.2%; EPA, 0.3%; and DPA, 0.02%) and varied directly with precursor concentrations and inversely with concentrations of fatty acids of the alternative series. [13C]DHA formation was very low (<0.01%) with no dietary influences.

Low-density lipoprotein size and subclasses are markers of clinically apparent and non-apparent atherosclerosis in type 2 diabetes

The atherogenic lipoprotein phenotype is characterized by an increase in plasma triglycerides, a decrease in high-density lipoprotein (HDL), and the prevalence of small, dense low-density lipoprotein (LDL) particles. The present study investigated the clinical significance of LDL size and subclasses as markers of atherosclerosis in diabetes type 2. Thirty-eight patients with type 2 diabetes, total cholesterol of less than 6.5 mmol/L, and hemoglobin A 1c (HbA1c) of less than 9% were studied. Median age was 61 years, mean (±SD) body mass index 29 ± 4.3 kg/m 2, and mean HbA1c 7.1 ± 0.9 %. Laboratory parameters included plasma lipids and lipoproteins, lipoprotein (a), apolipoprotein (apo) A-I, apo B-100, apo C-III, and high-sensitivity C-reactive protein. Low-density lipoprotein size and subclasses were measured by gradient gel electrophoresis and carotideal intima media thickness (IMT) by duplex ultrasound. By factor analysis, 10 out of 21 risk parameters were selected: age, body mass index, systolic blood pressure, smoking (in pack-years), HbA1c, high-sensitivity C-reactive protein, lipoprotein (a), LDL cholesterol, HDL cholesterol, and LDL particle size. Multivariate analysis of variance of these 10 risk parameters identified LDL particle size as the best risk predictor for the presence of coronary heart disease ( P = .002). Smaller LDL particle size was associated with an increase in IMT ( P = .03; cut-off >1 mm). Within the different lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides, apo B, apo A-I, apo C-III, LDL particle size), LDL particle size was most strongly associated with the presence of coronary heart disease ( P = .002) and IMT ( P = .03). It is concluded that LDL size is the strongest marker for clinically apparent as well as non-apparent atherosclerosis in diabetes type 2.

Mutations in MTP gene in abeta- and hypobeta-lipoproteinemia

Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are inherited disorders of apolipoprotein B (apo B)-containing lipoproteins that result from mutations in apo B and microsomal triglyceride transfer protein (MTP) genes, respectively. Here we report three patients with severe deficiency of plasma low-density lipoprotein (LDL) and apo B. Two of them (probands F.A. and P.E.) had clinical and biochemical phenotype consistent with ABL. Proband F.A. was homozygous for a minute deletion/insertion (c.1228delCCCinsT) in exon 9 of MTP gene predicted to cause a truncated MTP protein of 412 amino acids. Proband P. E. was heterozygous for a mutation in intron 9 (IVS9-1G>A), previously reported in an ABL patient. We failed to find the second pathogenic mutation in MTP gene of this patient. No mutations were found in apo B gene. The third proband (D.F.) had a less severe lipoprotein phenotype which was similar to that of heterozygous FHBL and appeared to be inherited as a co-dominant trait. However, he had no mutations in apo B gene. He was found to be a compound heterozygote for two missense mutations (D384A and G661A), involving highly conserved regions of MTP. Since this proband was also homozygous for ɛ2 allele of apolipoprotein E (apo E), it is likely that his hypobetalipoproteinemia derives from a combined effect of a mild MTP deficiency and homozygosity for apo E2 isoform.

Lipid Triad or Atherogenic Lipoprotein Phenotype: A Role in Cardiovascular Prevention?

The term "lipid triad" or "atherogenic lipoprotein phenotype" has been introduced to describe a common form of dyslipidemia, characterized by three lipid abnormalities: increased plasma triglyceride levels, decreased HDL-cholesterol concentrations and the presence of small, dense LDL particles. It has been suggested that the clinical importance of the atherogenic lipoprotein phenotype probably exceeds that of LDL-cholesterol, because many more patients with coronary artery disease are found to have this trait than hypercholesterolaemia. There is a body of evidence that therapies effective against plasma HDL-cholesterol and triglycerides are associated with a strong reduction of cardiovascular risk; in addition, hypolipidemic treatment is able to increase LDL particle size and this increment correlates with regression of coronary stenosis. Recently, the Coordinating Committee of the National Cholesterol Education Program suggested that very high-risk patients may benefit from stronger lipid-lowering measures, a category of individuals that includes those with the atherogenic lipoprotein phenotype. Since the therapeutical modulation of each of the three components of the lipid triad is associated with a strong reduction in the risk of cardiovascular events, LDL size measurement may be extended as much as possible to patients at high risk of cardiovascular diseases.

LDL size: does it matter?

The atherogenic lipoprotein phenotype is characterised by a moderate increase in plasma triglycerides, a decrease in high density lipoprotein cholesterol and the prevalence of smaller denser low density lipoprotein particles. The prevalence of this partially inheritable phenotype is approximately 30% and is a feature of the metabolic syndrome associated with an increased risk for cardiovascular events. The predominance of small dense LDL has been accepted as an emerging cardiovascular risk factor by the adult treatment panel (ATP) III.

Effect of cholesteryl ester transfer protein (CETP) expression on diet-induced hyperlipidemias in transgenic rats

Objective: In order to determine the influence of the lipid status on the ability of cholesteryl ester transfer protein (CETP) to modify the plasma lipoprotein profile, the effect of hypercholesterolemia versus hypertriglyceridemia were compared in wild-type and CETP-transgenic (CETPTg) rats expressing CETP at a constant level. Methods and results: Wild-type and CETPTg rats were fed either a chow diet, a high fat/high cholesterol (HF/HC) diet, or a sucrose diet. As compared to wild-type rats, CETPTg rats fed the standard chow exhibited lower high-density lipoproteins (HDL)–cholesterol concentration (−65%, p < 0.01), but similar non-HDL–cholesterol concentrations. Both wild-type and CETPTg rats fed the HF/HC diet displayed pronounced increases in total and non-HDL–cholesterol levels, with no influence of CETP expression in this case. In contrast, the sucrose diet produced significant changes only in CETPTg rats which then exhibited a 82% increase in non-HDL–cholesterol in addition to a 80% reduction in HDL cholesterol when compared to sucrose-fed, wild-type rats ( p < 0.01 in both cases). The triglyceride to cholesterol ratio in very low-density lipoprotein (VLDL) was 10-fold lower in ‘HF/HC’ rats than in ‘chow’ and ‘sucrose’ rats ( p < 0.005 and p < 0.01, respectively), and VLDL from ‘HF/HC’ animals were proven to constitute poor cholesteryl ester acceptors. Conclusions: CETP expression modified dramatically the lipoprotein phenotype in ‘sucrose’ rats but not in ‘HF/HC’ rats. These observations suggest that a CETP inhibitor treatment is susceptible to produce profound changes in hypertriglyceridemia or combined hyperlipidemia.

LDL size: does it matter?

The atherogenic lipoprotein phenotype is characterised by a moderate increase in plasma triglycerides, a decrease in high density lipoprotein cholesterol and the prevalence of smaller denser low density lipoprotein particles. The prevalence of this partially inheritable phenotype is approximately 30% and is a feature of the metabolic syndrome associated with an increased risk for cardiovascular events. The predominance of small dense LDL has been accepted as an emerging cardiovascular risk factor by the adult treatment panel (ATP) III.