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Hypertriglyceridemia (triglycerides 200-499 mg/dL) is relatively common in the United States, whereas more severe triglyceride elevations (very high triglycerides, ≥500 mg/dL) are far less frequently observed. Both are becoming increasingly prevalent in the United States and elsewhere, likely driven in large part by growing rates of obesity and diabetes mellitus. In a 2002 American Heart Association scientific statement, the omega-3 fatty acids (n-3 FAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were recommended (at a dose of 2-4 g/d) for reducing triglycerides in patients with elevated triglycerides. Since 2002, prescription agents containing EPA+DHA or EPA alone have been approved by the US Food and Drug Administration for treating very high triglycerides; these agents are also widely used for hypertriglyceridemia. The purpose of this advisory is to summarize the lipid and lipoprotein effects resulting from pharmacological doses of n-3 FAs (>3 g/d total EPA+DHA) on the basis of new scientific data and availability of n-3 FA agents. In treatment of very high triglycerides with 4 g/d, EPA+DHA agents reduce triglycerides by ≥30% with concurrent increases in low-density lipoprotein cholesterol, whereas EPA-only did not raise low-density lipoprotein cholesterol in very high triglycerides. When used to treat hypertriglyceridemia, n-3 FAs with EPA+DHA or with EPA-only appear roughly comparable for triglyceride lowering and do not increase low-density lipoprotein cholesterol when used as monotherapy or in combination with a statin. In the largest trials of 4 g/d prescription n-3 FA, non-high-density lipoprotein cholesterol and apolipoprotein B were modestly decreased, indicating reductions in total atherogenic lipoproteins. The use of n-3 FA (4 g/d) for improving atherosclerotic cardiovascular disease risk in patients with hypertriglyceridemia is supported by a 25% reduction in major adverse cardiovascular events in REDUCE-IT (Reduction of Cardiovascular Events With EPA Intervention Trial), a randomized placebo-controlled trial of EPA-only in high-risk patients treated with a statin. The results of a trial of 4 g/d prescription EPA+DHA in hypertriglyceridemia are anticipated in 2020. We conclude that prescription n-3 FAs (EPA+DHA or EPA-only) at a dose of 4 g/d (>3 g/d total EPA+DHA) are an effective and safe option for reducing triglycerides as monotherapy or as an adjunct to other lipid-lowering agents.

Familial type III hyperlipoproteinemia (HLP) was first recognized as a distinct entity over 60 years ago. Since then, it has proven to be instructive in identifying the key role of apolipoprotein E (apoE) in removal of the remnants of very low density lipoproteins and chylomicrons produced by the action of lipoprotein lipase on these triglyceride-transporting lipoproteins. It has additionally shed light on the potent atherogenicity of the remnant lipoproteins. This review describes the history of development of our understanding of type III HLP, discusses the several genetic variants of apoE that play roles in the genesis of type III HLP, and describes the remarkable responsiveness of this fascinating disorder to lifestyle modification, especially carbohydrate restriction and calorie restriction, and, when required, the addition of pharmacotherapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The aim of the study was to describe the prevalence and utilization patterns of methylphenidate (MPH) in children and adolescents in France., Methods: This was a population-based retrospective study in which the cohort consisted of patients for whom data were extracted from the dispensation drug claims database of the national health insurance (NHI) fund for self-employed workers. Annual prevalence of MPH use was evaluated on patients aged 6-18 years who were reimbursed for at least one MPH prescription a year. Between January 2004 and June 2005, features of MPH medication and user profile were described for the "new starters" having a screening period of 1 year without receiving a MPH prescription and a follow-up >or=12 months. Time to interruption of MPH regular use was analysed by Kaplan-Meier survival analysis. Mean duration of exposure to MPH treatment was computed with the 95% confidence interval (CI)., Results: Annual prevalence of MPH per 1000 persons was 1.1 in 2003, 1.5 in 2004 and 1.8 in 2005 (relative increase of 63.5%). New starters (n = 447) received their first MPH prescription through the hospital (65.1%) or through private practitioners (34.9%). The user profiles were: short (16.6%), occasional (33.8%) and regular (49.6%). Among the new starters, the median time to interruption of MPH regular use was 10.2 months (95% CI: 7.9-12.4). The mean duration of exposure to MPH treatment was: occasional (4.9 months, 95% CI: 4.3-5.5) and regular (25.7 months, 95% CI: 24.6-26.8)., Conclusion: Although there is a low prevalence of MPH use in France, this survey revealed a wide profile of users and heterogeneous use patterns.

This report describes the effects of sirolimus on plasma lipids, and uses the Framingham risk model to assess the clinical importance of these effects. Lipid data from two large controlled studies of 1295 renal transplant patients were analyzed retrospectively. Sirolimus 2 mg/day and 5 mg/day were compared with placebo or azathioprine, and administered concomitantly with steroids and cyclosporine over 12 months. Hypercholesterolemia and hypertriglyceridemia occurred in all treatment groups and were maximal at 2-3 months. The sirolimus groups evidenced higher lipid levels than the controls, but the elevations diminished over time. At 1 year, the patients given sirolimus 2 mg/day had a mean cholesterol level 17 mg/dL greater and a mean triglyceride level 59 mg/dL greater than the controls. Among the patients given sirolimus 5 mg/day, mean cholesterol was 30 mg/dL greater and mean triglycerides were 103 mg/dL greater than the controls. Treatment with statins and fibrates was effective in reducing cholesterol and triglyceride levels, respectively, in the sirolimus-treated patients. The Framingham risk model predicted that the 17 mg/dL elevation in cholesterol would increase the incidence of coronary heart disease (CHD) by 1.5 new cases per 1000 persons per year and CHD death by 0.7 events per 1000 persons per year. Lipid elevations observed in the sirolimus-treated patients were manageable, improved over time, and responded to lipid-lowering therapy. Based on the Framingham risk model, the CHD risks associated with these cholesterol elevations are small compared with the baseline risks of the transplant population.

The guidelines of the Adult Treatment Panel III (ATP III) of the National Cholesterol Education Program are similar to prior recommendations in focusing on elevations of low-density lipoprotein (LDL) cholesterol as the primary target of therapy and in gauging the intensity of therapy to the degree of coronary heart disease risk. New elements in the current guidelines include: quantification of risk, heightened attention to the risk imparted by low high-density lipoprotein levels, utilization of non-high-density lipoprotein cholesterol levels in risk assessment for hypertriglyceridemic individuals, and emphasis on the metabolic syndrome. Nonetheless, the current guidelines are not perfect. The recommended algorithm for treatment is excessively complex; this complexity may keep the guidelines from being widely used. This complexity is generated by a hybrid scheme of risk assessment utilizing both counting of categorical coronary heart disease risk factors and calculation of coronary heart disease using the Framingham model. This hybrid method also results in undesirable inconsistencies in treatment. ATP III explicitly agrees that the therapeutic LDL goal should be determined by the burden of non-LDL risk factors. However, the current guidelines violate this principle by giving the baseline LDL cholesterol level a role in determining the therapeutic LDL goal. Additionally, the ATP III guidelines lead to under-treatment of women. Simplification should be a goal of the next iteration of the guidelines. Specific suggestions are given for simplification of the guidelines and for enhanced treatment of women. Furthermore, it is urged that the risk-assessing spreadsheet be provided in an "unlocked" form so that its details can be inspected., ((c)2002 CHF, Inc.)

Beverages stored in lead-crystal glass accumulate extraordinary concentrations of lead. We obtained a lead-crystal decanter manufactured with lead from Australia, where the ratio of 206Pb/207Pb is distinctly different from that in the United States. We sought to determine the bioavailability of crystal-derived lead, using the technique of stable isotope dilution in blood. We conducted a single-dose, nonrandomized cross-over study in which participants were admitted to the Clinical Research Center twice, 1 week apart. During the first admission, subjects ingested sherry obtained from the original bottle. During the second admission, they ingested sherry that had been stored in the crystal decanter and that had achieved a lead concentration of 14.2 mu mol/l. After ingesting decanter-stored sherry, mean blood lead rose significantly (p = 0.0003) from 0.10 to 0.18 mu mol/l, while mean 206Pb/207Pb fell from 1.202 to 1.137 (p = 0.0001). On average, 70% of the ingested dose of lead was absorbed. We conclude that lead derived from crystal glass is highly bioavailable; repeated ingestions could cause elevated blood lead concentration. The technique of stable isotope dilution lends itself to the study of the bioavailability of lead in other matrices, including soil.

Meso-2,3-dimercaptosuccinic acid (DMSA, or succimer) is an oral chelating agent for heavy-metal poisoning. While studying the urinary elimination of unaltered DMSA, altered DMSA (i.e., its mixed disulfides), and lead in children with lead poisoning, we observed a pattern of urinary drug elimination after meals suggestive of enterohepatic circulation. The excretion of lead in urine patterned the elimination of altered DMSA rather than the parent molecule. In addition, the half-life of elimination of DMSA via the kidney was positively associated with blood lead concentration. Two additional crossover studies of DMSA kinetics were conducted in normal adults to confirm the presence of enterohepatic circulation of DMSA after meals. In one, increases in plasma total DMSA concentration were observed after meals in all six subjects; these increases were prevented by cholestyramine administration 4, 8, and 12 hr after DMSA. In the second, the administration of neomycin also prevented increases in DMSA after meals. These studies indicate that 1) a metabolite(s) of DMSA undergoes enterohepatic circulation and that microflora are required for DMSA reentry; 2) in children, moderate lead exposure impairs renal tubular drug elimination; and 3) a metabolite of DMSA appears to be an active chelator.

Four inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase have been approved for treatment of hypercholesterolemia. Three of these are fungal metabolites or derivatives thereof: lovastatin, simvastatin, and pravastatin. The fourth, fluvastatin, is totally synthetic. Its structure, containing a fluorophenyl-substituted indole ring, is distinct from that of the fungal metabolites. Lovastatin and simvastatin are administered as prodrugs, which undergo in vivo transformation to active inhibitory forms; fluvastatin and pravastatin are administered as active agents. The HMG-CoA reductase inhibitors are all effective in reducing plasma concentrations of low density lipoprotein. They have differing pharmacokinetic properties, which may be of importance in some patients. All of these drugs are very well tolerated, and there do not appear to be major differences in toxicity or adverse effects. When LDL reductions > 30% are needed, simvastatin is the most cost-effective HMG-CoA reductase inhibitor. However, these drugs are most commonly used in dosages that reduce LDL-C by 20-30%. For this degree of LDL reduction, fluvastatin is the most cost-effective HMG-CoA reductase inhibitor.

Background: A large and consistent body of evidence supports the judgment that elevation of total plasma blood cholesterol is a cause of myocardial infarction (MI) and that high levels of low density lipoprotein (LDL) cholesterol have a positive relation and high levels of high density lipoprotein (HDL) cholesterol an inverse relation with MI. At present, however, the roles, if any, of the major subfractions of HDL, namely, HDL2 and HDL3, have not been clarified. In addition, the relation of plasma apolipoprotein concentrations to MI and whether they provide predictive information over and above their lipoprotein cholesterol associations is unknown., Methods and Results: We evaluated these questions in a case-control study of patients hospitalized with a first MI and neighborhood controls of the same age and sex. Cases had significantly lower levels of total HDL (p less than 0.0001) as well as HDL2 (p less than 0.0001) and HDL3 (p less than 0.0001) cholesterol. These differences persisted after controlling for a large number of demographic, medical history, and behavioral risk factors and levels of other lipids. There were significant (p less than 0.0001) inverse dose-response relations with odds ratios for those in the highest quartile relative to those in the lowest of 0.15 for total HDL, 0.17 for HDL2, and 0.29 for HDL3 cholesterol levels. Levels of LDL and very low density lipoprotein cholesterol and triglycerides were also higher among cases than controls, but only for triglycerides was the difference statistically significant after adjustment for coronary risk factors and other lipids (p = 0.044). Apolipoproteins A-I and A-II were both significantly (p less than 0.0001) lower in cases, and differences remained even after adjustment for coronary risk factors and lipids. There were significant dose-response relations for both apolipoprotein A-I (p = 0.026) and A-II (p = 0.002). Neither apolipoprotein B nor E was significantly related to MI after adjustment for lipids and other coronary risk factors. When all four apolipoproteins were taken together, there was an increased level of prediction of MI over the information provided by the lipids and other coronary risk factors (p = 0.003), but this appeared present only for the individual apolipoproteins A-I (p = 0.027) and A-II (p = 0.011)., Conclusions: These data indicate that both HDL2 and HDL3 cholesterol levels are significantly associated with MI. They also raise the possibility that apolipoprotein levels, especially A-I and A-II, may add importantly relevant information to determination of risk of MI.

A type III hyperlipoproteinemic subject having the apolipoprotein E (apo E) phenotype E3/2 was identified. From isoelectric focusing experiments in conjunction with cysteamine treatment (a method that measures cysteine content in apo E), the E2 isoform of this subject was determined to have only one cysteine residue, in contrast to all previously studied E2 apoproteins, which had two cysteines. This single cysteine was shown to be at residue 112, the same site at which it occurs in apo E3. From amino acid and sequence analyses, it was determined that this apo E2 differed from apo E3 by the occurrence of glutamine rather than lysine at residue 146. When phospholipid X protein recombinants of the subject's isolated E3 and E2 isoforms were tested for their ability to bind to the human fibroblast apo-B,E receptor, it was found that the E3 bound normally (compared with an apo E3 control) but that the E2 had defective binding (approximately 40% of normal). Although they contained E3 as well as E2, the beta-very low density lipoproteins (beta-VLDL) from this subject were very similar in character to the beta-VLDL from an E2/2 type III hyperlipoproteinemic subject; similar subfractions could be obtained from each subject and were shown to have a similar ability to stimulate cholesteryl ester accumulation in mouse peritoneal macrophages. The new apo E2 variant has also been detected in a second type III hyperlipoproteinemic subject.

This report describes the development and first applications of a sensitive and specific double antibody radioimmunoassay for human apoplipoprotein E (apoE). ApoE was purified from the very low density lipoproteins of hypertriglyceridemic patients by heparin-agarose affinity chromatography, DEAE-cellulose chromatography, and preparative polyacrylamide gel electrophoresis. The purified apoprotein had an amino acid composition characteristic of apoE and resulted in the production of monospecific antisera when injected into rabbits. The radioimmunoassay, which was carried out in the presence of 5 mM sodium decyl sulfate, had a working range of 0.8-12 ng. The withinassay coefficient of variation was 9% and the coefficient of variation for systematic between-assay variability was 3%. Prior delipidation of samples with organic solvents did not alter their immunoreactivity. In 26 normal volunteers, the mean plasma apoE concentration was 36 +/- 13 microgram/ml. Hyperlipidemic patients (n = 68) had higher mean apoE levels. A single patient with type III hyperlipoproteinemia had a plasma apoE level of 664 microgram/ml. The plasma apoE level was independently related to plasma cholesterol and triglyceride levels in a population of 108 normal and nonchylomicronemic hyperlipidemic patients. The multiple correlation coefficient for this relationship was 0.73. Thus, variation in plasma cholesterol and triglyceride concentrations described 53% of the variation in apoE concentrations in this population. The lipoprotein distribution of apoE was investigated by agarose column chromatography and ultracentrifugation of plasma. Agarose column chromatography demonstrated that all or nearly all plasma apoE is associated with lipoproteins. In plasma from normal volunteers and hypercholesterolemic patients, apoE was found in two discrete lipoprotein classes: very low density lipoproteins and a set of lipoprotein particles with size and density characteristics similar to HDL2. In hypertriglyceridemic patients, nearly all apoE was associated with the triglyceride-rich lipoproteins.

Human tissues were incubated in vitro with radiolabeled amino acids to determine whether plasma apolipoproteins are synthesized in human kidney. Subsequently, tissue extracts were screened with antisera directed against apolipoprotein E (apo E), apolipoprotein B (apo B), apolipoprotein AI (apo AI), and bulk apolipoproteins of high density lipoprotein (HDL). Newly synthesized apo E, but not apo AI or apo B, was identified in kidney and adrenal cortex. Estimates of relative rates of apo E synthesis in vitro suggest that a substantial portion of adrenal and kidney protein synthesis is committed to apo E synthesis. The relative rate of apo E synthesis was 4-6 times greater in kidney cortex than in kidney medulla. Analysis of immunoreactive apo E showed that kidney and adrenal apo E species have the same electrophoretic mobility in NaDodSO4/polyacrylamide gels as does plasma apo E. Further characterization by high resolution two-dimensional gel analysis indicated that the isoforms of newly synthesized kidney and adrenal apo E correspond to specific isoforms of plasma apo E. These findings suggest that apolipoproteins arising from peripheral tissues may play an important role in lipid transport and metabolism.

The concentrations and lipoprotein distributions of apolipoprotein E (apoE) in normal human umbilical cord blood plasma were determined. The mean plasma apoE level of 95 neonates was considerably higher than that of 49 normal adults (58.1 vs 35.8 micrograms/ml). This elevation of apoE levels was in striking contrast to the lower than adult levels of cholesterol (72 mg/dl vs 185 mg/dl), triglyceride (37.8 mg/dl vs 97.6 mg/dl), and LDL cholesterol (25 mg/dl vs 110 mg/dl) in neonatal plasma. For the group of 95 neonates, the plasma apoE concentration correlated significantly with total plasma cholesterol concentration (r = 0.60), with LDL cholesterol concentration (r = 0.27) and with HDL cholesterol concentration (r = 0.50). Among the neonates, 87% of plasma apoE was associated with a less dense subfraction of high density lipoprotein compared to a mean of 58% for 30 normal adults. Thus, for neonates, despite hypolipidemia, the absolute concentration of apoE in HDL (50 micrograms/ml) was 2.5 times that of adults (20 micrograms/ml). We speculate that the very low level of neonatal VLDL, providing limited substrate for lipolysis, may result in retarded removal of apoE from plasma and the observed high level of apoE in neonatal HDL. We hypothesize that in the fetus and neonate, as has been demonstrated in abetalipoproteinemia, apoE-rich HDL may functionally substitute for LDL in delivering cholesterol to cells.

Apolipoproteins B, A-I, and A-IV were localized in human intestinal epithelium using immunoperoxidase techniques. Staining was most obvious in villus tip cells. Lipid absorption resulted in an increase in intraepithelial staining for each apoprotein. The pattern for apo-B in the biopsy specimens taken after lipid absorption revealed a marked redistribution of staining to the intercellular spaces and an increase in the supranuclear staining of apo-A-I and apo-A-IV. After lipid absorption, staining appeared to extend further down the villus than in the fasting biopsy specimens. Quantitation of apo-A-I and apo-A-IV in isolated epithelial cells confirmed that the mass of these apoproteins increases in response to lipid absorption. Apolipoprotein B and apo-A-I were absent in the epithelium of 3 patients with abetalipoproteinemia while apo-A-IV was present in 2 patients. These studies demonstrate differences in the localization and quantitation of apoproteins in the villus-crypt unit as well as differences in the localization pattern of the different apoproteins.

Studies were designed to explore the association of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities with lipoproteins in human postheparin plasma (PHP). The major peak of LPL activity after gel filtration of PHP eluted after the triglyceride-rich lipoproteins and just before the peak of low density lipoprotein (LDL) cholesterol. When PHP contained chylomicrons, an additional peak of LPL activity eluted in the void volume of the column. Most HTGL activity eluted after the LDL and preceded the elution of high density lipoprotein cholesterol. LPL activity in preheparin plasma eluted in the same position, relative to lipoproteins, as did LPL in PHP. Gel filtration of purified human milk LPL mixed with plasma or isolated LDL produced a peak of activity eluting before LDL. During gel filtration of PHP in high salt buffer (1 M NaCl) or after isolation of lipoproteins by ultracentrifugation in high salt density solutions, most of the lipase activity was not associated with lipoproteins. LPL activity was removed from PHP by elution through immunoaffinity columns containing antibodies to apolipoprotein (apo) B and apo E. Since lipoproteins in PHP have undergone prior in vivo lipolysis, LPL activity in PHP may be bound to remnants of chylomicrons and very low density lipoproteins.

Nine patients with familial hypercholesterolemia (type II hyperlipoproteinemia) and two normal volunteers were studied to ascertain the effectiveness of cholestyramine in lowering plasma cholesterol when a twice-a-day dosage regimen was compared with the same total dosage administered four times a day. The study showed that in these subjects the two regimens were equally effective. The ability to administer cholestyramine twice daily in working adults and school children should greatly enhance adherence to this agent.

The effect of inhibiting cholesteryl ester transfer protein (CETP) on the in vitro redistribution of apolipoproteins(apo) A-IV and apoE among lipoproteins in whole plasma was studied in seven normal male subjects. Plasmas were incubated in the presence of a purified monoclonal antibody TP2 (Mab TP2) that neutralizes the activity of CETP. Mab TP2 had no effect on lecithin:cholesterol acyltransferase (LCAT) activity. Prior to and following a 6-h incubation at 37 degrees C in the presence of Mab TP2 or a control mouse myeloma immunoglobulin (IgG), plasmas were gel-filtered on Sephacryl S-300 and the distribution of apoA-IV and apoE among lipoproteins was determined by radioimmunoassay. Incubation (i.e., with active LCAT and CETP) increased the amount of apoA-IV associated with lipoproteins by 240%. When CETP activity was inhibited during incubation, the amount of apoA-IV that became lipoprotein-associated was significantly increased (315% of basal). Plasma incubation also caused a redistribution of apoE from high density lipoproteins (HDL) to larger lipoproteins (131% of basal); however, when CETP was inhibited, significantly greater amounts of apoE became associated with the larger particles (155% of basal). These effects were observed in all seven subjects. Increased movement of apoE from HDL to triglyceride-rich particles was not due to displacement by apoA-IV since loss of apoE from HDL was still observed when no movement of apoA-IV onto HDL occurred, such as during LCAT or combined LCAT and CETP inhibition. We speculate that low CETP activity (e.g., in species such as rats) may lead to an increased content of HDL apoA-IV and also to apoE enrichment of triglyceride-rich lipoproteins, augmenting their clearance.

The incorporation of orally administered phospholipid into plasma high-density lipoproteins (HDL) was studied in three subjects. Plasma was analyzed by equilibrium density gradient ultracentrifugation, 5, 6, and 8 h after ingestion of 1.1 g [3H-choline, 14C-dilinoleoyl]phosphatidylcholine. At all time points in all subjects, there was a peak of phosphatidylcholine specific activity in fractions of density approximately 1.10-1.13 g/ml, corresponding to the subclass previously designated HDL2a. There was also a more variable, smaller peak of specific activity of phospholipids in HDL2b (1.063-1.100 g/ml) and in fractions of density approximately 1.19 g/ml. In the 1.10-1.13 fraction, 97 and 71%, respectively, of the 3H and 14C radioactivity were in phospholipids. The 3H/14C ratio was similar in phospholipids of HDL subfractions, the d less than 1.07 fraction, and in the administered phospholipid. The results show preferential transfer or exchange or absorbed phosphatidylcholine into specific subclasses of HDL.

Neonatal umbilical cord blood plasma low density lipoproteins (LDL, d = 1.019-1.063 g/ml) were subfractionated by density gradient ultracentrifugation into seven fractions (from 1.024 to 1.062 g/ml); the bulk of the LDL mass was in a density region of 1.034-1.042 g/ml. Apolipoprotein B by 10% SDS-polyacrylamide gel electrophoresis varied inversely with density, with only trace amounts present in the most dense fraction. The distribution of apolipoprotein B molecular weight forms was assessed by both 3% SDS-polyacrylamide gel electrophoresis and relative aminoacyl mass determination. Lower molecular weight forms of apolipoprotein B (B74 and B26) increased relative to apolipoprotein B100 with increasing density, ranging from undetectable in fraction 1 to apolipoproteins B26 and B74 comprising 30% of the total mass of apolipoprotein B in fraction 6. No apolipoprotein B48 was detectable in the LDL. Apolipoprotein E as determined by both SDS-polyacrylamide gel electrophoresis and radioimmunoassay increased with density with a maximum (14% of the protein) in the most dense fraction, fraction 7. Apolipoprotein A-I by SDS-polyacrylamide gel electrophoresis increased with increasing density and was the major apolipoprotein in fraction 7. Electron microscopic analysis revealed spherical particles whose diameters decreased with increasing density, ranging from 28.6 nm in the top fraction (fraction 1) to 15.6 nm in the bottom fraction (fraction 7). Gradient gel electrophoresis revealed that most of the fractions contained several different sized particles. The bottom fraction (fraction 7), enriched in apolipoproteins E and A-I, had a unique, poorly defined peak at 14.6 nm on gradient gel electrophoresis and showed a tendency to pack hexagonally upon electron microscopy. The unusual composition and apolipoprotein distribution in neonatal LDL fractions suggests that the LDL in the neonate are metabolically very diverse.

A large and convincing body of evidence links increased coronary risk with elevated plasma levels of low-density lipoprotein (LDL) cholesterol. Cholesterol in atherosclerotic lesions originates from that circulating in the blood bound to LDL. Even mild degrees of hypercholesterolemia (cholesterol greater than 180 mg/dl) when due to increased levels of LDL are associated with increased risk. Lowering plasma levels of LDL has been clearly shown to reduce coronary risk. We are able to modify plasma levels of LDL by restricting the dietary content of cholesterol and saturated fats. Such diets are safe and can be adhered to by large populations. Available information, reviewed here in detail, supports vigorous efforts to lower cholesterol levels by dietary means, even in the patient with so-called mild hypercholesterolemia. The evidence is overwhelming, the risk is nil, and the potential benefits are substantial.

The turnover of (125)I-high density lipoprotein (HDL) was examined in a total of 14 studies in eight normal volunteers in an attempt to determine the metabolic relationship between apolipoproteins A-I (apoA-I) and A-II (apoA-II) of HDL and to define further some of the determinants of HDL metabolism. All subjects were first studied under conditions of an isocaloric balanced diet (40% fat, 40% carbohydrate). Four were then studied with an 80% carbohydrate diet, and two were studied while receiving nicotinic acid (1 g three times daily) and ingesting the same isocaloric balanced diet. The decay of autologous (125)I-HDL and the appearance of urinary radioactivity were followed for at least 2 wk in each study. ApoA-I and apoA-II were isolated by Sephadex G-200 chromatography from serial plasma samples in each study. The specific activities of these peptides were then measured directly. It was found that the decay of specific activity of apoA-I and apoA-II were parallel to one another in all studies. The mean half-life of the terminal portion of decay was 5.8 days during the studies with a balanced diet.Mathematical modeling of the decay of plasma radioactivity and appearance of urinary radioactivity was most consistent with a two-compartment model. One compartment is within the plasma and exchanges with a nonplasma component. Catabolism occurs from both of these compartments. With a balanced isocaloric diet, the mean synthetic rate for HDL protein was 8.51 mg/kg per day. HDL synthesis was not altered by the high carbohydrate diet and was only slightly decreased by nicotinic acid treatment. These perturbations had effects on HDL catabolic pathways that were reciprocal in many respects. With an 80% carbohydrate diet, the rate of catabolism from the plasma compartment rose by a mean of 39.1%; with nicotinic acid treatment, it fell by 42.2%. Changes in the rate of catabolism from the second compartment were generally opposite those in the rate of catabolism from the plasma compartment, suggesting that these two catabolic pathways may be reciprocally regulated.

The factors involved in regulating parameters of whole body cholesterol metabolism in humans have been explored in a series of investigations. Several physiological variables have been identified (weight, excess weight, plasma cholesterol, and age) that can predict 53-76% of the variation in production rate (PR) and in the sizes of the rapidly exchanging pool of body cholesterol (M1) and of the minimum estimates of the slowly exchanging pool of body cholesterol (M3min) and of total body cholesterol (Mtotmin). Surprisingly, measurements of the plasma levels of HDL cholesterol and of the major HDL apolipoproteins (apoA-I, A-II, and E) did not provide additional information useful in predicting parameters of whole body cholesterol metabolism. A study was therefore conducted to investigate possible relationships of the plasma levels of subfractions of lipoproteins, determined by analytic ultracentrifugation, and of apoprotein E phenotype, with the parameters of whole body cholesterol metabolism. Ultracentrifugal analysis of plasma lipoprotein subfractions was performed at the Donner Laboratory in 49 subjects; all of these subjects were currently undergoing whole body cholesterol turnover studies or had previously had such studies and were in a similar metabolic state as judged by plasma lipid and lipoprotein values. Apoprotein E phenotyping was carried out in 71 subjects. Differences in model parameters were sought among subjects with various apoprotein E phenotypes. Ultracentrifugal LDL subfractions Sof 0-2 (the region of LPa), Sof 0-7 (smaller LDL), Sof 7-12 (larger LDL), Sof 12-20 (IDL), and ultracentrifugal HDL subfractions Fo1.20 0-1.5 (smaller HDL3), Fo1.20 2-9 (larger HDL3 plus HDL2), and Fo1.20 5-9 (larger HDL2 or HDL2b) were examined for correlations with each other and with parameters of whole body cholesterol metabolism.

The effect of cholesterol esterification on the distribution of apoA-IV in human plasma was investigated. Human plasma was incubated in the presence or absence of the lecithin:cholesterol acyltransferase (LCAT) inhibitor 5,5-dithiobis(2-nitrobenzoic acid) (DTNB) and immediately fractionated by 6% agarose column chromatography. Fractions were monitored for apoA-IV, apoE, and apoA-I by radioimmunoassay (RIA). Incubation resulted in an elevated plasma concentration of cholesteryl ester and in an altered distribution of apoA-IV. After incubation apoA-IV eluted in the ordinarily apoA-IV-poor fractions of plasma that contain small VLDL particles, LDL, and HDL2. Inclusion of DTNB during the incubation resulted in some enlargement of HDL; however, both cholesterol esterification and lipoprotein binding of apoA-IV were inhibited. Addition of DTNB to plasma after incubation and prior to gel filtration had no effect on the apoA-IV distribution when the lipoproteins were immediately fractionated. Fasting plasma apoE was distributed in two or three peaks; in some plasmas there was a small peak that eluted with the column void volume, and, in all plasmas, there were larger peaks that eluted with the VLDL-LDL region and HDL2. Incubation resulted in displacement of HDL apoE to larger lipoproteins and this effect was observed in the presence or absence of DTNB. ApoA-I was distributed in a single broad peak that eluted in the region of HDL and the gel-filtered distribution was unaffected by incubation either in the presence or absence of DTNB. Incubation of plasma that was previously heated to 56 degrees C to inactivate LCAT resulted in no additional movement of apoA-IV onto lipoproteins, unless purified LCAT was present during incubation. The addition of heat-inactivated LCAT to the incubation, had no effect on movement of apoA-IV. These data suggest that human apoA-IV redistribution from the lipoprotein-free fraction to lipoprotein particles appears to be dependent on LCAT action. The mechanism responsible for the increased binding of apoA-IV to the surface of lipoproteins when LCAT acts may involve the generation of "gaps" in the lipoprotein surface due to the consumption of substrate from the surface and additional enlargement of the core. ApoA-IV may bind to these "gaps," where the packing density of the phospholipid head groups is reduced.

Nine normal women, 22 to 37 years old, consumed controlled quantities of natural foods to test their responses to dietary cholesterol and saturated fat. All diets contained, as percentage of calories, 14% protein, 31% fat, and 55% carbohydrate. The main sources of polyunsaturated and saturated fats were corn oil and lard, respectively, and egg yolk was used for cholesterol supplementation. All subjects participated in four diet protocols of 15 days duration, and each diet period was separated by 3 weeks without diet control. The first diet (corn) was based on corn oil, had a polyunsaturated to saturated fat ratio (P/S) of 2.14, and contained 130 mg of cholesterol. The second diet (corn+) was identical to the first but contained a total of 875 mg of cholesterol. The third diet (lard) was based on lard, had a P/S ratio of 0.64, and contained 130 mg of cholesterol. The fourth diet (lard+) was identical to the third, but contained 875 mg of cholesterol per day. Changes of the plasma lipid, lipoprotein and apoprotein parameters relative to the corn diet were as follows: the corn+ diet significantly increased total plasma cholesterol, HDL-cholesterol, LDL-cholesterol, and apoB levels; the lard diet significantly increased total cholesterol, HDL-cholesterol, and apoB; and the lard+ diet significantly increased the total cholesterol, HDL-cholesterol, LDL-cholesterol, and apoA-I and apoB levels. There were no significant variations in VLDL-cholesterol, triglyceride, or apoE levels with these diets. The diets affected both the number of lipoprotein particles as well as the composition of LDL and HDL. Compared to the corn diet, cholesterol and saturated fat each increased the number of LDL particles by 17% and 9%, respectively, and the cholesterol per particle by 9%. The combination of saturated fat and cholesterol increased particle number by 18% and particle size by 24%. Switching from lard+ to lard, corn+, or corn diets reduced LDL-cholesterol of the group by 18%, 11%, and 28%, respectively, while a large inter-individual variability was noted. In summary, dietary fat and cholesterol affect lipid and lipoprotein levels as well as the particle number and chemical composition of both LDL and HDL. There is, however, considerable inter-individual heterogeneity in response to diet.

Following ingestion of a fatty meal there is an increase in concentration of phospholipids and proteins in the plasma high density lipoproteins (HDL). To evaluate the resulting changes in HDL subclasses, the plasma HDL of six subjects were analyzed 4 to 8 h after ingestion of 100 ml of corn oil or 80 ml of corn oil with four eggs. Isopycnic density gradient ultracentrifugation of fasting plasma showed two broad components of HDL: a major peak of density (d) 1.11 to 1.17 g/ml (HDL3) and a smaller peak of d 1.07 to 1.11 g/ml (HDL2). Following ingestion of either type of fatty meal, there was an increase in lipoprotein mass in both peaks of HDL and their centers of mass were shifted to lower density (1.140 leads to 1.120 to 1.130 g/ml; 1.095 leads to 1.090 g/ml). Calculation of changes in HDL concentration (lipemic minus fasting) showed that the alterations in density gradient profile were due to a major increase in lipoproteins of d 1.102 to 1.137 g/ml, a smaller increase in a separate lipoprotein peak of 1.080 to 1.102 g/ml, and a small decrease in lipoproteins of d 1.137 to 1.165 g/ml. Redistribution of HDL mass into larger, less dense lipoproteins was also demonstrated by agarose gel chromatography or by minimal spin density gradient ultracentrifugation in a vertical rotor. The increase in mass of 1.080 to 1.102 lipoproteins was largely due to increased concentrations of phospholipid, cholesterol ester, and apoA-I, while the increase in 1.102 to 1.137 lipoproteins was due to increased concentrations of apoA-I, apoA-II, phospholipids, cholesterol, and cholesterol esters. Analytical ultracentrifugation of representative samples within these density intervals showed lipoprotein species with molecular weights and sedimentation coefficients, respectively, of 378,000, 5.8 (d 1.080 to 1.095); 248,000, 3.5 (d 1.110 to 1.120); and 173,000, 1.6 (d 1.135 to 1.150). Polyacrylamide gradient gel electrophoresis showed that the 1.080 to 1.102 lipoproteins contained a single lipoprotein band of diameter approximately 10.7 nm; the 1.102 to 1.137 lipoproteins contained a single band which varied in size fro 10.0 to 9.2 nm: and the 1.137 to 1.165 lipoproteins contained three species of diameters approximately 9.2, 8.8, and 8.2 nm. Within density intervals, the molecular weights, sedimentation coefficients, and diameters of the different lipoproteins were similar in fasting and lipemic plasma. Calculation of average molecular compositions shows that the major incremental HDL of d approximately 1.12 g/ml could be derived by addition of lipids to the largest species of fasting HDL3. Within density intervals, the particle contents of apoA-I and apoA-II were unchanged during lipemia, suggesting that apoprotein transfer causes interconversion of existing HDL species or formation of new particles with the same content of apoA-I and apoA-II as existing species.

The inverse relationship between plasma levels of high density lipoprotein (HDL) and coronary heart disease rates has suggested that HDL might influence body stores of cholesterol. Therefore, we have investigated potential relationships between the parameters of body cholesterol metabolism and the plasma levels of HDL cholesterol and the major HDL apoproteins. The study involved 55 human subjects who underwent long-term cholesterol turnover studies, as well as plasma lipoprotein and apolipoprotein assays. In order to maximize the likelihood of detecting existing relationships, the subjects were selected to span a wide range of plasma levels of lipids, lipoproteins, and apolipoproteins. Single univariate correlation analyses suggested weak but statistically significant inverse relationships of HDL cholesterol and apoA-I levels with the following model parameters: production rate (PR), the mass of rapidly exchanging body cholesterol (M1), the minimum estimate of the mass of slowly exchanging body cholesterol (M3min), and of the mass of total exchangeable body cholesterol (Mtotmin). These correlations, however, were quantitatively quite small (/r/ = 0.28-0.42) in comparison to the strength of the univariate relationships between body weight and PR (r = 0.76), M1 (r = 0.61), M3min (r = 0.58), and Mtotmin (r = 0.78). Correlations for apoA-II and apoE levels were even smaller than those for apoA-I and HDL cholesterol. In additional analyses using multivariate approaches, HDL cholesterol, apoA-I, apoA-II, and apoE levels were all found not to be independent determinants of the parameters of body cholesterol metabolism (/partial r/ less than 0.17, P greater than 0.3 in all cases). Thus the weak univariate correlations reflect relationships of HDL cholesterol and apoA-I levels with physiological variables, such as body size, which are primarily related to the model parameters. We conclude that plasma levels of HDL cholesterol and apoproteins A-I, A-II, and E are not quantitatively important independent determinants of the mass of slowly exchanging body cholesterol or of other parameters of long-term cholesterol turnover in humans. These studies give no support to the hypothesis that the inverse relationship between HDL cholesterol levels and coronary heart disease rates is mediated via an influence of HDL on body stores of cholesterol.

The dynamics of human apoE metabolism were explored by examining the effects of alimentary lipemia and postheparin lipolysis on the plasma level and lipoprotein distribution of apoE. In the studies of alimentary lipemia, fasting and postprandial plasma samples were obtained from five normal adult males, each of whom drank 100 g of corn oil. Although no change in the plasma concentration of apoE accompanied alimentary lipemia, a major redistribution of apoE among lipoproteins occurred. The portion of apoE associated with triglyceride-rich lipoproteins as assessed by agarose column chromatography increased by a mean of 44%. Furthermore, in the two subjects in whom multiple postprandial samples were taken, there were striking linear correlations between plasma triglyceride concentrations and the fraction of apoE in triglyceride-rich lipoproteins (r = 0.96 and 0.73). In contrast, the plasma concentration of apoE fell in each of the seven studies of postheparin lipolysis. The fall averaged 17% of the control plasma apoE level. In hypertriglyceridemic patients, the decline in plasma triglyceride concentration preceded the decline in apoE concentration, suggesting that the decline in apoE was due to removal of remnants of triglyceride-rich lipoproteins. Lipoprotein fractionation demonstrated substantial loss of apoE from triglyceride-rich lipoproteins; the data suggested that this loss of apoE from triglyceride-rich lipoproteins was due both to removal of apoE from plasma and to transfer of apoE to an HDL fraction. During the recovery phase, as plasma triglyceride levels rose, opposite changes occurred: the plasma apoE level rose, apoE in triglyceride-rich lipoproteins increased in concentration, and apoE in HDL decreased in concentration. Furthermore, it became apparent during the recovery phase that apoE in triglyceride-rich lipoproteins was composed of two discrete subfractions. The first subfraction consisted of apoE on larger, probably recently synthesized lipoproteins; the second consisted of apoE on much smaller lipoproteins. These studies provide evidence in intact humans for a dynamic traffic of apoE between triglyceride-rich lipoproteins and high density lipoprotein. This traffic is a prominent phenomenon of normal alimentary lipemia and of lipolysis. By modulating the lipoprotein distribution of apoE, it probably plays a key functional role in lipoprotein metabolism.-Blum, C. B. Dynamics of apolipoprotein E metabolism in humans.

Detailed studies of apolipoprotein E (apoE)-containing lipoproteins in abetalipoproteinemia have been performed in an attempt to resolve the apparent paradox of a suppressed low density lipoprotein (LDL) receptor pathway in the absence of apoB-containing lipoproteins. It was hypothesized that apoE-containing high density lipoproteins (HDL) in abetalipoproteinemia might functionally substitute for LDL in regulation of cholesterol metabolism in these patients. The mean (+/-standard deviation) plasma concentration of apoE in nine patients with abetalipoproteinemia was 44.8+/-8.2 mug/ml, slightly higher than the corresponding value for a group of 50 normal volunteers, 36.3+/-11 mug/ml. Fractionation of plasma lipoproteins by agarose column chromatography or by ultracentrifugation indicated that in abetalipoproteinemia, plasma apoE was restricted to a subfraction of HDL. This was in contrast to the results obtained with plasma from 30 normal volunteers, in whom apoE was distributed between very low density lipoproteins (VLDL) and HDL. Consequently, the mean apoE content of HDL in abetalipoproteinemia (44.8 mug/ml) was more than twice that found in the normal volunteers (20.3 mug/ml).ApoE-rich and apoE-poor subfractions of HDL(2) were isolated by heparin-agarose affinity chromatography. ApoE comprised a mean of 81% of the protein mass of the apoE-rich subfraction. Compared with the apoE-poor subfraction, the apoE-rich HDL(2) was of larger mean particle diameter (141+/-7 vs. 115+/-15 A) and had a higher ratio of total cholesterol/protein (1.01+/-0.11 vs. 0.63+/-0.14). Plasma and HDL fractions from three patients were studied with respect to their ability to compete with (125)I-LDL in specific binding to receptors on cultured human fibroblasts. The binding activity of plasma from patients (per milligram of protein) was about half that of plasma from normal volunteers. All binding activity in the patients' plasma was found to reside in the HDL fraction. The binding activity of the patients' HDL (on a total protein basis) was intermediate between that of normal HDL and normal LDL. However, the large differences in binding between patients' HDL and normal HDL entirely disappeared when data were expressed in terms of the apoE content of these lipoproteins. This suggested that the binding activity was restricted to that subfraction of HDL particles that contain apoE. These apoE-rich HDL particles had calculated binding potencies per milligram of protein 10-25 times that of normal LDL. Direct binding studies using (125)I-apoE-rich HDL(2) and (125)I-apoE-poor HDL(2), confirmed the suggestion that binding is restricted to the subfraction of HDL particles containing apoE. The apoE-rich HDL(2) were found to be very potent inhibitors of 3-hydroxy-3-methyl-glutaryl coenzyme A reductase activity in cultured fibroblasts, providing direct evidence of the ability of these lipoproteins to regulate cholesterol metabolism. On the basis of binding potencies of apoE-rich HDL, apoE concentrations, and the composition of apoE-rich HDL, it could be calculated that apoE-rich HDL in abetalipoproteinemia have a capacity to deliver cholesterol to tissues via the LDL receptor pathway equivalent to an LDL concentration of 50-150 mg/dl of cholesterol. Thus, these apoE-rich lipoproteins are capable of producing the suppression of cholesterol synthesis and LDL receptor activity previously observed in abetalipoproteinemia.

Levels of apolipoprotein B, the protein component of low-density lipoproteins, correlate with the risk of coronary heart disease. We examined whether genetic variation in apolipoprotein B is associated with myocardial infarction by studying apolipoprotein B-gene restriction-fragment-length polymorphisms in 84 patients with myocardial infarction and an equal number of matched controls. Southern blot analysis with apolipoprotein B-gene probes, performed after DNA was digested with the endonucleases XbaI and EcoRI, revealed alleles that we designated as X1, X2, and X3 and as R1 and R2, respectively. Similar studies with the endonuclease MspI revealed alleles of many different sizes (the difference was due to an insertion-deletion polymorphism), which we grouped as larger and smaller alleles and designated as ID1 and ID2, respectively. The frequencies of the X1, R1, and ID1 alleles were all significantly higher (P less than 0.01) in the cases than in the controls. None of the alleles, however, was significantly associated with variation in levels of low-density lipoprotein cholesterol or apolipoprotein B, and the functional importance of these alleles is therefore uncertain. Nonetheless, in addition to quantitative variation in apolipoprotein B levels in plasma, genetic variation at the apolipoprotein B locus may be a new and independent risk factor for myocardial infarction.

To define the metabolic defect in Tangier disease, we studied the kinetics of [125I]-high-density lipoprotein apolipoproteins (apolipoproteins A-I and A-II) in 11 normal subjects, two obligate heterozygotes, and two homozygotes. Mean synthesis of apolipoproteins A-1 and A-11 was 8.24 mg per kilogram per day in the normal group, 7.94 in heterozygotes and 3.66 in homozygotes. The mean plasma-residence time for both apolipoproteins was 5.21 days in the normal subjects, 3.41 days in heterozygotes, and 0.52 days in homozygotes. In normal subjects and heterozygotes the apolipoproteins were catabolized at similar rates, whereas in homozygotes apolipoprotein A-I was catabolized at a much greater fractional rate than apolipoprotein A-II. These findings indicate that the deficiency of these apolipoproteins in Tangier disease is largely due to rapid and altered catabolism.

Nine normolipidemic males (18-37 years) were fed formula diets containing (as % of calories) egg white protein (15%), glucose polymer:sucrose, 3:1 (54%), and fats (31%) as one of the following: corn oil (corn), corn oil plus 1 gram/day cholesterol (corn+), coconut oil (coco), coconut oil plus 1 gram/day cholesterol (coco+). Two dietary periods of 18 days each were separated by 1 month during which plasma lipid levels returned to prestudy values. A given dietary period consisted of 9 days of either corn or coco feeding allowed by 9 days of corn+ or coco+, respectively. Fasting plasma samples were taken the last 3 days of each 9-day interval. Lipids were determined by standard procedures and the apoE levels in lipoprotein fractions isolated by discontinuous density gradient ultracentrifugation were determined by radioimmunoassay. The biochemical variables measured were: total plasma, VLDL, IDL + LDL, and HDL, cholesterol, triglyceride, and apoE levels, as well as the apoE of plasma d greater than 1.17 g/ml. The effects of apoE phenotype, the type of dietary oil (corn versus coco), the presence or absence of dietary cholesterol, and the day of sampling within triplicates on the above variables were assessed statistically. The type of oil had the only significant effect on any variable. At P less than 0.01, the coconut oil diets were associated with significant elevations (as compared to corn oil) of the following nine variables: total, VLDL, IDL + LDL, and HDL cholesterol; total, VLDL, and IDL + LDL apoE; total and VLDL triglycerides.

Although hyperlipidemia is a common feature of the nephrotic syndrome, the distribution of cholesterol among the plasma lipoproteins and the mechanism of the enhanced hepatic synthesis of lipoprotein lipids are not well understood. We studied the distribution of cholesterol among the plasma lipoproteins, as well as the relation between total cholesterol and plasma albumin concentration, oncotic pressure, and viscosity in 20 consecutive adult patients with uncomplicated nephrotic syndrome. The total plasma cholesterol (mean +/- S.D., 302 +/- 100 mg per deciliter [7.8 +/- 2.6 mmol per liter]) and low-density-lipoprotein cholesterol concentrations (215 +/- 89 mg per deciliter [5.6 +/- 2.3 mmol per liter]) were elevated in most patients, but the high-density-lipoprotein cholesterol level was normal or low (46 +/- 18 mg per deciliter [1.2 +/- 0.5 mmol per liter]) in 95 per cent of the patients. Thus, many hypercholesterolemic patients with unremitting nephrotic syndrome may be at increased risk for atherosclerotic heart disease. A significant inverse correlation was found between the total plasma cholesterol concentration and both the plasma albumin concentration (r = -0.528) and the plasma oncotic pressure (r = -0.674), but not the plasma viscosity (r = +0.319). Enhanced hepatic synthesis of lipoprotein lipids may be stimulated by a decreased plasma albumin concentration or oncotic pressure but does not appear to be due to changes in plasma viscosity.

To explore the role of the human intestine as a source of apolipoproteins, we have studied intestinal lipoproteins and apoprotein secretion in two subjects with chyluria (mesenteric lymphatic-urinary fistulae). After oral corn oil, apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II) output in urine increased in parallel to urinary triglyceride. One subject, on two occasions, after 40 g of corn oil, excreted 8.4 and 8.6 g of triglyceride together with 196 and 199 mg apoA-I and on one occasion, 56 mg apoA-II. The other subject, after 40 g corn oil, excreted 0.3 g triglyceride and 17.5 mg apoA-I, and, after 100 g of corn oil, excreted 44.8 mg apoA-I and 5.8 mg apoA-II. 14.5+/-2.1% of apoA-I and 17.7+/-4.3% of apoA-II in chylous urine was in the d < 1.006 fraction (chylomicrons and very low density lipoprotein). Calculations based on the amount of apoA-I and apoA-II excreted on triglyceride-rich lipoproteins revealed that for these lipid loads, intestinal secretion could account for 50 and 33% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Similarly, subject 2 excreted 48-70% and 14% of the calculated daily synthetic rate of apoA-I and apoA-II, respectively. Chylous urine contained chylomicrons, very low density lipoproteins and high density lipoproteins, all of which contained apoA-I. Chylomicrons and very low density lipoproteins contained a previously unreported human apoprotein of 46,000 mol wt. We have called this apoprotein apoA-IV because of the similarity of its molecular weight and amino acid composition to rat apoA-IV. In sodium dodecyl sulfate gels, chylomicron apoproteins consisted of apoB 3.4+/-0.7%, apoA-IV 10.0+/-3.3%, apoE 4.4+/-0.3%, apoA-I 15.0+/-1.8%, and apoC and apoA-II 43.3+/-11.3%. Very low density lipoprotein contained more apoB and apoA-IV and less apoC than chylomicrons. Ouchterlony immunodiffusion of chylomicron apoproteins revealed the presence of apoC-I, apoC-II, and apoC-III. In contrast, plasma chylomicrons isolated during a nonchyluric phase revealed a markedly altered chylomicron apoprotein pattern when compared with urinary chylomicrons. The major apoproteins in plasma chylomicrons were apoB, apoE, and the C peptides: no apoA-I or apoA-IV were present in sodium dodecyl sulfate gels indicating that major changes in chylomicron apoproteins occur during chylomicron metabolism. When incubated in vitro with plasma, urinary chylomicrons lost apoA-I and apoA-IV and gained apoE and apoC. Loss of apoA-I and apoA-IV was dependent upon the concentration of high density lipoproteins in the incubation mixture. These studies demonstrate that the human intestine secretes significant amounts of apoA-I and apoA-II during lipid absorption. Subsequent transfer of apoproteins from triglyceride-rich lipoproteins to other plasma lipoproteins may represent a mechanism whereby the intestine contributes to plasma apoprotein levels.