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BACKGROUND - Postprandial lipemia (PPL) is likely a risk factor for cardiovascular disease but these changes have not been well described and characterized in a large cohort. We assessed acute changes in the size and concentration of total and subclasses of LDL, HDL, and VLDL particles in response to a high-fat meal. Participants (n = 1048) from the Genetics of Lipid-Lowering Drugs and Diet Network (GOLDN) Study who ingested a high-fat meal were included in this analysis. Lipids were measured at 0 hr (fasting), 3.5 hr, and 6 hr after a standardized fat meal. Particle size distributions were determined using nuclear magnetic resonance spectroscopy. Analyses were stratified by baseline triglycerides (normal vs. elevated) and gender. The effect of PPL on changes in lipoprotein subclasses was assessed using repeated measures ANOVA.
RESULTS - Postprandially, LDL-C, HDL-C, VLDL-C, and triglycerides increased regardless of baseline triglyceride status, with the largest increases in VLDL-C and TG; however, those with elevated triglycerides demonstrated larger magnitude of response. Total LDL particle number decreased over the 6-hour time interval, mostly from a decrease in the number of small LDL particles. Similarly, total VLDL particle number decreased due to reductions in medium and small VLDL particles. Large VLDL particles and chylomicrons demonstrated the largest increase in concentration. HDL particles demonstrated minimal overall changes in total particle number.
CONCLUSIONS - We have characterized the changes in LDL and VLDL particle number, and their subclass patterns following a high-fat meal.
Apolipoprotein E (apoE) deficiency causes severe hyperlipidemia and atherosclerosis in humans and in gene-targeted mice. Although the majority of apoE in plasma is of hepatic origin, apoE is synthesized by a variety of cell types, including macrophages. Because macrophages derive from hematopoietic cells, bone marrow transplantation was used to examine the potential of apoE synthesized by bone marrow-derived cells to correct the hyperlipidemia and atherosclerosis caused by apoE deficiency. After transplantation of bone marrow from mice with the normal apoE gene into apoE-deficient mice, apoE was detected in serum and promoted clearance of lipoproteins and normalization of serum cholesterol levels. ApoE-deficient mice given transplants of normal bone marrow showed virtually complete protection from diet-induced atherosclerosis.
Levels of plasma very low density lipoprotein (VLDL) and low density lipoprotein (LDL) constituents increase with age. In an attempt to further define the mechanisms responsible for these changes, kinetic studies of VLDL and LDL apolipoprotein (apo) B-100 were carried out in 19 normolipidemic male subjects with plasma total cholesterol and triglyceride levels below the 90th percentile whose ages ranged from 24 to 73 years. Subjects were maintained on standardized diets consisting of 47-49% of calories as carbohydrate, 15% protein, and 36-40% fat (15-17% saturated, 15-17% monounsaturated, 6% polyunsaturated) with 150 mg cholesterol/1000 kcal. At the end of the diet period, the metabolism of apoB-100 within VLDL, intermediate density lipoprotein (IDL), and LDL was studied in the fed state using a primed-constant infusion of [2H3]leucine. Data were fit to a multicompartmental model to determine residence times and production rates of apoB-100 in each fraction. There were significant positive correlations between age and VLDL, IDL, and LDL apoB-100 concentrations (r = 0.50, 0.62, and 0.69; P = 0.03, 0.004, and 0.001, respectively). There was a positive correlation between age and the production rate of VLDL apoB-100 (r = 0.50, P = 0.03), but there was no significant relationship between age and either IDL or LDL apoB-100 production rates. Age was also positively correlated with the residence time of LDL apoB-100 (r = 0.68 P = 0.001). Our data suggest that the age-associated increase in VLDL apoB-100 is due to an increased production rate of this constituent, whereas the age-associated increase in LDL apoB-100 is due to an increased residence time of these particles in plasma.
Previous studies in our laboratory have shown that very-low-density lipoproteins (VLDL) synthesized by the intestine of the diet-induced hypercholesterolemic rat are enriched in cholesteryl esters and unesterified cholesterol compared with intestinal VLDL from control rats. In these studies, we isolated and characterized nascent intestinal Golgi intermediate-density lipoproteins (IDL, d 1.006-1.040 g/ml) and studied isotope incorporation into apoliproteins of Golgi VLDL from control and hypercholesterolemic rats. IDL were triacylglycerol-rich lipoproteins but contained more cholesteryl ester and protein than the corresponding Golgi VLDL fractions. IDL from hypercholesterolemic rats were enriched in cholesteryl esters to a greater extent than IDL from control rats. The apolipoprotein patterns of IDL fractions were the same as those of intestinal Golgi VLDL, consisting of apolipoproteins (apo) B-48, A-I and A-IV. Time-course isotope incorporation curves for apo A-I and A-IV in Golgi VLDL were similar, but they differed from curves for apo B-48. None of these curves was markedly altered in the hypercholesterolemic rat. We conclude that the major effect of increased dietary cholesterol on intestinal lipoprotein biosynthesis is to increase the percentage of cholesteryl esters in Golgi lipoproteins. Dietary cholesterol does not alter the apolipoprotein composition of Golgi lipoproteins, nor does it have a significant effect on the pattern of isotope incorporation into apolipoproteins of Golgi VLDL. The effect of cholesteryl ester enrichment on the subsequent metabolism of these particles in the circulation and the effect of these particles on hepatic lipoprotein production remain to be determined.