Combined Hyperlipidemic Subjects Research Articles

The spectrum of type III hyperlipoproteinemia

Type III hyperlipoproteinemia is a highly atherogenic dyslipoproteinemia characterized by hypercholesterolemia and hypertriglyceridemia due to markedly increased numbers of cholesterol-enriched chylomicron and very-low-density lipoprotein (VLDL) remnant lipoprotein particles. Type III can be distinguished from mixed hyperlipidemia based on a simple diagnostic algorithm, which involves total cholesterol, triglycerides, and apolipoprotein B (apoB). However, apoB is not measured routinely. The objective of the present study was to determine if patients with type III could be distinguished from mixed hyperlipidemia based on lipoprotein lipids. Classification was based first on total cholesterol and triglyceride and then on the apoB diagnostic algorithm using apoB plus total cholesterol plus triglycerides, and validated by sequential ultracentrifugation. Four hundred and forty normals, 637 patients with hypertriglyceridemia, and 714 with hypertriglyceridemia and hypercholesterolemia were studied. Plasma lipoproteins were separated by sequential ultracentrifugation and heparin-manganese precipitation. Cholesterol, triglyceride, and apoB were measured in plasma and isolated lipoprotein fractions. Of the 1351 patients with hypertriglyceridemia, 49 had type III hyperlipoproteinemia, as diagnosed by the apoB algorithm and validated by ultracentrifugation. Plasma triglycerides were higher in the type III subjects: 4.16mmol/L (3.35-6.08, 25th-75th percentile), but there was considerable overlap with the hypertriglyceridemic subjects 2.65mmol/L (1.91-4.20, 25th-75th percentile) and the combined hyperlipidemic subjects 3.02mmol/L (2.07-5.32, 25th-75th percentile). Similarly, total cholesterol was 4.79mmol/L (4.31-5.58, 25th-75th percentile) for type III vs 5.5 mmol/L (4.64-5.78, 25th-75th percentile) and 7.02 mmol/L (6.39-7.96, 25th-75th percentile), respectively. By contrast, as identified by the apoB algorithm, the VLDL-C/TG, VLDL-C/VLDL-TG, VLDL-C/VLDL apoB, and VLDL apoB/LDL apoB ratios were all higher in type III than in the other hypertriglyceridemic dyslipoproteinemias with the exception of type V as diagnosed by the apoB algorithm. Cholesterol and triglycerides cannot reliably distinguish type III hyperlipoproteinemia from mixed hyperlipidemia. Adding apoB and applying the apoB algorithm makes reliable diagnosis possible and easy. However, unless apoB is introduced into routine clinical care, type III hyperlipoproteinemia will often not be recognized. Given the cardiovascular risk associated with type III and its responsiveness to treatment, this should not be acceptable.

Reactive oxygen species generation in peripheral blood monocytes and oxidized LDL are increased in hyperlipidemic patients

Objectives Experimental and in vitro evidences have established that reactive oxygen species (ROS) generated by vascular wall cells play a key role in atherogenesis. Here, we evaluated the rate of ROS generation by resting peripheral monocytes in naive hyperlipidemic subjects. Design and methods Primary hypercholesterolemic, combined hyperlipidemic, and normolipidemic individuals were studied. ROS generation and the mitochondrial electrical transmembrane potential were estimated by flow cytometry. Plasma oxidized (ox) LDL levels and lipid profile were measured by ELISA and enzymatic colorimetric methods. Results Both hyperlipidemic groups presented significantly higher rates of monocyte ROS generation and elevated plasma levels of ox-LDL. Combined hyperlipidemic subjects presented increased levels of small dense LDL and insulin. Significant positive correlations between monocyte ROS generation and ox-LDL concentrations were found in pooled data. Conclusions These data provide evidence that ROS production by circulating monocytes from hyperlipidemic subjects may contribute to the systemic oxidative stress and possibly to atherogenesis.

One-Year Effects of Increasingly Fat-Restricted, Carbohydrate-Enriched Diets on Lipoprotein Levels in Free-Living Subjects

Abstract. Restriction of all dietary fat is a popular strategy for restricting saturated fat intake to lower LDL cholesterol. Some authorities advise the restriction of fat intake to the extreme of less than 10% of daily energy on the assumption that more fat restriction is better. The two studies described herein address questions relating to whether increasing fat restriction produces proportionally increasing benefit on cardiovascular risk factors in hyperlipidemic subjects.The first study is the Dietary Alternatives Study (DAS). The DAS was conducted in 531 male Boeing employees over a 2-year period. Subjects were defined as hypercholesterolemic (HC) or combined hyperlipidemic (CHL) based on age-specific 75th percentiles for plasma LDL-C and triglyceride levels. Hypothesis test analyses were performed at 1 year. HC subjects were randomized to diets taught to attain fat intakes of 30, 26, 22, and 18% (Diets levels 1–4, respectively). CHL subjects (slightly fewer in number) were randomized to Diets 1–3. After 1 year, subjects' total fat intakes were 27, 26, 25, and 22% of energy (en%), resulting in saturated fat intakes of 8, 7, 7, and 6%, respectively. In HC subjects the greatest LDL-C decrease was with Diet 2 (mean of 13.4%) and in CHL subjects with Diet 1 (7.0%). Surprisingly, plasma triglyceride concentrations rose in HC subjects 20% and 40% above baseline on Diets 3 and 4, respectively, with reciprocal reductions in HDL cholesterol of 2.5% and 3%, respectively. Furthermore, apo B reductions were attenuated below Diet 2 in HC subjects and Diet 1 in CHL subjects, and no further reductions were seen in plasma glucose and insulin concentrations, blood pressure, or body weight. Measurements of plasma total fatty acid composition showed a slight increase in plasma palmitate, whereas stearate decreased slightly, supporting the idea that de novo synthesis of palmitic acid was increased in the chronic high-carbohydrate feeding condition. The second study asked if the most effective diet in HC subjects, Diet 2, has an equivalent effect in women and men. To answer this question, men and women Boeing employees were taught the closely similar National Cholesterol Education Program (NCEP) Step II diet. After 6 and 12 months, equivalent reductions in LDL cholesterol were observed in women compared with men. HDL cholesterol levels in men were unchanged from baseline at 6 and 12 months, but were reduced 8% in HC women, with accompanying decreases of 18% in HDL2-cholesterol and 5% in apoprotein A-I (all P < 0.01). These data indicate that intakes of fat below about 25 en% and carbohydrate intake above ≈ 60 en% yield no further LDL-C lowering in HC and CHL male subjects and can be counterproductive to triglyceride, HDL-C, and apo B levels. This lack of benefit appears to be explained by an enhanced endogenous synthesis of palmitic acid, which negates the benefit of further saturated fat restriction. The HDL-C decrease in HC women may have a similar cause and points to an underlying male-female difference. Alternative dietary approaches to limit saturated fat intake deserve intensive study.

Alterations of high-density lipoprotein subclasses in hypercholesterolemia and combined hyperlipidemia

Background Alterations in plasma lipid levels can influence the composition, content, and distribution of plasma lipoprotein subclasses that effect atherosclerosis risk. Hypercholesterolemia and combined hyperlipidemia are common forms of atherogenic dyslipoproteinemia. This study evaluates the alterations of high-density lipoprotein (HDL) subclasses in hypercholesterolemic and combined hyperlipidemic subjects. Methods Apolipoprotein A-I contents of plasma HDL subclasses were quantitated by 2-dimensional gel electrophoresis in 242 normolipidemic subjects, 66 hypercholesterolemic subjects and 59 combined hyperlipidemic subjects. Results Compared with the normolipidemic subjects, apolipoprotein A-I contents of small-sized pre-β 1-HDL, HDL 3c, HDL 3band HDL 3awere significantly higher in both hypercholesterolemic subjects ( p < .01, p < .05, p < .01 and p < .05, respectively) and combined hyperlipidemic subjects ( p < .01, p < .05, p < .01 and p < .01, respectively). In contrast, apolipoprotein A-I contents of large-sized HDL 2a and HDL 2b were significantly lower in hypercholesterolemic subjects ( p < .05 and p < .01, respectively) as well as combined hyperlipidemic subjects ( p < .01 and p < .01, respectively). In addition, pre-β 1-HDL increased significantly ( p < .05) while HDL 2aand HDL 2b decreased significantly ( p < .05 and p < .01, respectively) in combined hyperlipidemic group versus hypercholesterolemic subjects. With the elevation of triglyceride levels, pre-β 1-HDL, and HDL 3a increased successively, however, HDL 2aand HDL 2b decreased successively in subjects with total cholesterol levels greater than 240 mg/dl. Conclusions The particle size of HDL shifted towards smaller size in hypercholesterolemic subjects, and that the shift was more prominent in combined hyperlipidemic subjects. The alternations mentioned above indicate that HDL maturation might be abnormal, and reverse cholesterol transport (RCT) might be weakened.

Identification of a Novel C5L2 Variant (S323I) in a French Canadian Family With Familial Combined Hyperlipemia

A functional acylation stimulating protein (ASP) receptor, C5L2, has been recently identified in ASP-responsive cells. Impaired ASP-mediated triglyceride synthesis has previously been described in a subset of hyperapolipoprotein B/familial combined hyperlipidemia subjects. DNA sequencing of C5L2 coding region in 61 unrelated probands identified a heterozygous variant (G968-->T) in 1 subject, resulting in Ser323-->Ile substitution in the carboxyl terminal region. This variant was not detected in 2176 additional chromosomes by restriction fragment length polymorphism or fluorescence polarization genotyping. Eight family members of the proband were identified with one altered (+/-)C5L2 allele. Nine other family members had the wild-type (+/+)C5L2 sequence. The abnormal allele was associated with increased plasma triglyceride, plasma cholesterol, low-density lipoprotein (LDL) cholesterol, apolipoprotein B and ASP. Of 23 subjects tested in cell-based ASP bioactivity assays, those with C5L2(+/-) variant (n = 2) had a 50% reduction in ASP-stimulated triglyceride synthesis, glucose transport and marked reduction in maximal binding (B(max)). By contrast, a C5L2(+/+) family member responded normally, as did hyperapolipoprotein B normal ASP subjects compared with C5L2(+/+) controls (n = 6). The S323I variant may alter C5L2 function and might be one molecular basis contributing to familial combined hyperlipidemia.

Postprandial triglyceride levels in familial combined hyperlipidemia. The role of apolipoprotein E and lipoprotein lipase polymorphisms

The effect of apolipoprotein E genotype and polymorphisms of lipoprotein lipase gene on plasma postprandial triglyceride levels in familial combined hyperlipidemic subjects and their relatives have not been sufficiently studied. This study included sixteen familial combined hyperlipidemic parents (G1): age: 52 ± 9 years with total-cholesterol: 7.2 ± 1.7 mmol/L, fasting triglycerides: 2.8 ± 1.4 mmol/L and sixteen children (G2) (twelve were normolipidemic): of age: 22 ± 5 years with total-cholesterol: 5.2 ± 1.1 mmol/L, fasting triglycerides: 2.06 ± 1.8 mmol/L and twelve normolipidemic, healthy controls. Blood samples were taken fasting and 2, 4, 6, 8, 10 hr postprandially after the standard fat rich test meal. We determined lipid parameters, apolipoprotein E and lipoprotein lipase HindIII and PvuII polymorphisms as well. The 6-hr critical postprandial triglyceride values were abnormal in both G1: 5.88 ± 2.7 mmol/L and G2: 3.53 ± 2.7 mmol/L (p <0.001), respectively, and differed significantly (p <0.001) from each other. The subjects of familial combined hyperlipidemic families with E4 allele in both generations exhibited significantly (p <0.001) higher and extended postprandial lipemia. We did not find significant effects of lipoprotein lipase HindIII or PvuII polymorphisms on the fasting lipid values alone, however in normolipidemic subjects from the same families the homozygosity of HindIII variation was associated with higher triglyceride postprandial peak (p <0.01). The main findings of our study are that i.) normolipidemic G2 subjects in familial combined hyperlipidemic families have already abnormal postprandial status, and ii.) the 6 h postprandial triglyceride values were correlated with fasting triglyceride levels, which showed association with the apolipoprotein E4 allele.

Influence of atorvastatin and simvastatin on apolipoprotein B metabolism in moderate combined hyperlipidemic subjects with low VLDL and LDL fractional clearance rates

Subjects with moderate combined hyperlipidemia ( n=11) were assessed in an investigation of the effects of atorvastatin and simvastatin (both 40 mg per day) on apolipoprotein B (apoB) metabolism. The objective of the study was to examine the mechanism by which statins lower plasma triglyceride levels. Patients were studied on three occasions, in the basal state, after 8 weeks on atorvastatin or simvastatin and then again on the alternate treatment. Atorvastatin produced significantly greater reductions than simvastatin in low density lipoprotein (LDL) cholesterol (49.7 vs. 44.1% decrease on simvastatin) and plasma triglyceride (46.4 vs. 39.4% decrease on simvastatin). ApoB metabolism was followed using a tracer of deuterated leucine. Both drugs stimulated direct catabolism of large very low density lipoprotein (VLDL 1) apoB (4.52±3.06 pools per day on atorvastatin; 5.48±4.76 pools per day on simvastatin versus 2.26±1.65 pools per day at baseline (both P<0.05)) and this was the basis of the 50% reduction in plasma VLDL 1 concentration; apoB production in this fraction was not significantly altered. On atorvastatin and simvastatin the fractional transfer rates (FTR) of VLDL 1 to VLDL 2 and of VLDL 2 to intermediate density lipoprotein (IDL) were increased significantly, in the latter instance nearly twofold. IDL apoB direct catabolism rose from 0.54±0.30 pools per day at baseline to 1.17±0.87 pools per day on atorvastatin and to 0.95±0.43 pools per day on simvastatin (both P<0.05). Similarly the fractional transfer rate for IDL to LDL conversion was enhanced 58–84% by statin treatment ( P<0.01) LDL apoB fractional catabolic rate (FCR) which was low at baseline in these subjects (0.22±0.04 pools per day) increased to 0.44±0.11 pools per day on atorvastatin and 0.38±0.11 pools per day on simvastatin (both P<0.01). ApoB-containing lipoproteins were more triglyceride-rich and contained less free cholesterol and cholesteryl ester on statin therapy. Further, patients on both treatments showed marked decreases in all LDL subfractions. In particular the concentration of small dense LDL (LDL-III) fell 64% on atorvastatin and 45% on simvastatin. We conclude that in patients with moderate combined hyperlipidemia who initially have a low FCR for VLDL and LDL apoB, the principal action of atorvastatin and simvastatin is to stimulate receptor-mediated catabolism across the spectrum of apoB-containing lipoproteins. This leads to a substantial, and approximately equivalent, percentage reduction in plasma triglyceride and LDL cholesterol.

Long-term Cholesterol-Lowering Effects of 4 Fat-Restricted Diets in Hypercholesterolemic and Combined Hyperlipidemic Men

The long-term effect of aggressively vs moderately fat-restricted diets has not been studied extensively in free-living subjects with different types of hyperlipidemia. To compare the cholesterol-lowering effects of 4 levels of dietary fat intake restriction after 1 year. Randomized, parallel, comparison trial. Male employees of a large industry. A total of 444 men had low-density lipoprotein cholesterol (LDL-C) levels above the 75th age-specific percentile. Subjects with triglyceride (TG) levels less than the 75th age-specific percentile were defined as hypercholesterolemic (HC) and those with TG levels at or above the 75th age-specific percentile were defined as combined hyperlipidemic (CHL). Hypercholesterolemic subjects were randomized to diets 1, 2, 3, and 4 taught to contain 30%, 26%, 22%, and 18% fat, and the CHL subjects were randomized to diets 1, 2, and 3. All 4 diets were taught to subjects and spouses or partners in 8 weekly 2-hour classes. Plasma lipoprotein levels after 1 year. Fat intake after 1 year declined from a mean of 34% to 36% of energy to 27%, 26%, 25%, and 22% in the 4 HC diet groups and 28%, 26%, and 25% in the 3 CHL diet groups. Mean+/-SD percent LDL-C reductions were 5.3%+/-16.2%, 13.4%+/-12.6%, 8.4%+/-11.2%, and 13.0%+/-15.7% in the HC diet groups and 7.0%+/-16.2%, 2.8%+/-15.8%, and 4.6%+/-13.5% in the CHL diet groups (P<.01 in all but 1 instance). Apoprotein B levels decreased 8.6%, 10.7%, 4.3%, and 5.3% in the HC groups and 14.6%, 11.4%, and 9.9% in the CHL groups (P<.05-.01 in each instance). Triglyceride levels increased significantly in subjects following HC diets 3 and 4, 21.7% and 38.7% (P<.05 and .01), but not in any CHL subjects. High-density lipoprotein cholesterol decreased 2.8% and 3.2% in subjects on HC diets 3 and 4, respectively (P<.05 in both cases). After 1 year, moderate restriction of dietary fat intake attains meaningful and sustained LDL-C reductions in HC subjects and apoprotein B reductions in both HC and CHL subjects. More extreme restriction of fat intake offers little further advantage in HC or CHL subjects and potentially undesirable effects in HC subjects.

Interaction of the lipoprotein lipase asparagine 291–>serine mutation with body mass index determines elevated plasma triacylglycerol concentrations: a study in hyperlipidemic subjects, myocardial infarction survivors, and healthy adults.

A mutation in the lipoprotein lipase (LPL) gene, resulting in the substitution of asparagine by serine at residue 291 (LPL-S291), was found to occur in young survivors of a myocardial infarction from Sweden, combined hyperlipidemic subjects from the United Kingdom, and type III hyperlipidemic subjects from Germany at allelic carrier frequencies no different from those found in companion healthy control subjects (3.63 vs. 3.37; 1.85 vs. 1.60; and 2.00 vs. 1.56%, respectively). In a group of 620 healthy middle-aged men from the United Kingdom with baseline and three subsequent annual lipid measurements, mean plasma triacylglycerol (TG), (but not plasma cholesterol) concentrations in carriers of the mutation were significantly elevated over non-carriers (1.95 vs. 1.61 mmol/l, P = 0.05, and 5.83 vs. 5.65 mmol/l, P = 0.29, respectively). When these healthy control subjects were divided according to tertiles of body mass index (BMI), as expected, non-carriers whose BMI was in the upper two tertiles (BMI > or = 25.0 kg/m2) had higher plasma TG concentrations than those in the lowest tertile (1.90 vs. 1.54 mmol/l), but this difference was much greater in LPL-S291 carriers (2.33 vs. 1.36 mmol/l, P = 0.01, BMI x genotype interaction, P = 0.02). To confirm this effect, a second group of 319 healthy subjects from the United Kingdom was screened for LPL-S291. The allelic frequency of the mutation was found to be 1.88% and the effect on plasma lipid concentrations was very similar to that observed in the first control group (plasma TG, 2.31 vs. 1.27 mmol/l, P < 0.001 for LPL-S291 carriers vs. non-carriers, respectively). As before, those carriers whose BMI was in the top two tertiles for this sample (BMI > or = 23.3 kg/m2) had higher plasma TG concentrations than non-carriers (2.31 vs. 1.42 mmol/l). Thus, the LPL-S291 variant may predispose individuals to elevated plasma TG concentrations under conditions such as increased BMI.

Changes in plasma triacylglycerol concentrations among free-living hyperlipidemic men adopting different carbohydrate intakes over 2 y: the Dietary Alternatives Study

We reported previously that low-fat, high-carbohydrate diets containing < 26% of energy as fat and > 57% of energy as carbohydrate induce hypertriacylglycerolemia (hypertriglyceridemia) in hypercholesterolemic but not in combined hyperlipidemic (CHL) subjects. Because subjects may not consistently adhere to an assigned diet long term, we examined the extent to which plasma triacylglycerols (triglycerides) increase at four consistently reported carbohydrate intakes at intervals of up to 2 y. Three hundred seventy-two subjects reported consistent carbohydrate intakes of < 45%, 45-51.9%, 52-59.9%, or > or = 60% of energy on food records for 3, 12, and 24 mo. Among hypercholesterolemic subjects reporting a carbohydrate intake > or = 60% of energy, triacylglycerols increased by 0.25, 0.18, and 0.27 mmol/L (22, 16, and 24 mg/dL) over baseline at 3, 12, and 24 mo, respectively (P < 0.01 in each instance), and 0.32 mmol/L (28 mg/dL) above the group with a carbohydrate intake 52-59.9% of energy (P < 0.05) after 3 mo. No statistically significant effects were observed among CHL subjects, but compared with baseline, triacylglycerols decreased during the first 3 mo (-0.29 to -0.04 mmol/L, or -26 to -4 mg/dL), were unchanged over 12 mo, and were increased after 24 mo in three of four carbohydrate intake strata (0.27-0.36 mmol/L, or 24-32 mg/dL). These data confirm our previous observation that a moderately but not extremely low-fat, high-carbohydrate diet can be used long-term without deleterious effects on plasma triacylglycerols in the management of hypercholesterolemia, whereas CHL is unaffected by the amount of carbohydrate ingested.

Alternative fat-restricted diets for hypercholesterolemia and combined hyperlipidemia: feasibility, design, subject recruitment, and baseline characteristics of the dietary alternatives study.

Dietary recommendations for the treatment of hypercholesterolemia (HC) emphasize stepwise reductions in fat intake, but there is no agreement on what lower limit is desirable or achievable. These recommendations have applied broadly to persons with HC alone, as well as to those with a combined elevation in triglyceride (TG) and cholesterol, even though they may differ in pathophysiological mechanisms and response. In this paper, we describe the design and feasibility of recruiting and randomizing subjects with HC or combined hyperlipidemia (CHL) to an outpatient dietary intervention study of progressively fat-restricted diets. Diets were designed to contain 30, 26, 22, and 18% of calories from fat; 300, 200, 100, and 100 mg cholesterol/day; and a polyunsaturated/saturated fat ratio of approximately 1.0. Triglyceride and low-density-lipoprotein cholesterol (LDL-C) cutpoints were based on the age-specific 75th percentile value. Over 18 months, 8372 men were screened, yielding 320 HC subjects randomized to the four diets and 211 CHL subjects randomized to the first three diets (because of fewer CHL subjects). At baseline, HC and CHL subjects were similar in age, education, lifestyle, dietary intake, and LDL-C, but CHL subjects were heavier, more hyperglycemic, hyperinsulinemic, and hypertensive. Recruiting a large cohort of HC and CHL subjects from an industrial workforce is feasible in a restricted time frame. CHL subjects demonstrate features of the insulin resistance/hypertension syndrome, differing from HC subjects. CHL is sufficiently common relative to HC (2:3) to permit a comparison of dietary responses between the two conditions. Finally, the randomization of HC and CHL subjects to the diets yielded statistically indistinguishable groups, permitting a test of the efficacy of the alternative diets within each hyperlipidemic (HL) category.

Lovastatin therapy reduces low density lipoprotein apoB levels in subjects with combined hyperlipidemia by reducing the production of apoB-containing lipoproteins: implications for the pathophysiology of apoB production.

We investigated the metabolism of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), and low density lipoprotein (LDL) apolipoprotein B (apoB) in seven patients with combined hyperlipidemia (CHL), using 125I-labeled VLDL and 131I-labeled LDL and compartmental modeling, before and during lovastatin treatment. Lovastatin therapy significantly reduced plasma levels of LDL cholesterol (142 vs 93 mg/dl, P less than 0.0005) and apoB (1328 vs 797 micrograms/ml, P less than 0.001). Before treatment, CHL patients had high production rates (PR) of LDL apoB. Three-fourths of this LDL apoB flux was derived from sources other than circulating VLDL and was, therefore, defined as "cold" LDL apoB flux. Compared to baseline, treatment with lovastatin was associated with a significant reduction in the total rate of entry of apoB-containing lipoproteins into plasma in all seven CHL subjects (40.7 vs. 25.7 mg/kg.day, P less than 0.003). This reduction was associated with a fall in total LDL apoB PR and in "cold" LDL apoB PR in six out of seven CHL subjects. VLDL apoB PR fell in five out of seven CHL subjects. Treatment with lovastatin did not significantly alter VLDL apoB conversion to LDL apoB or LDL apoB fractional catabolic rate (FCR) in CHL patients. In three patients with familial hypercholesterolemia who were studied for comparison, lovastatin treatment increased LDL apoB FCR but did not consistently alter LDL apoB PR. We conclude that lovastatin lowers LDL cholesterol and apoB concentrations in CHL patients by reducing the rate of entry of apoB-containing lipoproteins into plasma, either as VLDL or as directly secreted LDL.

Relationships between LDL density and kinetic heterogeneity in subjects with normolipidemia and familial combined hyperlipidemia using density gradient ultracentrifugation.

The metabolism of heterogeneous subpopulations of low density lipoprotein (LDL) apoB100 was examined in three normolipidemic and two familial combined hyperlipidemic subjects. Autologous radioiodinated plasma LDL (1.019 less than d less than 1.063 g/ml) were injected into each subject and the disappearance and appearance of radiolabeled lipoproteins into various LDL subpopulations were examined using density gradient ultracentrifugation. Eleven to 13 fractions (-320 microliter each) were collected within LDL defined uniquely in each subject. In all subjects, the disappearance of radiolabeled LDL from plasma was biexponential. However, changes with time in the distribution of radiolabeled LDL among the various LDL density subpopulations revealed complex metabolic behavior that differed among the subjects. When the relationships between density and kinetic characteristics were examined in more detail by following the disappearance of individual fractions defining LDL in each subject, the data suggested that: 1) the kinetic behavior of the LDL fractions was more complex than suggested by the disappearance of radiolabeled LDL from plasma: 2) certain fractions within specific density ranges were kinetically similar; 3) distinct differences in the disappearance curves among the fractions occurred within narrow density ranges; and 4) precursor-product relationships were seen among specific LDL density fractions and varied from subject to subject. These studies underscore the complexities of plasma LDL apoB-100 metabolism. More detailed characterizations of the kinetic behavior of various LDL subpopulations should help in our understanding of the origin(s) and potential physiological consequences of different LDL subpopulations.