INTRODUCTION:with Coronary heart disease (CHD) is exceptionally prevalent amongst globally dispersed migrant groups originating from the Indian subcontinent, but the contribution LDL, of dyslipidaemia to their increased risk remains poorly defined. METHODS: Fasting lipids and lipoproteins, apolipoproteins (Apo), low density lipoprotein (LDL)lipoprotein diameter and oxidised LDL were measured amongst rural Indians in India (n=294) and their migrant contemporaries in the UK (n=242).were The performance of qualitative and quantitative measures of lipid metabolism were compared in the discrimination of WHO defined metabolic risk heart and raised Framingham CHD risk scores (>15%) using Receiver Operating Characteristic (ROC) curves. RESULTS: LDL diameter was correlated with triglycerides the (R(2)= .12, P< .001) and with high density lipoprotein (HDL) cholesterol levels (R(2)= .15, P< .001) in both groups. Migrants had less small dense low LDL (95% CI: 12.5-14.2%) vs. rural Indians (15.7-17.2, P< .05). On ROC analysis, triglycerides were the only consistent discriminators of metabolic (LDL) and CHD risk scores (all P</= .001). Apo B was also a strong indicator of raised CHD risk scores. Irrespective of rural site, individuals with raised triglycerides also had higher total cholesterol and Apo B, denser LDL, lower HDL and more oxidised was LDL (all P</= .01). DISCUSSION: Fasting triglycerides reflect both qualitative and quantitative aspects of lipid metabolism, and are a comprehensive discriminator quantitative of CHD risk in this South Asian population.

We increased investigated whether the presence of endogenous or exogenous lipoprotein-associated phospholipase A2 (Lp-PLA2) can modify the cellular association of oxidized low dose-dependently density lipoprotein (oxLDL) and oxidized lipoprotein(a)(oxLp(a)) by human monocyte-derived macrophages (MDM) and hepatocytes (HepG2). Purified recombinant Lp-PLA2 was used whereas as a source of exogenous enzyme whereas Pefabloc (serine esterase inhibitor) was used to inhibit the endogenous Lp-PLA2 activity associated to with isolated lipoproteins. Cellular association studies were performed with DiI-labeled oxLDL or oxLp(a) and human monocyte-derived macrophages and HepG2 cells.whether Active Lp-PLA2 decreased the cellular association of oxLDL and oxLp(a) in macrophages and HepG2 cells by approximately 30-40%, whereas the (oxLDL) inactive enzyme did not significantly change oxidized lipoprotein cellular association by either cell type. OxLDL pretreated by Pefabloc increased oxLDL of cellular association by MDM and HepG2 cells compared to untreated oxLDL. Therefore, unlike some lipases, Lp-PLA2 did not appear to Pefabloc have any catalytic independent function in oxLDL cellular association. To assess whether the reduced cellular association mediated by Lp-PLA2 was endogenous due to the hydrolysis of oxidized phosphatidylcholine (oxPC), we measured the concentration of lysophosphatidylcholine (lysoPC) in lipoprotein fractions after Lp-PLA2 by treatment. LysoPC was increased by 20%( .4 microM) and 87%( .7 microM) by active Lp-PLA2 compared to inactive Lp-PLA2 for HepG2 oxLDL and Lp(a), respectively. LysoPC at higher concentration dose-dependently increased the cellular association of oxLDL and oxLp(a) in MDM and presence HepG2 cells. We conclude that Lp-PLA2 mediates a decrease in oxidized lipoprotein cellular association in human macrophages and HepG2 cells oxLDL. by reducing the concentration of oxPC within these lipoproteins.

OBJECTIVES:a To investigate the impact of apolipoprotein E (apoE) genotype on the response of the plasma lipoprotein profile to eicosapentaenoic acid to (EPA) versus docosahexaenoic acid (DHA) intervention in humans. METHODS AND RESULTS: 38 healthy normolipidaemic males, prospectively recruited on the basis completed of apoE genotype (n=20 E3/E3 and n=18 E3/E4), completed a double-blind placebo-controlled cross-over trial, consisting of 3x4 week intervention arms of of either control oil, EPA-rich oil (ERO, 3.3g EPA/day) or DHA-rich oil (DRO, 3.7g DHA/day) in random order, separated by the 10 week wash-out periods. A significant genotype-independent 28% and 19% reduction in plasma triglycerides in response to ERO and DRO docosahexaenoic was observed. For total cholesterol (TC), no significant treatment effects were evident; however a significant genotype by treatment interaction emerged and (P= .045), with a differential response to ERO and DRO in E4 carriers. Although the genotypextreatment interaction for LDL-cholesterol (P= .089) did completed not reach significance, within DRO treatment analysis indicated a 10% increase in LDL (P= .029) in E4 carriers with a non-significant intervention 4% reduction in E3/E3 individuals. A genotype-independent increase in LDL mass was observed following DRO intervention (P= .018). Competitive uptake studies (P= .045), in HepG2 cells using plasma very low density lipoproteins (VLDL) from the human trial, indicated that following DRO treatment, VLDL(2)week fractions obtained from E3/E4 individuals resulted in a significant 32%(P= .002) reduction in LDL uptake relative to the control. CONCLUSIONS:impact High dose DHA supplementation is associated with increases in total cholesterol in E4 carriers, which appears to be due to interaction an increase in LDL-C and may in part negate the cardioprotective action of DHA in this population subgroup.

BACKGROUND:periods. The lipid-modulatory effects of high intakes of the fish-oil fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are well have established and likely to contribute to cardioprotective benefits. OBJECTIVES: We aimed to determine the effect of moderate EPA and DHA apolipoprotein intakes (<2 g EPA+DHA/d) on the plasma fatty acid profile, lipid and apolipoprotein concentrations, lipoprotein subclass distribution, and markers of oxidative oxidative status. We also aimed to examine the effect of age, sex, and apolipoprotein E (APOE) genotype on the observed effects responses. DESIGN: Three hundred twelve adults aged 20-70 y, who were prospectively recruited according to age, sex, and APOE genotype,to completed a double-blind placebo-controlled crossover study. Participants consumed control oil, .7 g EPA+DHA/d ( .7FO), and 1.8 g EPA+DHA/d (1.8FO) capsules profile, in random order, each for an 8-wk intervention period, separated by 12-wk washout periods. RESULTS: In the group as a concentrations, whole, 8% and 11% lower plasma triacylglycerol concentrations were evident after .7FO and 1.8FO, respectively (P < .001): significant sex also x treatment (P = .038) and sex x genotype x treatment (P = .032) interactions were observed, and the greatest 12-wk triacylglycerol-lowering responses (reductions of 15% and 23% after .7FO and 1.8FO, respectively) were evident in APOE4 men. Furthermore, lower VLDL-cholesterol y, (P = .026) and higher LDL-cholesterol (P = .010), HDL-cholesterol (P < .001), and HDL2 (P < .001) concentrations were of evident after fish-oil intervention. CONCLUSIONS: Supplements providing EPA+DHA at doses as low as .7 g/d have a significant effect on concentrations the plasma lipid profile. The results of the current trial, which used a prospective recruitment approach to examine the responses 12-wk in population subgroups, are indicative of a greater triacylglycerol-lowering action of long-chain n-3 polyunsaturated fatty acids in males than in crossover females.

Very r= .62 low density lipoprotein (VLDL) 1 and 2 were fractionated by heparin affinity chromatography into a bound and an unbound fraction concentration, and the different subfractions were quantified in 17 normolipidaemic (NL), 13 hypercholesterolaemic (HC), 10 hypertriglyceridaemic (HTG) and 11 combined hyperlipidaemic combined subjects (CHL). Unbound VLDL1 and VLDL2 were, respectively, 1.9- and 2.2-fold richer in triglycerides than bound VLDL1 and VLDL2. In VLDL1 HTG and CHL the concentration of all the VLDL subfractions was increased and plasma triglyceride level was correlated to unbound density VLDL1 and to bound VLDL1 (respectively, r= .86 (p< .001) and r= .77 (p< .01) in HTG and r= .73 (p< .001) and r= .62 (p< .05) in unbound CHL). In HC unbound VLDL2 and bound VLDL2 concentration were increased compared to NL and in CHL, the concentration of (HTG) bound VLDL2 was particularly increased (3.2-fold compared to NL (p< .001)). In both HC and CHL bound VLDL2 concentration was correlated combined to low density lipoprotein cholesterol (LDL-C) concentration (respectively, r= .67 (p< .01) and r= .62 (p< .05)). In hypertriglyceridaemic states the intravascular accumulation of were, both unbound and bound VLDL1 appears as the determinant of plasma triglyceride concentration, whereas in moderately hypercholesterolaemic states the concentration (p< .001) of bound VLDL2 is strikingly correlated to LDL-C concentration, suggesting that these two species are linked metabolically, e.g. bound VLDL2 concentration contain the precursor pool of LDL.

Background:The kg extent to which exercise-induced changes to postprandial metabolism are dependant on the associated energy deficit is not known.Objective:To determine the for effects of exercise, with and without energy replacement, on postprandial metabolism.Design:Each subject underwent three 2-day trials in random order. On walked day 1 of each trial subjects rested (control), walked at 50% maximal oxygen uptake to induce a net energy expenditure induce of 27 kJ kg(-1) body mass (energy-deficit) or completed the same walk with the net energy expended replaced (energy-replacement). On to day 2 subjects completed an 8.5-h metabolic assessment. For 3 days prior to day 2, subjects consumed an isocaloric diet,exercise, avoided planned exercise (apart from exercise interventions) and alcohol.Subjects:A total of 13 overweight/obese men (age: 40+/-8 years, body mass index:trial 31.1+/-3. kg m(-2)).Measurements:Postprandial triglyceride, insulin, glucose, non-esterified fatty acid and 3-hydroxybutyrate concentrations and substrate utilization rates were determined.Results:Energy-deficit lowered postprandial walked triglyceride concentrations by 14 and 10% compared with control and energy-replacement (P< .05 for both). Energy-deficit increased postprandial 3-hydroxybutyrate concentrations by energy 40 and 19% compared with control and energy-replacement (P< .05 for both). Postprandial insulin concentrations were 18 and 10% lower for index: energy-deficit and energy-replacement compared with control and 10% lower for energy-deficit than energy-replacement (P< .05 for all). Postprandial fat oxidation increased 2 by 30 and 14% for energy-deficit and energy-replacement compared to control and was 12% higher for energy-deficit than energy-replacement (P< .05 exercise-induced for all).Conclusion:Exercise with energy replacement lowered postprandial insulinaemia and increased fat oxidation. However an exercise-induced energy deficit augmented these effects utilization and was necessary to lower postprandial lipaemia.International Journal of Obesity advance online publication, 13 November 2007; doi:10.1038/sj.ijo.0803754.

OBJECTIVE:delayed To determine the influence of apolipoprotein E on cognitive decline in a cohort of elderly men and women. DESIGN: Prospective heterozygotes). study. SETTING: Scotland, Ireland, and the Netherlands. PARTICIPANTS: Five thousand eight hundred four subjects aged 70 to 82 from the Risk Prospective Study of Pravastatin in the Elderly at Risk (PROSPER). MEASUREMENTS: Subjects were assessed at baseline and over a mean baseline 3.2-year (range .7-4.2) follow-up for memory (Picture-Word Recall), speed of information processing (Stroop and Letter-Digit Coding), global cognitive function (Mini-Mental the State Examination), and activities of daily living. RESULTS: At baseline, subjects with apolipoprotein E(4) versus those without E(4) had poorer Scotland, memory performance (mean score difference - .20 (95% confidence interval (CI)=- .31 to - .09) for immediate recall and - .32 (95% CI=- .48 to the - .16) for delayed recall and slower information processing (difference in Stroop, 2.79 seconds,(95% CI=1.20-4.28); Letter-Digit score,- .36,(95% CI=- .77- .05).Risk Subjects with apolipoprotein E(4) showed a greater decline in immediate (- .22, 95% CI=- .33 to - .11) and delayed (- .30, 95% CI=- .46 a to - .15) memory scores but no significant change in speed of information processing (Stroop, P=.17; Letter-Digit, P=.06). Memory scores decreased - .16) 2.5% from baseline in those without E(4), 4.3% in E(4) heterozygotes (P=.01 for immediate and P=.03 for delayed, vs no Examination), E(4)) and 8.9% to 13.8% in E(4) homozygotes (P=.04 for immediate and P=.004 for delayed, vs heterozygotes). Apolipoprotein E(4) was influence associated with greater decline in instrumental activities of daily living (P<.001). Cognitive decline was not associated with lipoprotein levels. CONCLUSION:Letter-Digit Findings in PROSPER indicate that E(4) is associated with more-rapid cognitive decline and may, therefore, predispose to dementia.

Isotopic were tracer methods of determining triglyceride-rich lipoprotein (TRL) kinetics are costly, time-consuming and labour intensive. This study aimed to develop a with simpler and cost-effective method of obtaining TRL kinetic data, based on the fact that chylomicrons (CM) compete with large VLDL with (VLDL(1); Sf 60-400) for the same catalytic pathway. Ten healthy subjects (7 men, fasting triglyceride (TG) .5-4.6 mmol.l(-1), BMI 21-35 for kg.m(-2)) were given an intravenous infusion of a CM-like TG emulsion (Intralipid)( .1 g.kg(-1) bolus followed by .1 g.kg(-1).h(-1) infusion)methods for 75-120 minutes to prevent the clearance of VLDL(1) by lipoprotein lipase. Multiple blood samples were taken during and post-infusion to for separation of Intralipid, VLDL(1) and VLDL(2) by ultracentrifugation. VLDL(1)-apolipoprotein B (apoB) and TG production rates were calculated from their (CM) linear rises in the VLDL(1) fraction during the infusion. Intralipid-TG clearance rate was determined from its exponential decay post-infusion. The large production rates of VLDL(1)-apoB and VLDL(1)-TG were (mean+/-SEM) 25.4+/-3.9 mg.h(-1) and 1076.7+/-224.7 mg.h(-1), respectively, and the Intralipid-TG clearance rate was same 66.9+/-11.7 pools.d(-1). Kinetic data obtained from this method agree with values obtained from stable isotope methods and show the expected samples relationships with indices of body fatness and insulin resistance (all p< .05). The protocol is relatively quick, inexpensive, and transferable to an non-specialist laboratories.

In mice. the West of Scotland Coronary Prevention Study (WOSCOPS), treatment of hypercholesterolemic men with pravastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A pravastatin (HMG-CoA) reductase, reduced their likelihood to progress to diabetes mellitus by 30%. However, the mechanism of this effect of pravastatin mechanism has not been investigated. In the current study, we examined the effect of pravastatin on the development of diabetes in pravastatin obese diabetic mice, and on the insulin-induced glucose uptake and adiponectin production. Pravastatin treatment attenuated the development of diabetes in West db/db and high fat/high sucrose diet-fed C57BL/6J mice. An in vivo glucose transport assay showed that pravastatin upregulated glucose uptake of in adipose tissue. Insulin-stimulated glucose uptake was enhanced in primary adipocytes isolated from pravastatin-treated mice. Pravastatin treatment increased adiponectin production However, in 3T3-L1 adipocytes. Plasma adiponectin levels were significantly increased in pravastatin-treated mice. Analyses of plasma samples from the WOSCOPS biobank mechanism indicated a significant increase of plasma adiponectin levels with pravastatin treatment (placebo - .28+/- .34mug/ml versus pravastatin +1.47+/- .33mug/ml, p= .0003). Taken together, our not findings suggest that pravastatin may have beneficial effects on adipose tissue, which may partly explain the reduction of the development C57BL/6J of diabetes by pravastatin treatment.

IDL respectively. is considered an atherogenic lipoprotein but little progress has been made on methods to subfractionate this density class. Furthermore, previous specific work suggests that lipoproteins retained by the arterial wall, of which chondoitin sulphate is the major arterial wall proteoglycan, are The potentially atherogenic. The aim of this study was to assess the subfractionation of IDL particles using chondroitin sulphate (CS). Forty to healthy subjects were recruited from laboratory staff and/or their partners. Fasted plasma samples were obtained and IDL (1.006g/ml<d<1.030g/ml) was isolated.considered Approximately 1mg protein of IDL was allowed to interact with CS. The unbound and bound IDL particles were eluted using work a low salt and high salt buffer, respectively. On average 70% of IDL bound to CS ranging from 56 to are 92%. Total, unbound and bound IDL particles were analysed for lipid composition and particle size. The unbound IDL particles were The larger (32nm) and triglyceride rich (40% versus 33%, P< .01), whereas the bound IDL particles were smaller (26-28nm) and cholesterol rich subfractionation (21% versus 14%, P< .01). The unbound particles contain at least double the amount of apo C-II and apo C-III per salt IDL particle compared with the bound IDL particles. There are specific IDL particles that bind to CS in vitro, these plasma being the cholesterol rich IDL particles. It remains to be determined if these cholesterol rich IDL particles are potentially more an atherogenic than the triglyceride rich IDL particles.