Small VLDL Research Articles

Diets containing barley significantly reduce lipids in mildly hypercholesterolemic men and women

Barley has high amounts of soluble fiber but is not extensively consumed in the US diet. This study investigated whether consumption of barley would reduce cardiovascular disease risk factors comparably with that of other sources of soluble fiber. Mildly hypercholesterolemic subjects (9 postmenopausal women, 9 premenopausal women, and 7 men) consumed controlled American Heart Association Step 1 diets for 17 wk. After a 2-wk adaptation period, whole-grain foods containing 0, 3, or 6 g beta-glucan/d from barley were included in the Step 1 diet menus. Diets were consumed for 5 wk each and were fed in a Latin-square design. Fasting blood samples were collected twice weekly. Total cholesterol was significantly lower when the diet contained 3 or 6 g beta-glucan/d from barley than when it contained no beta-glucan; the greatest change occurred in the men and postmenopausal women. HDL and triacylglycerol concentrations did not differ with the 3 amounts of dietary beta-glucan. Large LDL and small VLDL fractions and mean LDL particle size significantly decreased when whole grains were incorporated into the 3 diets. Large LDL and large and intermediate HDL fractions were significantly higher, mean LDL particle size was significantly greater, and intermediate VLDL fractions were significantly lower in the postmenopausal women than in the other 2 groups. A group-by-diet interaction effect was observed on LDL fractions and small LDL particle size. The addition of barley to a healthy diet may be effective in lowering total and LDL cholesterol in both men and women.

Fish Consumption Shifts Lipoprotein Subfractions to a Less Atherogenic Pattern in Humans

The effect of fish consumption on plasma lipoprotein subfraction concentrations was studied in 22 men and women (age > 40 y). Subjects were provided an average American diet (AAD, 35% of energy as fat, 14% as saturated fat, and 35 mg cholesterol/MJ) for 6 wk before being assigned to a National Cholesterol Education Program (NCEP) Step 2 high-fish diet (n = 11, 26% of energy as fat, 4.5% as saturated fat, and 15 mg cholesterol/MJ) or a NCEP Step 2 low-fish diet (n = 11, 26% of energy as fat, 4.0% as saturated fat, and 11 mg cholesterol/MJ) for 24 wk. All food and drink were provided to study participants. Consumption of the high-fish NCEP Step 2 diet was associated with a significant reduction in medium and small VLDL, compared with the AAD diet, whereas the low-fish diet did not affect VLDL subfractions. Both diets significantly reduced LDL cholesterol concentrations, without modifying LDL subfractions. Both diets also lowered HDL cholesterol concentrations. However, the high-fish diet significantly lowered only the HDL fraction containing both apolipoprotein (apo) AI and AII (LpAI:AII) and did not change HDL subfractions assessed by NMR, whereas the low-fish diet significantly lowered the HDL fraction containing only apo AI (LpAI) and the large NMR HDL fractions, resulting in a significant reduction in HDL particle size. Neither diet affected VLDL and LDL particle size. Our data indicate that within the context of a diet restricted in fat and cholesterol, a higher fish content favorably affects VLDL and HDL subspecies.

Effects of pravastatin on lipoproteins and endothelial function in patients receiving human immunodeficiency virus protease inhibitors

Background Although recommended as initial therapy for patients with dyslipidemia who are taking human immunodeficiency virus protease inhibitors (HIV PIs), the effects of pravastatin on lipoproteins and arterial reactivity have not been elucidated. The purpose of this study was to determine the effects of pravastatin on lipoprotein subfractions and endothelial function in patients with dyslipidemia who are receiving HIV PIs. Methods This was a placebo-controlled, double-blind, crossover study comparing pravastatin (40 mg) to placebo in 20 patients who were taking HIV PIs. Lipoprotein subfractions were measured with nuclear magnetic resonance spectroscopic analysis. Flow-mediated vasodilation (FMD) of the brachial artery was evaluated with high-resolution ultrasound scanning. Results At baseline, subjects had an increased concentration of low-density lipoprotein (LDL) particles (1756 ± 180 nmol/L), which tended to be small (19.9 ± 0.2 nm), a low concentration of large high-density lipoproteins (HDL; 0.94 ± 0.07 mmol/L), and an increased concentration of large very low-density lipoproteins (VLDL; 1.90 ± 0.58 mmol/L). FMD was impaired (4.5% ± 1.1%). Compared with placebo, pravastatin resulted in a 20.8% reduction in LDL particles ( P = .030), a 26.7% reduction in small LDL ( P = .100), and a 44.9% reduction in small VLDL ( P = .023). Total and non-HDL cholesterol levels decreased by 18.3% ( P <.001) and 21.7% ( P <.001), respectively. FMD tended to increase in patients receiving pravastatin (0.7% ± 0.6%); however, the difference between treatment phases was not statistically significant ( P = .080). Conclusions This is the first double-blind, placebo-controlled study of the effects of statin therapy on lipids, lipoprotein subfractions, and endothelial function in patients taking HIV PIs. Pravastatin reduced concentrations of atherogenic lipoproteins, particularly those most associated with future coronary events.

Diabetic retinopathy and serum lipoprotein subclasses in the DCCT/EDIC cohort.

To determine associations between retinopathy status and detailed serum lipoprotein subclass profiles in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study (DCCT/EDIC) cohort. Persons with type 1 diabetes (440 women, 548 men) from the DCCT/EDIC cohort were studied. Retinopathy was characterized by Early Treatment Diabetic Retinopathy Study (ETDRS) scores, hard exudate scores, and ETDRS scores minus the hard exudate component. Lipoproteins were characterized by conventional lipid profile, nuclear magnetic resonance lipoprotein subclass profile (NMR-LSP), apoA1, apoB, lipoprotein(a), and susceptibility of LDL to oxidation. Data were analyzed with and without the following covariates: age, gender, duration of diabetes, HbA(1c), albumin excretion rate (AER), creatinine clearance, hypertension, body mass index, waist-hip ratio, DCCT treatment group, smoking status. The severity of retinopathy was positively associated with triglycerides (combined cohort) and negatively associated with HDL cholesterol (men, combined cohort). NMR-LSP identified retinopathy as being positively associated with small and medium VLDL and negatively with VLDL size. In men only, retinopathy was positively associated with small LDL, LDL particle concentration, apoB concentration, and small HDL and was negatively associated with large LDL, LDL size, large HDL, and HDL size. No associations were found with apoA1, Lp(a), or susceptibility of LDL to oxidation. All three measures of retinopathy revealed the same associations. NMR-LSP reveals new associations between serum lipoproteins and severity of retinopathy in type 1 diabetes. The data are consistent with a role for dyslipoproteinemia involving lipoprotein subclasses in the pathogenesis of diabetic retinopathy.

Serum lipoproteins in the diabetes control and complications trial/epidemiology of diabetes intervention and complications cohort: associations with gender and glycemia.

To relate the nuclear magnetic resonance (NMR)-determined lipoprotein profile, conventional lipid and apolipoprotein measures, and in vitro oxidizibility of LDL with gender and glycemia in type 1 diabetes. In the 1997-1999 Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications (DCCT/EDIC) cohort, serum from 428 women and 540 men were characterized by conventional lipids, NMR, apolipoprotein levels, and LDL susceptibility to in vitro oxidation. Simple and partial correlation coefficients were calculated for each lipoprotein-related parameter versus gender, with and without covariates (age, diabetes duration, concurrent HbA(1c), DCCT randomization, hypertension, BMI, waist-to-hip ratio, and albuminuria). For concurrent HbA(1c), data were analyzed as above, exchanging gender for HbA(1c). Associations were significant if P < 0.05. Although men and women had similar total and LDL cholesterol and triglycerides, men exhibited the following significant percent differences in NMR profiles versus women: small VLDL 41; IDL -30; medium LDL 39; small LDL 21; large HDL -32; small HDL 35; LDL particle concentration 4; VLDL and HDL diameters -8 and -4, respectively. Small VLDL, small HDL, medium LDL (women only), small LDL (men only), and LDL particle concentration were positively correlated, and HDL size was inversely correlated, with concurrent HbA(1c). NMR profile was unrelated to prior DCCT randomization. Susceptibility of LDL to oxidation was unrelated to gender and glycemia. Male gender and poor glycemia are associated with a potentially more atherogenic NMR lipoprotein profile. Neither gender nor glycemia influence LDL oxidation in vitro.

Hypertriglyceridemia but not diabetes status is associated with VLDL containing apolipoprotein CIII in patients with coronary heart disease

High apoCIII concentration in apoB lipoproteins is a prominent component of atherogenic dyslipidemia, and explains the risk of coronary heart disease (CHD) associated with high triglyceride (TG). We hypothesized that diabetic people have atherogenic dyslipidemia with apoCIII in excess of that accounted for by their high TG levels. We selected 30 diabetic and 30 nondiabetic persons, 15 of each with fasting TG<160 mg/dl and 15 with TG≥200 mg/dl. Using immunoaffinity chromatography and ultracentrifugation, we prepared large and small VLDL, IDL and LDL with or without apoCIII or apoE. The groups with TG≥200 mg/dl, regardless of diabetes status, had higher concentrations of large and small VLDL particles with apoCIII and higher apoCIII concentrations than the groups with fasting TG<160 mg/dl. The diabetes groups did not have higher concentrations of these lipoproteins than the nondiabetes groups within the same fasting TG criteria. In conclusion, high concentrations of apoCIII-containing VLDL are associated with hypertriglyceridemia, which may play a critical role in identifying the high risk of CHD in hypertriglyceridemic patients whether diabetic or nondiabetic. Diabetes status per se does not appear to be associated with high concentrations of apoCIII-containing TG-rich lipoprotein particles, if the plasma TG levels are similar.

The effect of atorvastatin on serum lipids, lipoproteins and NMR spectroscopy defined lipoprotein subclasses in type 2 diabetic patients with ischaemic heart disease

The effect of statin therapy on subclasses of LDL, VLDL and HDL lipoproteins is unclear. We compared changes in serum lipids, apolipoproteins and nuclear magnetic resonance (NMR) spectroscopy measured lipoprotein subclass concentration and average particle size over a minimum 6 months treatment period of atorvastatin 10 mg vs. placebo in 122 men and women. All subjects had type 2 diabetes and a modest dyslipidaemia (mean LDL-cholesterol 3.2 mmol/l and median triglycerides 1.8 mmol/l) and had a previous myocardial infarction. Compared with placebo, atorvastatin therapy was associated with a greater decrease in medium VLDL (median within person change −13.4 vs. −5.9 nmol/l, P<0.001 adjusted for baseline level), small VLDL (median change −17.8 vs. −8.1 nmol/l, P=0.002), large LDL (mean within person change −167.9 vs. −48.6 nmol/l, P<0.001) and medium LDL (median within person change −101.8 vs. −22.3 nmol/l, P=0.017). Atorvastatin therapy was also associated with a greater increase in large HDL than placebo (median change 1.40 vs. 0.80 μmol/l, P=0.02) and there was little change in small HDL so that average HDL particle size increased significantly with atorvastatin ( P=0.04). In addition to reducing levels of (enzymatically measured) triglyceride, LDL-cholesterol and apolipoprotein B in diabetic patients, atorvastatin significantly reduces NMR measured medium and small VLDL and large and medium LDL, and increases large HDL.

Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance.

The insulin resistance syndrome (IRS) is associated with dyslipidemia and increased cardiovascular disease risk. A novel method for detailed analyses of lipoprotein subclass sizes and particle concentrations that uses nuclear magnetic resonance (NMR) of whole sera has become available. To define the effects of insulin resistance, we measured dyslipidemia using both NMR lipoprotein subclass analysis and conventional lipid panel, and insulin sensitivity as the maximal glucose disposal rate (GDR) during hyperinsulinemic clamps in 56 insulin sensitive (IS; mean +/- SD: GDR 15.8 +/- 2.0 mg. kg(-1). min(-1), fasting blood glucose [FBG] 4.7 +/- 0.3 mmol/l, BMI 26 +/- 5), 46 insulin resistant (IR; GDR 10.2 +/- 1.9, FBG 4.9 +/- 0.5, BMI 29 +/- 5), and 46 untreated subjects with type 2 diabetes (GDR 7.4 +/- 2.8, FBG 10.8 +/- 3.7, BMI 30 +/- 5). In the group as a whole, regression analyses with GDR showed that progressive insulin resistance was associated with an increase in VLDL size (r = -0.40) and an increase in large VLDL particle concentrations (r = -0.42), a decrease in LDL size (r = 0.42) as a result of a marked increase in small LDL particles (r = -0.34) and reduced large LDL (r = 0.34), an overall increase in the number of LDL particles (r = -0.44), and a decrease in HDL size (r = 0.41) as a result of depletion of large HDL particles (r = 0.38) and a modest increase in small HDL (r = -0.21; all P < 0.01). These correlations were also evident when only normoglycemic individuals were included in the analyses (i.e., IS + IR but no diabetes), and persisted in multiple regression analyses adjusting for age, BMI, sex, and race. Discontinuous analyses were also performed. When compared with IS, the IR and diabetes subgroups exhibited a two- to threefold increase in large VLDL particle concentrations (no change in medium or small VLDL), which produced an increase in serum triglycerides; a decrease in LDL size as a result of an increase in small and a reduction in large LDL subclasses, plus an increase in overall LDL particle concentration, which together led to no difference (IS versus IR) or a minimal difference (IS versus diabetes) in LDL cholesterol; and a decrease in large cardioprotective HDL combined with an increase in the small HDL subclass such that there was no net significant difference in HDL cholesterol. We conclude that 1) insulin resistance had profound effects on lipoprotein size and subclass particle concentrations for VLDL, LDL, and HDL when measured by NMR; 2) in type 2 diabetes, the lipoprotein subclass alterations are moderately exacerbated but can be attributed primarily to the underlying insulin resistance; and 3) these insulin resistance-induced changes in the NMR lipoprotein subclass profile predictably increase risk of cardiovascular disease but were not fully apparent in the conventional lipid panel. It will be important to study whether NMR lipoprotein subclass parameters can be used to manage risk more effectively and prevent cardiovascular disease in patients with the IRS.

Non-denaturing polyacrylamide gradient gel electrophoresis for the diagnosis of dysbetalipoproteinemia

Dysbetalipoproteinemia, an uncommon but highly atherogenic mixed hyperlipidemia due to the accumulation of remnants of triglyceride-rich lipoproteins, is characterized by cholesterol-enriched VLDL that migrates in the beta-position on agarose gels. The demonstration of a broad beta-band on agarose gel electrophoresis of plasma is an insensitive method and ultracentrifugation is an impractical method of diagnosing this condition. Non-denaturing polyacrylamide gradient gel electrophoresis (PGGE) was investigated as a screening method for the diagnosis of dysbetalipoproteinemia. A minigel procedure separating the Sudan Black prestained apolipoprotein B (apoB)-containing lipoproteins on a 2-8% polyacrylamide gel at 4 degrees C overnight was analyzed for ultracentrifugally and genetically proven dysbetalipoproteinemic subjects as well as matched controls for mixed hyperlipidemia. Visual inspection revealed that the presence of only small VLDL- and IDL-like particles in untreated patients was highly sensitive (72%) and specific (95%) for dysbetalipoproteinemia. Videodensitometric analysis of area under the curve for large and small VLDL, as well as IDL and LDL, permitted even better discrimination in subjects whose profiles included some staining in the LDL-like region. A ratio of area under the curve of more than 0.5 for IDL-LDL allowed for a specificity of 100% and a sensitivity of 89% for the diagnosis of dysbetalipoproteinemia. This modified PGGE system may be useful in screening for dysbetalipoproteinemia.

Differential Reactivity of Two Homogeneous LDL-Cholesterol Methods to LDL and VLDL Subfractions, as Demonstrated by Ultracentrifugation and HPLC

The analytical and clinical performance of homogeneous LDL-cholesterol assays has been reported, but their reactions with subfractions of LDL and VLDL have not been described in detail. We evaluated reaction selectivity of two homogeneous LDL-cholesterol assays, LDLk (Kyowa Medex) and LDLd (Daiichi Pure Chemical), with ultracentrifugally isolated VLDL and LDL subfractions to identify the lipoprotein particles from which the cholesterol recognized by these assays originates. The LDLd (y) and LDLk (x) methods correlated highly for whole serum samples: y = 0.986x - 39.5 mg/L (r = 0.966; n = 34). In isolated VLDL, the LDLk and the LDLd methods recovered 17.3% and 23.8% of cholesterol, respectively; but correlation analysis revealed differential reactivity to small and large VLDL particles. For the isolated LDL subfraction of density 1.019-1.040 kg/L, the LDLd method had significantly higher reactivity (95.6-98.7%) than the LDLk (88.4-92.0%). Both methods, however, demonstrated poor recovery (approximately 50%) for the 1.050-1.063 kg/L fraction, indicating incomplete reactivity with small, dense LDL. Reactivity with lipoprotein(a) was better (71.2-90.8%) for both methods than with small LDL. For intermediate-density lipoprotein (IDL), there was no significant difference in recovery between the two methods (71.7% for LDLk and 68.9% for LDLd), but the LDLk method appeared to be more sensitive to IDL particle size. The two homogeneous assays for LDL-cholesterol demonstrate only partial reactivity to small, dense LDL and nonspecific reactions to VLDL particles. Modification will be required in the homogeneous methods to obtain LDL-cholesterol values equivalent to those obtained by ultracentrifugation.

Differences in the relation of obesity to serum triacylglycerol and VLDL subclass concentrations between black and white children: the Bogalusa Heart Study

Obese children and adults, particularly those with abdominal obesity, have an elevated serum triacylglycerol concentration. Furthermore, triacylglycerol concentrations are generally higher in whites than in blacks, and the relation of obesity to triacylglycerol concentrations may be stronger in whites. However, there is little information on the relation of obesity to the metabolically distinct subclasses of VLDL in children. The objective was to examine possible differences between blacks (n = 367) and whites (n = 549) in mean concentrations of triacylglycerols, in mean concentrations of small and large VLDL, and in the relation of waist circumference to concentrations of triacylglycerol and VLDL subclasses. We measured VLDL subclass concentrations and assessed the relation of various obesity indexes to triacylglycerols in a cross-sectional study of 10- to 17-y-olds. The mean triacylglycerol concentration was 0.3 mmol/L (25 mg/dL) higher in white than in black children, primarily because of a 0.2-mmol/L (140%) difference in mean concentrations of large VLDL. In contrast, the mean concentrations of small VLDL differed by only 0.05 mmol/L (29%). In addition, the relations of waist girth to concentrations of triacylglycerol and large VLDL were 2- to 6-fold stronger among white children than among black children. Although white children had higher concentrations of large VLDL than did black children, this difference increased from 0.1 to 0.4 mmol/L across quintiles of waist circumference. Waist circumference was not significantly related to concentrations of small VLDL. These contrasting associations with obesity, which differ between white and black children, suggest that information on VLDL subclasses could provide additional information on the risk of obesity-related ischemic heart disease.

Comparison of apolipoprotein B metabolism in familial defective apolipoprotein B and heterogeneous familial hypercholesterolemia

Both defective LDL receptors (familial hypercholesterolaemia, FH) and mutations in apolipoprotein B (apoB) on LDL (familial defective apoB, FDB) give rise to a phenotype of elevated LDL cholesterol. We sought to compare the metabolic basis of the two conditions by examining apoB turnover in FDB and FH subjects. A group comprising three heterozygous and one homozygous FDB subjects were compared with five FH heterozygotes and 17 control subjects using a deuterated leucine tracer. Kinetic parameters were derived by multicompartmental modelling. FH heterozygotes had a reduced delipidation rate for VLDL, which led to a moderate increase in plasma triglyceride. Compared with controls and FH, the FDB subjects converted 44% less IDL to LDL. The LDL FCR was reduced to a similar extent in FDB and FH. In all subjects LDL plasma levels appeared to be regulated by the LDL FCR and the rate of production of small VLDL. We conclude that disturbances in IDL metabolism provide the basis for understanding why FDB is less severe than FH. Our findings suggest that an apoB-LDL receptor interaction is important in the IDL to LDL conversion.

Postprandial changes of apoB-100 and apoB-48 in TG rich lipoproteins in familial combined hyperlipidemia

Impaired chylomicron (chylo) remnant clearance and small VLDL overproduction are major metabolic abnormalities in familial combined hyperlipidemia (FCHL). Quantitative data on postprandial apolipoprotein B-48 (apoB-48) and apolipoprotein B-100 (apoB-100) in TG rich lipoproteins (TRL) in FCHL have not been reported before. Eight untreated FCHL patients and 10 matched controls underwent a 24 h oral fat load. Fasting apoB-48 and apoB-100 were significantly higher in all TRL in FCHL. Maximal concentrations of chylo-[Svedberg's flotation rate (Sf) >400] apoB-48 and apoB-100 were reached later in FCHL (at t = 6 h), in contrast to controls (t = 4 h). Maximal VLDL1-(Sf60–400)-apoB-48 occurred at the same time point (t = 2 h) in both, whereas VLDL1-apoB-100 was maximal at t = 4 h in both, most likely representing delayed VLDL clearance by preferential clearance of chylo and their remnants by competition for the same clearance mechanisms. VLDL2-(Sf20–60)-apoB-48 and VLDL2-apoB-100 decreased in FCHL, in contrast to an increase of apoB-48, and no change of apoB-100 in controls, suggesting impaired conversion of VLDL1-apoB-48 into VLDL2-apoB-48 in FCHL, and partly also of VLDL1-apoB-100. In conclusion, in FCHL clearance of large postprandial Sf >400 apoB-48 and apoB-100 TRL is delayed. ApoB-100 accumulates in the VLDL1 range postprandially in both FCHL and controls, reaching higher levels in FCHL and thereby conferring a higher atherogenic burden in the postprandial situation in FCHL.—Verseyden, C., S. Meijssen, and M. Castro Cabezas. Postprandial changes of apoB-100 and apoB-48 in TG rich lipoproteins in familial combined hyperlipidemia.

Association of the A/T54 polymorphism in the intestinal fatty acid binding protein with variations in plasma lipids in The Framingham Offspring Study

We investigated the potential role of the genetic variation at the intestinal fatty acid binding protein gene ( FABP2) in influencing lipid levels in a representative sample of the Framingham Offspring Study participants ( n=1930). In men, the T54 allele was associated with significantly higher LDL-cholesterol (3.47±0.83 vs 3.36±0.83 mmol/l; P<0.047), and ApoB (1.04±0.23 vs 1.01±0.24 g/l; P<0.020) after adjustment for familial relationship, age, BMI, smoking, alcohol intake and the use of beta-blockers compared with the A54 allele. This relationship with ApoB continued to be significant after adjustment for APOE genotype ( P<0.034). In women, the T54 allele was associated with significantly higher total-cholesterol (5.32±1.01 vs 5.17±0.98 mmol/l; P<0.049) and LDL-cholesterol (3.31±0.93 vs 3.18±0.85 mmol/l; P<0.023) after adjustment for covariates and menopausal status, estrogen therapy and APOE genotype. In men, the T54 allele was associated with significantly higher levels of small VLDL and lower levels of large HDL. Moreover, there was no significant relationship between FABP2 alleles and lipoprotein diameter or the prevalence of coronary heart disease in both genders. Our data are consistent with the T54 IFABP increasing the flux of lipids through the enterocyte leading to an increase in chylomicron secretion.

The changes of fibrinogen and lipoprotein a levels after six months treatment with statins

It has been suggested that the postprandial elevation of plasma triglycerides is more closely linked to coronary heart disease (CHD) than the fasting triglyceride level. However, the postprandial situation is complex, as hepatogenous triglyceride-rich lipoprotein (TRL) particles (apolipoprotein [apo]B-100 and very—low-density lipoprotein [VLDL]) are mixed in the blood with apoB-48—containing lipoproteins secreted from the intestine. To analyze the relative proportion of liver-derived and intestinal apoB-containing TRL in subjects with and without CHD, we performed standardized oral fat-loading tests in young survivors of myocardial infarction, a large proportion of whom are hypertriglyceridemic (HTG), as well as sex- and population-matched healthy control subjects. A special effort was made to recruit healthy HTG subjects as controls for the HTG patients. Fasting plasma triglycerides (3.74 ± 1.35 v 3.01 ± 0.83, NS), low-density lipoprotein (LDL) cholesterol, and VLDL lipids, and apoB-100 and apoB-48 content at Svedberg flotation rate (Sf) 60–400, Sf 20–60, and Sf 12–20 did not differ between HTG patients (n = 10) and HTG controls (n = 14). Normotriglyceridemic (NTG) patients (n = 15) had higher fasting plasma triglycerides (1.44 ± 0.39 v 0.98 ± 0.33 mmol/L, P < .05) and LDL cholesterol (4.07 ± 0.71 v 3.43 ± 0.64, P < .05) than NTG controls (n = 34). The triglyceride elevation was accounted for by a higher level of small VLDL (apoB-100 in the Sf 20–60 fraction, 52 ± 17 v 29 ± 20 mg/L, P < .05). HTG patients responded with clearly elevated plasma triglycerides in the late postprandial phase, ie, 7, 8, and 9 hours after fat intake. Essentially, this was explained by a retention of large VLDL particles, since HTG patients exhibited no major differences in apoB-48 concentrations in the Sf > 400, Sf 60–400, and Sf 20–60 fractions but showed marked differences in the level of apoB-100 at Sf 60–400 (large VLDL) 9 hours after fat intake when compared with HTG controls (101 ± 13 v 57 ± 5 mg/L, P < .01). NTG patients were characterized by a more rapid increase of large VLDL in the early postprandial state, ie, 3 hours after fat intake, with a mean increase from baseline to 3 hours of 24.1 ± 6.7 mg/L for NTG patients and 11.8 ± 2.0 mg/L for controls (P < .05). ApoB-48 levels were also slightly higher, but all TRL parameters returned to baseline within 9 hours after fat intake. In conclusion, elevated triglyceride levels in the postprandial state in CHD patients are explained to a large extent by the accumulation of endogenous TRL. This suggests that the postprandial dyslipidemia encountered in CHD is more dependent on a failure of regulation of endogenous TRL versus the exogenous TRL species.

A High Carbohydrate versus a High Monounsaturated Fatty Acid Diet Lowers the Atherogenic Potential of Big VLDL Particles in Patients with Type 1 Diabetes

The objective of the present study was to compare the effects of two diets on the atherogenic potential of two VLDL subfractions harvested from fasting subjects by measuring the number and composition of particles and the amount of esterified cholesterol accumulated in macrophages. A high (25%) monounsaturated fatty acid (Mono) diet and a high (61%) carbohydrate (CHO) diet were provided for 4 wk in a randomized crossover design to 19 normolipidemic, nonobese patients with type 1 diabetes. The two diets were matched for protein, polyunsaturated/saturated fatty acids, cholesterol and fiber content. The number of circulating big VLDL (S:(f) 100-400) particles was greater during the high Mono than during the high CHO diet based on the levels of apolipoprotein B (means +/- SEM): 31.4 +/- 7.4 versus 20.0 +/- 3.8 mg/L (P: < 0.025, paired t test). The following variables did not differ during the diet periods: number of small VLDL (S:(f) 20-100) particles, esterified cholesterol accumulated in THP-1 macrophages incubated with the same number of big and small VLDL particles and particle composition. We conclude that a high CHO diet might be preferable to a high Mono diet, on the basis of the premise that more big VLDL particles could increase the atherosclerotic risk in patients with diabetes.

Apolipoprotein C-III displacement of apolipoprotein E from VLDL: effect of particle size

ApoC-III and apoE are important determinants of intravascular lipolysis and clearance of triglyceride-rich chylomicrons and VLDL from the blood plasma. Interactions of these two apolipoproteins were studied by adding purified human apoC-III to human plasma at levels observed in hypertriglyceridemic subjects and incubating under specific conditions (2 h, 37 degrees C). As plasma concentrations of apoC-III protein were increased, the contents in both VLDL and HDL were also increased. Addition of apoC-III at concentrations up to four times the intrinsic concentration resulted in the decreasing incremental binding of apoC-III to VLDL while HDL bound increasing amounts without evidence of saturation. No changes were found in lipid content or in particle size of any lipoprotein in these experiments. However, distribution of the intrinsic apoE in different lipoprotein particles changed markedly with displacement of apoE from VLDL to HDL. The fraction of VLDL apoE that was displaced from VLDL to HDL at these high apoC-III concentrations varied among individuals from 20% to 100% its intrinsic level. The proportion of VLDL apoE that was tightly bound (0% to 80%) was found to be reproducible and to correlate with several indices of VLDL particle size. In the group of subjects studied, strongly adherent apoE was essentially absent from VLDL particles having an average content of less than 50,000 molecules of triglyceride. Addition of apoC-III to plasma almost completely displaces apoE from small VLDL particles. Larger VLDL contain tightly bound apoE which are not displaced by increasing concentration of apoC-III.

Overexpression of human hepatic lipase and ApoE in transgenic rabbits attenuates response to dietary cholesterol and alters lipoprotein subclass distributions.

The effect of the expression of human hepatic lipase (HL) or human apoE on plasma lipoproteins in transgenic rabbits in response to dietary cholesterol was compared with the response of nontransgenic control rabbits. Supplementation of a chow diet with 0.3% cholesterol and 3.0% soybean oil for 10 weeks resulted in markedly increased levels of plasma cholesterol and VLDL and IDL in control rabbits as expected. Expression of either HL or apoE reduced plasma cholesterol response by 75% and 60%, respectively. The HL transgenic rabbits had substantial reductions in medium and small VLDL and IDL fractions but not in larger VLDL. LDL levels were also reduced, with a shift from larger, more buoyant to smaller, denser particles. In contrast, apoE transgenic rabbits had a marked reduction in the levels of large VLDLs, with a selective accumulation of IDLs and large buoyant LDLs. Combined expression of apoE and HL led to dramatic reductions of total cholesterol (85% versus controls) and of total VLDL+IDL+LDL (87% versus controls). HDL subclasses were remodeled by the expression of either transgene and accompanied by a decrease in HDL cholesterol compared with controls. HL expression reduced all subclasses except for HDL2b and HDL2a, and expression of apoE reduced large HDL1 and HDL2b. Extreme HDL reductions (92% versus controls) were observed in the combined HL+apoE transgenic rabbits. These results demonstrate that human HL and apoE have complementary and synergistic functions in plasma cholesterol and lipoprotein metabolism.

Differences in postprandial concentrations of very—low-density lipoprotein and chylomicron remnants between normotriglyceridemic and hypertriglyceridemic men with and without coronary heart disease

It has been suggested that the postprandial elevation of plasma triglycerides is more closely linked to coronary heart disease (CHD) than the fasting triglyceride level. However, the postprandial situation is complex, as hepatogenous triglyceride-rich lipoprotein (TRL) particles (apolipoprotein [apo]B-100 and very—low-density lipoprotein [VLDL]) are mixed in the blood with apoB-48—containing lipoproteins secreted from the intestine. To analyze the relative proportion of liver-derived and intestinal apoB-containing TRL in subjects with and without CHD, we performed standardized oral fat-loading tests in young survivors of myocardial infarction, a large proportion of whom are hypertriglyceridemic (HTG), as well as sex- and population-matched healthy control subjects. A special effort was made to recruit healthy HTG subjects as controls for the HTG patients. Fasting plasma triglycerides (3.74 ± 1.35 v 3.01 ± 0.83, NS), low-density lipoprotein (LDL) cholesterol, and VLDL lipids, and apoB-100 and apoB-48 content at Svedberg flotation rate (Sf) 60–400, Sf 20–60, and Sf 12–20 did not differ between HTG patients (n = 10) and HTG controls (n = 14). Normotriglyceridemic (NTG) patients (n = 15) had higher fasting plasma triglycerides (1.44 ± 0.39 v 0.98 ± 0.33 mmol/L, P < .05) and LDL cholesterol (4.07 ± 0.71 v 3.43 ± 0.64, P < .05) than NTG controls (n = 34). The triglyceride elevation was accounted for by a higher level of small VLDL (apoB-100 in the Sf 20–60 fraction, 52 ± 17 v 29 ± 20 mg/L, P < .05). HTG patients responded with clearly elevated plasma triglycerides in the late postprandial phase, ie, 7, 8, and 9 hours after fat intake. Essentially, this was explained by a retention of large VLDL particles, since HTG patients exhibited no major differences in apoB-48 concentrations in the Sf > 400, Sf 60–400, and Sf 20–60 fractions but showed marked differences in the level of apoB-100 at Sf 60–400 (large VLDL) 9 hours after fat intake when compared with HTG controls (101 ± 13 v 57 ± 5 mg/L, P < .01). NTG patients were characterized by a more rapid increase of large VLDL in the early postprandial state, ie, 3 hours after fat intake, with a mean increase from baseline to 3 hours of 24.1 ± 6.7 mg/L for NTG patients and 11.8 ± 2.0 mg/L for controls ( P < .05). ApoB-48 levels were also slightly higher, but all TRL parameters returned to baseline within 9 hours after fat intake. In conclusion, elevated triglyceride levels in the postprandial state in CHD patients are explained to a large extent by the accumulation of endogenous TRL. This suggests that the postprandial dyslipidemia encountered in CHD is more dependent on a failure of regulation of endogenous TRL versus the exogenous TRL species.

Effects of estrogenic oral contraceptives on the lipoprotein B particle system defined by apolipoproteins E and C-III content

Apolipoproteins E and C-III are modulators of lipoprotein metabolism that could affect development of atherosclerosis. The prevalence in plasma of apoB-containing particles (LpB) that contain either apoE or apoC-III, both or neither, and the effect of estrogen on these lipoproteins are unknown. The LpB particle system, defined by the presence or absence of apoE or C-III, was studied in 13 normolipidemic women, 7 nonusers and 6 users of oral contraceptives. Fasting plasma was separated by anti-apoE and C-III affinity chromatography and ultracentrifugation into four types of VLDL, IDL, and LDL particles: with apoE but not apoC-III (E+C−), apoC-III but not apoE (E−C+), both (E+C+) or neither (E−C−). The predominant VLDL particles were E−C− (42% in nonusers, 56% in users) and E+C+ (39% in nonusers, 24% in users), suggesting that apoE and apoC-III mainly exist together in VLDL. In IDL, E−C− was the major fraction (74% nonusers, 81% users), and in LDL, it was 99% in both groups. The triglycerides in VLDL and IDL were mainly contained in C+ particles (79% and 66% of the total VLDL and IDL triglycerides, respectively). Within VLDL, IDL, and LDL, E−C− particles had the smallest size and E+C+ or E−C+ the largest. Users had higher concentrations of VLDL E−C− (280%) and IDL E−C− (90%) particles than nonusers. They also had higher free cholesterol and cholesteryl ester concentrations associated with these fractions and with VLDL E−C+. The triglyceride contents of VLDL E−C− particles were lower in users of oral contraceptives than in nonusers. This study demonstrates that the elevated VLDL TG concentrations in users of estrogen-dominant oral contraceptives is mainly caused by an increased concentration of small VLDL particles that have reduced TG content, and that do not have apoE and C-III. These particles may have lower atherogenicity than particles enriched with apoE and C-III.—Khoo, C., H. Campos, H. Judge, and F. M. Sacks. Effects of estrogenic oral contraceptives on the lipoprotein B particle system defined by apolipoproteins E and C-III content. J. Lipid Res. 1999. 40: 202–212.