Alterations in lipid transfer to High-Density Lipoprotein (HDL) and activity of paraoxonase-1 in HIV+ patients

HIV+ patients often develop alterations of the plasma lipids that may implicate in development of premature coronary artery disease. High-density lipoprotein (HDL) has an important role in preventing atherogenesis and the aim of this study was to investigate aspects of HDL function in HIV+ patients. HIV+ patients (n = 48) and healthy control subjects (n = 45) of both sexes with similar age were studied. Twenty-five were not being treated with antiretroviral agents, 13 were under reverse transcriptase inhibitor nucleosidic and non-nucleosidic (NRTI+NNRTI) and 10 were under NRTI + protease inhibitors (NRTI+PI) treatment. Paraoxonase 1 (PON1) activity and the transfer of free and esterified cholesterol, tryglicerides and phospholipids from a lipidic nanoemulsion to HDL were analyzed. In comparison with healthy controls, HIV+ patients presented low PON-1 activity and diminished transfer of free cholesterol and tryglicerides. In contrast, phospholipid transfer was increased in those patients, whereas the transfer of cholesteryl esters was unchanged. NRTI+NNRTI increases the transfer of cholesteryl esters and triglycerides but in NRTI+PI there was no difference in respect to non-treated HIV+ patients. HDL from HIV+ patients has smaller antioxidant properties, as shown by lower PON-1 activity, and the transfer of lipids to this lipoprotein fraction is also altered, suggesting that HDL function is defective in those patients.

Etofibrate but not controlled-release niacin decreases LDL cholesterol and lipoprotein (a) in type IIb dyslipidemic subjects

Etofibrate is a hybrid drug which combines niacin with clofibrate. After contact with plasma hydrolases, both constituents are gradually released in a controlled-release manner. In this study, we compared the effects of etofibrate and controlled-release niacin on lipid profile and plasma lipoprotein (a) (Lp(a)) levels of patients with triglyceride levels of 200 to 400 mg/dl, total cholesterol above 240 mg/dl and Lp(a) above 40 mg/dl. These patients were randomly assigned to a double-blind 16-week treatment period with etofibrate (500 mg twice daily, N = 14) or niacin (500 mg twice daily, N = 11). In both treatment groups total cholesterol, VLDL cholesterol and triglycerides were equally reduced and high-density lipoprotein cholesterol was increased. Etofibrate, but not niacin, reduced Lp(a) by 26% and low-density lipoprotein (LDL) cholesterol by 23%. The hybrid compound etofibrate produced a more effective reduction in plasma LDL cholesterol and Lp(a) levels than controlled-release niacin in type IIb dyslipidemic subjects.

Oxidized low-density lipoproteins and their antibodies: Relationships with the reverse cholesterol transport and carotid atherosclerosis in adults without cardiovascular diseases

Background: Metabolic predictors and the atherogenicity of oxidized LDL (oxLDL) and the specific antibodies against oxLDL (oxLDL Ab) are unclear and controversial. Methods: In 107 adults without atherosclerotic manifestations, we measured oxLDL and oxLDL Ab, and also the activities of CETP. PLTP, lipases and the carotid intima-media thickness (cIMT). Comparisons were performed for the studied parameters between the lowest and the highest tertile of oxLDL and oxLDL Ab, and the relationships between studied variables were evaluated. Results: Subjects with higher oxLDL Ab present reduced hepatic lipase activity and borderline increased cIMT. In the highest oxLDL tertile, besides the higher levels of total cholesterol, LDL-C and apoB100, we found reduced CETP activity and higher cIMT. A significant correlation between oxLDL Ab and cIMT, independent of oxLDL, and a borderline correlation between oxLDL and cIMT independent of oxLDL Ab were found. In the multivariate analysis, apoAl was a significant predictor of oxLDL Ab, in contrast to regulation of oxLDL by apoB100, PLTP and inverse of CETP. Conclusions: In adults without atherosclerotic disease, the metabolic regulation and carotid atherosclerosis of oxLDLAb and oxLDL groups, characterized a dual trait in oxLDL Ab, as a contributor to carotid atherosclerosis, much less so than oxidized LDL, and with a modest atheroprotective role. (C) 2012 Elsevier B.V. All rights reserved.

Plasma lipases and lipid transfer proteins increase phospholipid but not free cholesterol transfer from lipid emulsion to high density lipoproteins.

Abstract Background Plasma lipases and lipid transfer proteins are involved in the generation and speciation of high density lipoproteins. In this study we have examined the influence of plasma lipases and lipid transfer protein activities on the transfer of free cholesterol (FC) and phospholipids (PL) from lipid emulsion to human, rat and mouse lipoproteins. The effect of the lipases was verified by incubation of labeled (3H-FC,14C-PL) triglyceride rich emulsion with human plasma (control, post-heparin and post-heparin plus lipase inhibitor), rat plasma (control and post-heparin) and by the injection of the labeled lipid emulsion into control and heparinized functionally hepatectomized rats. Results In vitro, the lipase enriched plasma stimulated significantly the transfer of 14C-PL from emulsion to high density lipoprotein (p<0.001) but did not modify the transfer of 3H-FC. In hepatectomized rats, heparin stimulation of intravascular lipolysis increased the plasma removal of 14C-PL and the amount of 14C-PL found in the low density lipoprotein density fraction but not in the high density lipoprotein density fraction. The in vitro and in vivo experiments showed that free cholesterol and phospholipids were transferred from lipid emulsion to plasma lipoproteins independently from each other. The incubation of human plasma, control and control plus monoclonal antibody anti-cholesteryl ester transfer protein (CETP), with 14C-PL emulsion showed that CETP increases 14C-PL transfer to human HDL, since its partial inhibition by the anti-CETP antibody reduced significantly the 14C-PL transfer (p<0.05). However, comparing the nontransgenic (no CETP activity) with the CETP transgenic mouse plasma, no effect of CETP on the 14C-PL distribution in mice lipoproteins was observed. Conclusions It is concluded that: 1-intravascular lipases stimulate phospholipid transfer protein mediated phospholipid transfer, but not free cholesterol, from triglyceride rich particles to human high density lipoproteins and rat low density lipoproteins and high density lipoproteins; 2-free cholesterol and phospholipids are transferred from triglyceride rich particles to plasma lipoproteins by distinct mechanisms, and 3 - CETP also contributes to phospholipid transfer activity in human plasma but not in transgenic mice plasma, a species which has high levels of the specific phospholipid transfer protein activity.

Metabolism of plasma cholesterol and lipoprotein parameters are related to a higher degree of insulin sensitivity in high HDL-C healthy normal weight subjects

Abstract Background We have searched if plasma high density lipoprotein-cholesterol (HDL-C) concentration interferes simultaneously with whole-body cholesterol metabolism and insulin sensitivity in normal weight healthy adult subjects. Methods We have measured the activities of several plasma components that are critically influenced by insulin and that control lipoprotein metabolism in subjects with low and high HDL-C concentrations. These parameters included cholesteryl ester transfer protein (CETP), phospholipid transfer protein (PLTP), lecithin cholesterol acyl transferase (LCAT), post-heparin lipoprotein lipase (LPL), hepatic lipase (HL), pre-beta-1HDL, and plasma sterol markers of cholesterol synthesis and intestinal absorption. Results In the high-HDL-C group, we found lower plasma concentrations of triglycerides, alanine aminotransferase, insulin, HOMA-IR index, activities of LCAT and HL compared with the low HDL-C group; additionally, we found higher activity of LPL and pre-beta-1HDL concentration in the high-HDL-C group. There were no differences in the plasma CETP and PLTP activities. Conclusions These findings indicate that in healthy hyperalphalipoproteinemia subjects, several parameters that control the metabolism of plasma cholesterol and lipoproteins are related to a higher degree of insulin sensitivity.

Delayed loss of cholesterol from a localized lipoprotein depot in apolipoprotein A-I-deficient mice

The anti-atherogenic role of high density lipoprotein is well known even though the mechanism has not been established. In this study, we have used a novel model system to test whether removal of lipoprotein cholesterol from a localized depot will be affected by apolipoprotein A-I (apo A-I) deficiency. We compared the egress of cholesterol injected in the form of cationized low density lipoprotein into the rectus femoris muscle of apo A-I K-O and control mice. When the injected lipoprotein had been labeled with [3H]cholesterol, the t½ of labeled cholesterol loss from the muscle was about 4 days in controls and more than 7 days in apo A-I K-O mice. The loss of cholesterol mass had an initial slow (about 4 days) and a later more rapid component; after day 4, the disappearance curves for apo A-I K-O and controls began to diverge, and by day 7, the loss of injected cholesterol was significantly slower in apo A-I K-O than in controls. The injected lipoprotein cholesterol is about 70% in esterified form and undergoes hydrolysis, which by day 4 was similar in control and apo A-I K-O mice. The efflux potential of serum from control and apo A-I K-O mice was studied using media containing 2% native or delipidated serum. A significantly lower efflux of [3H]cholesterol from macrophages was found with native and delipidated serum from apo A-I K-O mice. In conclusion, these findings show that lack of apo A-I results in a delay in cholesterol loss from a localized depot in vivo and from macrophages in culture. These results provide support for the thesis that anti-atherogenicity of high density lipoprotein is related in part to its role in cholesterol removal.

Low and moderate, rather than high intensity strength exercise induces benefit regarding plasma lipid profile

Background: The effects of chronic aerobic exercise upon lipid profile has been previously demonstrated, but few studies showed this effect under resistance exercise conditions. Objective: The aim of this study was to examine the effects of different resistance exercise loads on blood lipids. Methods: Thirty healthy, untrained male volunteers were allocated randomly into four groups based at different percentages of one repetition maximum (1 RM); 50%-1 RM, 75%-1 RM, 90%-1 RM, and 110%-1 RM. The total volume (sets x reps x load) of the exercise was equalized. The lipid profile (Triglycerides [TG], HDL-cholesterol [HDL-c], LDL-cholesterol, and Total cholesterol) was determined at rest and after 1, 24, 48 and 72 h of resistance exercise. Results: The 75%-1 RM group demonstrated greater TG reduction when compared to other groups (p < 0.05). Additionally, the 110%-1 RM group presented an increased TG concentration when compared to 50% and 75% groups (p = 0.01, p = 0.01, respectively). HDL-c concentration was significantly greater after resistance exercise in 50%-1 RM and 75%-1 RM when compared to 110%-1 RM group (p = 0.004 and p = 0.03, respectively). Accordingly, the 50%-1 RM group had greater HDL-c concentration than 110%-1 RM group after 48 h (p = 0.05) and 72 h (p = 0.004), respectively. Finally, The 50% group has showed lesser LDL-c concentration than 110% group after 24 h (p = 0.007). No significant difference was found in Total Cholesterol concentrations. Conclusion: These results indicate that the acute resistance exercise may induce changes in lipid profile in a specific-intensity manner. Overall, low and moderate exercise intensities appear to be promoting more benefits on lipid profile than high intensity. Long term studies should confirm these findings.

Lipid Metabolism in Subclinical Hypothyroidism: Plasma Kinetics of Triglyceride-Rich Lipoproteins and Lipid Transfers to High-Density Lipoprotein Before and After Levothyroxine Treatment

Background: Subclinical hypothyroidism (SCH) has been associated with atherosclerosis, but the abnormalities in plasma lipids that can contribute to atherogenesis are not prominent. The aim of this study was to test the hypothesis that patients with normocholesterolemic, normotriglyceridemic SCH display abnormalities in plasma lipid metabolism not detected in routine laboratory tests including abnormalities in the intravascular metabolism of triglyceride-rich lipoproteins, lipid transfers to high-density lipoprotein (HDL), and paraoxonase 1 activity. The impact of levothyroxine (LT4) treatment and euthyroidism in these parameters was also tested. Methods: The study included 12 SCH women and 10 matched controls. Plasma kinetics of an artificial triglyceride-rich emulsion labeled with radioactive triglycerides and cholesteryl esters as well as in vitro transfer of four lipids from an artificial donor nanoemulsion to HDL were determined at baseline in both groups and after 4 months of euthyroidism in the SCH group. Results: Fractional clearance rates of triglycerides (SCH 0.035 +/- 0.016 min(-1), controls 0.029 +/- 0.013 min(-1), p=0.336) and cholesteryl esters (SCH 0.009 +/- 0.007 min(-1), controls 0.009 +/- 0.009 min(-1), p=0.906) were equal in SCH and controls and were unchanged by LT4 treatment and euthyroidism in patients with SCH, suggesting that lipolysis and remnant removal of triglyceride-rich lipoproteins were normal. Transfer of triglycerides to HDL (SCH 3.6 +/- 0.48%, controls 4.7 +/- 0.63%, p=0.001) and phospholipids (SCH 16.2 +/- 3.58%, controls 21.2 +/- 3.32%, p=0.004) was reduced when compared with controls. After LT4 treatment, transfers increased and achieved normal values. Transfer of free and esterified cholesterol to HDL, HDL particle size, and paraoxonase 1 activity were similar to controls and were unchanged by treatment. Conclusions: Although intravascular metabolism of triglyceride-rich lipoproteins was normal, patients with SCH showed abnormalities in HDL metabolism that were reversed by LT4 treatment and achievement of euthyroidism.

Size at birth and lipoprotein concentrations in adulthood: two prospective studies in Latin American cities

Background The relationship between birth weight and plasma lipoproteins is inconsistent. Aims To assess the association between birth weight and (1) body mass index (BMI) at birth and (2) lipoproteins in young adults, and also to explore the possible effect of current obesity as a possible effect modifier. Methods Two prospective studies based on representative samples of subjects born in the 1970s were carried out in Ribeirao Preto, Brazil (n = 2063) and Limache, Chile (n = 999). The surveys were carried out between 2001 and 2004. Results Mean birth weights were 3267 g and 3177 g and mean adult BMIs were 24.3 kg/m(2) and 25.8 kg/m(2) in the Brazilian and Chilean samples, respectively. Total adult cholesterol was 4.57 mmol/l in Chileans, 0.26 mmol/l higher than in Brazilians (p < 0.001). The main finding was an interaction between adult obesity (BMI 30 or over) and birth weight and also BMI at birth and low-density lipoprotein (LDL) and total cholesterol. A birth-weight increment of 1 kg was associated with a decrease in total cholesterol (-0.374 mmol/l, 95% CI -0.567 to -0.181) and LDL (-0.304 mmol/l (-0.479 to -0.129) in obese participants only. These associations persisted after allowing for gestational age in a smaller sample. This finding was consistent in separate analyses in the Brazilian and Chilean samples. No associations were found in relation to high-density lipoprotein and triglyceride concentrations. Conclusion The results suggest that those who were of low birth weight and are obese are more likely to have high cholesterol and LDL concentrations. Thus preventing obesity may be especially rewarding in subjects with a low birth weight.

Is acute supramaximal exercise capable of modulating lipoprotein profile in healthy men?

P>Background This study examined the effects of acute supramaximal exercise (similar to 115% VO(2max)) on the blood lipid profile for three different carbohydrate (CHO) storage levels (control, low and high). Methods Six male subjects were randomly divided into three different groups: control, low CHO and high CHO. These groups differed in the diet to which the subjects were submitted before each exercise session. The lipid profile [triglycerides (TG), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein (LDL)-cholesterol, TG/HDL-C ratio and total cholesterol) was determined at rest, immediately after exercise and 1 h after exercise bouts. Results The time to exhaustion was lower in the low CHO condition compared with the control and high CHO condition (3 center dot 59 +/- 0 center dot 72; 2 center dot 91 +/- 0 center dot 56; and 4 center dot 26 +/- 0 center dot 69 min; P < 0 center dot 05). The energy expenditure (control: 251 center dot 1 +/- 56 center dot 0 kJ; low CHO: 215 center dot 2 +/- 28 center dot 6 kJ; and high CHO: 310 center dot 4 +/- 64 center dot 9 kJ) was significantly different between the low and high CHO conditions (P < 0 center dot 05). There were no significant changes in the lipid profile for any of the experimental conditions (control, low and high; P < 0 center dot 05). Glucose and insulin levels did not show time-dependent changes in any of the conditions (P > 0 center dot 05). Conclusions These results indicate that a supramaximal exercise session has no significant effects on lipid metabolism.

Paclitaxel associated with cholesterol-rich nanoemulsions promotes atherosclerosis regression in the rabbit

A cholesterol-rich nanoemulsion (LDE) that resembles LDL binds to the LDL receptors and after injection into the blood stream may concentrate in cells with LDL receptor overexpression, as occurs in neoplasias and other proliferative processes. Thus, LDE can be used as vehicle to target drugs against those cells. The current study was designed to verify in rabbits whether LDE concentrates in the lesioned rabbit artery and whether a paclitaxel derivative, paclitaxel oleate, associated to LDE could reduce the atherosclerotic lesions. Sixteen male New Zealand rabbits were fed a 1% cholesterol diet for 60 days. Starting from day 30 under cholesterol feeding, eight animals were treated with four weekly intravenous injections of LDE-paclitaxel (4 mg/kg) and eight with four weekly intravenous saline solution injections for additional 30 days. On day 60, the animals were sacrificed for analysis. The uptake of LDE labeled with [C-14]-cholesteryl oleate by the aortic arch of cholesterol-fed rabbits was twice as much that observed in animals fed only regular chow. LDE-paclitaxel reduced the lesion areas of cholesterol-fed animals by 60% and intima-media ratio fourfold and inhibited the macrophage migration and the smooth muscle cell proliferation and invasion of the intima. LDE-paclitaxel treatment had no toxicity. In conclusion, LDE-paclitaxel produced pronounced atherosclerosis regression without toxicity and has shown remarkable potential in cardiovascular therapeutics. (c) 2008 Published by Elsevier Ireland Ltd.

Cu and Fe metallic ions-mediated oxidation of low-density lipoproteins studied by NMR, TEM and Z-scan technique

In this work we report on a study of the morphological changes of LDL induced in vitro by metallic ions (Cu(2+) and Fe(3+)). These modifications were characterized by transmission electron microscopy, nuclear magnetic resonance and the Z-scan technique. The degree of oxidative modification of LDL was determined by the TBARS and lipid hydroperoxides assays. It is shown that distinct pathways for modifying lipoproteins lead to different morphological transformations of the particles characterized by changes in size and/or shape of the resulting particles, and by the tendency to induce aggregation of the particles. There were no evidence of melting of particles promoted by oxidative processes with Cu and Fe. (C) 2010 Elsevier Ireland Ltd. All rights reserved.

Acute ingestion of yerba mate infusion (Ilex paraguariensis) inhibits plasma and lipoprotein oxidation

Yerba mate extract (Ilex paraguariensis) is a Source of phenolic compounds that possesses in vitro antioxidant activities and may contribute to a reduction in the risk of cardiovascular disease. In this Study we examined the acute effects of the consumption of mate infusion on ex vivo plasma and low-density lipoprotein (LDL) oxidation, plasma antioxidant capacity, and platelet aggregation. Twelve healthy fasted subjects ingested 500 mL. of mate infusion and blood samples were collected before and I h after mate intake. Lipid peroxidation of plasma and LDL was monitored by the measurement of cholesteryl-ester hydroperoxides (CE-OOH) and cholesterol oxides. The plasma antioxidant capacity was measured as ferric-reducing antioxidant potential (FRAP). Platelet aggregation was evaluated in platelet-rich plasma Stimulated with adenosine diphosphate and coagulation was tested in platelet-poor plasma. Ingestion of mate infusion diminished the ex vivo oxidizability of both plasma and LDL particles. After mate intake, the CE-OOH levels were around 50% lower in plasma oxidized with copper or 2,2`-azobis[-2-amidine-propane-hydrochloride] (AAPH) and the lag time to plasma oxidation increased 2-fold (P < 0.05). Copper- and AAPH-induced LDL peroxidation were also inhibited by around 50% and 20%, respectively, after mate Consumption (P < 0.05). The levels of various oxysterols were significantly reduced in oxidized-plasma and LDL (P < 0.05) and FRAP increased by 7.7% after mate intake (P < 0.01). However. mate consumption did not inhibit platelet aggregation or blood coagulation. In summary, intake of yerba mate infusion improved the antioxidant capacity and the resistance of plasma and LDL particles to ex vivo lipid peroxidation. (C) 2008 Elsevier Ltd. All rights reserved.

Impact of cholesterol on ABC and SLC transporters expression and function and its role in disposition variability to lipid-lowering drugs

This report focuses on the effects of cholesterol on the expression and function of the ATP-binding cassette (ABCB1, ABCG2 and ABCC2) and solute-linked carrier (SLCO1B1 and SLCO2B1) drug transporters with a particular focus on the potential impact of cholesterol on lipid-lowering drug disposition. Statins are the most active agents in the treatment of hypercholesterolemia. However, considerable interindividual variation exists in the response to statin therapy. Therefore, it would be huge progress if factors were identified that reliably differentiate between responders and nonresponders. Many studies have suggested that plasma lipid concentrations can affect drug disposition of compounds, such as ciclosporin and amphotericin B. Both compounds are able to affect the expression and function of ABC transporters. Although still speculative, these effects might be owing to the regulation of drug transporters by plasma cholesterol levels. Studies with normo- and hyper-cholesterolemic individuals, before and after atorvastatin treatment, have demonstrated that plasma cholesterol levels are correlated with drug transporter expression, as well as being related to atorvastatin`s cholesterol-lowering effect. The mechanism influencing the correlation between cholesterol levels and the expression and function of drug transporters remains unclear. Some studies provide strong evidence that nuclear receptors, such as the pregnane X receptor and the constitutive androstane receptor, mediate this effect. In the near future, pharmacogenomic studies with individuals in a pathological state should be performed in order to identify whether high plasma cholesterol levels might be a factor contributing to interindividual oral drug bioavailability.

Anti-Lipoprotein Lipase Antibodies in Patients with Hypertriglyceridemia without Associated Autoimmune Disease

Background: Anti-lipoprotein lipase antibodies have been described in rare cases of patients with hypertriglyceridemia. However, no systematic study evaluating these antibodies in patients with this lipid abnormality has been undertaken. Objectives: To analyze the correlation of anti-lipoprotein lipase (anti-LPL) antibodies with other laboratory findings in patients with hypertriglyceridemia but no autoimmune disease. Methods: We evaluated 44 hypertriglyceridemic patients without autoimmune disease. Clinical and laboratory evaluations included analyses of comorbidities, fasting lipid profile and anti-LPL antibodies. Results: Mean patient age was 55 +/- 10 years; 46% of the patients were female and 64% were Caucasian. The mean disease duration was 94.4 months and mean body mass index 28.7 +/- 3.6 kg/m(2); 34.0% were diabetic, 25.0% were obese, 72.7% had systemic arterial hypertension, 75% were sedentary, 15.9% were smokers, 56.8% had a family history of dyslipidemia, 45.5% had a family history of coronary insufficiency, 20.5% had acute myocardial infarction, 9.0% had undergone revascularization and 11.0% angioplasty, 79.5% were being treated with statins and 43.2% were taking fibrates. Median triglyceride levels were 254 mg/dl (range 100-3781 mg/dl), and total cholesterol level was 233 +/- 111 mg/dl. High-density lipoprotein was 42.6 +/- 15.4 mg/dl, low-density lipoprotein 110.7 +/- 42.4 mg/dl and very low-density lipoprotein 48 +/- 15 mg/dl. Anti-LPL antibodies were identified in 2 patients (4.5%), both of whom had a family history of dyslipidemia, coronary insufficiency and acute myocardial infarction; one had undergone myocardial revascularization and percutaneous transluminal coronary angioplasty, and both were using fibrates and had normal triglyceride levels. Conclusions: Our findings demonstrate a correlation between the immune response and dyslipoproteinemia in hypertriglyceridemic patients, suggesting that autoimmune disease contributes to the dyslipidemia process.