Changes In Plasma Lipoprotein Levels Research Articles

Effect of the R92H and A379V genotypes of platelet-activating factor acetylhydrolase on its enzyme activity, oxidative stress and metabolic profile in Chinese women with polycystic ovary syndrome

BackgroundThe G994T polymorphism in platelet-activating factor acetylhydrolase (PAF-AH) gene is associated with the risk of polycystic ovary syndrome (PCOS). The aim of this study was to investigate the relationship between R92H and A379V variants of the PAF-AH gene and the risk of PCOS and to evaluate the effects of the genotypes on PAF-AH activities and clinical, metabolic and oxidative stress indexes in Chinese women.MethodsA total of 862 patients with PCOS based on the Rotterdam consensus criteria and 750 control women from a population of Chinese Han nationality in the Chengdu area were studied from 2006–2015. PAF-AH genotypes were determined by PCR and restriction fragment length polymorphism analysis. Plasma PAF-AH, high-density lipoprotein (HDL)-associated PAF-AH (H-PAF-AH) and apolipoprotein (apo) B-containing lipoprotein-associated PAF-AH (apoB-PAF-AH) activities were measured using the trichloroacetic acid precipitation procedure with PAF C-16 as a substrate. Circulating markers of oxidative stress, including serum total oxidant status, total antioxidant capacity, oxidative stress index and malondialdehyde levels, and clinical and metabolic parameters were also analyzed.ResultsNo significant differences were observed in the frequencies of R92H and A379V genotypes and alleles of the PAF-AH gene between PCOS and control groups (P > 0.05). Compared with patients with the 92RR genotype, patients with H allele of R92H (RH + HH genotype) had significantly higher plasma PAF-AH and apoB-PAF-AH activities (P < 0.05) and tended to exhibit increased H-PAF-AH activity (P = 0.063) after adjusted for age and BMI. However, when serum LDL-C, HDL-C, TG and HOMA index were added as covariates, the comparisons no longer remained statistical significance (P > 0.05). There were no significant differences in clinical, hormonal, metabolic and circulating oxidative stress parameters and the frequencies of PAF-AH G449T genotype according to PAF-AH R92H or A379V genotyping in patients with PCOS and control women.ConclusionsThere were no significant associations between R92H and A379V variants of PAF-AH gene and risk of PCOS in Chinese women. The increased plasma PAF-AH and apoB-PAF-AH activities in patients with H allele of R92H are related to the R92 → H variation, changes in plasma lipoprotein levels, insulin resistance, aging, and gaining weight and thus may be involved in the pathogenesis of PCOS and the increased risks of future cardiovascular diseases.

Guías de práctica clínica de manejo de la dislipemia en diabéticos y otros grupos de riesgo

Diabetes mellitus, kidney failure, genetically inherited dyslipidemia and autoimmune disease are all associated with premature atherosclerosis and accelerated progression of the disease. Therefore, these conditions all engender a high cardiovascular risk, which should be treated using preventive strategies with clearly defined objectives. These conditions are characterized by qualitative and quantitative changes in plasma lipoprotein levels which can be partially corrected by lifestyle modification and the adoption of healthier habits, although generally it is necessary to resort to pharmacologic treatment. Statins are very effective for reducing levels of cholesterol and, to a lesser extent, triglycerides. Moreover, they induce a moderate increase in the high-density lipoprotein cholesterol level and reduce the incidence of atherosclerotic cardiovascular disease. Consequently, they are considered the drugs of first choice in the treatment of atherogenic dyslipidemia. Control of other cardiovascular risk factors should be dealt with systematically.

Effect of phytosterols on copper lipid peroxidation of human low-density lipoproteins

Objective Phytosterols and stanols have received much attention in the past several years because of their cholesterol-lowering properties, and several studies have shown a protective effect against cardiovascular disease and colon and breast cancer development. A significant decrease of plasma low-density lipoprotein (LDL) cholesterol and apolipoprotein B has been demonstrated in subjects whose diet was supplemented with 2 g/d of plant sterols. Changes in plasma lipoprotein levels were associated with a decrease of oxidized LDL, suggesting that plant sterols could exert an antioxidant effect. The aim of the present study was to further investigate the interaction between the major dietary phytosterols and plasma lipoproteins. Moreover, their antioxidant effect against in vitro–induced lipid peroxidation of human LDL was investigated. Methods Susceptibility to copper-induced lipid peroxidation was investigated in LDLs isolated from plasma of normolipemic subjects. Concentrations of β-sitosterol, campesterol, and stigmasterol ranging from 5 to 50 μM were studied. Analyses of the emission fluorescence spectra of tryptophan and of the probe 6-dodecanoyl-2-dimethyl-aminoaphthalene were used to investigate the effect of phytosterols on apoprotein structure and physicochemical properties of LDL. Results Our results demonstrated that phytosterols exert an inhibitory effect against copper-induced lipid peroxidation of LDLs, as shown by the lowered levels of conjugated dienes in oxidized lipoproteins incubated with different concentrations of plant sterols (5–50 μM). Moreover, analysis of fluorescence emission spectra of tryptophan and 6-dodecanoyl-2-dimethyl-aminoaphthalene demonstrated that phytosterols prevent the alterations of apoprotein structure and physicochemical properties associated with copper-triggered lipid peroxidation of lipoproteins. Conclusion We suggest that the effect exerted by β-sitosterol, stigmasterol, and campesterol against lipid peroxidation of LDL possibly related to phytosterol–lipoprotein interactions could be of physiologic relevance.

Rapid regression of atherosclerosis: insights from the clinical and experimental literature

Looking back at animal and clinical studies published since the 1920s, the notion of rapid regression and stabilization of atherosclerosis in humans has evolved from a fanciful goal to one that might be achievable pharmacologically, even for advanced plaques. Our review of this literature indicates that successful regression of atherosclerosis generally requires robust measures to improve plasma lipoprotein profiles. Examples of such measures include extensive lowering of plasma concentrations of atherogenic apolipoprotein B (apoB)-lipoproteins and enhancement of 'reverse' lipid transport from atheromata into the liver, either alone or in combination. Possible mechanisms responsible for lesion shrinkage include decreased retention of apoB-lipoproteins within the arterial wall, efflux of cholesterol and other toxic lipids from plaques, emigration of foam cells out of the arterial wall, and influx of healthy phagocytes that remove necrotic debris and other components of the plaque. Unfortunately, the clinical agents currently available cause less dramatic changes in plasma lipoprotein levels, and, thereby, fail to stop most cardiovascular events. Hence, there is a clear need for testing of new agents expected to facilitate atherosclerosis regression. Additional mechanistic insights will allow further progress.

Interrelationship between serum lipid profile, serum hormones and other components of the metabolic syndrome.

The aim of the present study was to investigate the association between the serum lipid profile and components of the metabolic syndrome, such as central obesity (anthropometric, computed tomography and fat cell data), insulin, sex-hormone-binding-globulin (SHBG) and different hormones influencing this important syndrome, e.g. sex steroids, leptin and tumor necrosis factor-alpha (TNF-alpha). The sample consisted of 85 obese patients (30 men and 55 women) who had undergone abdominal surgery. Fasting serum lipids were analysed, as well as anthropometric and computed tomography data, perivisceral and subcutaneous fat cell size and serum glucose and hormones. Abdominal fat revealed itself as an important correlator of the adverse changes in plasma lipoprotein levels, the waist-to-hip-ratio and waist-to-thigh-ratio being the best morphological correlators in men and women, respectively. Intra-abdominal fat (VA) correlated significantly and positively to perivisceral fat cell size in women, while no correlation was found between subcutaneous fat accumulation (SA) and adipocyte size in both genders. Perivisceral fat cell size showed the greatest number of correlations with the adverse plasma lipid profile compared to that in the subcutaneous depot. SHBG and sex steroids showed a negative correlation with serum lipids considered a cardiovascular risk. In contrast, TNF-alpha and C-peptide were inversely correlated with potential protector lipids. In conclusion, abdominal obesity, adipocyte hypertrophy from visceral fat, serum TNF-alpha and C-peptide seem to be the best correlators of the lipoprotein disturbance characteristic of the metabolic syndrome, whereas SHBG and sex steroids could play a protective role regarding the lipid profile associated to this syndrome.

Heterozygous osteopetrotic (op) mutation reduces atherosclerosis in LDL receptor- deficient mice.

Previous studies of osteopetrotic (op) mice lacking macrophage colony-stimulating factor (M-CSF) have revealed an inhibition of atherosclerosis development in the apolipoprotein E (apo E)-deficient model and in a diet-induced model. Using LDL receptor-deficient mice, we now show that atheroma development depends on M-CSF concentration, as not only did homozygous osteopetrotic (op/op) mice have dramatically reduced lesions (approximately 0.3% of control lesion size) but heterozygous (op/+) mice had lesions < 1% of controls. Mice heterozygous for the op mutation (op/+) had plasma levels of M-CSF about half those in controls (+/+). The finding that an approximately 2-fold reduction in M-CSF expression reduced lesion size approximately 100-fold suggests the requirement for a threshold level of M-CSF. The effect of M-CSF on atherosclerosis did not appear to be mediated either by changes in plasma lipoprotein levels or alterations in the number of circulating monocytes, since both op/op and op/+ mice exhibited higher levels of atherogenic lipoprotein particles and (op/+) mice showed a near normal number of circulating monocytes. LDL receptor-null littermates of genotypes from op/op, op/+, to +/+ showed monocyte differentials of approximately 4.5, 8, and 10%, respectively. Taken together, these results suggest that the effects of M-CSF on atherogenesis may not be mediated by expression of M-CSF systemically or by modulation of the number of circulating monocytes. These studies support the conclusion that M-CSF participates critically in fatty streak formation and progression to a complex fibrous lesion.

The metabolic consequences of treating postmenopausal women with non-oral hormone replacement therapy.

To define the metabolic profile of postmenopausal hormone replacement therapies when delivered through gels, patches, implants or other non-oral routes. Such information may be useful in the absence of reliable clinical data on the effects of these therapies on the risk of cardiovascular disease. Selective literature review. Postmenopausal women. Non-oral oestrogen therapies fail to invoke the hepatic response associated with oral therapy. Changes in hepatic protein synthesis are minimal and so plasma levels of binding globulins and other proteins tend to be normal. Many of the perturbations of the haemostatic system seen with oral therapy are avoided. In the absence of hepatic over-synthesis of apolipoproteins, plasma lipoprotein levels are unchanged or reduced. The direct effects of oestrogen on vascular function are apparent when the hormone is administered non-orally. The net effect of non-oral estrogen therapies on the risk of cardiovascular disease is difficult to predict on the basis of current data. Some changes in plasma lipoprotein levels, such as the reduced fasting levels of triglycerides, would be considered desirable, but the cardioprotective increase in levels of high-density lipoproteins is absent. The differential effect on haemostasis markers is promising, but preliminary data relating to transdermal patches fail to support the idea that non-oral therapies will avoid the increased risk of venous thromboembolism associated with oral therapy. The ability of non-oral therapies to improve vascular function implies that they will offer postmenopausal women at least some of the cardiovascular protection seen with oral therapy.

Differential effects of subcutaneous estrogen and progesterone on low-density lipoprotein size and susceptibility to oxidation in postmenopausal rhesus monkeys

Objective: To study the differential effects of subcutaneous E 2 alone or in combination with P on the susceptibility of low-density lipoprotein (LDL) cholesterol to oxidation in naturally postmenopausal diet-controlled rhesus monkeys. Design: Prospective, longitudinal controlled study. Setting: Oregon Health Sciences University, Portland, Oregon, and Oregon Regional Primate Research Center, Beaverton, Oregon. Patient(s): Five naturally postmenopausal rhesus monkeys. Intervention(s): Estradiol was administered subcutaneously for the first 4 weeks, followed by E 2 plus P for 4 weeks, followed by a third 4-week washout period. Main Outcome Measure(s): Changes in plasma lipoprotein levels and oxidation of LDL and serum concentrations of E 2 and P. Result(s): Levels of LDL cholesterol fell after 4 weeks of treatment with E 2, compared with baseline. The lag time to half maximal light absorbancy after 4 weeks of E 2 treatment was significantly increased compared with baseline. The maximal absorbance values and the slope of the propagation phase after 4 weeks of treatment with E 2 were decreased compared with baseline. After 4 weeks of combined E 2 and P treatment, all values were comparable to baseline. Conclusion(s): These results suggest that subcutaneous E 2 therapy appears to enhance LDL resistance to oxidation and that this effect is attenuated by the addition of the P.

Changes in plasma lipoproteins and liver lipids in neonatal rats

Transient increases in triglycerides and cholesterol were found in rat liver immediately after birth. Plasma VLDL and HDL increased after birth and reached a plateau after one week of life. The content of cholesterol ester was low at birth in all lipoproteins and increased in LDL and HDL during the first week of life. After birth, VLDL became enriched in apolipoproteins C and E, whereas HDL was enriched in apolipoprotein C and depressed in apolipoprotein E. The developmental changes in plasma lipoprotein levels and compositions in rats during the first week of life are comparable to those described in humans.

Dietary Fat Saturation and Chain Length Modulate Guinea Pig Hepatic Cholesterol Metabolism

AbstractThe effects of dietary fat saturation and saturated fatty acid composition on plasma lipoprotein concentrations and hepatic cholesterol metabolism were investigated in guinea pigs. Animals were fed semipurified diets containing 15 g fat/100 g diet, as palm kernel, palm oil, beef tallow, lard, olive oil or corn oil. Plasma lipoprotein concentrations were significantly altered by the type of dietary fat. The LDL cholesterol concentration was highest in animals fed the diet with palm kernel and lowest in animals fed the diet with corn oil, whereas HDL cholesterol was lowest in beef tallow-fed guinea pigs (P < 0.01). Hepatic cholesteryl ester concentrations were 100% higher in animals fed diets containing polyunsaturated corn oil and monounsaturated olive oil compared with animals fed any of the saturated fat diets (P < 0.01). Hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity varied in the different dietary fat groups independent of hepatic cholesterol pools or plasma LDL concentrations. In contrast, hepatic acyl-CoA: cholesterol acyltransferase (ACAT) activity was significantly correlated with plasma LDL cholesterol across all dietary groups (r = 0.63, P < 0.001). These data demonstrate that regulation of hepatic HMG-CoA reductase activity is relatively independent of changes in plasma lipoprotein levels, whereas hepatic ACAT activity exhibits a positive correlation with plasma LDL cholesterol concentrations.

Hypercholesterolemia induces differential expression of rabbit apolipoprotein A and C genes

We have compared steady-state mRNA levels of apolipoproteins AI, AII, AIV, CI, CII and CIII in liver and small intestine of rabbits fed on a cholesterol-rich diet for up to 16 weeks. Apolipoprotein (apo) AIV mRNA was detected in both liver and small intestine, while apo AII was not detected in either organ. Apo CI, apo CII and apo CIII were expressed only in liver and apo AI mRNA was detected only in small intestine. In small intestine, apo AIV and apo AI mRNA levels increased to a maximum at the 4th and 12th week of treatment, respectively. In liver there was a parallel increase in the mRNA levels of apo AIV, apo CI, apo CII and apo CIII, with maximum levels after 4 weeks of treatment. A 3-fold increase was found in apo CII and apo CIII hepatic transcription rates between hypercholesterolemic and control rabbits after 4 weeks of treatment, no longer detectable after 8 weeks. However, no changes were found in apo AIV and apo CI transcription rates. Changes in apolipoprotein mRNA levels were accompanied by changes in plasma lipoprotein levels. Overall, these changes correlate well with the variations detected in the expression of the different apolipoprotein genes. Our results indicate that dietary cholesterol plays an important role in the regulation of these genes and that this regulation is tissue dependent.

Changes in plasma lipoprotein levels during a hiking expedition in South America.

Eleven males participated in a hiking expedition over a period of 6 weeks during which they walked an average of 15 km per day, resting days included. The participants completed a seven-day estimated dietary record before and during the expedition. Their habitual dietary intake before the expedition was typical of a Western diet. During the expedition most animal products, with the exception of canned fish, were excluded from the diet. The dietary intake of fat and carbohydrate changed from 36.9% and 40.6% to 14.0% and 76.4% respectively. Cholesterol intake dropped from 557 mg to 92 mg. Mean plasma total cholesterol (TC) decreased from 190.9 mg/100 ml to 142.0 mg/100 ml. These changes were mainly due to changes in low density lipoprotein cholesterol (LDL-C). Although high density lipoprotein cholesterol (HDL-C) did not change, the ratio of HDL-C to TC increased significantly. It can be concluded that drastic dietary changes, together with increased physical activity and weight loss resulted in major plasma lipoprotein changes. The expected fall in HDL-C due to a high carbohydrate diet was counteracted by the increased physical activity and weight loss.

Beta-blockade with intrinsic sympathetic activity modifies favorably exercise-induced changes in plasma lipoproteins

The effects of beta-blockade on acute exercise-induced changes in plasma lipoprotein levels were investigated in 12 healthy normotensive subjects by use of beta-blockers of three types: a nonselective agent, a beta 1-selective agent, and a nonselective agent with intrinsic sympathomimetic activity (ISA) or partial agonist activity. Each subject received each drug and a placebo for 1 wk each according to a randomized double-blind crossover design. After placebo, exercise caused 10-20% increases in total plasma cholesterol and the high-density lipoprotein (HDL)-cholesterol fraction. The total-to-HDL cholesterol ratio fell, particularly during the 30-min recovery phase. Pindolol treatment increased resting values of HDL cholesterol (from 43 +/- 4 to 48 +/- 4 mg/dl) and potentiated the response to exercise (to 59 +/- 5 vs. 51 +/- 4 mg/dl after placebo). The total-to-HDL cholesterol ratio was significantly lower after pindolol treatment than after placebo. In contrast, neither atenolol nor timolol affected exercise-induced changes in plasma lipoprotein levels. The effects of pindolol on other study parameters (exercise endurance and exercise-induced increases in systolic blood pressure, heart rate, and potassium) were similar to the effects of the nonselective agent, timolol. We conclude that the effects of pindolol on the plasma lipid profile are due to its ISA and that the process activated (possibly plasma lecithin-cholesterol acyltransferase activity) is under minimal sympathetic control and, therefore, sensitive to the expression of ISA both at rest and in response to exercise.

Effects of Calcium Antagonists and Adrenergic Antihypertensive Drugs on Plasma Lipids and Cellular Cholesterol Metabolism

Calcium antagonists and antihypertensive alpha-adrenergic and beta-adrenergic drugs may cause changes in plasma lipoprotein levels. Different mechanisms by which these antihypertensive agents effect cellular lipid metabolism have been proposed. The activity of lipoprotein lipase that determines the catabolism of very low density lipoproteins (VLDL) is decreased by the beta-blocker propranolol and increased by alpha 1-antagonists. The plasma cholesterol or low density lipoprotein (LDL) level is inversely associated with the number of LDL receptors. Catecholamines suppress the LDL receptor activity, thus leading to an increase in plasma cholesterol concentration. The calcium antagonist verapamil and the beta-blocker propranolol may increase LDL receptor activity either per se or by its antagonizing effect on the catecholamine action. The metabolism of high density lipoproteins (HDL) may be affected directly by catecholamines, which might increase HDL binding activity, thereby enhancing efflux of cholesterol from cells. Catecholamines inhibit cholesterol biosynthesis in extrahepatic cells. The effects are mediated by alpha 2- and beta 2-adrenergic receptors. Accordingly, the alpha 2-agonists clonidine and alpha-methyldopa mimicked and propranolol opposed the catecholamine action. In contrast, the alpha 1 antagonists indoramin, prazosin, and urapidil had no effect on cholesterol synthesis. The results provide evidence that calcium antagonists and various antihypertensive drugs, depending upon their action on beta- or alpha-adrenergic receptors, affect lipid metabolism differently. The metabolic effect may play a role in atherogenesis and may be of clinical importance when antihypertensive treatment is considered.

Clofibrate and tiadenol treatment in hyperlipoproteinemias: A comparative trial of drugs affecting lipoprotein catabolism and biosynthesis

Changes in plasma lipoprotein levels and platelet reactivity were evaluated during sequential treatments with clofibrate and tiadenol, two hypolipidemic agents with apparently different mechanisms, in 27 hyperlipoproteinemic patients. The objective of the study was to determine the pattern of plasma lipoprotein variations, induced by a drug mainly affecting lipoprotein catabolism (clofibrate) and by a drug affecting biosynthesis (tiadenol), and to single out-patients specifically responding to either treatment. Both drugs proved significantly active in type IIA and IV hyperlipoproteinemias, not in type IIB. Clofibrate significantly lowered very low density lipoprotein (VLDL) associated cholesterol in all three hyperlipoproteinemia phenotypes, and it also lowered VLDL triglycerides in type IV, while increasing high density lipoprotein (HDL) cholesterol in type IIA patients. Low density lipoprotein (LDL) cholesterol levels were minimally reduced by clofibrate in type IIA (−4%), and increased in types IIB (+14.2%) and IV (+6.1%) patients. Conversely, tiadenol lowered VLDL cholesterol and triglycerides to a lesser extent, but it did significantly reduce LDL cholesterolemia in type IIA (−17.6%), while increasing HDL cholesterol in type IIB. Statistical evaluation of the results did not permit identification of parameters associated with the response to either drug, although individuals specifically responding to one or the other agent, or to both, were detected in all three phenotypes. The sensitivity to the major platelet aggregating factors, ADP, adrenaline and collagen, was not significantly altered after drug treatments. Evaluation of the hypolipidemic response to agents with different mechanisms may be of help in selecting the best treatment for individual patients.