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 v3.01+/-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 v29+/-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.     

Small dense LDL phenotype is associated with postprandial increases of large VLDL and remnant-like particles in patients with acute myocardial infarction

BACKGROUND: The small dense low-density lipoprotein (LDL) phenotype (pattern B), high concentrations of remnant-like particles (RLPs), and postprandial lipemia are newly recognized risk factors for coronary heart disease (CHD). However, the associations of these lipoprotein abnormalities remain unclear. The aim of this study was to investigate the relationships among LDL phenotype, very-low-density lipoprotein (VLDL) subclasses, and postprandial lipoprotein metabolism in CHD patients. METHOD: We performed an oral fat tolerance test in 32 patients with acute myocardial infarction and compared the following parameters between patients characterized by either large buoyant LDL (pattern A) versus pattern B: lipids and apolipoproteins (apo) in the plasma and Svedberg flotation rates (Sf) >400 (chylomicron), Sf 60-400 (large VLDL), and Sf 20-60 (small VLDL) fractions. RESULT: Fasting levels of triglyceride, RLP-cholesterol and RLP-triglyceride were slightly higher in the pattern B patients. Postprandial increases of RLP-cholesterol and the cholesterol and triglyceride of large VLDL fractions were significantly greater in the pattern B patients. The areas under the curves of cholesterol, triglyceride, and apo-B in large VLDL fractions were significantly higher in pattern B, while those in small VLDL were not. RLP-cholesterol and RLP-triglyceride in fasting and fed states correlated very highly with the corresponding cholesterol and triglyceride concentrations in large VLDL fractions. CONCLUSION: These results suggest that postprandial increase of large VLDL fractions and RLPs contribute to the formation of small dense LDL in CHD patients.     

Effects of atorvastatin on the clearance of triglyceride-rich lipoproteins in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) patients have an impaired catabolism of postprandial triglyceride (TG)-rich lipoproteins (TRLs). We investigated whether atorvastatin corrects the delayed clearance of large TRLs in FCHL by evaluating the acute clearance of Intralipid (10%) and TRLs after oral fat-loading tests. Sixteen matched controls were included. Atorvastatin reduced fasting plasma TG (from 3.6 +/- 0.4 to 2.5 +/- 0.3 mM; mean +/- SEM) without major effects on fasting apolipoprotein B48 (apoB48) and apoB100 in large TRLs. Atorvastatin significantly reduced fasting intermediate density lipoprotein (Svedberg flotation, 12-20)-apoB100 concentrations. After Intralipid, TG in plasma and TRL showed similar kinetics in FCHL before and after atorvastatin treatment, although compared with controls, the clearance of large TRLs was only significantly slower in untreated FCHL, suggesting an improvement by atorvastatin. Investigated with oral fat-loading tests, the clearance of very low density lipoprotein (Sf20-60)-apoB100 improved by 24%, without major changes in the other fractions. The most striking effects of atorvastatin on postprandial lipemia in FCHL were on hepatic TRL, without major improvements on intestinal TRLs. Fasting plasma TG should be reduced more aggressively in FCHL to overcome the lipolytic disturbance causing delayed clearance of postprandial TRLs.     

Effects of a moderate exercise session on postprandial lipoproteins, apolipoproteins and lipoprotein remnants in middle-aged men

Prior moderate exercise reduces postprandial triglyceride concentrations. Its effects on the concentrations, compositions and potential atherogenicity of lipoprotein subfractions were investigated in the present study. Twenty normoglycaemic middle-aged men each underwent two fat tolerance tests (blood taken fasting and for 8 h after a meal containing 80 g fat and 70 g carbohydrate). On the afternoon before one test, subjects performed a 90-min treadmill walk (exercise); no exercise was performed before the control test. Prior exercise significantly reduced postprandial concentrations of chylomicrons (Sf >400) by 28.6% (absolute reduction 14.6 mg dl(-1)), of large VLDL1 (Sf 60-400) by 34.4% (39.7 mg dl(-1)) and of small VLDL2 (Sf 20-60) by 23.0% (9.6 mg dl(-1)). Over 95% of VLDL1 and VLDL2 comprised apolipoprotein (apo) B100-containing particles. Exercise also reduced postprandial remnant-like lipoprotein cholesterol (by 35%) and triglyceride concentrations (by 29%). Postprandial apo CIII/apo B and apo E/apo B ratios in VLDL1 were lower following exercise. Postprandial cholesteryl ester/triglyceride ratios were lower in VLDL1 and VLDL2 and higher in HDL2 following exercise. These data suggest that the effect of prior moderate exercise on VLDL1 is quantitatively greater than its effect on chylomicrons and that, in addition to reducing lipoprotein concentrations, exercise induces compositional changes to lipoprotein species which are likely to influence their metabolism and atherogenicity.     

Differential effect of fenofibrate and atorvastatin on in vivo kinetics of apolipoproteins B-100 and B-48 in subjects with type 2 diabetes mellitus with marked hypertriglyceridemia

The specific impact of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates on the in vivo metabolism of apolipoprotein (apo) B has not been systematically investigated in patients with type 2 diabetes mellitus with high plasma triglyceride (TG) levels. Therefore, the objective of this 2-group parallel study was to examine the differential effects of a 6-week treatment with atorvastatin or fenofibrate on in vivo kinetics of apo B-48 and B-100 in men with type 2 diabetes mellitus with marked hypertriglyceridemia. Apolipoprotein B kinetics were assessed at baseline and at the end of the intervention using a primed constant infusion of [5,5,5-D(3)]-l-leucine for 12 hours in the fed state. Fenofibrate significantly decreased plasma TG levels with no significant change in plasma low-density lipoprotein cholesterol (LDL-C) and apo B levels. On the other hand, atorvastatin significantly reduced plasma levels of TG, LDL-C, and apo B. After treatment with fenofibrate, very low-density lipoprotein (VLDL) apo B-100 pool size (PS) was decreased because of an increase in the fractional catabolic rate (FCR) of VLDL apo B-100. No significant change was observed in the kinetics of LDL apo B-100. Moreover, fenofibrate significantly decreased TG-rich lipoprotein (TRL) apo B-48 PS because of a significant increase in TRL apo B-48 FCR. After treatment with atorvastatin, VLDL and IDL apo B-100 PSs were significantly decreased because of significant elevations in the FCR of these subfractions. Low-density lipoprotein apo B-100 PS was significantly lowered because of a tendency toward decreased LDL apo B-100 production rate (PR). Finally, atorvastatin reduced TRL apo B-48 PS because of a significant decrease in the PR of this subfraction. These results indicate that fenofibrate increases TRL apo B-48 as well as VLDL apo B-100 clearance in men with type 2 diabetes mellitus with marked hypertriglyceridemia, whereas atorvastatin increases both VLDL and IDL apo B-100 clearance and decreases TRL apo B-48 and LDL apo B-100 PR.     

Effect of acute variations in dietary fat and carbohydrate intake on retinyl ester content of intestinally derived lipoproteins.

Vitamin A was administered to eight patients with noninsulin-dependent diabetes mellitus in conjunction with the two different test meals containing (as percentage of total calories) either 15% protein, 60% carbohydrate (CHO), and 25% fat or 15% protein, 40% CHO, and 45% fat. The vitamin A and test meals were given at noon (4 h after a standard breakfast), and blood was obtained hourly from noon to midnight for measurement of plasma glucose, insulin, triglyceride (TG), and cholesterol concentrations; concentrations of TG and cholesterol in Sverdberg floatation (Sf) unit above 400 and Sf 20-400 lipoproteins; retinyl ester concentration in plasma; and both Sf more than 400 and Sf 20-400 lipoproteins. The postprandial TG response in plasma, Sf more than 400 lipoproteins, and Sf 20-400 lipoproteins from noon to midnight was only slightly higher than values seen after consumption of the 60% CHO diet, which contained much less fat (25% vs. 45%) and the retinyl ester concentration was actually higher in both lipoprotein fractions after the diet containing the smallest amount of fat (60% CHO). Furthermore, the cholesterol concentration in the plasma and two lipoprotein fractions was identical after the two diets, despite the great difference in fat content. These data indicate that the acute ingestion of high CHO (60%), low fat (25%) diets by patients with noninsulin-dependent diabetes mellitus led to little or no decrease in postprandial plasma or lipoprotein TG or cholesterol concentrations and an actual increase in concentration of potentially atherogenic small chylomicron and/or chylomicron remnants.     

Relationships between the responses of triglyceride-rich lipoproteins in blood plasma containing apolipoproteins B-48 and B-100 to a fat-containing meal in normolipidemic humans.

The concentration of triglyceride-rich lipoproteins containing apolipoprotein (apo) B-48 (chylomicrons) and apo B-100 (very low density lipoproteins) was measured in blood plasma of healthy young men after an ordinary meal containing one-third of daily energy and fat. Plasma obtained in the postabsorptive state and at intervals up to 12 hr after the meal was subjected to immunoaffinity chromatography against a monoclonal antibody to apo B-100 that does not bind apo B-48 and a minor fraction of apo B-100 rich in apo E. Measurements of the concentrations of components of the total and unbound triglyceride-rich lipoproteins separated from plasma by ultracentrifugation showed that about 80% of the increase in lipoprotein particle number was in very low density lipoproteins containing apo B-100 and only 20% was in chylomicrons containing apo B-48 that carry dietary fat from the intestine. The maximal increments and the average concentrations of apo B-48 and B-100 during the 12 hr were highly correlated (r2 = 0.80), suggesting that preferential clearance of chylomicron triglycerides by lipoprotein lipase leads to accumulation of hepatogenous very low density lipoproteins during the alimentary period. The composition of the bulk of very low density lipoproteins that were bound to the monoclonal antibody changed little and these particles contained about 90% of the cholesterol and most of the apo E that accumulated in triglyceride-rich lipoproteins. The predominant accumulation of very low density lipoprotein rather than chylomicron particles after ingestion of ordinary meals is relevant to the potential atherogenicity of postprandial lipoproteins.     

Improved metabolic control reduces the number of postprandial apolipoprotein B-48-containing particles in type 2 diabetes

Postprandial lipoproteins are raised in diabetes and there is increasing evidence for the atherogenicity of the chylomicron remnant. Increased postprandial cholesteryl ester transfer has also been demonstrated in diabetes and may contribute to the atherogenic lipoprotein profile. The present study examined the effect of improving metabolic control on postprandial lipoproteins in 13 Type 2 diabetic patients. Blood was taken fasting and at 2-h intervals following a high fat, 1100 kcal meal. Patients were brought into good control by intensified dietary advice and oral hyperglycaemic agents or insulin if blood glucose failed to respond. Fasting and postprandial cholesteryl ester transfer protein (CETP) and lecithin:cholesteryl acyltransferase (LCAT) were determined in six patients. Lipoproteins were isolated by sequential ultracentrifugation. Chylomicron and very low density lipoprotein (VLDL) apolipoprotein B-48 and apolipoprotein B-100 were isolated by polyacrylamide gradient gel electrophoresis and quantified by densitometric scanning. CETP and LCAT were determined by an endogenous method which determined cholesterol esterification and transfer between the patients' lipoproteins. There was a significant reduction in postprandial chylomicron apo B-48 (P<0.005), apo B-100 (P<0.0005) and chylomicron cholesterol (P<0.001) following improved diabetic control. The chylomicron lipid/apo B ratio increased with improved control (P<0.01). Postprandial CETP and LCAT were significantly reduced in good control (P<0.01 and P<0.05, respectively) and there were significant changes in HDL composition. The study shows that improvement in metabolic control in Type 2 diabetic patients leads to a reduction in postprandial chylomicron particles and less transfer of cholesterol to apo B-containing lipoproteins.     

Isolation of remnant particles by immunoseparation: a new approach for investigation of postprandial lipoprotein metabolism in normolipidemic subjects.

Abnormal postprandial lipoproteins are associated with an increased risk for cardiovascular disease. Postprandial remnant lipoproteins were usually analyzed indirectly using retinyl esters (RE) as a chylomicron core label during an oral fat loading test. Apo B-100 containing VLDL remnants in addition to apo B-48 containing chylomicron remnants can also be directly quantified using the RLP-Cholesterol Immunoseparation Assay. This recently available method uses monoclonal antibodies to apo A-I and apo B-100 to remove non-remnant lipoproteins and quantifies cholesterol in the remaining apo E-rich remnant fraction. In the present study we compared the analysis of retinyl ester with the immuno-based RLP-Cholesterol (RLP-C) analysis in measuring postprandial remnant lipoproteins in healthy normolipidemic subjects. Sixteen healthy normolipidemic subjects were selected for this study. Postprandial plasma retinyl esters peaked at 5.0+/-1.2 h, whereas plasma RLP-C showed a peak significantly earlier (P<0.001) at 3.5+/-0.6 h. In comparison, postprandial plasma TG and FFA peaked at 3.3+/-1.1 h (P<0.005 compared to retinyl esters). In conclusion, levels of RLP-C changed, during the postprandial phase, in parallel with plasma TG and FFA concentrations and peaked significantly earlier than retinyl esters. Postprandial measurements of RLP-C can be considered as a fast alternative method for the more laborious retinyl-ester analysis in clinical studies.     

Postprandial apolipoprotein B48-and B100-containing lipoproteins in type 2 diabetes: do statins have a specific effect on triglyceride metabolism?

There is little information about the effect of an alteration of low-density lipoprotein (LDL) turnover on chylomicron and very-low-density lipoprotein (VLDL) metabolism, yet chylomicron remnant particles are thought to be particularly atherogenic. This study examined the effect of inhibition of cholesterol synthesis on postprandial lipoproteins. Eight type 2 diabetic patients were examined before treatment with the 3-hydroxy-3-methyl glutaryl coenzyme A (HMGCoA) reductase inhibitor cerivastatin, after 4 weeks on active treatment, and 4 weeks after stopping treatment. On each occasion, blood was collected fasting and at 2-hour intervals for up to 8 hours after a high-fat meal. Chylomicrons and VLDLs were isolated by sequential ultracentrifugation. Compositional analysis was performed including the measurement of apolipoprotein B48 (apo B48) and apo B100 using polyacrylamide gradient gel electrophoresis. During statin treatment, there was a significant reduction in the postprandial chylomicron apo B48 area under the curve (AUC) from 23 +/- 16 to 17 +/- 10 (P < .01) and apo B100 in the chylomicron fraction from 166 +/- 148 to 70 +/- 70 (P < .05). Postprandial cholesterol (362 +/- 193 to 74 +/- 39, P < .005), triglyceride (2,222 +/- 1,440 to 746 +/- 329), and phospholipid (518 +/- 267 to 205 +/- 94) also decreased (P < .005). In the VLDL fraction, the postprandial cholesterol and triglyceride AUC were significantly reduced by statin (316 +/- 228 to 171 +/- 78, P < .05, and 1,733 +/- 833 to 857 +/- 468, P < .02, respectively). Four weeks after cessation of treatment, the chylomicron fraction triglyceride AUC had returned to the pretreatment level, but postprandial chylomicron cholesterol and VLDL cholesterol, triglyceride, and phospholipid were significantly lower than baseline (P < .05). Plasma total cholesterol and LDL cholesterol were significantly reduced with treatment (6.2 +/- 0.5 to 4.3 +/- 1.0 mmol/L, P < .001, and 4.5 +/- 0.4 to 2.8 +/- 1.0 mmol/L, P < .01, respectively) and returned to baseline following cessation of treatment. Fasting plasma triglycerides decreased significantly on treatment (2.4 +/- 1.0 to 1.7 +/- 0.2 mmol/L, P < .05) but remained significantly lower than baseline 4 weeks later (1.8 +/- 0.3 mmol/L, P < .05). This study suggests major postprandial lipoprotein changes on statin therapy which may account, in part, for the beneficial effects of statins in the prevention of myocardial infarction.     

Fasting and postprandial apolipoprotein B-48 levels in healthy, obese, and hyperlipidemic subjects

Apolipoprotein (apo) B-48 is the only specific marker of intestinal lipoproteins. We evaluated a novel enzyme-linked immunosorbent assay (ELISA) standardized with recombinant apo B-48 to measure apo B-48 in plasma and triglyceride-rich lipoproteins (TRLs, density <1.006 g/mL). Coefficients of variation were less than 2.5%. Assay values correlated well (r = 0.82, P < .001) with values obtained by gel scanning of TRLs (n = 75 samples); however, the gel scanning method yielded values that were about 50% lower than ELISA values. About 60% to 70% of apo B-48 was found in TRLs. In 12 healthy subjects, median fasting plasma apo B-48 levels were 0.51 mg/dL and were increased by 121% to 147% in the fed state. In 63 obese subjects, median fasting apo B-48 values were 0.82 mg/dL; and feeding resulted in almost no change in total cholesterol, non–high-density lipoprotein cholesterol, or total apo B values, whereas triglyceride, remnant lipoprotein cholesterol, and apo B-48 levels were significantly higher (P < .05; by +73%, +58%, and +106%), and direct low-density lipoprotein cholesterol and direct high-density lipoprotein cholesterol were significantly lower (P < .001, by −13% and −20%) than fasting values. Relative to controls, 270 hyperlipidemic subjects had significantly higher (P < .001, +115%) fasting total apo B and higher apo B-48 values (P = .06, +37%). Our data indicate that the apo B-48 ELISA tested provides highly reproducible results and is excellent for research studies. Median apo B-48 values in healthy subjects are about 0.5 mg/dL and increase more than 100% in the fed state. Elevated levels are observed in obese and hyperlipidemic subjects.     

Postprandial lipemia associates with liver fat content

CONTEXT/OBJECTIVE: Postprandial lipemia and low adiponectin represent novel risk factors for vascular disease. This study aimed to determine whether liver fat content and adiponectin are predictors of postprandial triglyceride (TG)-rich lipoproteins (TRL). PATIENTS/INTERVENTIONS: Twenty-nine men were allocated into subgroups with either low (< or =5%) or high (>5%) liver fat measured with magnetic resonance proton spectroscopy. Subjects underwent an oral fat tolerance test with measurements of postprandial TG, cholesterol, apolipoprotein B-48 (apoB-48), and apoB-100 in TRL fractions, a euglycemic hyperinsulinemic clamp, and determination of abdominal fat volumes by magnetic resonance imaging. RESULTS: Subjects with high liver fat displayed increased response of postprandial lipids in plasma, chylomicron, and very-low-density lipoprotein 1 (VLDL1) (Svedberg flotation rate 60-400) fractions. Liver fat correlated positively with postprandial responses (area under the curve) of TG (r = 0.597; P = 0.001), cholesterol (r = 0.546; P = 0.002), apoB-48 (r = 0.556; P = 0.002), and apoB-100 (r = 0.42; P = 0.023) in the VLDL1 fraction. Respective incremental areas under the curve correlated significantly with liver fat. Fasting adiponectin levels were inversely correlated with both postprandial lipids and liver fat content. Liver fat remained the only independent correlate in a multiple linear regression analysis for chylomicron and VLDL1 responses. CONCLUSIONS: Liver fat content is a close correlate of postprandial lipids predicting the responses of TRL in chylomicrons and VLDL1 better than measures of glucose metabolism or body adiposity. Low adiponectin concentration is closely linked to high liver fat content and impaired TRL metabolism. High liver fat content associated with postprandial lipemia represents potential risk factors for cardiovascular disease.     

Alterations of lipids and apolipoprotein CIII in very low density lipoprotein subspecies in type 2 diabetes

Aims/hypothesis Very low density lipoprotein (VLDL) particles are heterogeneous, comprising two main subspecies, VLDL 1 (Sf 60-400) and VLDL 2 (Sf 20-60). The aim of the study was to examine the distribution and composition of VLDL subspecies in type 2 diabetes.Subjects, materials and methods We studied the composition and concentration of triglyceride-rich lipoproteins (TRLs) in 217 type 2 diabetic patients and 93 control subjects between 50 and 75 years of age. Lipoprotein subspecies were separated by density-gradient ultracentrifugation. Apolipoprotein (apo) CIII and apo E in plasma and apo CIII in TRL subspecies were measured by nephelometry and apo CII in serum by a commercial kit using a single radial immunodiffusion method.Results The concentrations of VLDL 1, VLDL 2 and intermediate density lipoprotein were significantly increased in type 2 diabetes subjects, the change being most marked for VLDL 1. There was a strong linear correlation between VLDL 1 triglycerides and plasma triglycerides in both groups (r=0.879, p<0.001 and r=0.899, p<0.001). Diabetic subjects had markedly higher plasma ratios of apo CII:apo CIII and apo CIII:apo E. Despite elevated plasma apo CIII, type 2 diabetic subjects had a relative deficiency of apo CIII in all TRL subspecies, suggesting profound disturbances of apo CIII metabolism.Conclusions/interpretation The elevation of VLDL 1 triglycerides is the major determinant of plasma triglyceride concentration in normal subjects and in type 2 diabetic individuals. Both apo CIII and apo E metabolism are disturbed in type 2 diabetes.     

Action of ciprofibrate in type IIb hyperlipoproteinemia: modulation of the atherogenic lipoprotein phenotype and stimulation of high-density lipoprotein-mediated cellular cholesterol efflux

The effects of ciprofibrate (100 mg/d) on apolipoprotein (apo)B- and apoAI-containing lipoprotein subclasses, cholesteryl ester (CE) transfer protein activity, and plasma high-density lipoprotein (HDL)-mediated cellular cholesterol efflux were evaluated in 10 patients displaying type IIB hyperlipidemia. Plasma concentrations of large very low-density lipoprotein (VLDL)-1 (Sf 60-400) and of small VLDL-2 (Sf 20-60) were markedly diminished after fibrate treatment (-40%, P = 0.001; and -25%, P = 0.003, respectively). We observed a reduction (-17%; P = 0.005) in plasma low-density lipoprotein (LDL) levels resulting from significant reductions in concentrations of dense LDL particles (-46%; P < 0.0001). Ciprofibrate induced elevation in plasma total HDL (+13%; P = 0.005) levels; such elevation occurred preferentially in HDL-3 (+22%; P = 0.009). Marked reduction in numbers of atherogenic apoB100-containing particle acceptors was associated with a 25% decrease (P < 0.02) in CE transfer protein-mediated CE transfer from HDL. Finally, a significant fibrate-mediated elevation (+13%; P = 0.01 compared with baseline) in the capacity of plasma from type IIB subjects to mediate free cholesterol efflux from scavenger receptor class B, type I-expressing Fu5AH hepatoma cells was observed. In conclusion, the action of ciprofibrate in type IIB dyslipidemia leads to preferential reduction in particle numbers of atherogenic VLDL-1, VLDL-2, and dense LDL and, concomitantly, to elevation in HDL-3 levels that are associated with stimulation of HDL-mediated cellular free cholesterol efflux through the scavenger receptor class B, type I receptor pathway.     

Slower catabolism of apo B48 than of apo B100 in triglyceride-rich lipoproteins during heparin infusions in type 5 hyperlipoproteinemic subjects

The catabolism of chylomicrons plus remnants and of VLDL was studied in four subjects with type 5 hyperlipoproteinemia. Large triglyceride-rich lipoproteins Sf greater than 60 were labeled with 125I, reinjected, and the removal of radioactivity in apo B48 and in apo B100 was measured before and during intravenous heparin. The constant infusion of heparin stimulated lipolytic activity and accelerated the disappearance of apo B100 radioactivity (VLDL and their remnants) from the Svedberg flotation unit (Sf) greater than 60 fraction by 27%, 33%, 51%, and 55% in the four subjects. However, the removal rate of radioactivity in apo B48 (chylomicrons and their remnants) was unaffected by heparin in three subjects; in the fourth the fall in radioactivity was less in apo B48 than in apo B100. There were corresponding rises with heparin in Sf 12 to 60 apo B48 radioactivity in only one subject. Thus, increased plasma lipolytic activity accelerated chylomicron (remnant) catabolism very much less than of VLDL (remnant) removal of type 5 hyperlipoproteinemic subjects. It suggests that a major defect leading to type 5 hyperlipoproteinemia is failure of chylomicrons to become degraded to the point where the particles can interact optimally with the hepatic chylomicron remnant receptor.     

The apolipoprotein CI content of triglyceride-rich lipoproteins independently predicts early atherosclerosis in healthy middle-aged men

OBJECTIVES: In this study, we examined the apolipoprotein (apo) CI content of triglyceride-rich lipoproteins (TRLs) in relation to established coronary heart disease (CHD) risk factors and early atherosclerosis. BACKGROUND: In Western society, the postprandial state constitutes a nearly constant stress on the vasculature and the metabolism of lipoproteins. Delayed clearance of postprandial TRL remnants has repeatedly been associated with premature CHD and may include the enrichment of these remnants with apoCI. METHODS: We examined 72 healthy 50-year-old men with an apoE3/E3 genotype who had undergone an oral fat load test and B-mode ultrasound examination of the intima-media thickness (IMT) of the common carotid artery. RESULTS: In the fasting state, plasma, very-low-density lipoprotein (VLDL), and low-density lipoprotein cholesterol, proinsulin, and apoB100-containing intermediate density lipoprotein levels were related to IMT (p < 0.05). In the postprandial state, IMT was related to triglycerides at 2 h (p < 0.01), large VLDL concentration at 3 h (p < 0.05), the apoCI plasma and TRL concentrations at 6 h (p < 0.05, p < 0.05), and the apoCI content of TRLs at 6 h (p < 0.002). Multivariate analysis revealed that the apoCI content of TRLs at 6 h (p < 0.0001), plasma triglyceride concentrations at 2 h (p < 0.006), and fasting plasma cholesterol concentration (p < 0.05) independently predicted IMT. In addition, the apoCI content of postprandial TRLs correlated strongly with the cholesterol content (r = 0.64, p < 0.0001). CONCLUSIONS: Our results indicate that the apoCI content of postprandial TRLs is a novel independent risk factor for early atherosclerosis in normolipidemic healthy middle-aged men with possible implication for the enrichment of TRL remnant lipoproteins with cholesterol.     

Intestinal rather than hepatic microsomal triglyceride transfer protein as a cause of postprandial dyslipidemia in diabetes

Postprandial dyslipidemia may be a major cause of atherosclerosis in diabetes. Microsomal triglyceride transfer protein (MTP) is essential for the synthesis of the chylomicron particle in the intestine and very low-density lipoprotein (VLDL) in the liver. The purpose of the present study was to examine the effect of diabetes on MTP mRNA expression in a rabbit model of diabetes, which develops atherosclerosis. Male New Zealand white rabbits were fed a 0.5% cholesterol diet. Diabetes was induced with alloxan monohydrate. The lymphatic duct was cannulated and lymph collected for isolation of chylomicrons by ultracentrifugation. Apolipoprotein B48 (apo B48) and apo B100 were separated by polyacrylamide gradient gel electrophoresis and quantified by densitometry. MTP mRNA was determined in liver and intestine by RNase protection analysis, and MTP activity was measured. Diabetic animals had significantly increased plasma triglyceride and decreased high-density lipoprotein (HDL) cholesterol (P <.05). They also secreted more lymph chylomicron apo B48 and apo B100 (P <.05) and more lymph chylomicron total and esterified cholesterol/h (P <.05). Lymph chylomicron particles in the diabetic animals contained significantly less lipid/apo B (P <.05). Intestinal MTP activity and mRNA were significantly higher in diabetic compared with control rabbits (0.07 +/- 0.01 v 0.04 +/- 0.015 fluorescent units/microg microsomal protein and 66 +/- 21 v 37 +/- 11 amol MTP mRNA/microg total RNA (P <.005). There was no difference in MTP activity or mRNA expression in the liver. This study suggests that MTP may play an important role in the postprandial dyslipidemia of diabetes.     

Action of atorvastatin in combined hyperlipidemia : preferential reduction of cholesteryl ester transfer from HDL to VLDL1 particles

Combined hyperlipidemia (CHL) is characterized by a concomitant elevation of plasma levels of triglyceride-rich, very low density lipoproteins (VLDLs) and cholesterol-rich, low density lipoproteins (LDLs). The predominance of small, dense LDLs contributes significantly to the premature development of coronary artery disease in patients with this atherogenic dyslipoproteinemia. In the present study, we evaluated the impact of atorvastatin, a newly developed inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase, on the cholesteryl ester transfer protein (CETP)-mediated remodeling of apolipoprotein (apo) B-containing lipoprotein subspecies, and more specifically, the particle subpopulations of VLDL and LDL in CHL. In parallel, we evaluated the atorvastatin-induced modulation of the quantitative and qualitative features of atherogenic apo B-containing and cardioprotective apo AI-containing lipoprotein subspecies. Atorvastatin therapy (10 mg/d for a 6-week period) in patients with a lipid phenotype typical of CHL (n=18) induced reductions of 31% (P<0.0001) and 36% (P<0.0001) in plasma total cholesterol and LDL cholesterol, respectively. In addition, atorvastatin significantly reduced VLDL cholesterol, triglycerides, and apo B levels by 43% (P<0.0001), 27% (P=0.0006), and 31% (P<0.0001), respectively. The plasma concentrations of triglyceride-rich lipoproteins (VLDL1, Sf 60 to 400; VLDL2, Sf 20 to 60; and intermediate density lipoproteins, Sf 12 to 20) and of LDL, as determined by chemical analysis, were markedly diminished after drug therapy (-30% and -28%, respectively; P<0.0007). Atorvastatin significantly reduced circulating levels of all major LDL subspecies, ie, light (-28%, P<0.0008), intermediate (-27%, P<0.0008), and dense (-32%, P<0.0008) LDL; moreover, in terms of absolute lipoprotein mass, the reduction in dense LDL levels (mean -62 mg/dL) was preponderant. In addition, the reduction in plasma dense LDL concentration after therapy was significantly correlated with a reduction in plasma VLDL1 levels (r=0.429, P=0.0218). Atorvastatin induced a significant reduction (-7%, P=0.0039) in total CETP-dependent CET activity, which accurately reflects a reduction in plasma CETP mass concentration. Total CETP-mediated CET from high density lipoproteins to apo B-containing lipoproteins was significantly reduced (-26%, P<0.0001) with drug therapy. Furthermore, CETP activity was significantly correlated with the atorvastatin-induced reduction in plasma VLDL1 levels (r=0.456, P=0. 0138). Indeed, atorvastatin significantly and preferentially decreased CET from HDL to the VLDL1 subfraction (-37%, P=0.0064), thereby reducing both the levels (-37%, P=0.0001) and the CE content (-20%, P<0.005) of VLDL1. We interpret our data to indicate that 2 independent but complementary mechanisms may be operative in the atorvastatin-induced reduction of atherogenic LDL levels in CHL: first, a significant degree of normalization of both the circulating levels and the quality of their key precursors, ie, VLDL1, and second, enhanced catabolism of the major LDL particle subclasses (ie, light, intermediate, and dense LDL) due to upregulation of hepatic LDL receptors.     

Elevated triglyceride-rich lipoproteins in diabetes

The role of the intestine in cholesterol metabolism in human diabetes in unclear, although abnormalities have been demonstrated in cholesterol synthesis and absorption in diabetic animals. This study examines the relationship between fasting and post-prandial apolipoprotein B-48 in type 2 (non-insulin-dependent) diabetic and non-diabetic subjects. Eight type 2 diabetic patients and ten healthy non-diabetic control subjects were given a high-fat meal (1300 kcal), and the triglyceride-rich lipoprotein fraction was isolated by ultracentrifugation (d<1.006 g/ml) from fasting and post-prandial plasma. Apolipoprotein B-48 and apo B-100 were separated on 4%–15% gradient gels and quantified by densitometric scanning with reference to a purified low-density lipoprotein (LDL) apo B-100 preparation. Diabetic patients had significantly higher concentrations of apo B-48 and apo B-100 in both the fasting (P<0.05) and post-prandial (P<0.001) triglyceride-rich lipoprotein samples compared with non-diabetic subjects. The diabetic patients also exhibited a significantly different post-prandial profile for apo B-48 and apo B-100, with a prolonged increase and a later post-prandial peak, than the non-diabetic subjects (P<0.01). These results suggest that the raised fasting triglyceride-rich lipoproteins, often found in diabetes, are associated with apo B-48 and may be derived from increased intestinal chylomicron production. The post-prandial pattern suggests an abnormality in intestinal production as well as hepatic clearance of apo B-48 in type 2 diabetes.     

Early alterations in the postprandial VLDL1 apoB-100 and apoB-48 metabolism in men with strong heredity for type 2 diabetes

OBJECTIVES: To study the postprandial triglyceride-rich lipoprotein (TRL) metabolism, specifically the concentrations of very low-density lipoproteins (VLDL); from intestine (apoB-48) and liver (apoB-100), in men with normal fasting triglycerides but at increased risk of developing type 2 diabetes. DESIGN: Cross-sectional study. SUBJECTS AND SETTINGS: Sixteen healthy men with at least two first-degree relatives with type 2 diabetes were individually matched with 16 control subjects without known diabetes heredity for: age, body mass index, and fasting triglyceride level. They underwent an 8-h meal tolerance test (919 kcal, 51 g fat) during which lipoproteins were separated by density gradient ultracentrifugation. They were characterized by euglycaemic hyperinsulinaemic clamp, peak VO2, 7-day diet registration and computed tomography. RESULTS: The relatives were, as expected, more insulin resistant than the controls and had increased concentration of postprandial VLDL1 particles (49% higher for VLDL1 apoB-48, P = 0.04 and 21% higher for VLDL1 apoB-100, P = 0.048). The elevation was related to insulin sensitivity, but not to lifestyle and body composition. Moreover, the concentration of postprandial triglycerides in VLDL1 fraction was inversely related to low-density lipoprotein (LDL) size in both relatives (rs = -0.60, P = 0.03) and controls (rs = -0.72, P = 0.004). There were no differences in the concentration of triglycerides or apoB-48 and apoB-100 particles in the other fractions (plasma, chylomicron or VLDL2). CONCLUSION: Increased postprandial concentration of TRLs in the VLDL1 fraction seems to be present at an early stage in the development of diabetes and probably contributes to the excess risk of future coronary events in insulin-resistant men.