Relationship between the presence of small, dense low-density lipoprotein and plasma lipid phenotypes in Japanese children

To clarify the relationship between the expression of atherogenic small, dense low-density lipoprotein (SDLDL) and underlying lipid metabolic abnormalities, the prevalence of SDLDL in relation to the serum lipid phenotype was analyzed in 229 children. The LDL particle size was measured using gradient gel electrophoresis, and a particle size of less than 25.5 nm was considered to represent SDLDL. The overall prevalence of SDLDL in the sample population was 8.2% (19/229; 11/117 for boys and 8/112 for girls). Hyperlipidemia phenotype IIb (elevated concentrations of both triglyceride [TG] and total cholesterol [TC]) was strongly associated with SDLDL in 83% (5/6) of the subjects. An elevated TG concentration (phenotype IV) was associated with SDLDL in 55% (10/18) of the subjects. The association between hyperlipidemia phenotype IIa (elevated TC but a normal TG concentration) and SDLDL was quite low (2%; 1/56), but SDLDL was detected in 5% (8/155) of the subjects who presented with normolipidemia. Therefore, these findings suggest that the expression of SDLDL is largely related to lipid abnormalities characterized by phenotype IIb or IV, the underlying metabolic abnormality of which is suspected to be insulin resistance; however, an additional mechanism for the formation of SDLDL that functions independently of plasma lipid abnormalities also seems to exist.     

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 A1c (HbA1c) of less than 9% were studied. Median age was 61 years, mean (+/-SD) body mass index 29 +/- 4.3 kg/m2 , 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.     

PAI-1 activity, but not fibrinogen or von Willebrand factor, is inversely related to LDL particle size in type 2 diabetes

BACKGROUND: Levels of fibrinogen, von Willebrand factor (vWF) and plasminogen activator inhibitor-1 (PAI-1) have been associated with small low-density lipoprotein (LDL) particles. However, it is not clear whether these associations are independent of visceral adiposity or other components of the metabolic syndrome such as triglycerides or insulin resistance. METHODS: Visceral adipose tissue (VAT; CT-scan), fibrinogen, von Willebrand factor antigen (vWF:Ag), PAI-1 activity and different metabolic parameters such as total cholesterol (chol), HDL-chol, triglycerides, insulin resistance (homeostasis model assessment; HOMA-IR) were determined in 41 women and 78 men with type 2 diabetes. LDL particle size was assessed by polyacrylamide gradient gel electrophoresis. RESULTS: PAI-1 activity was inversely related to LDL particle size after adjustment for age and body mass index (BMI) (r=-0.28; p=0.006) or age and VAT (r=-0.26; p=0.01), but not after adjustment for age and HOMA-IR (r=-0.15; p=0.148) or age and triglycerides (r=-0.04; p=0.679). In multiple regression analysis, LDL particle size did not independently determine PAI-1 activity levels. Fibrinogen and vWF:Ag did not seem to be related to LDL size. CONCLUSIONS: PAI-1 activity levels, in contrast to fibrinogen and vWF:Ag, seem to be related to the small LDL phenotype in patients with type 2 diabetes. However, this relationship was not independent of insulin resistance or triglycerides.     

Visceral adipose tissue accumulation, secretory phospholipase A2-IIA and atherogenecity of LDL

OBJECTIVE: The aim of the present study was to investigate the combined impact of visceral adipose tissue (VAT) and secretory group IIA phospholipase A(2) (sPLA(2)-IIA) concentrations on the atherogenicity of low-density lipoprotein (LDL) particles among men. SUBJECTS: Analyses were conducted in 74 mid-obese healthy men (age: (mean+/-s.d.) 37.9+/-11.7 years). METHODS: Plasma levels of sPLA(2)-IIA were measured with a commercial ELISA and VAT levels were assessed by computed tomography. Distinct subpopulations of LDL particles were characterized from whole plasma using nondenaturating 2-16% gradient gel electrophoresis.Results:Data indicated that plasma sPLA(2)-IIA levels were approximately 29% (P=0.007) higher among men characterized by a higher accumulation of VAT (>142 vs < or =142 cm(2)). Men having high plasma sPLA(2)-IIA levels (> or =127.2 ng/dl, the median value), were characterized by higher levels of plasma cholesterol (C) and apolipoprotein (apo) B, LDL-C, LDL-apoB, oxidized LDL (OxLDL) and by smaller LDL particles compared to men with sPLA(2)-IIA<127.2 ng/dl. Multiple regression analyses showed that plasma triglycerides and sPLA(2)-IIA levels explained 22.7 and 11.8% of the variance in LDL peak particle size, respectively. Levels of VAT and of sPLA(2)-IIA were the strongest correlates of OxLDL levels explaining, respectively, 15.0 and 5.5% of their variability. CONCLUSION: Both VAT and sPLA(2)-IIA levels modulate the atherogenecity of LDL by accounting for the reduction in their size and their susceptibility to oxidation.     

Apolipoprotein E polymorphism modulates the association between obesity and dyslipidemias during young adulthood: The Bogalusa Heart Study

To elucidate to what extent apolipoprotein (apo) E polymorphism modulates obesity-induced dyslipidemias during young adulthood, longitudinal data on 759 individuals (72% white/28% black; initial and follow-up mean age, 25.9 and 32.7 years) were examined. Among both races and the total sample, the apo E2 group (with E2/2 or E2/3 phenotype) had significantly lower and the apo E4 (with E4/4 or E3/4 phenotype) group higher low-density lipoprotein (LDL) cholesterol than the apo E3 (with E3/3 phenotype) group at both examinations. In addition, the apo E2 group displayed higher high-density lipoprotein (HDL) cholesterol in the total sample. No allele-specific effect was noted for the longitudinal changes (Delta). An increase in Delta adiposity, measured as Delta body mass index (BMI), was accompanied by higher increase in Delta LDL cholesterol in the e4 carriers than the e2 carriers among the whites (P <.05) and the total sample (P <.01); an increase in Delta triglycerides and decrease in Delta HDL cholesterol in the e2 carriers than the e4 carriers among all the groups (P <.05 to.001). Among the apo E phenotype groups, the incidence of high (>75th percentile specific for race and sex) LDL cholesterol at follow-up was in the order E4 > E3 > E2 both in the obese (BMI > 30; P for trend =.033) and the nonobese (BMI < 25; P for trend =.035) groups. Although the increase of low (<25th percentile specific for race and sex) HDL cholesterol or high triglycerides showed no apo E phenotype-specific trend, the incidence of high triglycerides without high LDL cholesterol was in the order E2 > E3 > E4 only in the obese group (P for trend =.025). The prevalence trend for dyslipidemias at follow-up among the persistently obese and nonobese groups also gave similar results. Thus, apo E gene locus influences not only the levels of certain lipoprotein variables during young adulthood, but also modulates the association between obesity and dyslipidemias.     

The effect of insulin resistance and obesity on low-density lipoprotein particle size in children

Objective: In adults, it was shown that obesity and insulin resistance affect low−density lipoprotein (LDL) particle size and small dense (sd) LDL is associated with cardiovascular diseases. In this study, we investigated the effect of obesity and insulin resistance on LDL particle size.Methods: Twenty−six obese children (13 girls, 13 boys) with a median age of 10.5 years and 27 healthy control subjects (17 girls, 10 boys) with a median age of 11.5 were enrolled in the study.Results: The number of patients with insulin resistance in the obese group was 15 out of 26. In the control group, there was no subject with insulin resistance. Serum triglyceride and very LDL (VLDL) levels were higher and serum high−density lipoprotein levels (HDL) were lower in the obese patients than in the controls. There was no statistical difference in the LDL particle size between the two groups (medians: 26.6 vs. 26.7 nm (p=0.575)). The size of LDL particle was not correlated with body mass index (BMI) standard deviation score (SDS), homeostasis model assessment of insulin resistance (HOMA−IR), or serum lipids.Conclusion: Measurement of LDL particle size as a routine procedure is not necessary in childhood obesity.Conflict of interest:None declared.     

Visceral adipose tissue and low-density lipoprotein particle size in middle-aged versus young men.

Age is associated with increased deposition of visceral adipose tissue. We examined whether this age-related change in regional adipose tissue distribution had an impact on low-density lipoprotein (LDL) particle size. For this purpose, the plasma lipoprotein-lipid profile, including LDL peak particle diameter as determined by gradient gel electrophoresis, was assessed in 38 young men (aged 26.4 +/- 4.2 years, mean +/- SD) and compared with 40 middle-aged men (55.9 +/- 6.2 years). Middle-aged men had higher values for total body fat and visceral adipose tissue area as measured by computed tomography than young men (P < .001). Although significant differences were noted between the two age groups for plasma cholesterol, triglyceride (TG), apolipoprotein B (apo B), LDL cholesterol, and LDL apo B, as well as the cholesterol to high-density lipoprotein (HDL) cholesterol ratio (P < .001), no difference was found for LDL peak particle size between young and middle-aged men. While visceral adipose tissue was a significant correlate of plasma lipoprotein levels, the fasting TG concentration was the best predictor of LDL particle size, and the regression of TG levels on LDL peak particle diameter was not different between the two age groups. These results suggest that middle-aged men are characterized by an increased concentration of LDL particles (reflected by increased LDL apo B levels) but not by a reduced LDL peak particle size compared with young men. It is therefore proposed that in the absence of an important age-related change in TG levels, age per se is associated with an increased concentration of atherogenic LDL particles rather than a reduction of LDL particle diameter.     

Association of apo A-IV 360 (Gln --> His) polymorphism with plasma lipids and lipoproteins: the Framingham Offspring Study

The effect of a common apolipoprotein (apo) A-IV polymorphism (substitution of histidine for glutamine at position 360) on plasma lipid, lipoprotein cholesterol and lipoprotein(a) (Lp(a)) levels, and on low-density lipoprotein (LDL) particle size was examined by genotyping in 2322 Caucasian men and women (mean age: 48.9+/-10.1 years) participating in the Framingham Offspring Study (FOS). The relative frequencies of the apo A-IV-Gln (apo A-IV-1) and the apo A-IV-His (apo A-IV-2) alleles were 0.932 and 0.068, respectively, and were in Hardy-Weinberg equilibrium. No effect of the apo A-IV-2 genotype was observed on plasma triglyceride, total and lipoprotein cholesterol, and LDL particle size in either men or women after adjustment for age and body mass index. To avoid a possible interaction between the apo E genotype and the apo A-IV genotype, subgroup analyses were undertaken in 1,414 male and female subjects with the apo E3/3 genotype. Among women in this group there was a significant effect of the apo A-IV-2 allele on triglyceride levels (p=0.046). This effect was no longer significant after adjustment for age and BMI (p=0.074). No significant allele effect on other lipoprotein levels, including Lp(a), was noted in apo E3/3 men or women. We have also conducted a meta-analysis of our own data and of other studies found in the literature, indicating a significant lowering effect of apo A-IV-2 on plasma triglycerides, but no effects on other parameters. In conclusion, the apo A-IV-2 allele is associated with a modest reduction in plasma triglyceride levels in the general population.     

Interaction between LDL receptor and lipoproteins containing apo B]

The physiocochemically defined lipoproteins such as VLDL, LDL are comprised of subpopulations with different lipid and apolipoprotein composition. In order to determine the respective roles of different apolipoproteins (B, C-III, E) in their metabolism, four species (LpB, LpB:E, LpB: C-III and LpB: C-III: E) have been separated by sequential immunoaffinity chromatography. We examined the binding characteristics of each lipoprotein to HeLa cells and expressed the results in relation to the number of moles of apo B. LpB particles which contained apo B as their sole apolipoprotein had lower affinity for the LDL receptor that did total LDL but an apparently higher number of binding sites. The presence of apo E of phenotype E3 or E4 on one particle increased the affinity for the receptor. The apparent number of binding sites decreased probably due to the fact that a particle containing multiple copies of apo E bound to more than one molecule of receptor. Interaction with several LDL receptors would also explain the higher binding affinity which we observed. When the apo E phenotype was E2/E2, the LpB: E particle did not bind to the receptor. We showed also that apo C-III, when present, diminished the binding of apo B containing lipoproteins. These data suggest that apolipoproteins E and C-III impaired the interaction of apo B with the LDL receptor. It is likely that in LpB: E only apo E (in the case of E3 or E4 phenotype) participates in the LDL receptor binding.     

The triglyceride/high-density lipoprotein cholesterol ratio, the small dense low-density lipoprotein phenotype, and ischemic heart disease risk

This study investigated the relevance of using the plasma triglyceride to high-density lipoprotein cholesterol ratio (Log TG/HDL-C) for the prediction of the small dense lowdensity lipoprotein (LDL) phenotype and the risk of ischemic heart disease (IHD). Analyses were based on data from the Quebec Cardiovascular Study in a cohort of 2072 men free of IHD at baseline, among whom 262 had a first IHD event (coronary death, non fatal myocardial infarction and unstable angina) during a 13-year follow-up period. LDL particle size phenotype was characterized using 2-16% polyacrylamide gradient gel electrophoresis (PAGGE) of whole plasma. There were significant associations between the Log TG/HDL-C ratio and features of LDL size phenotype such as the proportion of LDL with a diameter <255A (r = 0.43, p < 0.001) and LDL peak particle size (r = -20.55, p < 0.001). However, the Log TG/HDL-C ratio brought no additional value (p a yen 0.1) in predicting the small dense LDL phenotype (area under the receiver operating curve (AUROC = 71.9%) compared to TG alone (AUROC = 71.2%) or to a combination of Log TG and HDL-C (AUROC = 72.4%) after multivariate adjustment for non lipid risk factors. Finally, elevations in the Log TG/HDL-C ratio did not improve the discrimination of incident IHD cases from non IHD cases compared to the use of plasma TG levels alone (p = 0.5) or a combination of the individual TG and HDL-C values (p = 0.5). The Log TG/HDL-C ratio does not improve our ability to identify individuals with the small dense LDL phenotype compared to plasma TG levels alone. The Log TG/HDLC is also not superior to plasma TG levels alone in predicting IHD risk in men of the QuA(c)bec Cardiovascular Study.     

Hypothyroidism results in small dense LDL independent of IRS traits and hypertriglyceridemia

There is evidence of an association between hypothyroidism and coronary heart disease. We decided to look at the relationship between hypothyroidism and LDL subclasses' pattern including small, dense LDL to define a biochemical basis for better management of the CHD risk of these patients. We utilized a case-control design to evaluate differences in lipid parameters between cases and controls. Univariate analysis revealed that many factors were associated with LDL particle size. Binary logistic regression however revealed that only thyroid status and serum triglyceride (TG) levels were independently associated with LDL particle size. Results from this study support an independent association between LDL particle size phenotype and both plasma TG concentrations and thyroid status. After adjusting for TG levels, other insulin resistance syndrome (IRS) traits were not associated with LDL size phenotype, suggesting that the IRS related sdLDL is linked most strongly to alterations in TG levels.     

Influence of common variants in the CETP,LPL, HL and APO E genes on LDL heterogeneity in healthy,middle-aged men

Low density lipoprotein (LDL) particle size is a genetically influenced trait associated with coronary heart disease (CHD). This study investigates the effects of genetic variation in plasma factors with important roles in lipoprotein metabolism on LDL heterogeneity. Common variants in the cholesteryl ester transfer protein (CETP-629C/A), lipoprotein lipase (LPL S447X), hepatic lipase (HL-480C/T) and apolipoprotein E (apoE e2/e3/e4) genes were studied in relation to LDL particle size distribution in 377 healthy, middle-aged men. A high-resolution polyacrylamide gradient gel electrophoresis technique was used to measure plasma concentrations of four LDL subfractions. The CETP-629A and LPL 447X alleles were associated with moderately increased LDL peak particle size. In contrast, the apoE e4 allele was associated with a marked reduction in LDL peak particle size and an increased relative proportion and plasma concentration of small, dense LDL. An interaction between the HL-480C/T and apo E polymorphisms contributed significantly to increased plasma concentration of small, dense LDL (LDL-III) in HL-480T carriers. In summary, the investigated polymorphisms were associated with diverse effects on the LDL particle size distribution, consistent with respect to protein function and proposed association with CHD risk. The observed associations were further modulated by gene-gene and gene-environment interactions.     

Effect of weight loss on postprandial lipemia and low-density lipoprotein receptor binding in overweight men

Obestity is associated with a range of metabolic abnormalities including fasting and postprandial dyslipidemia, both of which may contribute to increased atherosclerotic risk. Male obese subjects have a decreased level of low-density lipoprotein (LDL) receptor binding in mononuclear cells, the level of which reflects binding in the liver, compared with lean controls. In this study, we investigated whether the implementation of a weight loss regimen in viscerally obese subjects improves LDL receptor binding level. We examined apolipoprotein B(48) (apo B(48)) and retinyl palmitate (RP) metabolism following an oral fat challenge to determine whether weight loss improves postprandial dyslipidemia in viscerally obese subjects. Male obese, mildly dyslipidemic, and insulin-resistant subjects were randomly assigned to either a weight loss (n = 12) or control weight maintenance (n = 10) group. In response to weight loss of 10 kg, insulin sensitivity improved as evidenced by decreased fasting insulin and homeostatic model assessment (HOMA) score. In addition, LDL receptor binding in mononuclear cells increased significantly by 27.5% and LDL-cholesterol was significantly reduced. However, despite the increased LDL receptor levels, fasting apo B(48) levels did not fall. Postprandially, the area under the curve (AUC) for RP was significantly reduced after weight loss, but the incremental and total AUCs for apo B(48) were not altered. Apo B(48) is an unequivocal marker of chylomicron particle number; hence, the reduction in RP metabolism achieved with weight reduction may reflect decreased lipid incorporation into nascent chylomicrons or improved hydrolysis of triglyceride-rich chylomicrons resulting from a decreased competition with hepatic lipoproteins for lipoprotein lipase. Our findings suggest that the improvement in LDL receptor binding following weight reduction of 10 kg in insulin-resistant male obese subjects is insufficient to reduce the elevated chylomicron remnant levels.     

Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women.

The effects of oral estrogen replacement (ethinyl estradiol 0.02 mg/d) on plasma triglyceride, total cholesterol, very-low-density lipoprotein (VLDL) cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and apolipoprotein (apo) A-I and B levels and LDL particle size were assessed in 20 postmenopausal women with a previous hysterectomy and various forms of dyslipidemia (LDL cholesterol > or = 4.14 mmol/L [160 mg/dL] and/or HDL cholesterol < or = 1.03 mmol/L [40 mg/dL]). All subjects were studied while on a standard cholesterol-lowering diet, and were sampled in the fasting state before beginning estrogen therapy and after a mean of 13 weeks of estrogen therapy. Lipids were measured by standardized enzymatic techniques, apos were measured by enzyme-linked immunoassays, and LDL particle size was measured by gradient gel electrophoresis. Mean values for plasma lipid parameters (mmol/L) at baseline and during estrogen replacement were as follows: triglyceride, 2.11 and 2.75 (30% increase); total cholesterol, 7.45 and 6.52 (13% decrease); VLDL cholesterol, 1.09 and 1.22 (12% increase); LDL cholesterol, 5.09 and 3.70 (27% decrease); and HDL cholesterol, 1.27 and 1.58 (24% increase). Mean values for apo A-I were 163 and 254 mg/dL (56% increase), and for apo B they were 170 and 148 mg/dL (13% decrease). The LDL particle score was 4.09 and 4.52 (11% smaller). Changes in all parameters were statistically significant (P = .05) except for VLDL cholesterol. These data indicate that estrogen replacement is effective in decreasing LDL cholesterol and apo B concentrations and increasing HDL cholesterol and apo A-I concentrations in dyslipidemic postmenopausal women, but it should not be used in patients with baseline fasting triglyceride levels higher than 2.82 mmol/L (250 mg/dL) unless it is accompanied by a progestin. Our data indicate that this form of estrogen replacement could lower the risk of coronary artery disease (CAD) by more than 50% in these women, based on favorable alterations in plasma lipoproteins.     

Predominance of small dense LDL differentiates metabolically unhealthy from metabolically healthy overweight adults in Korea

Objective

The purposes of this study were (1) to determine the association between lipoprotein subfraction profiles and metabolically healthy overweight (MHO) phenotype, as defined by visceral adiposity; and (2) to identify the strongest predictor of metabolic health among the lipoprotein measurements.

Materials/Methods

This cross-sectional study was comprised of 462 overweight patients, who were classified as MHO or non-MHO based on their visceral adipose tissue (VAT) area to subcutaneous adipose tissue area (SAT) ratio (VAT/SAT ratio). Serum lipoprotein subfraction analyses and other metabolic parameters were measured.

Results

Among the overweight participants, two hundred fifty-five individuals (53.7%) had the MHO phenotype. After adjusting for age, sex, medication, lifestyle factors, and confounding metabolic characteristics, the non-MHO group showed significantly higher lipid levels and a greater prevalence of unfavorable lipid profiles. LDL subclass pattern type B was the most significant predictor of the non-MHO phenotype (odds ratio 2.70; 95% CI 1.55–4.69), while serum LDL cholesterol level was not a significant predictor of the non-MHO phenotype.

Conclusions

Lipoprotein subfraction particle measurements were significantly associated with the non-MHO phenotype and a higher VAT/SAT ratio, with small dense LDL predominance being the most significant predictor of MHO phenotype. These findings will help identify MHO and non-MHO phenotypes and perhaps lead to a development of cost-effective individualized treatments.     

Lipoprotein Lp(a) in homozygous familial hypercholesterolemia: density profile, particle heterogeneity and apolipoprotein(a) phenotype.

Homozygous familial hypercholesterolemia (FH) is a genetic disorder featuring a functional defect in cellular LDL receptors, marked elevation in circulating LDL concentrations, and premature atherosclerosis. The potential atherogenic role of apo B-containing lipoproteins other than LDL in this disease is indeterminate. We describe the quantitative and qualitative characteristics of Lp(a) as a function of apo(a) phenotype in a group of eight, unrelated homozygous FH patients. Plasma Lp(a) levels were significantly elevated (2.5-fold; mean 50 +/- 32 mg/dl) as compared to those in healthy subjects. The S2 isoform of apo(a) occurred most frequently (6 of eight patients); the rare B isoform presented in three patients. Plasma Lp(a) levels in homozygous FH did not correspond to those predicted by apo(a) phenotype. Analyses of the density distribution of Lp(a) and of Lp(a) particle size and heterogeneity as a function of density did not reveal any anomalies characteristic of homozygous FH. However, comparison of the hydrated density of Lp(a) particles as a function of apo(a) isoform content revealed a clear influence of isoform on this parameter; thus, in a B/S2 heterozygous patient, the density distribution of Lp(a) fractions containing isoform B alone, B and S2, and S2 alone, demonstrated that the apparent molecular weight of apo(a) plays a determining role in controlling the hydrated density and size of the resulting Lp(a) particle. Indeed, patients expressing the high molecular weight, S2 isoform uniformly displayed a dense form of Lp(a) (hydrated density approximately 1.055 g/ml). In subjects presenting two apo(a) isoforms, each isoform resided on distinct lipoprotein particles; in such cases, the plasma levels of the denser isoform predominated, suggesting differences in rates of formation, or rates of tissular catabolism, or in the plasma stability of the particles, or a combination of these mechanisms. Considered together, our data may be interpreted to suggest that the elevated circulating levels of Lp(a) in homozygous FH patients may reflect either an increased biosynthesis, or diminished catabolism via the cellular LDL receptor pathway, or a combination of both.     

High density lipoprotein cholesterol and apolipoprotein a-1 concentrations in non-insulin dependent diabetics treated by diet and chlorpropamide

Fasting serum concentrations of high density lipoprotein cholesterol (HDLC) and apolipoprotein A-I (apo A-I) were determined in non-insulin dependent diabetes at diagnosis, diabetics treated by diet alone, diabetics treated by diet plus chlorpropamide, and normal controls matched for sex, age and body weight. Serum concentrations of HDLC and apo A-I were decreased in all groups of diabetics. There were no significant differences in HDLC and apo A-I concentrations between the diabetics at diagnosis and those treated by diet alone or diet plus chlorpropamide. Neither HDLC nor apo A-I concentrations were correlated with glucose concentrations. The results indicate that serum concentrations of HDLC and apo A-I are reduced in non-insulin dependent diabetics at diagnosis, and are not significantly affected by chronic diet and chlorpropamide therapy.     

Effects of androgen manipulation on postprandial triglyceridaemia, low-density lipoprotein particle size and lipoprotein(a) in men.

Although androgenic hormones decrease HDLC concentration, no direct evidence has linked them to atherosclerosis. The present study was undertaken to extend our ability to assess risk associated with androgen induced lipoprotein(Lp) changes by simultaneously gathering information about postprandial triglyceridaemia (PPT), LDL particle size, HDL and Lp(a) in men either taking exogenous androgens or with suppressed endogenous androgen concentrations. The experimental groups comprised nine male bodybuilders who self-administered anabolic-androgenic steroids (AAS) for a mean period of 6.5 weeks, and 10 healthy men whose testosterone concentration had been reversibly suppressed for 5 weeks using the GnRH agonist triptorelin (Decapeptyl; D-Trp-6-LHRH). A separate group receiving no hormonal treatment provided analytical control (n=7). Lipoprotein size was assessed by gradient gel electrophoresis categorisation (GGE), lipoprotein concentrations by immuno and enzymatic assays and PPT by a standardised oral fat tolerance test (65g /m(2)). Testosterone concentration was significantly reduced on triptorelin from 7.32+/-1.92 to 1.15+/-0.57 ng/ml (P=0.002). High dose AAS use was confirmed by urinalysis. With AAS use, mean HDLC and Lp(a) concentrations and PPT decreased from 0.9+/-0.3 to 0.7+/-0.3 mmol/l (P=0.004), 125+/-128 to 69+/-73 U/l (P=0.008) and 11.6+/-10.0 mmol/l h to 7.5+/-5.4 mmol/l h (P=0.027) respectively. Mean total cholesterol and LDLC were unchanged. LDL size was unchanged in six AAS users, decreased in one but remaining in the normal size range, and increased in two from small LDL to the normal range. Size changes in the latter two subjects were associated with 42 and 58% reductions in PPT respectively. In the triptorelin group, mean total cholesterol, HDLC and Lp(a) were increased from 4.8+/-0.8 mmol/l to 5.2+/-1.0 mmol/l (P=0.039), 1.1+/-0.2 to 1.4+/-0.3 mmol/l (P=0.002) and 278+/-149 to 377+/-222 U/l (P=0.004) respectively. Mean LDLC concentration and PPT were unchanged. LDL particle size increased in four, decreased in two, and was unchanged in four subjects. LDL size decreased in two and showed no change in the other five control subjects. Other lipid measures were unchanged in the control group. Thus, apart from lowering HDLC concentrations, no other potentially atherogenic effects of endogenous androgens or AAS were observed. A suppression of Lp(a) as well as a reduced PPT and increased LDL size in predisposed individuals may be antiatherogenic effects of AAS.     

Regulation of plasma low density lipoprotein levels in postmenopausal women

To study the regulation of plasma low density lipoprotein (LDL) cholesterol in postmenopausal women (n = 79), fasting plasma lipids and lipoproteins, the fractional catabolic rate (FCR) and production rate for LDL apolipoprotein B (apo B), cholesterol absorption, apolipoprotein E phenotype and polymorphisms of the apo B and 7alpha-hydroxylase genes were determined. The level of LDL cholesterol was related to FCR (r= -0.757, P < 0.001) and the production (r= 0.531, P < 0.001) of LDL apo B and body mass index (r = 0.265, P <0.05). In contrast, cholesterol absorption efficiency, apolipoprotein E phenotype, EcoRI and XbaI polymorphisms of the apo B gene and the polymorphism of 7alpha-hydroxylase gene were found to have no significance for the regulation of LDL cholesterol concentration in these postmenopausal women.     

Relationship of visceral adipose tissue to metabolic risk factors for coronary heart disease: is there a contribution of subcutaneous fat cell hypertrophy?

Visceral adipose tissue (VAT) accumulation is an important correlate of the metabolic complications found in obese patients. The aim of this study was to evaluate the respective contribution of VAT deposition versus subcutaneous abdominal or femoral fat cell hypertrophy as correlates of the metabolic risk profile in 69 men and 65 premenopausal women (aged 35+/-5 years) with a wide range of fatness (body mass index, 18 to 57 kg/m2). In both genders, VAT accumulation was positively correlated with fasting plasma insulin, triglyceride (TG), and low-density lipoprotein (LDL)-apolipoprotein B (apo B) levels and the cholesterol (CHOL)/high-density lipoprotein (HDL)-CHOL ratio (.24 < or = r < or = .71, P < .05). A similar pattern of positive relationships was found between subcutaneous abdominal fat cell weight and metabolic risk variables in men and women (.33 < or = r < or = .60, P < .01). Positive associations were also observed in women between femoral fat cell weight and fasting plasma insulin, TG, and CHOL levels and the CHOL/HDL-CHOL ratio (.29 < or = r < or = .42, P < .05). However, only plasma TG concentrations and the CHOL/HDL-CHOL ratio were positively correlated with femoral fat cell weight in men (r = .30, P < .05). To better investigate the relationships between the metabolic risk profile and hypertrophic subcutaneous obesity, individuals with small versus large subcutaneous abdominal adipocytes were matched according to VAT accumulation. Men with large abdominal fat cells displayed higher plasma TG and LDL-apo B levels compared with men characterized by small abdominal adipocytes (P < .05). Stepwise multiple regression analyses showed that subcutaneous abdominal fat cell weight was the best independent variable predicting plasma TG and LDL-apo B levels in men. No significant difference was found in the metabolic profile of subjects displaying small versus large femoral adipocytes. Taken together, these results suggest that for a given VAT deposition, the presence of hypertrophied subcutaneous abdominal adipocytes in men appears to be associated with further deterioration in the metabolic risk profile. On the other hand, the hypertrophy of femoral adipocytes does not further alter the metabolic complications generally related to obesity in both men and women.