Similar lipid level changes in early rheumatoid arthritis patients following 1-year treat-to-target strategy with adalimumab plus methotrexate versus placebo plus methotrexate: secondary analyses from the randomised controlled OPERA trial.

To compare changes in low-density lipoprotein cholesterol and other lipids in patients with rheumatoid arthritis (RA) randomised to a 1-year treat-to-target strategy with either adalimumab plus methotrexate or placebo plus methotrexate. Prespecified secondary analyses from the OPERA trial, where 180 early and treatment-naïve RA patients received methotrexate 20 mg once weekly in combination with either placebo or subcutaneous adalimumab 40 mg every other week. Serum lipid levels were measured at baseline and after 1 year. Changes in lipid levels were analysed using mixed linear models based on the intention-to-treat (ITT) population. Overall, 174 patients were included in the ITT population (adalimumab plus methotrexate n = 86; placebo plus methotrexate n = 88). Differences between changes in lipid levels were low-density lipoprotein cholesterol 0.18 mmol/l [95% CI - 0.05 to 0.42], total cholesterol 0.27 mmol/l [- 0.002 to 0.54], high-density lipoprotein cholesterol 0.05 mmol/l [- 0.06 to 0.15], triglycerides 0.11 mmol/l [- 0.08 to 0.29], very-low-density lipoprotein cholesterol 0.03 mmol/l [- 0.05 to 0.12], and non-high-density lipoprotein cholesterol 0.22 mmol/l [- 0.02 to 0.46]. In early RA patients treated to tight control of inflammation over a period of 1 year with either adalimumab plus methotrexate or placebo plus methotrexate, changes in lipid levels were similar. Trial registration number: NCT00660647.

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet.

BACKGROUND: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. METHODS: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. RESULTS: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. CONCLUSIONS: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

The effects of flaxseed supplementation on metabolic status in women with polycystic ovary syndrome: a randomized open-labeled controlled clinical trial.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is known as the most common endocrine disorder of women in reproductive ages. With the increasing prevalence of PCOS in different countries, the use of herbal medicine as an alternative treatment is growing in these patients. This study aimed to evaluate the effects of flaxseed powder supplementation on metabolic biomarkers of patients with PCOS. METHODS: This randomized open-labeled controlled clinical trial was conducted on 41 patients with PCOS. The participants were randomized to take either flaxseed powder (30 g/day) plus lifestyle modification or only lifestyle modification for 12 weeks. Anthropometric and biochemical evaluations were performed for all patients at the beginning and end of the study. RESULTS: The flaxseed group showed a significant reduction in body weight, insulin concentration, Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Triglycerides (TG), high-sensitivity C-Reactive Protein (hs-CRP), and leptin and an increase in Quantitative Insulin-Sensitivity Check Index (QUICKI), High Density Lipoprotein (HDL), and adiponectin compared to the baseline (p < 0.05). Flaxseed supplementation also led to a significant reduction in insulin concentration, HOMA-IR, TG, hs-CRP, Interleukin 6 (IL- 6), and leptin and an increase in QUICKI, HDL, and adiponectin compared to the control group (p < 0.05). No significant changes were observed in other parameters. CONCLUSIONS: Flaxseed supplementation plus lifestyle modification was more effective compared to lifestyle modification alone in biochemical and anthropometric variables in patients with PCOS. TRIAL REGISTRATION: The trial protocol was approved by the Ethics Board at Ahvaz Jundishapur University of Medical Sciences and was registered at Iranian Registry of Clinical Trials (code: IRCT20120704010181N11).

Translating Evidence of HDL and Plaque Regression.

Considerable evidence from preclinical and population studies suggests that HDLs (high-density lipoproteins) possess atheroprotective properties. Reports from HDL infusion studies in animals and early clinical imaging trials reported evidence of plaque regression. These findings have stimulated further interest in developing new agents targeting HDL. However, the results of more recent imaging studies in the setting of high-intensity statin use have been disappointing. As the concept of plaque changes with HDL therapeutics evolves and imaging technology to evaluate these effects advances, there will become increasing opportunity to determine the effects of HDL agents on atherosclerotic plaque (Graphic Abstract).

Attenuation of atherogenic apo B-48-dependent hyperlipidemia and high density lipoprotein remodeling induced by vitamin C and E combination and their beneficial effect on lethal ischemic heart disease in mice.

BACKGROUND AND AIMS: Atherosclerotic cardiovascular disease is highly prevalent and its underlying pathogenesis involves dyslipidemia including pro-atherogenic high density lipoprotein (HDL) remodeling. Vitamins C and E have been proposed as atheroprotective agents for cardiovascular disease management. However, their effects and benefits on high density lipoprotein function and remodeling are unknown. In this study, we evaluated the role of vitamin C and E on non HDL lipoproteins as well as HDL function and remodeling, along with their effects on inflammation/oxidation biomarkers and atherosclerosis in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. METHODS AND RESULTS: Mice were pre-treated for 5 weeks before and during atherogenic diet feeding with vitamin C and E added to water and diet, respectively. Compared to a control group, combined vitamin C and E administration reduced serum total cholesterol and triglyceride levels by decreasing apo B-48-containing lipoproteins, remodeled HDL particles by reducing phospholipid as well as increasing PON1 and apo D content, and diminished PLTP activity and levels. Vitamin supplementation improved HDL antioxidant function and lowered serum TNF-α levels. Vitamin C and E combination attenuated atherogenesis and increased lifespan in atherogenic diet-fed SR-B1 KO/ApoER61h/h mice. CONCLUSIONS: Vitamin C and E administration showed significant lipid metabolism regulating effects, including HDL remodeling and decreased levels of apoB-containing lipoproteins, in mice. In addition, this vitamin supplementation generated a cardioprotective effect in a murine model of severe and lethal atherosclerotic ischemic heart disease.

Effects of High Density Lipoprotein Raising Therapies on Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus, with or without Renal Impairment: The Action to Control Cardiovascular Risk in Diabetes Study.

BACKGROUND: The role of high density lipoprotein-raising interventions in addition to statin therapy in patients with diabetes remains controversial. Chronic kidney disease (CKD) is a strong modifier of cardiovascular (CV) outcomes. We therefore investigated the impact of CKD status at baseline on outcomes in patients with diabetes randomized to standard statin or statin plus fenofibrate treatment in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) lipid trial. METHODS: Among 5,464 participants in the ACCORD lipid trial, 3,554 (65%) were free of CKD at baseline, while 1,910 (35%) had mild to moderate CKD. Differences in CV outcomes during follow-up between CKD and non-CKD subgroups were examined. In addition, the effect of fenofibrate as compared to placebo on CV outcomes was examined for both subgroups. RESULTS: All CV outcomes were 1.4-3 times higher among patients with CKD as compared to non-CKD patients. In patients with CKD, the addition of fenofibrate had no effect on any of the primary or secondary outcomes. In patients without CKD, however, the addition of fenofibrate was associated with a significant 36% reduction of CV mortality (hazards ratio [HR] 0.64; 95% CI 0.42-0.97; p value for treatment interaction <0.05) and 44% lower rate of fatal or non-fatal congestive heart failure (CHF; HR 0.56; 95% CI 0.37-0.84; p value treatment interaction <0.03). CONCLUSIONS: For patients with type 2 diabetes at high CV risk but no CKD, fenofibrate therapy added to statin reduced the CV mortality and the rate of fatal and non-fatal CHF.

Associations between intensive diabetes therapy and NMR-determined lipoprotein subclass profiles in type 1 diabetes.

Our objective is to define differences in circulating lipoprotein subclasses between intensive versus conventional management of type 1 diabetes during the randomization phase of the Diabetes Control and Complications Trial (DCCT). NMR-determined lipoprotein subclass profiles (NMR-LSPs), which estimate molar subclass concentrations and mean particle diameters, were determined in 1,294 DCCT subjects after a median of 5 years (interquartile range: 4-6 years) of randomization to intensive or conventional diabetes management. In cross-sectional analyses, we compared standard lipids and NMR-LSPs between treatment groups. Standard total, LDL, and HDL cholesterol levels were similar between randomization groups, while triglyceride levels were lower in the intensively treated group. NMR-LSPs showed that intensive therapy was associated with larger LDL diameter (20.7 vs. 20.6 nm, P = 0.01) and lower levels of small LDL (median: 465 vs. 552 nmol/l, P = 0.007), total IDL/LDL (mean: 1,000 vs. 1,053 nmol/l, P = 0.01), and small HDL (mean: 17.3 vs. 18.6 µmol/l, P < 0.0001), the latter accounting for reduced total HDL (mean: 33.8 vs. 34.8 µmol/l, P = 0.01). In conclusion, intensive diabetes therapy was associated with potentially favorable changes in LDL and HDL subclasses in sera. Further research will determine whether these changes contribute to the beneficial effects of intensive diabetes management on vascular complications.

High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target.

High-density lipoprotein (HDL) is a complex mixture of lipoproteins that is associated with many minor proteins and lipids that influence the function of HDL. Although HDL is a promising marker and potential therapeutic target based on its epidemiological data and the effects of healthy HDL in vitro in endothelial cells and macrophages, as well as based on infusion studies of reconstituted HDL in patients with hypercholesterolemia, it remains still uncertain whether or not HDL cholesterol-raising drugs will improve outcomes. Recent studies suggest that HDL becomes modified in patients with coronary artery disease or acute coronary syndrome because of oxidative processes that result in alterations in its proteome composition (proteome remodelling) leading to HDL dysfunction.

Differential Effects of Cyproterone Acetate vs Spironolactone on Serum High-Density Lipoprotein and Prolactin Concentrations in the Hormonal Treatment of Transgender Women.

INTRODUCTION: Spironolactone and cyproterone acetate (CPA) are the two main antiandrogen medications used in feminizing hormone therapy in transgender women. Previous studies have suggested that these two agents might have opposite effects on high-density lipoprotein (HDL) level when used in this context, and limited data have suggested CPA increases prolactin more than spironolactone. AIM: To compare the effects of spironolactone and CPA on HDL and prolactin serum concentrations in transgender women. METHODS: A retrospective chart review was conducted at three clinical sites in Toronto, Ontario, Canada. Patients were selected if they (i) identified as a transgender woman, (ii) had newly started spironolactone or CPA with estrogen or restarted spironolactone or CPA after a washout period of at least 6 months, and (iii) had not used other antiandrogens within the previous 6 months. MAIN OUTCOME MEASURES: HDL and prolactin concentrations between the two treatment groups at baseline and at 12 months. RESULTS: Eighty-two patients were included in the spironolactone group and 31 patients were included in the CPA group. Baseline HDL and prolactin levels were not significantly different between the two groups. At 12 months, HDL increased by 0.10 mmol/L (SD = 0.24) in the spironolactone group but decreased by 0.07 mmol/L (SD = 0.21) in the CPA group (P = .002). The difference remained significant after adjusting for baseline HDL, use of lipid-lowering drugs, and age. The change in prolactin was +3.10 µg/L (SD = 5.70) in the spironolactone group and +11.8 µg/L (SD = 8.63) in the CPA group (P < 0.001). This difference also remained significant after adjusting for baseline prolactin level. CONCLUSION: These data suggest that spironolactone use in transgender women increases HDL levels and that CPA has the opposite effect. CPA also is associated with a larger increase in prolactin. These factors should be considered when choosing between these two antiandrogen agents.

The therapeutic efficacy of intensive medical therapy in ameliorating high-density lipoprotein dysfunction in subjects with type two diabetes.

BACKGROUND: To determine whether 12 months of intensive medical therapy (IMT) improves HDL functionality parameters in subjects with type II diabetes (T2D). METHODS: Retrospective, randomized, and controlled 12-month IMT intervention trial that enrolled 13-subjects with T2D (age 51- years, fasting glucose 147 mg/dL, body mass index [BMI] 36.5 kg/m(2)) and nine healthy control (46-years, fasting glucose 90 mg/dL, BMI 26.5 kg/m2). Subjects with T2D underwent IMT and HDL functionality measures (pro-inflammatory index of high-density lipoprotein (pHDL)), paraoxonase one (PON1), ceruloplasmin (Cp), and myeloperoxidase (MPO) activity were performed on samples at baseline and at 12-months following IMT. RESULTS: At baseline, pHDL index was significantly higher in subjects with T2D (p < 0.001) and apolipoprotein A-1 levels were significantly lower (p = 0.013) vs. CONTROLS: After 12-months, there was a trend for improved pHDL activity (p = 0.083), as indicated by intent-to-treat analysis, but when the non-adherent subject was omitted (per-protocol), significant attenuations in pHDL activity (p = 0.040) were noted; Δ pHDL activity at 12-months was associated with Δ weight (r = 0.62, p = 0.032) and Δ fasting glucose (r = 0.65, p = 0.022). Moreover, PON1 activity significantly improved (p < 0.001). The aforementioned occurred in association with improvements in inflammatory markers (i.e., C-reactive protein & tumor necrosis factor), hemoglobin A1C, fasting glucose, triglycerides, high-density lipoprotein levels and adipokines. CONCLUSION: IMT ameliorates pHDL index and significantly improves anti-oxidative function, as measured by PON1. Improvements in weight and fasting glucose mediated the decrease in pHDL index. Pharmacological aids and lifestyle modification are required to improve cardiovascular risk factors, subsequent mortality risk, and promote T2D remission. Application of either form of therapy alone may only have relatively miniscule effects on the aforementioned factors, in relation to the aggregate.

Effects of continuous long-term testosterone therapy (TTh) on anthropometric, endocrine and metabolic parameters for up to 10 years in 115 hypogonadal elderly men: real-life experience from an observational registry study.

Subnormal levels of testosterone are associated with significant negative health consequences, with higher risks of all-cause and cardiovascular mortality. The numbers of studies reporting on the benefits of normalisation of testosterone is increasing but longer-term data on (elderly) men receiving testosterone treatment are almost nonexistent. In this single-centre, cumulative, prospective, registry study, 115 hypogonadal men (mean age 59.05 years) received injections with testosterone undecanoate in 12-week intervals for up to 10 years. Waist circumference, body weight and mean BMI dropped progressively with statistical significance versus previous year for 7 years and, respectively, 8 years for weight and body mass index. Similarly, fasting glucose displayed a significant decrease after the first year continuing to decrease thereafter. A decline in HbA1c , from 6.4% to 5.6% (mean <6%), was observed from year 2 on, together with a decrease in the ratio of triglycerides:high-density lipoprotein (HDL), a surrogate marker of insulin resistance, with an increase in HDL levels. The total cholesterol:HDL ratio and non-HDL cholesterol declined significantly. A decrease was also observed in systolic and diastolic blood pressure, with a decrease in levels of the inflammation marker C-reactive protein. No major adverse cardiovascular events were observed throughout the study.

Olive oil polyphenols enhance high-density lipoprotein function in humans: a randomized controlled trial.

OBJECTIVE: Olive oil polyphenols have shown beneficial properties against cardiovascular risk factors. Their consumption has been associated with higher cholesterol content in high-density lipoproteins (HDL). However, data on polyphenol effects on HDL quality are scarce. We, therefore, assessed whether polyphenol-rich olive oil consumption could enhance the HDL main function, its cholesterol efflux capacity, and some of its quality-related properties, such HDL polyphenol content, size, and composition. APPROACH AND RESULTS: A randomized, crossover, controlled trial with 47 healthy European male volunteers was performed. Participants ingested 25 mL/d of polyphenol-poor (2.7 mg/kg) or polyphenol-rich (366 mg/kg) raw olive oil in 3-week intervention periods, preceded by 2-week washout periods. HDL cholesterol efflux capacity significantly improved after polyphenol-rich intervention versus the polyphenol-poor one (+3.05% and -2.34%, respectively; P=0.042). Incorporation of olive oil polyphenol biological metabolites to HDL, as well as large HDL (HDL2) levels, was higher after the polyphenol-rich olive oil intervention, compared with the polyphenol-poor one. Small HDL (HDL3) levels decreased, the HDL core became triglyceride-poor, and HDL fluidity increased after the polyphenol-rich intervention. CONCLUSIONS: Olive oil polyphenols promote the main HDL antiatherogenic function, its cholesterol efflux capacity. These polyphenols increased HDL size, promoted a greater HDL stability reflected as a triglyceride-poor core, and enhanced the HDL oxidative status, through an increase in the olive oil polyphenol metabolites content in the lipoprotein. Our results provide for the first time a first-level evidence of an enhancement in HDL function by polyphenol-rich olive oil.

Anti-inflammatory therapies for cardiovascular disease.

Atherothrombosis is no longer considered solely a disorder of lipoprotein accumulation in the arterial wall. Rather, the initiation and progression of atherosclerotic lesions is currently understood to have major inflammatory influences that encompass components of both the innate and acquired immune systems. Promising clinical data for 'upstream' biomarkers of inflammation such as interleukin-6 (IL-6) as well as 'downstream' biomarkers such as C-reactive protein, observations regarding cholesterol crystals as an activator of the IL-1ß generating inflammasome, and recent Mendelian randomization data for the IL-6 receptor support the hypothesis that inflammatory mediators of atherosclerosis may converge on the central IL-1, tumour necrosis factor (TNF-α), IL-6 signalling pathway. On this basis, emerging anti-inflammatory approaches to vascular protection can be categorized into two broad groups, those that target the central IL-6 inflammatory signalling pathway and those that do not. Large-scale Phase III trials are now underway with agents that lead to marked reductions in IL-6 and C-reactive protein (such as canakinumab and methotrexate) as well as with agents that impact on diverse non-IL-6-dependent pathways (such as varespladib and darapladib). Both approaches have the potential to benefit patients and reduce vascular events. However, care should be taken when interpreting these trials as outcomes for agents that target IL-6 signalling are unlikely to be informative for therapies that target alternative pathways, and vice versa. As the inflammatory system is redundant, compensatory, and crucial for survival, evaluation of risks as well as benefits must drive the development of agents in this class.

Antihyperlipidemic effect of fisetin, a bioflavonoid of strawberries, studied in streptozotocin-induced diabetic rats.

Chronic hyperglycemia in diabetes is associated with profound changes in lipid and lipoprotein metabolism, with resultant alterations in particle distribution within lipoprotein classes. In the present study, an attempt has been made to explore the antihyperlipidemic effect of fisetin in streptozotocin-induced experimental diabetes in rats. Upon fisetin treatment to diabetic rats, the levels of blood glucose were significantly reduced with an improvement in plasma insulin. The increased levels of lipid contents in serum, hepatic, and renal tissues observed in diabetic rats were normalized upon fisetin administration. Also, the decreased levels of high-density lipoprotein cholesterol, and increased levels of low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol in serum of diabetic rats were normalized. Oil Red O staining established a large number of intracellular lipid droplets accumulation in the diabetic rats. Fisetin treatment exacerbated the degree of lipid accumulation. The results of the present study exemplify the antihyperlipidemic property of the fisetin.

Induction of apolipoprotein A-I gene expression by black seed (Nigella sativa) extracts.

CONTEXT: Black seed [Nigella sativa L. (Ranunculaceae)] has been shown in animal models to lower serum cholesterol levels. OBJECTIVES: In order to determine if extracts from black seed have any effects on high-density lipoprotein (HDL), we characterized the effects of black seed extract on apolipoprotein A-I (apo A-I) gene expression, the primary protein component of HDL. MATERIALS AND METHODS: Hepatocytes (HepG2) and intestinal cells (Caco-2) were treated with black seed extracts, and Apo A-I, peroxisome proliferator-activated receptor α (PPARα), and retinoid-x-receptor α (RXRα) were measured by Western blot analysis. Apo A-I mRNA levels were measured by quantitative real-time polymerase chain reaction and apo A-I gene transcription was measured by transient transfection of apo A-I reporter plasmids. RESULTS: Extracts from black seeds significantly increased hepatic and intestinal apo A-I secretion, as well as apo A-I mRNA and gene promoter activity. This effect required a PPARα binding site in the apo A-I gene promoter. Treatment of the extract with either heat or trypsin had no effect on its ability to induce apo A-I secretion. Treatment with black seed extract induced PPARα expression 9-fold and RXRα expression 2.5-fold. Furthermore, the addition of PPARα siRNA but not a control siRNA prevented some but not all the positive effects of black seed on apo A-I secretion. DISCUSSION: Black seed extract is a potent inducer of apo A-I gene expression, presumably by enhancing PPARα/RXRα expression. CONCLUSIONS: We conclude that black seed may have beneficial effects in treating dyslipidemia and coronary heart disease.

[Protective role of high density lipoproteins in sepsis: basic issues and clinical implications]. / Papel protector de las lipoproteínas de alta densidad en sepsis: aspectos básicos e implicancias clínicas.

High density lipoproteins (HDL) are responsible of reverse cholesterol transport and play an important antiatherogenic role. In recent years, several studies suggest that HDL have additional functions, including a possible anti-inflammatory activity in infectious conditions. Furthermore, available evidence indicates that the presence of lipopolysaccharide (LPS) within the circulation during infectious states induced by gram-negative bacteria may be involved in the decrease in HDL cholesterol levels and changes in lipoprotein composition, which have been associated with a higher mortality due to sepsis in animal models and in humans. In this article, we review this subject and also discuss possible mechanisms that explain the positive impact achieved by native HDL, reconstituted HDL, or HDL apolipoprotein peptides on the inflammatory response and mortality in models of endotoxemia. In this regard, it has been proposed that one of the mechanisms by which HDL protect against sepsis may be mediated by its binding ability and/or neutralizing capacity on LPS, avoiding an excessive response of the immune system. Thus, increasing blood levels of HDL and/or parenteral HDL administration may represent a new anti-inflammatory tool for managing septic states in humans.

Does a diet high or low in fat influence the oxidation potential of VLDL, LDL and HDL subfractions?

BACKGROUND AND AIMS: High-fat diets have become increasingly popular for weight-loss, but their effect on the oxidation potential of lipoprotein subfractions has not been studied. Therefore, this study compared the effects of high-fat vs. low-fat weight reduction diets on this parameter. METHODS AND RESULTS: Very-low, low- and high-density lipoprotein (VLDL, LDL & HDL) subfractions were isolated by rapid ultracentrifugation from 24-overweight/obese subjects randomised to a high- or low-fat diet. The lipoprotein subfractions were assessed for oxidation potential by measuring conjugated diene (CD) production and time at half maximum. We found a significant between-group difference in oxidation potential. Specifically, a high-fat diet led to increased CD production in VLDL(A-D) and HDL(2&3), and a prolongation of time at half maximum. Within-group differences found that CDs increased in VLDL(A&D), LDL(I-III) and HDL(2&3) in the high-fat group and fell in VLDL(A-C) and HDL(2&3) and increased in LDL(I&II), in the low-fat group. Furthermore, following both diets all lipoprotein subfractions, except LDL(II) in the low-fat group, were protected against oxidation. CONCLUSION: These results demonstrate that at first glance, a high-fat diet may be indicative of having heart-protective properties. However, this may be erroneous, as although the time for oxidation to occur was prolonged, once this occurred these lipoproteins had the potential to produce significantly more oxidised substrate. Conversely, a low-fat diet may be considered anti-atherogenic, as these subfractions were protected against oxidation and mainly contained fewer oxidised substrate. Thus, increased fat intake may, by increasing the oxidation product within lipoprotein subfractions, increase cardiovascular disease.

Comparative characteristics of lipemia models induced by injections of Triton WR-1339 and poloxamer 407 in mice.

Lipemia modeled by injections of Triton WR-1339 (500 mg/kg) and poloxamer 407 (500 mg/kg) to mice were compared. LP fraction and subfraction compositions were compared by small-angle X-ray scattering on a diffractometer. Both compounds in the same dose caused a sharp increase in serum concentrations of total cholesterol (CH) and triglycerides (TG), the increases in response to poloxamer 407 being more pronounced. The differences in the models consisted in the levels of atherogenic fractions: CH-VLDL (subfractions CH-VLDL1-2) and CH-LDL, which were higher under the effect of poloxamer 407. Similar increases were observed for atherogenic fractions: TG-VLDL (subfractions TG-VLDL1-2) and TG-LDL (subfractions TG-LDL1-3). A specific feature of the model induced by poloxamer 407 was elevation of the concentrations of antiatherogenic CH-HDL and TG-HDL (subfractions CH-HDL2 and TG-HDL2). Both models exhibited high similarity, but changes in atherogenic fractions were more pronounced under the effect of poloxamer 407.

Effect of dalcetrapib plus pravastatin on lipoprotein metabolism and high-density lipoprotein composition and function in dyslipidemic patients: results of a phase IIb dose-ranging study.

BACKGROUND: Cholesteryl ester transfer protein (CETP) is involved in high-density lipoprotein (HDL) remodeling and transfer of lipids between HDL particles and other lipoproteins. Epidemiologic studies show that both elevated HDL-cholesterol (HDL-C) and reduced CETP activity attenuate cardiovascular risk, making inhibition or modulation of CETP a potential therapeutic target. This study analyzed the effect of dalcetrapib on lipoprotein profile, CETP activity, and cellular cholesterol efflux when co-administered with pravastatin in patients with low or average HDL-C. METHODS: Patients were randomized in a double-blind fashion to receive placebo or dalcetrapib 300, 600, or 900 mg once daily for 12 weeks. All patients were concomitantly treated to their low-density lipoprotein cholesterol target with pravastatin. Lipoprotein profile was analyzed by nuclear magnetic resonance spectroscopy and polyacrylamide gradient gel electrophoresis. Composition of the HDL fraction was assessed after polyethylene glycol precipitation. Contribution of this fraction to cholesterol efflux was assessed using radiolabeled donor cells. RESULTS: Co-administration of dalcetrapib with pravastatin increased HDL-C, apolipoproteins (apo) A-I and A-II, and CETP mass, and decreased CETP activity. A relative increase in large HDL and low-density lipoprotein subparticle fractions was observed. High-density lipoprotein composition showed increased association of esterified cholesterol, free cholesterol, phospholipids, apo A-I, and apo E. Adenosine 5'-triphosphate-binding cassette A1- and scavenger receptor type BI-mediated cholesterol efflux increased. CONCLUSIONS: Dalcetrapib up to 600 mg, combined with pravastatin, increased HDL-C and altered lipoprotein profile, HDL composition, and HDL function, with little further change at a 900-mg dose. The impact on cardiovascular events in dyslipidemic patients is being evaluated.

Effects of ethanol intake on lipoproteins.

These review discusses the effects of ethanol on lipoprotein levels and function as related to atherosclerosis and cardiovascular disease (CVD), with special emphasis on recent publications. Ethanol's effects on high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), triglycerides (TG), and other CVD risk factors recently have been explored. Other new data address genetic and demographic predictors and mechanisms of these responses. Not surprisingly, the results of some recent studies corroborate, whereas others differ from, earlier seemingly well-established findings. Prior and recent evidence shows favorable changes in HDL, other CVD risk factors, and CVD event rates with moderate, regular ethanol intake, and recent publications have explored the mechanisms of this relationship. Application of these findings in clinical practice remains problematic, however, due to the lack of randomized, controlled clinical trials of ethanol and due to the potential hazards of ethanol consumption.