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Context:Postprandial triglyceride (TG) concentration is independently associated with cardiovascular disease risk. Exercise reduces postprandial TG concentrations, but the mechanisms responsible are unclear.Objective:The objective was to determine the effects of exercise on affinity of chylomicrons, large very low-density lipoproteins (VLDL1), and smaller VLDL (VLDL2) for lipoprotein lipase (LPL)-mediated TG hydrolysis.Design:This was designed as a within-participant crossover study.Setting:The setting was a university metabolic investigation unit.Participants:Participants were 10 overweight/obese men.Interventions:Participants undertook two oral fat tolerance tests, separated by 7–14 days, in which they had blood taken while fasting and for 4 hours after a high-fat mixed meal. On the afternoon before one test, they performed a 90-minute treadmill walk at 50% maximal oxygen uptake (exercise trial [EX]); no exercise was performed before the control trial (CON).Main Outcome Measures:We measured circulating TG-rich lipoprotein concentrations and affinity of chylomicrons, VLDL1, and VLDL2for LPL-mediated TG hydrolysis.Results:Exercise significantly reduced fasting VLDL1-TG concentration (CON, 0.49 [0.33–0.72] mmol.L-1; EX, 0.36 [0.22–0.59] mmol.L-1; geometric means [95% confidence interval]; P= .04). Time-averaged postprandial chylomicron-TG (CON, 0.55 ± 0.10 mmol.L-1; EX, 0.39 ± 0.08 mmol.L-1; mean ± SEM; P= .03) and VLDL1-TG (CON, 0.85 ± 0.13 mmol.L-1; EX, 0.66 ± 0.10 mmol.L-1; P= .01) concentrations were both lower in EX than CON. Affinity of VLDL1for LPL-mediated TG hydrolysis increased by 2.2 (1.3–3.7)-fold [geometric mean (95% confidence interval)] (P= .02) in the fasted state and 2.6 (1.8–2.6)-fold (P= .001) postprandially. Affinity of chylomicrons and VLDL2was not significantly different between trials.Conclusions:Exercise increases affinity of VLDL1for LPL-mediated TG hydrolysis both fasting and postprandially. This mechanism is likely to contribute to the TG-lowering effect of exercise.

Isotopic tracer methods of determining triglyceride-rich lipoprotein (TRL) kinetics are costly, time-consuming, and labor-intensive. This study aimed to develop a simpler and cost-effective method of obtaining TRL kinetic data, based on the fact that chylomicrons compete with large VLDL (VLDL1; Sf= 60–400) for the same catalytic pathway. Ten healthy subjects [seven men; fasting triglyceride (TG), 44.3–407.6 mg/dl; body mass index, 21–35 kg/m2] were given an intravenous infusion of a chylomicron-like TG emulsion (Intralipid; 0.1 g/kg bolus followed by 0.1 g/kg/h infusion) for 75–120 min to prevent the clearance of VLDL1by lipoprotein lipase. Multiple blood samples were taken during and after infusion for separation of Intralipid, VLDL1, and VLDL2by ultracentrifugation. VLDL1-apolipoprotein B (apoB) and TG production rates were calculated from their linear increases in the VLDL1fraction during the infusion. Intralipid-TG clearance rate was determined from its exponential decay after infusion. The production rates of VLDL1-apoB and VLDL1-TG were (mean ± SEM) 25.4 ± 3.9 and 1,076.7 ± 224.7 mg/h, respectively, and the Intralipid-TG clearance rate was 66.9 ± 11.7 pools/day. Kinetic data obtained from this method agree with values obtained from stable isotope methods and show the expected relationships with indices of body fatness and insulin resistance (all P < 0.05). The protocol is relatively quick, inexpensive, and transferable to nonspecialist laboratories.

Isotopic tracer methods of determining triglyceride-rich lipoprotein (TRL) kinetics are costly, time-consuming, and labor-intensive. This study aimed to develop a simpler and cost-effective method of obtaining TRL kinetic data, based on the fact that chylomicrons compete with large VLDL (VLDL1; Sf= 60–400) for the same catalytic pathway. Ten healthy subjects [seven men; fasting triglyceride (TG), 44.3–407.6 mg/dl; body mass index, 21–35 kg/m2] were given an intravenous infusion of a chylomicron-like TG emulsion (Intralipid; 0.1 g/kg bolus followed by 0.1 g/kg/h infusion) for 75–120 min to prevent the clearance of VLDL1by lipoprotein lipase. Multiple blood samples were taken during and after infusion for separation of Intralipid, VLDL1, and VLDL2by ultracentrifugation. VLDL1-apolipoprotein B (apoB) and TG production rates were calculated from their linear increases in the VLDL1fraction during the infusion. Intralipid-TG clearance rate was determined from its exponential decay after infusion. The production rates of VLDL1-apoB and VLDL1-TG were (mean ± SEM) 25.4 ± 3.9 and 1,076.7 ± 224.7 mg/h, respectively, and the Intralipid-TG clearance rate was 66.9 ± 11.7 pools/day. Kinetic data obtained from this method agree with values obtained from stable isotope methods and show the expected relationships with indices of body fatness and insulin resistance (all P< 0.05). The protocol is relatively quick, inexpensive, and transferable to nonspecialist laboratories.

Risk factors identified by the Framingham Heart Study are useful for assessing a person's risk of cardiovascular disease; however, additional risk factors are needed. In this review, the potential role of lipoprotein-associated phospholipase A2as a novel inflammatory marker for cardiovascular risk assessment is discussed.

The use of stable isotopes in conjunction with compartmental modeling analysis has greatly facilitated studies of the metabolism of the apolipoprotein B (apoB)-containing lipoproteins in humans. The aim of this study was to develop a multicompartment model that allows us to simultaneously determine the kinetics of apoB and triglyceride (TG) in VLDL1and VLDL2after a bolus injection of [2H3]leucine and [2H5]glycerol and to follow the catabolism and transfer of the lipoprotein particles. Here, we describe the model and present the results of its application in a fasting steady-state situation in 17 subjects with lipid values representative of a Western population. Analysis of the correlations showed that plasma TG was determined by the VLDL1and VLDL2apoB and TG fractional catabolic rate. Furthermore, the model showed a linear correlation between VLDL1TG and apoB production. A novel observation was that VLDL TG entered the circulation within 21 min after its synthesis, whereas VLDL apoB entered the circulation after 33 min.

Response to statin treatment can vary widely from person to person as a result of inherited traits (genotype) and acquired characteristics such as obesity (phenotype). The aim of this review is to describe what is known about factors that determine a patient's response, and to offer a mechanism to explain how plasma triglyceride influences the nature and magnitude of lipid lowering on statin therapy.

Plasma lipoproteins carry a number of highly active enzymes in the circulation. One of these is lipoprotein-associated phospholipase A2(Lp-PLA2), also known as platelet-activating factor acetylhydrolase. This review addresses the molecular properties of Lp-PLA2, the controversy surrounding its role in atherosclerosis and the regulation of its plasma levels in humans.

The association between possession of the APOE ε4 allele and unfavourable outcome after traumatic brain injury (TBI) suggests that the apolipoprotein E protein (apoE) plays a key role in the response of the human brain to injury. ApoE is known to regulate cholesterol metabolism in the periphery through its action as a ligand for receptor mediated uptake of lipoprotein particles (Lps). Greater understanding of cholesterol metabolism in the human central nervous system may identify novel treatment strategies applicable to acute brain injury. We report findings from the analysis of lipoproteins in the cerebrospinal fluid (CSF) of patients with TBI and non-injured controls, testing the hypothesis that remodeling of CSF lipoproteins reflects the response of the brain to TBI. CSF Lps were isolated from the CSF of controls and patients with severe TBI by size exclusion chromatography, and the lipoprotein fractions analysed for cholesterol, phospholipid, apoAI, and apoE. There was a marked decrease in apoE containing Lps in the TBI CSF compared to controls (p = 0.002). After TBI there was no significant decrease in apoAI containing CSF Lps (CSF LpAI), but the apoAI resided on smaller sized particles than in control CSF. There was a population of very small sized Lps in TBI CSF, which were associated with the increased cholesterol (p = 0.0001) and phospholipid (p = 0.040) seen after TBI. The dramatic loss of apoE containing Lps from the CSF, and the substantial increase in CSF cholesterol, support the concept that apoE and cholesterol metabolism are intimately linked in the context of acute brain injury. Treatment strategies targeting CNS lipid transport, required for neuronal sprouting and synaptogenesis, may be applicable to traumatic brain injury.

Heparin, when administered to patients undergoing operations using cardiopulmonary bypass, induces plasma changes that gradually impair platelet macroaggregation, but heparinization of whole blood in vitro does not have this effect. The plasma changes induced by heparin in vivo continue to progress in whole blood ex vivo. Heparin releases several endothelial proteins, including lipoprotein lipase, hepatic lipase, platelet factor-4 and superoxide dismutase. These enzymes, which remain active in plasma ex vivo, may impair platelet macroaggregation after in vivo heparinization and during cardiopulmonary bypass. In the present study, proteins were added in vitro to hirudin (200units·ml-1)-anticoagulated blood from healthy volunteers, and the platelet macroaggregatory responses to ex vivo stimulation with collagen (0.6μg·ml-1) were assessed by whole-blood impedance aggregometry. Over a 4h period, human lipoprotein lipase and human hepatic lipase reduced the platelet macroaggregatory response from 17.0±2.3 to 1.5±1.3 and 1.2±0.6Ω respectively (means±S.D.) (both P<0.01; n = 6). Other lipoprotein lipases also impaired platelet macroaggregation, but platelet factor-4 and superoxide dismutase did not. Platelet macroaggregation showed an inverse linear correlation with plasma concentrations of non-esterified fatty acids (r2 = 0.69; two-sided P<0.0001; n = 8), suggesting that heparin-induced lipolysis inhibits platelet macroaggregation. Lipoprotein degradation products may cause this inhibition by interfering with eicosanoids and other lipid mediators of metabolism.

End-stage renal failure (ESRF) is associated with dyslipidemia and accelerated atherosclerosis. Triglyceride-rich lipoproteins accumulate and qualitative changes take place in low-density lipoprotein (LDL), with a predominance of the small dense LDL phenotype. Increased small dense LDL (LDLIII) is a known risk factor for cardiovascular disease. To assess the extent of LDLIII formation in ESRF and identify factors contributing to LDLIII production, we analyzed LDL subfractions by density-gradient ultracentrifugation, very low-density lipoprotein subfractions, and lipase activity in 75 patients with ESRF (25 hemodialysis [HD], 25 peritoneal dialysis [PD], and 25 predialysis patients) and 40 age- and sex-matched controls. The percentage of LDLIII was increased in all three patient groups compared with controls (PD, 33% ± 29% [mean ± SD]; P< 0.005; HD, 30% ± 22%; P< 0.01; predialysis, 26% ± 26%; P< 0.01; all versus controls, 14% ± 10%). Plasma LDLIII concentration was increased only in PD patients (median, 84 mg/dL; interquartile range [IQR], 29 to 160 mg/dL versus controls; median, 31 mg/dL; IQR, 26 to 54 mg/dL). In other patient groups, total LDL level was less, with heterogeneity in LDLIII concentrations. Forty percent of PD patients and 28% of HD and predialysis patients had LDLIII concentrations greater than 100 mg/dL compared with 2.5% of controls (P= 0.002). Plasma triglyceride levels (r2= 38.4%; P< 0.001) and hepatic lipase activity (r2= 6.7%; P< 0.03) were independent predictors of LDLIII concentration. The strong association between LDLIII concentration and triglyceride level was present in all three patient groups (HD, r2= 47.9%; PD, r2= 45.2%; predialysis, r2= 25.8%); plasma triglyceride levels greater than 177 mg/dL (2.0 mmol/L) had an 86% specificity and 79% sensitivity for predicting an LDLIII concentration greater than 100 mg/dL. We conclude that the atherogenic lipoprotein phenotype predominates in ESRF, with excess LDLIII particularly prominent in PD patients. Atherogenic levels of LDLIII are found in patients with triglyceride levels greater than 177 mg/dL. This is likely to represent a further cardiovascular risk factor in this population.

High resolution density gradient ultracentrifugation (DGUC) and non-denaturing gradient gel electrophoresis (GGE) indicate that low density lipoprotein (LDL) in both normal and hyperlipidaemic subjects is composed of overlapping particle populations. A new centrifugation procedure has been developed which permits the separation of LDL subspecies directly from plasma within 24 h. The profiles obtained were analogous to those seen on gradient gel electrophoresis. LDL was divided into 3 fractions. The plasma concentration of LDL-I seen in young females was twice that in men (85.6 ± 28.8 vs. 42.3 ± 25.7 mg/dl, P< 0.005). LDL-II was not significantly different in any group while LDL-III was specifically elevated in coronary artery disease (CAD) patients (207.1 ± 92.6 mg/dl inCAD vs. 87.4 ± 79.6 mg/dl in normal men, P< 0.05). The presence of small, dense LDL detected either by density gradient centrifugation or gel electrophoresis was associated with raised triglyceride (TG) and low high density lipoprotein (HDL) cholesterol and may be a risk marker for coronary artery disease.