WITHDRAWN: GLP-1 Has an Anti-Inflammatory Effect on Adipose Tissue Expression of Cytokines, Chemokines, and Receptors in Obese Women.

The above-named article by Manning PJ, Dixit P, Satthenapalli VR, Katare R, and Sutherland WHF (J Clin Endocrinol Metab. [published online ahead of print 21 May 2019]; doi: 10.1210/jc.2018-00197) has been withdrawn by the authors. The authors report, "The reason for this decision is that the statistical methodology we used did not adequately limit the impact of outlier data points on our findings. This was evident after reanalysis of the data using a different method." doi: 10.1210/jc.2019-01393.

The effect of lipoic acid and vitamin E therapies in individuals with the metabolic syndrome.

The metabolic syndrome is associated with abnormal glucose and lipid metabolism, insulin resistance, increased oxidative stress and pro-inflammatory activity that increase the risk of type 2 diabetes and cardiovascular disease. The aim of this study was to investigate the effect of treatment with the antioxidant α-lipoic acid (ALA) with or without vitamin E supplementation, on markers of insulin resistance and systemic inflammation and plasma nonesterified fatty acid (NEFA) concentrations in individuals with the metabolic syndrome. In a randomized, double-blind, placebo-controlled trial, subjects with the metabolic syndrome received ALA (600 mg/day, n = 34), vitamin E (100 IU/day, n = 36), both ALA and vitamin E (n = 41), or matching placebo (n = 40) for 1 year. Fasting circulating concentrations of glucose and insulin were measure every 3 months and NEFA, markers of inflammation, adiponectin and vitamin E were measured at 6 monthly intervals. Plasma NEFA concentrations decreased [-10 (-18, 0)%] at a marginal level of significance (p = 0.05) in those who received ALA alone compared with placebo and decreased [-8 (-14, -1)% (95% CI)] significantly (P = 0.02) in participants who were randomised to ALA with and without vitamin E compared with those who did not receive ALA. Fasting glucose, insulin, homeostatic model assessment of insulin resistance, adiponectin, and markers of inflammation did not change significantly during the study. These data suggest that prolonged treatment with ALA may modestly reduce plasma NEFA concentrations but does not alter insulin or glucose levels in individuals with the metabolic syndrome.

Effects of white and red wine on endothelial function in subjects with coronary artery disease.

BACKGROUND: Levels of anti-oxidant polyphenols are higher in red than in white wine and are thought to contribute to the reduced cardiovascular risk associated with moderate consumption of wine observed in epidemiological studies. AIM: To compare the acute effects of acute ingestion of white and red wine on endothelial function in subjects with coronary artery disease (CAD). METHODS: Fourteen subjects with proven CAD were randomised to consume white and red wine with a light meal in a single blind cross-over study. Flow-mediated dilatation (FMD) of the brachial artery was measured using high-resolution ultrasonography. Endothelial function, lipid profile, plasma alcohol and polyphenols were measured at baseline, 60 and 360 min after wine consumption. RESULTS: At baseline, FMD was similar (white wine 1.6 +/- 1.9%, red wine 1.8 +/- 1.7%). At 360 min after ingestion of wine there was no difference in FMD, which improved nearly threefold after both wines (white wine 4.7 +/- 2.2%, red wine 3.4 +/- 2.9%; P = 0.002). There was no detectable change in plasma polyphenol levels after either wine. CONCLUSIONS: These data suggest that wine acutely improves endothelial function in patients with CAD. This improved endothelial function might contribute to a reduced risk of cardiovascular events.

Effect of changing from a cellulose acetate to a polysulphone dialysis membrane on protein oxidation and inflammation markers.

BACKGROUND: In vitro, synthetic dialysis membranes induce less activation of blood components to produce pro-inflammatory cytokines and reactive oxygen species compared with cellulose acetate membranes. However, the long-term effect of switching from a cellulose-based dialysis membrane to a synthetic membrane on protein oxidation and systemic inflammation in hemodialysis patients is not well defined. METHODS: Nineteen patients receiving hemodialysis were followed prospectively after changing from a low-flux cellulose acetate membrane to a low-flux polysulphone membrane for 11-17 months (n = 15) and then returning to the cellulose acetate membrane for 1 month (n = 13). Plasma markers of protein oxidation, cell activation and systemic inflammation and concentrations of soluble cell adhesion molecules were measured at baseline and at the end of each intervention period. RESULTS: Plasma levels of protein thiols (18%), IL-6 (34%), VCAM-1 (33%), ICAM-1 (21%) and beta2-microglobulin (21%) increased significantly and dityrosine fluorescence (-36%), protein lipofuscin-like fluorophores (-18%) and TNF-alpha (-20%) decreased significantly in the patients after they switched to the polysulphone membrane. After reverting to the cellulose acetate membrane for 1 month, plasma levels of protein thiols and IL-6 returned to baseline while levels of other variables were not significantly different from values at the end of the polysulphone dialysis period. There was substantial intra-individual variation between 2 baseline measurements of plasma cytokines. CONCLUSIONS: Switching from a cellulose acetate membrane to a low-flux polysulphone dialysis membrane for a year or more may decrease the level of protein oxidation suggesting a decrease in oxidant stress and greater biocompatibility of the polysulphone membrane. The effect of this change in dialysis membrane on systemic inflammation is uncertain due to increases in some but not other inflammation-sensitive molecules.

Effect of hormone replacement therapy on inflammation-sensitive proteins in post-menopausal women with Type 2 diabetes.

AIMS: To test the effect of oral hormone replacement therapy (HRT) on plasma C-reactive protein (CRP), soluble vascular cell adhesion molecule-1 (VCAM-1), soluble intercellular adhesion molecule-1 (ICAM-1) and IL-6 concentrations and leucocyte count in post-menopausal women with Type 2 diabetes. METHODS: Post-menopausal women with Type 2 diabetes (n = 61) were randomized in a double-blind fashion to receive either continuous combined hormone replacement therapy (n = 29) with conjugated equine oestrogen (0.625 mg/day) plus medroxyprogesterone acetate (2.5 mg/day) or placebo (n = 32) for 6 months. Study variables were measured at baseline and at the end of the study. RESULTS: Eight women randomized to hormone replacement therapy and four women assigned to placebo group dropped out of the study. Plasma CRP increased (2.2 mg/l, 95% confidence interval 0.3-4.1 mg/l) significantly (P = 0.02) in women treated with HRT (n = 21) compared with placebo (n = 29) taking baseline CRP, body mass index (BMI) and smoking status into account. Plasma levels of cell adhesion molecules, IL-6 and leucocyte count did not change significantly during the study. CONCLUSIONS: These findings indicate that oral HRT with conjugated equine oestrogen plus medroxyprogesterone acetate increases plasma CRP levels but not necessarily global inflammatory activity in post-menopausal diabetic women. An increase in plasma CRP may potentially increase risk of a cardiovascular event.

The effect of meals rich in thermally stressed olive and safflower oils on postprandial serum paraoxonase activity in patients with diabetes.

OBJECTIVE: To determine the effects of meals rich in thermally stressed safflower (TSAF) and olive (TSOL) oils on postprandial serum paraoxonase (PON1) arylesterase activity and low density lipoprotein (LDL) oxidation in patients with type 2 diabetes. DESIGN: A randomised cross-over study. SETTING: Diabetes clinic and general practice. SUBJECTS: Fourteen patients (six men and eight women) with type 2 diabetes, aged 48-67 y, glycated haemoglobin <10% and fasting blood glucose <11 mmol/l were recruited. INTERVENTIONS: Patients received a milkshake rich in TSAF or TSOL and at least a week later they received the alternate milkshake. These fats contained high levels of lipid oxidation and degradation products. Blood samples were taken fasted and 4 h after consumption of the milkshake. MAIN OUTCOME MEASURES: Serum PON1 activity and lag time in LDL oxidation. RESULTS: After the meal rich in TSOL, serum PON1 activity increased significantly in women (12 (2.22) micromol/ml/min, mean (95% confidence interval), P=0.03) and not in men (0 (-4.4) micromol/ml/min) during the postprandial period. The increase in PON1 activity after the TSOL meal was significantly (P=0.03) greater in women compared with men. In women, the increase in serum PON1 activity after the TSOL meal was significantly different (13 (1.25) micromol/ml/min, P=0.04) compared with the corresponding change (-1 micromol/ml/min) after the TSAF meal. The lag time in LDL oxidation and indices of oxidative stress and antioxidant capacity did not vary significantly during the meals. CONCLUSIONS: Meals rich in TSOL may increase postprandial serum PON1 activity in middle-aged and older diabetic women. This change is potentially anti-atherogenic and may favour the use of olive oil over polyunsaturated fats in the diet of patients with type 2 diabetes. SPONSORSHIP: The study was supported by a grant from the National Heart Foundation of New Zealand.

Normal endothelial function after meals rich in olive or safflower oil previously used for deep frying.

BACKGROUND AND AIM: Polyunsaturated fats are more susceptible to oxidation during heating than monounsaturated fats but their effects on endothelial function when heated are unknown. The aim of this study was to compare the effect of meals rich in heat-modified safflower and olive oils on postprandial flow-mediated endothelium-dependent dilation (EDD) in healthy men. METHODS AND RESULTS: Flow-mediated EDD and glyceryltrinitrate-induced endothelium-independent dilation of the brachial artery were investigated in 14 subjects before and 4 hours after meals rich in olive oil and safflower oil used hourly for deep-frying for 8 hours in a double-blind crossover study design. There were high levels of lipid oxidation products (peroxides and carbonyls) in both heated oils. Plasma triglycerides were markedly increased at 4 hours after heated olive oil (1.26 +/- 0.43 vs 2.06 +/- 0.97 mmol/L) and heated safflower oil (1.44 +/- 0.63 vs 1.99 +/- 0.88 mmol/L). There was no change in EDD between fasting and postprandial studies and the response during the postprandial period was not significantly (p = 0.51) different between the meals (heated olive oil: 4.9 +/- 2.2% vs 4.9 +/- 2.5%; heated safflower oil: 5.1 +/- 3.1% vs 5.6 +/- 3.4%). CONCLUSIONS: Meals rich in olive and safflower oils previously used for deep frying and containing high levels of lipid oxidation products increase postprandial serum triglycerides without affecting endothelial function. These findings suggest that relatively short-term use of these vegetable oils for frying may not adversely affect postprandial endothelial function when foods containing the heat-modified oils are consumed.

The effect of hormone replacement therapy on cardiovascular risk factors in type 2 diabetes: a randomized controlled trial.

BACKGROUND: Postmenopausal women with diabetes are at high risk for cardiovascular disease, compared with their nondiabetic counterparts. Combined continuous hormone replacement therapy (HRT) is associated with improvements in serum lipoprotein levels in nondiabetic women; however, the effect in women with diabetes has not been determined. We evaluated the effect of combined continuous HRT on lipoprotein and coagulation factor concentrations and glycemic control in postmenopausal women with type 2 diabetes mellitus. METHODS: In a randomized controlled crossover study, 61 subjects received combined continuous HRT or placebo. Each treatment phase was of 6 months' duration, with an 8-week washout phase between treatment phases. RESULTS: Total cholesterol concentration decreased by 7% (95% confidence interval [CI], 4%-11%) during HRT. For low-density lipoprotein concentration, the mean decrease with HRT was 12% (95% CI, 6%-17%). Apolipoprotein B levels decreased in keeping with the reduction in low-density lipoprotein cholesterol concentrations. There were no significant changes in concentrations of high-density lipoprotein, its subfractions, or triglycerides. Lipoprotein(a) and fibrinogen concentrations were reduced by 21% (95% CI, 10%-31%) and 8% (95% CI, 2%-13%), respectively, with HRT. Fructosamine concentrations declined by 5% (95% CI, 2%-9%) during HRT. CONCLUSIONS: In postmenopausal women with type 2 diabetes mellitus, combined continuous HRT has beneficial effects on lipoprotein concentrations and improves some markers of coagulation and glycemic control.

Vitamin C improves endothelial dysfunction in renal allograft recipients.

BACKGROUND: Endothelial function is impaired in renal allograft recipients but the effects of antioxidant vitamin therapy on endothelial function in such patients is unknown. METHODS: Thirteen renal allograft recipients were randomized to vitamin C or placebo in a double blind cross-over study design. Flow-mediated endothelium-dependent dilation and glyceryltrinitrate-induced endothelium-independent dilation of the brachial artery were assessed before and 2 h after oral administration of 2 g vitamin C or placebo. RESULTS: Plasma vitamin C levels increased from 33.5+/-17.0 micromol/l to 98.8+/-60.2 micromol/l after treatment (P=0.0001). Endothelium-dependent dilation improved (from 1.6+/-2.6 to 4.5+/-2.5%) after vitamin C administration but was unchanged after placebo (1.9+/-1.5 to 1.8+/-2.5%; P=0.003 for vitamin C vs placebo). There was no significant change in endothelium-independent dilation in response to vitamin C. Vitamin C was also associated with a significant increase in the lag time in dilute serum oxidation (P=0.001). CONCLUSIONS: Vitamin C acutely improves flow-mediated, endothelium-dependent dilation and increases the resistance of lipoproteins in dilute serum to oxidation in renal transplant recipients.

Hormone-replacement therapy increases serum paraoxonase arylesterase activity in diabetic postmenopausal women.

The paraoxonase (PON1) enzyme is associated with high-density lipoproteins (HDL) in the blood and is low in patients with type 2 diabetes. Hormone-replacement therapy (HRT) can increase HDL cholesterol levels, but its effect on serum PON1 arylesterase activity is uncertain. The aim of the present study was to determine the effect of 6 months' HRT with conjugated equine estrogen and medroxyprogesterone acetate on serum PON1 arylesterase activity in postmenopausal women with type 2 diabetes. Serum PON1 activity was measured immediately before and at the end of the second arm of a randomized, placebo-controlled, crossover with washout study originally designed to test the effect of HRT on plasma lipids in diabetic postmenopausal women. Baseline serum PON1 arylesterase activity was significantly (P <.001) lower in the postmenopausal diabetic women (149 +/- 38 micromol/mL/min; n = 47) than values in healthy postmenopausal women (173 +/- 32 micromol/mL/min; n = 51). Serum PON1 activity increased (10%) significantly (P =.009) in diabetic women treated with HRT compared with placebo. A significant (P =.02) interaction between baseline PON1 activity and treatment indicated a greater increase in PON1 activity during HRT in women with lower baseline activities. At baseline, serum PON1 arylesterase activity was correlated significantly with plasma HDL cholesterol levels in diabetic women (r = 0.333, P =.01, n = 47), and the increase in serum PON1 activity was correlated significantly with the change in plasma HDL cholesterol during HRT (r = 0.659, P =.0001, n = 28). These data suggest that serum PON1 activity is abnormally low in postmenopausal women with type 2 diabetes and increases during HRT, particularly in women with lower baseline levels and in those who show a concomitant increase in HDL cholesterol.

The effects of sequential combined oral 17beta-estradiol norethisterone acetate on insulin sensitivity and body composition in healthy postmenopausal women: a randomized single blind placebo-controlled study.

OBJECTIVE: The androgenic effect of progestogen, necessary in early postmenopausal hormone replacement therapy (HRT), may adversely affect insulin sensitivity as well as body fat distribution and thereby increase the cardiovascular risk profile. The impact of HRT with sequential combined oral 17beta-estradiol and norethisterone acetate on insulin sensitivity and body composition in early menopause has not been studied. DESIGN: A randomized single blind placebo-controlled 6-month study of sequential combined 17beta-estradiol norethisterone acetate on insulin sensitivity and body composition was carried out. Thirty fit healthy postmenopausal women were enrolled and completed this 6-month study. Body composition was measured by dual-energy x-ray absorptiometry scanning, and insulin sensitivity was measured using the euglycemic hyperinsulinemic clamp. Studies were undertaken at baseline and after 6 months of therapy. The studies were performed during the estrogen-only phase of therapy. RESULTS: All women demonstrated a degree of decreased insulin sensitivity that was not modified by 6 months of hormone replacement therapy. Body composition remained unchanged over 6 months. There was no alteration in total body fat or the distribution of body fat. The percentage of central abdominal fat (android) was not altered. CONCLUSION: Six months of HRT with sequential combined oral 17beta-estradiol norethisterone acetate does not have an adverse effect on insulin sensitivity and does not promote an increase in weight or the more android distribution of body fat, which could contribute to the increased cardiovascular risk profile that is evident in postmenopausal women.

Variants in the cholesterol ester transfer protein and lipoprotein lipase genes are predictors of plasma cholesterol response to dietary change.

There are no definitive explanations as to why individuals with hypercholesterolemia, a major cardiovascular risk factor, respond differently to dietary change. Fifty five free-living individuals completed a double crossover trial with two dietary regimens, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat), each phase continuing for 4 weeks. Extensive genotyping and several measures of dietary compliance have provided further insights regarding the determinants of extent of cholesterol response to changes in the nature of dietary fat. Individuals with the CETP B1B1 genotype and the LPL X447+ allele showed an average 0. 44 (95% CI: 0.22, 0.66) and 0.45 (95% CI: 0.18, 0.72) mmol/l greater change in total cholesterol, respectively, than those with one or more CETP B2 allele or homozygous for the LPL S447 allele when comparing diets high and low in saturated fat. Indices of dietary compliance including changes in reported saturated and polyunsaturated fat intake and change in triglyceride linoleate were not significantly different between the CETP genotypes. Change in reported saturated (r=0.36, P=0.04) and polyunsaturated (r=0.22, P=0. 05) fat intake and change in triglyceride linoleate (reflecting polyunsaturated fat intake) (r=0.21, P=0.07), also predicted total cholesterol response to dietary fat changes. In multivariate analyses, variation in the cholesterol ester transfer protein and lipoprotein lipase genes predicted response independent of measures of dietary compliance, suggesting that these two genes are important determinants of variation in cholesterol response to dietary change in free-living individuals.

Plasma cholesteryl ester fatty acid composition, insulin sensitivity, the menopause and hormone replacement therapy.

This study was designed to determine the effect of menopause and hormone replacement therapy (HRT) on plasma cholesteryl ester fatty acid (CEFA) composition and insulin sensitivity and the relationships between these variables in perimenopausal women (aged 40-55 years) including 49 who were premenopausal and 32 who were postmenopausal. Plasma cholesteryl ester proportions of dihomo-gamma-linolenic acid (20:3 n-6) were correlated significantly with insulin sensitivity index (r=-0.319, P=0.005), fasting serum insulin levels (r=0.230, P=0.038), body mass index (r=0.242, P=0.03) and per cent body fat (r=0.329, P=0.003) in perimenopausal women (n=81). Similar associations were observed in premenopausal women. Regression analysis suggested the relationships between 20:3 n-6 proportions and indices of insulin action may be partly mediated by levels of adiposity. In postmenopausal women, 6 months of HRT significantly (P=0.008) increased the ratio of arachidonic acid (20:4 n-6) to linoleic acid (18:2 n-6), which is an indicator of activity in the pathway of 20:4 n-6 synthesis, compared with placebo. These findings suggest that the type of fat in the diet indicated by plasma CEFA composition is linked to adiposity and insulin action. They also suggest that in postmenopausal women, HRT may increase the synthesis of 20:4 n-6, which is the precursor for eicosanoids with important cardiovascular functions.

Effect of supplementation with tomato juice, vitamin E, and vitamin C on LDL oxidation and products of inflammatory activity in type 2 diabetes.

OBJECTIVE: To compare the effects of short-term dietary supplementation with tomato juice, vitamin E, and vitamin C on susceptibility of LDL to oxidation and circulating levels of C-reactive protein (C-RP) and cell adhesion molecules in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: There were 57 patients with well-controlled type 2 diabetes aged <75 years treated with placebo for 4 weeks and then randomized to receive tomato juice (500 ml/day), vitamin E (800 U/day), vitamin C (500 mg/day), or continued placebo treatment for 4 weeks. Susceptibility of LDL to oxidation (lag time) and plasma concentrations of lycopene, vitamin E, vitamin C, C-RP, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 were measured at the beginning of the study, after the placebo phase, and at the end of the study. RESULTS: Plasma lycopene levels increased nearly 3-fold (P = 0.001), and the lag time in isolated LDL oxidation by copper ions increased by 42% (P = 0.001) in patients during supplementation with tomato juice. The magnitude of this increase in lag time was comparable with the corresponding increase during supplementation with vitamin E (54%). Plasma C-RP levels decreased significantly (-49%, P = 0.004) in patients who received vitamin E. Circulating levels of cell adhesion molecules and plasma glucose did not change significantly during the study. CONCLUSIONS: This study indicates that consumption of commercial tomato juice increases plasma lycopene levels and the intrinsic resistance of LDL to oxidation almost as effectively as supplementation with a high dose of vitamin E, which also decreases plasma levels of C-RP, a risk factor for myocardial infarction, in patients with diabetes. These findings may be relevant to strategies aimed at reducing risk of myocardial infarction in patients with diabetes.

Genetic factors associated with response of LDL subfractions to change in the nature of dietary fat.

A preponderance of dense low density lipoprotein (LDL) particles is associated with an increased risk of coronary heart disease. It has been shown that dense LDL levels can be modified by diet. We investigated the contribution of polymorphisms in the genes for apolipoprotein (apo) B, apo AIV, lipoprotein lipase (LPL) and cholesterol ester transfer protein (CETP) to variation in the changes in plasma concentrations of dense LDL between a high saturated and a high polyunsaturated fatty acid diet. A total of 46 freeliving individuals (19 men and 27 women) completed a crossover trial with two dietary interventions of 4 weeks each, a high saturated fat diet (providing 21% energy from saturated fat and 3% energy from polyunsaturated fat) and a high polyunsaturated fat diet (providing 11% energy as saturated fat and 10% energy as polyunsaturated fat). Overall, the change in dense LDL between the saturated and polyunsaturated fat period was 0.17+/-0.33 mmol/L and this change was similar in men and women. Of the polymorphisms studied only variation in the apo AIV gene causing the substitution of histidine for glutamine at position 360 (Q360H) was associated with significant differences in the change in dense LDL concentration. Apo AIV Q/H individuals (n=6) showed a three-fold greater change in dense LDL cholesterol unadjusted for Lp(a) levels than Q/Q individuals (0.46+/-0.27 versus 0.12+/-0.31 mmol/L, p=0.02). The greater decrease in dense LDL cholesterol with an increase in polyunsaturated fat seen in those with the apo AIV H360 variant, who represent roughly 10% of the general population, suggests that they may benefit most from a PUFA rich lipid lowering diet.

Variation in plasma cholesterol response to dietary change.

BACKGROUND AND AIMS: Previous studies have suggested that some individuals show an appreciably larger change in total cholesterol in response to dietary change (hyper-responders) than others (minimal responders), and also that some people are more likely to respond consistently. We have examined the role of individual dietary compliance in determining total cholesterol response to changes in the nature of dietary fat. METHODS AND RESULTS: Participants completed a randomised double dietary crossover trial with a diet high in saturated fat and a diet high in polyunsaturated fat. Each period continued for four weeks without washouts. Plasma lipoproteins were measured at the end of each period. Dietary compliance was assessed by change in the reported polyunsaturated:saturated fat ratio calculated from three-day diet records, and change in polyunsaturated fat intake, determined by change in plasma triglyceride linoleate. A wide range of individual responses was observed with no evidence of two distinct populations of hyper- and minimal responders. Variation in response to the three crossovers appeared to be due mainly to variation in compliance. CONCLUSIONS: The results of this study do not support earlier suggestions of two separate populations of hyper and minimal responders to change in the nature of dietary fat, rather there is a graded range of response. In a free-living population, the extent to which individuals comply with dietary advice varies considerably and this contributes to the magnitude of cholesterol response as well as consistency on repeated dietary challenges.

Plasma cholesterol esterification and transfer, the menopause, and hormone replacement therapy in women.

With the onset of the menopause, plasma lipids and lipoprotein metabolism changes toward a more atherogenic profile that is improved by HRT. To determine whether cholesterol esterification rate (CER) and transfer of cholesteryl esters from high density lipoproteins to apolipoprotein B-containing lipoproteins are affected by menopause and HRT, plasma newly synthesized cholesteryl ester transfer (NCET) activity, CER and plasma lipids, lipoproteins, and apolipoprotein concentrations were measured in perimenopausal women (age range: 40-55 yr), including 49 premenopausal women and 32 postmenopausal women who were subsequently randomized to receive either placebo or 17-beta estradiol/norethisterone for 6 months. Plasma NCET (P = 0.03) and CER (P = 0.008) were significantly higher in postmenopausal women. Plasma low density lipoprotein cholesterol concentration, high density lipoprotein concentration, and body mass index were independent predictors of plasma NCET in premenopausal women, and plasma triglyceride and apolipoprotein B concentrations were corresponding predictors in postmenopausal women. When data were adjusted for plasma triglyceride, plasma NCET activity was no longer significantly different (P = 0.81) between premenopausal and postmenopausal women. Plasma NCET and CER did not change significantly in postmenopausal women during HRT. These data suggest that the determinants of plasma NCET activity after menopause and increased levels of triglyceride-rich lipoprotein acceptors of cholesteryl esters may lead to increased plasma NCET that is not reduced by HRT in postmenopausal women.

Oxidation of heparin-treated low density lipoprotein by peroxidases.

Low density lipoproteins (LDL) can bind to glycosaminoglycans and proteoglycans rich in heparin and chondroitin sulphate in the arterial intima and may become a target for atherogenic modification by myeloperoxidase activity. We have examined the susceptibility of resolubilized LDL, that has been precipitated from serum with heparin (HepLDL), to peroxidase-H2O2-catalysed oxidation and the effects of antioxidants and components of human serum on the oxidation. HepLDL was oxidised rapidly by horse radish peroxidase (HRP) and H2O2 (mean t1/2max for conjugated diene formation, 3 min) while there was little oxidation of native LDL or native LDL precipitated with polyethyleneglycol and resolubilised during the 30 min incubation period. The formation of thiobarbituric acid reacting substances (TBARS) essentially paralleled that of conjugated dienes during oxidation of HepLDL. HepLDL was also more rapidly oxidised than native LDL by myeloperoxidase-H2O2. Oxidation of HepLDL by peroxidases did not require free tyrosine, was almost totally inhibited by butylated hydroxytoluene (BHT) and ascorbate, and was unaffected by vitamin E and urate. Increasing concentrations (0-14.9%) of beta-lipoprotein deficient serum (BLPDS) significantly (P<0.0001) inhibited the formation of TBARS during HepLDL oxidation catalysed by HRP and partially inhibited the corresponding myeloperoxidase-catalysed oxidation. This inhibitory activity was removed by dialysis and gel-filtration of BLPDS and was not restored by addition of magnesium ions used in the isolation of BLPDS, or physiological levels of ascorbate, tyrosine and reduced thiols (cysteine) to gel-filtered BLPDS. The results indicate that LDL from complexes with glycosaminoglycans are highly susceptible to oxidation by peroxidases, particularly at low levels of water soluble antioxidants, and that vulnerability of these LDL to myeloperoxidase oxidation remains in the presence of serum components that should exist in the arterial intima. These findings may be relevant to the oxidative modification of LDL that becomes trapped by binding to arterial proteoglycans and to the formation of myeloperoxidase-modified LDL in the artery wall.

Supplementation with tomato juice increases plasma lycopene but does not alter susceptibility to oxidation of low-density lipoproteins from renal transplant recipients.

AIM: Oxidative stress and susceptibility of low-density lipoproteins (LDL) to oxidation are increased in renal transplant recipients. The aim of this study was to determine the effect of dietary supplementation with tomato juice on plasma levels of the antioxidant lycopene, serum indices of lipid peroxidation (fluorescent lipid oxidation products (FLOP) and thiobarbituric acid-reacting substances (TBARS)) and the resistance of isolated low-density lipoprotein (LDL) to oxidation (lag time) in patients with a kidney graft. SUBJECTS AND METHODS: Fifteen patients were randomized to daily consumption of either tomato juice or synthetic orange drink for 4 weeks in a crossover study. Plasma lycopene levels were significantly higher (1.57 micromol/l versus 0.91 micromol/l, p = 0.015) while serum FLOP and TBARS and resistance of LDL to oxidation were not significantly different during supplementation with tomato juice compared with orange drink. At baseline, serum levels of lycopene and FLOP were abnormally high and serum FLOP was correlated significantly with plasma cyclosporine levels (r = 0.646, p = 0.016). CONCLUSION: In conclusion, these data suggest that increased oxidative stress and susceptibility of LDL to oxidation may not be reduced by increasing plasma lycopene levels with regular consumption of tomato juice in renal transplant recipients.

Reduced postprandial serum paraoxonase activity after a meal rich in used cooking fat.

Paraoxonase is an enzyme associated with HDL in human serum that hydrolyzes oxidized phospholipids and inhibits LDL oxidation, which is an important step in atherogenesis. In animals, addition of oxidized lipids to the circulation reduces paraoxonase activity, and diets rich in oxidized fat accelerate the development of atherosclerosis. The current randomized, crossover study was designed to compare the effect of a meal rich in oxidized lipids in the form of fat that had been used for deep-frying in a fast food restaurant and a control meal rich in the corresponding unused fat on postprandial serum paraoxonase (arylesterase) activity and peroxide content of LDL and its susceptibility to copper ion catalyzed oxidation in 12 healthy men. Four hours into the postprandial period, serum paraoxonase activity had decreased significantly after the used fat meal (-17%, P=0.005) and had increased significantly after the meal rich in unused fat (14%, P=0. 005). These changes were significantly (P=0.003) different. A time-course study indicated that serum paraoxonase activity remained lower than baseline for up to 8 hours after the used fat meal. Serum apoA1 concentration tended to decrease after the unused fat meal and tended to increase after the used fat meal. These changes were different at a marginal level of significance (P=0.07). Also, a significantly (P=0.03) greater decrease in apoA1 content of postprandial HDL was recorded after the unused fat meal. The peroxide content of LDL tended to decrease after the used fat meal and tended to increase after the control meal. These changes were significantly (P=0.04) different. Susceptibility of isolated LDL to copper ion oxidation and plasma levels of malondialdehyde were unchanged during the study. These data suggest that in the postprandial period after a meal rich in used cooking fat, the enzymatic protection of LDL against accumulation of peroxides and atherogenic oxidative modification may be reduced, possibly due to factors associated with apoA1, without acutely affecting the intrinsic resistance of LDL to in vitro oxidation.