Showing papers on "High-density lipoprotein published in 2000"

High density lipoprotein deficiency and foam cell accumulation in mice with targeted disruption of ATP-binding cassette transporter-1

Abstract: Recently, the human ATP-binding cassette transporter-1 (ABC1) gene has been demonstrated to be mutated in patients with Tangier disease. To investigate the role of the ABC1 protein in an experimental in vivo model, we used gene targeting in DBA-1J embryonic stem cells to produce an ABC1-deficient mouse. Expression of the murine Abc1 gene was ablated by using a nonisogenic targeting construct that deletes six exons coding for the first nucleotide-binding fold. Lipid profiles from Abc1 knockout (−/−) mice revealed an ≈70% reduction in cholesterol, markedly reduced plasma phospholipids, and an almost complete lack of high density lipoproteins (HDL) when compared with wild-type littermates (+/+). Fractionation of lipoproteins by FPLC demonstrated dramatic alterations in HDL cholesterol (HDL-C), including the near absence of apolipoprotein AI. Low density lipoprotein (LDL) cholesterol (LDL-C) and apolipoprotein B were also significantly reduced in +/− and −/− compared with their littermate controls. The inactivation of the Abc1 gene led to an increase in the absorption of cholesterol in mice fed a chow or a high-fat and -cholesterol diet. Histopathologic examination of Abc1−/− mice at ages 7, 12, and 18 mo demonstrated a striking accumulation of lipid-laden macrophages and type II pneumocytes in the lungs. Taken together, these findings demonstrate that Abc1−/− mice display pathophysiologic hallmarks similar to human Tangier disease and highlight the capacity of ABC1 transporters to participate in the regulation of dietary cholesterol absorption.

Effect of Niacin on Lipid and Lipoprotein Levels and Glycemic Control in Patients With Diabetes and Peripheral Arterial Disease: The ADMIT Study: A Randomized Trial

Abstract: ContextAlthough niacin increases low levels of high-density lipoprotein cholesterol (HDL-C), which frequently accompany diabetes, current guidelines do not recommend use of niacin in patients with diabetes because of concerns about adverse effects on glycemic control; however, this is based on limited clinical data.ObjectiveTo determine the efficacy and safety of lipid-modifying dosages of niacin in patients with diabetes.Design and SettingProspective, randomized placebo-controlled clinical trial conducted in 6 clinical centers from August 1993 to December 1995.ParticipantsA total of 468 participants, including 125 with diabetes, who had diagnosed peripheral arterial disease.InterventionsAfter an active run-in period, participants were randomly assigned to receive niacin (crystalline nicotinic acid), 3000 mg/d or maximum tolerated dosage (n = 64 with diabetes; n = 173 without diabetes), or placebo (n = 61 with diabetes; n = 170 without diabetes) for up to 60 weeks (12-week active run-in and 48-week double-blind).Main Outcome MeasuresPlasma lipoprotein, glucose, hemoglobin A1c (HbA1c), alanine aminotransferase, and uric acid levels; hypoglycemic drug use; compliance; and adverse events, in patients with diabetes vs without who were receiving niacin vs placebo.ResultsNiacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and low-density lipoprotein cholesterol (LDL-C) by 8% and 9%, respectively, in participants with and without diabetes (P<.001 for niacin vs placebo for all). Corresponding changes in participants receiving placebo were increases of 0% and 2% in HDL-C and increases of 7% and 0% in triglycerides, and increases of 1% and 1% in LDL-C. Glucose levels were modestly increased by niacin (8.7 and 6.3 mg/dL [0.4 and 0.3 mmol/L]; P = .04 and P<.001) in participants with and without diabetes, respectively. Levels of HbA1c were unchanged from baseline to follow-up in participants with diabetes treated with niacin. In participants with diabetes treated with placebo, HbA1c decreased by 0.3% (P = .04 for difference). There were no significant differences in niacin discontinuation, niacin dosage, or hypoglycemic therapy in participants with diabetes assigned to niacin vs placebo.ConclusionsOur study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to sufficiently correct hypertriglyceridemia or low HDL-C levels.

Association of Cholesteryl Ester Transfer Protein–TaqIB Polymorphism With Variations in Lipoprotein Subclasses and Coronary Heart Disease Risk : The Framingham Study

Abstract: —Cholesteryl ester transfer protein (CETP) facilitates the exchange of triglycerides and cholesteryl esters between lipoprotein particles, a key step in reverse cholesterol transport in humans. Variations at the CETP locus have been shown to be determinants of the levels and activity of CETP and high density lipoprotein (HDL) plasma concentration. The associations of the common CETP polymorphism, Taq IB in intron 1, with lipoprotein levels and particle size distribution, CETP activity, and coronary heart disease (CHD) risk were examined in a population-based sample of 1411 men and 1505 women from the Framingham Offspring Study. The B2 allele frequency was 0.444 in men and 0.433 in women, and its presence was significantly ( P P P P =0.035) in men. After adjusting for age, body mass index, systolic blood pressure, diabetes, smoking, alcohol consumption, β-blocker use, total cholesterol, and HDL-C, this odds ratio was 0.735 ( P =0.187), suggesting that the protective effect of the B2 allele was due in part to its association with HDL-C levels. No significant protective effects were observed in women. These data demonstrate that variation at the CETP gene locus is a significant determinant of HDL-C levels, CETP activity, and lipoprotein size in this population. Moreover, these effects appear to translate into a lower CHD risk among those men with the B2 allele.

Race, Visceral Adipose Tissue, Plasma Lipids, and Lipoprotein Lipase Activity in Men and Women The Health, Risk Factors, Exercise Training, and Genetics (HERITAGE) Family Study

Abstract: Abdominal obesity is associated with numerous metabolic alterations, such as hypertriglyceridemia and low levels of high density lipoprotein (HDL) cholesterol. However, compared with abdominally obese white individuals, abdominally obese black individuals have been characterized by higher plasma HDL cholesterol levels, suggesting that the impact of abdominal fat accumulation on the lipoprotein-lipid profile may differ among ethnic groups. Therefore, we have compared the associations between body fatness, visceral adipose tissue (AT) accumulation, and metabolic risk variables in a sample of 247 white men and 240 white women versus a sample of 93 black men and 143 black women. Although no difference in mean total body fatness was found between the 2 race groups, white men had higher levels of visceral AT than did black men (P<0.001). Despite the fact that black women had a greater body fat content than did white women, black women had levels of visceral AT that were similar to those of white women, suggesting a lower susceptibility to visceral obesity in black women. This lower accumulation of visceral AT in blacks was accompanied by significantly reduced apolipoprotein B concentrations and ratios of total cholesterol to HDL cholesterol as well as higher plasma HDL cholesterol levels (P<0.05) compared with those values in whites. Irrespective of sex, higher postheparin plasma hepatic lipase (HL) and lower lipoprotein lipase (LPL) activities were found in whites, resulting in an HL/LPL ratio that was twice as high in whites as in blacks (P<0.005). Although differences in lipoprotein-lipid levels were noted between whites and blacks, results from multiple regression analyses revealed that after control for morphometric and metabolic variables of the study (body fat mass, visceral AT, LPL, HL, and age), ethnicity had, per se, only a minor contribution to the variance in plasma lipoprotein levels. Thus, our results suggest that the higher plasma HDL cholesterol levels and the generally more cardioprotective plasma lipoprotein profile found in abdominally obese black versus white individuals are explained, at least to a certain extent, by a lower visceral AT deposition and a higher plasma LPL activity in black individuals.

Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects

Abstract: Background: Intensive therapy of HIV infection with highly active antiretroviral therapy (HAART) dramatically reduces viral loads and improves immune status. Abnormalities of lipid levels, body fat distribution, and insulin resistance have been commonly reported after starting HAART. Whether the lipid abnormalities result from changes in metabolism after an improvement in HIV status or are partly attributable to the effects of protease inhibitor use is unknown. Methods: Twenty-one healthy volunteers participated in a 2 week double-blind, placebo-controlled study on the effect of the protease inhibitor ritonavir on total lipids, apolipoproteins, and post-heparin plasma lipase activities. Results: Those taking ritonavir (n = 11) had significantly higher levels of plasma triglyceride, VLDL cholesterol, IDL cholesterol, apolipoprotein B, and lipoprotein (a) compared with placebo (n = 8). HDL cholesterol was lower with therapy as a result of a reduction in HDL 3 cholesterol. Post-heparin lipoprotein lipase (LpL) activity did not change but hepatic lipase activity decreased 20% (P < 0.01) in those taking ritonavirr-compared with placebo. Although all lipoprotein subfractions became triglyceride enriched, most of the increase in triglyceride was in VLDL and not in IDL particles. Conclusion: Treatment with ritonavir in the absence of HIV infection or changes in body composition results in hypertriglyceridemia that is apparently not mediated by impaired LpL activity or the defective removal of remnant lipoproteins, but could be caused by enhanced formation of VLDL. Long-term studies of patients with HIV infection receiving HAART will be necessary to determine the impact of these drugs and associated dyslipidemia on the risk of coronary artery disease.

Examination of the Relation between Periodontal Health Status and Cardiovascular Risk Factors: Serum Total and High Density Lipoprotein Cholesterol, C-reactive Protein, and Plasma Fibrinogen

Abstract: Using data from the Third National Health and Nutrition Examination Survey (1988-1994), the authors examined the relation between periodontal health and cardiovascular risk factors: serum total and high density lipoprotein cholesterol, C-reactive protein, and plasma fibrinogen. A total of 10,146 participants were included in the analyses of cholesterol and C-reactive protein and 4,461 in the analyses of fibrinogen. Periodontal health indicators included the gingival bleeding index, calculus index, and periodontal disease status (defined by pocket depth and attachment loss). While cholesterol and fibrinogen were analyzed as continuous variables, C-reactive protein was dichotomized into two levels. The results show a significant relation between indicators of poor periodontal status and increased C-reactive protein and fibrinogen. The association between periodontal status and total cholesterol level is much weaker. No consistent association between periodontal status and high density lipoprotein cholesterol was detectable. Similar patterns of association were observed for participants aged 17-54 years and those 55 years and older. In conclusion, this study suggests that total cholesterol, C-reactive protein, and fibrinogen are possible intermediate factors that may link periodontal disease to elevated cardiovascular risk.

Glycation impairs high-density lipoprotein function

Abstract: Aims/hypothesis. To examine the effects of incubation of high-density lipoprotein (HDL) under hyperglycaemic conditions on several functions of HDL in vitro.¶Methods. Human HDL (5 mg protein) was incubated for 1 week at 37 °C in the presence or absence of 25 mmol/l glucose. Additional samples of human HDL were incubated in butylated hydroxytoluene to control for oxidation.¶Results. High-density lipoprotein incubated for 1 week in 25 mmol/l glucose had significant increases in the glycation product, fructoselysine and in the advanced glycation end product, Nɛ-(carboxymethyl)-lysine. High-density lipoprotein apolipoprotein AI and AII concentrations were not altered but glycated HDL had a 65 % reduction in paraoxonase enzymatic activity. Glycated HDL did not inhibit monocyte adhesion to human aortic endothelial cells in response to oxidised low-density lipoprotein in vitro (43 ± 4 monocytes bound vs 21 ± 2 monocytes for control HDL, p < 0.0001). Hepatic lipase-mediated non-esterified fatty acid release from HDL lipids was enhanced in glycated HDL compared with control HDL (25 ± 1 vs 16 ± 1 nmol non-esterified fatty acid hydrolysed/min, respectively, p < 0.0001). Direct glycation of purified paraoxonase protein by incubation in 25 mmol/l glucose caused a 40 % reduction in enzymatic activity. This glycated paraoxonase did not inhibit monocyte adhesion to human aortic endothelial cells in vitro (68 ± 3 monocytes vs 49 ± 2 monocytes bound for control paraoxonase, respectively, p < 0.001). We also measured a 40 % reduction in paraoxonase activity in patients with Type II (non-insulin-dependent) diabetes mellitus and documented coronary artery disease compared with non-diabetic subjects, p < 0.0001.¶Conclusions/interpretation. Alterations in function of HDL caused by exposure to hyperglycaemic conditions could contribute to the accelerated atherosclerosis observed in Type II diabetes. [Diabetologia (2000) 43: 312–320]

Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study

Abstract: OBJECTIVES Insulin resistance (IR) has been increasingly implicated in the pathogenesis of gout. The lipoprotein abnormalities described in hyperuricaemic subjects are similar to those associated with IR, and insulin influences renal urate excretion. In this study it was investigated whether dietary measures, reported to be beneficial in IR, have serum uric acid (SU) and lipid lowering effects in gout. METHODS Thirteen non-diabetic men (median age 50, range 38–62) were enrolled. Each patient had had at least two gouty attacks during the four months before enrolment. Dietary recommendations consisted of calorie restriction to 6690 kJ (1600 kcal) a day with 40% derived from carbohydrate, 30% from protein, and 30% from fat; replacement of refined carbohydrates with complex ones and saturated fats with mono- and polyunsaturated ones. At onset and after 16 weeks, fasting blood samples were taken for determination of SU, serum cholesterol (C), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglycerides (TGs). Results were expressed as median (SD). RESULTS At onset, the body mass index (BMI) was 30.5 (8.1) kg/m 2 . Dietary measures resulted in weight loss of 7.7 (5.4) kg (p=0.002) and a decrease in the frequency of monthly attacks from 2.1 (0.8) to 0.6 (0.7) (p=0.002). The SU decreased from 0.57 (0.10) to 0.47 (0.09) mmol/l (p=0.001) and normalised in 7 (58%) of the 12 patients with an initially raised level. Serum cholesterol decreased from 6.0 (1.7) to 4.7 (0.9) mmol/l (p=0.002), LDL-C from 3.5 (1.2) to 2.7 (0.8) mmol/l (p=0.004), TGs from 4.7 (4.2) to 1.9 (1.0) mmol/l (p=0.001), and C:HDL-C ratios from 6.7 (1.7) to 5.2 (1.0) (p=0.002). HDL-C levels increased insignificantly. High baseline SU, frequency of attacks, total cholesterol, LDL-C and TG levels, and total C:HDL-C ratios correlated with higher decreases in the respective variables upon dietary intervention (p CONCLUSION The results suggest that weight reduction associated with a change in proportional macronutrient intake, as recently recommended in IR, is beneficial, reducing the SU levels and dyslipidaemia in gout. Current dietary recommendations for gout may need re-evaluation.

LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: The Strong Heart Study.

Abstract: —Diabetes has been shown to increase the risk of coronary heart disease in all populations studied. However, there is a lack of information on the relative importance of diabetes-associated risk factors for cardiovascular disease (CVD), especially the role of lipid levels, because low density lipoprotein (LDL) cholesterol often is not elevated in diabetic individuals. The objective of this analysis was to evaluate CVD risk factors in a large cohort of diabetic individuals and to compare the importance of dyslipidemia (ie, elevated triglycerides and low levels of high density lipoprotein [HDL] cholesterol) and LDL cholesterol in determining CVD risk in diabetic individuals. The Strong Heart Study assesses coronary heart disease and its risk factors in American Indians in Arizona, Oklahoma, and South/North Dakota. The baseline clinical examinations (July 1989 to January 1992) consisted of a personal interview, physical examination, and drawing of blood samples for 4549 study participants (2034 with ...

The metabolic pathways of high-density lipoprotein, low-density lipoprotein, and triglycerides: a current review.

Abstract: Three major interconnected pathways are involved in lipoprotein metabolism: (1) the transport of dietary or exogenous fat; (2) the transport of hepatic or endogenous fat; and (3) reverse cholesterol transport. These pathways are interdependent and disruptions in one will affect the function and products of the others. For example, a mutation such as one in the ABC1 protein can disrupt normal transport and processing of cholesterol. High-density lipoprotein cholesterol (HDL-C) appears to have cardioprotective properties because of its involvement in certain processes such as reverse cholesterol transport and inhibition of low-density lipoprotein cholesterol (LDL-C) oxidation. Certain agents, such as niacin, which increases HDL-C, lowers lipoprotein (a), and targets specific enzymes or receptors, may be highly beneficial for patients at risk of cardiovascular disease.

The db/db mouse, a model for diabetic dyslipidemia: Molecular characterization and effects of western diet feeding

Abstract: Diabetic dyslipidemia is a major factor contributing to the accelerated atherosclerosis in type 2 diabetes mellitus. Although several mouse models are available, the plasma lipoproteins in response to diet have not been fully characterized in these animals. In this study, we have characterized the plasma lipoproteins and related apolipoproteins, as well as the vascular lipases, in diabetes (db/db) mice and their nondiabetic controls (+/?) in the C57BL/KsJ strain. Within 6 weeks of age, db/db mice developed significant obesity, fasting hyperglycemia, and hyperinsulinemia. By FPLC analysis, db/db mice showed a prominent peak in the low-density lipoprotein (LDL) range that was absent in +/? mice, although high-density lipoprotein (HDL) was the predominant species in both groups of animals. Postheparin lipoprotein lipase (LPL) activity in db/db mice was 28% of the level in +/? mice. Upon feeding a human-like 0.15% (wt/wt) cholesterol and 21% (wt/wt) fat "Western" diet, db/db mice developed elevated plasma cholesterol, accompanied by an exaggerated apolipoprotein E (apoE) response compared with +/? mice. FPLC analysis showed that the marked hypercholesterolemic response in db/db mice was the result of a massive increase in the LDL region, which overshadowed a moderate increase in HDL. We next isolated lipoproteins by ultracentrifugation and characterized them by nondenaturing gradient gel electrophoresis. With regular chow, db/db mice had almost exclusively small dense LDL with a peak size at 21.4 nm, as compared with 26.6 nm in nondiabetic controls. On the Western diet, the small dense LDLs persisted but larger particles also appeared in db/db mice, whereas the size distribution in +/? mice was unchanged by the diet. Our results suggest that db/db mice fed a Western diet have a plasma lipoprotein phenotype that shows some similarities to that in patients with type 2 diabetes mellitus, and that db/db mice are a useful model to study the pathogenesis and treatment of diabetic dyslipidemia.

Functional loss of ABCA1 in mice causes severe placental malformation, aberrant lipid distribution, and kidney glomerulonephritis as well as high-density lipoprotein cholesterol deficiency.

Abstract: Tangier disease (TD) and familial HDL deficiency (FHA) have recently been linked to mutations in the human ATP-binding cassette transporter 1 (hABCA1), a member of the ABC superfamily. Both diseases are characterized by the lowering or lack of high-density lipoprotein cholesterol (HDL-C) and low serum cholesterol. The murine ABCA1−/− phenotype corroborates the human TD linkage to ABCA1. Similar to TD in humans, HDL-C is virtually absent in ABCA1−/− mice accompanied by a reduction in serum cholesterol and lipid deposition in various tissues. In addition, the placenta of ABCA1−/− mice is malformed, resulting in severe embryo growth retardation, fetal loss, and neonatal death. The basis for these defects appears to be altered steroidogenesis, a direct result of the lack of HDL-C. By 6 months of age, ABCA1−/− animals develop membranoproliferative glomerulonephritis due to deposition of immunocomplexes followed by cardiomegaly with ventricular dilation and hypertrophy, ultimately succumbing to congestive heart failure. This murine model of TD will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them.

Role of Serum Amyloid A During Metabolism of Acute-Phase HDL by Macrophages

Abstract: The serum amyloid A (SAA) family of proteins is encoded by multiple genes that display allelic variation and a high degree of homology in mammals. Triggered by inflammation after stimulation of hepatocytes by lymphokine-mediated processes, the concentrations of SAA may increase during the acute-phase reaction to levels 1000-fold greater than those found in the noninflammatory state. In addition to its role as an acute-phase reactant, SAA (104 amino acids, 12 kDa) is considered to be the precursor protein of secondary reactive amyloidosis, in which the N-terminal portion is incorporated into the bulk of amyloid fibrils. However, the association with lipoproteins of the high-density range and subsequent modulation of the metabolic properties of its physiological carrier appear to be the principal role of SAA. Because SAA may displace apolipoprotein A-I, the major protein component of native high density lipoprotein (HDL), during the acute-phase reaction, the present study was aimed at (1) investigating binding properties of native and acute-phase (SAA-enriched) HDL by J774 macrophages, (2) elucidating whether the presence of SAA on HDL particles affects selective uptake of HDL-associated cholesteryl esters, and (3) comparing cellular cholesterol efflux mediated by native and acute-phase HDL. Both the total and the specific binding at 4 degrees C of rabbit acute-phase HDL were approximately 2-fold higher than for native HDL. Nonlinear regression analysis revealed K(d) values of 7.0 x 10(-7) mol/L (native HDL) and 3.1 x 10(-7) mol/L (acute-phase HDL), respectively. The corresponding B(max) values were 203 ng of total lipoprotein per milligram of cell protein (native HDL) and 250 ng of total lipoprotein per milligram of cell protein (acute-phase HDL). At 37 degrees C, holoparticle turnover was slightly enhanced for acute-phase HDL, a fact reflected by 2-fold higher degradation rates. In contrast, the presence of SAA on HDL specifically increased (1. 7-fold) the selective uptake of HDL cholesteryl esters from acute-phase HDL by J774 macrophages, a widely used in vitro model to study foam cell formation and cholesterol efflux properties. Although ligand blotting experiments with solubilized J774 membrane proteins failed to identify the scavenger receptor-BI as a binding protein for both native and acute-phase HDL, 2 binding proteins with molecular masses of 100 and 72 kDa, the latter comigrating with CD55 (also termed decay-accelerating factor), were identified. During cholesterol efflux studies, it became apparent that the ability of acute-phase HDL with regard to cellular cholesterol removal was considerably lower than that for native HDL. This was reflected by a 1.7-fold increase in tau/2 values (22 versus 36 hours; native versus acute-phase HDL). Our observations of increased HDL cholesteryl ester uptake and reduced cellular cholesterol efflux (acute-phase versus native HDL) suggest that displacement of apolipoprotein A-I by SAA results in considerable altered metabolic properties of its main physiological carrier. These changes in the apolipoprotein moieties appear (at least in the in vitro system tested) to transform an originally antiatherogenic into a proatherogenic lipoprotein particle.

Effect of Simvastatin Therapy on Paraoxonase Activity and Related Lipoproteins in Familial Hypercholesterolemic Patients

Abstract: —Human paraoxonase (PON1) is a calcium-dependent esterase closely associated with high density lipoprotein (HDL)-containing apolipoprotein AI (apoAI), which has been shown to confer antioxidant properties to HDL. PON1 has been recently implicated in the pathogenesis of atherosclerosis. Low PON1 activities have been found in familial hypercholesterolemia (FH) and diabetes mellitus. We have undertaken a study of the effect of the lipid-lowering drug simvastatin on serum PON1 activity (in relation to paraoxon and arylesterase activity), on apoAI-containing and apolipoprotein B (apoB)-containing lipoproteins, and on lipid peroxide concentrations in 64 (39 women and 25 men) unrelated FH patients. We have also analyzed the influence of the PON1-192 and PON1-55 genetic polymorphisms on the response of PON1 activity to simvastatin therapy. A venous blood sample for a baseline analysis and another after 4 months of simvastatin therapy at a dosage of 20 mg per day were taken. The major effect of simvastatin...

Acute Elevations of Plasma Asymmetric Dimethylarginine and Impaired Endothelial Function in Response to a High-Fat Meal in Patients With Type 2 Diabetes

Abstract: —Asymmetric dimethylarginine (ADMA), a compound detectable in human plasma, is an endogenous inhibitor of NO synthase. Endothelial dysfunction is an early event in atherogenesis, and large-vessel atherosclerosis is a major cause of morbidity and mortality in patients with type 2 diabetes mellitus. Fifty patients with type 2 diabetes mellitus were studied at baseline and 5 hours after ingestion of a high-fat meal. Plasma ADMA measured by using high-performance liquid chromatography increased from 1.04±0.99 to 2.51±2.27 μmol/L ( P <0.0005). Brachial arterial vasodilation after reactive hyperemia, a NO-dependent function, measured by high-resolution ultrasound, decreased from 6.9±3.9% at baseline to 1.3±4.5% ( P <0.0001). These changes occurred in association with increased plasma levels of triglycerides and very low density lipoprotein triglycerides, with reduced low density lipoprotein cholesterol and high density lipoprotein cholesterol, and with no changes in total cholesterol. The increase in plasma ADMA in response to a high-fat meal was significantly and inversely related to the decrease in percent vasodilation. In 10 of the subjects studied with a similar protocol on another day, no significant changes in the brachial artery flow responses or in plasma ADMA were observed 5 hours after ingestion of a nonfat isocaloric meal. The data suggest that ADMA may contribute to abnormal blood flow responses and to atherogenesis in type 2 diabetics.

Human Plasma Phospholipid Transfer Protein Increases the Antiatherogenic Potential of High Density Lipoproteins in Transgenic Mice

Abstract: Plasma phospholipid transfer protein (PLTP) transfers phospholipids between lipoprotein particles and alters high density lipoprotein (HDL) subfraction patterns in vitro, but its physiological function is poorly understood Transgenic mice that overexpress human PLTP were generated Compared with wild-type mice, these mice show a 25- to 45-fold increase in PLTP activity in plasma This results in a 30% to 40% decrease of plasma levels of HDL cholesterol Incubation of plasma from transgenic animals at 37 degrees C reveals a 2- to 3-fold increase in the formation of pre-beta-HDL compared with plasma from wild-type mice Although pre-beta-HDL is normally a minor subfraction of HDL, it is known to be a very efficient acceptor of peripheral cell cholesterol and a key mediator in reverse cholesterol transport Further experiments show that plasma from transgenic animals is much more efficient in preventing the accumulation of intracellular cholesterol in macrophages than plasma from wild-type mice, despite lower total HDL concentrations It is concluded that PLTP can act as an antiatherogenic factor preventing cellular cholesterol overload by generation of pre-beta-HDL

The role of the high-density lipoprotein receptor SR-BI in cholesterol metabolism.

Abstract: The HDL receptor scavenger receptor class B type I (SR-BI), which mediates selective HDL cholesterol uptake, plays a role in murine HDL metabolism, reverse cholesterol transport and whole-body cholesterol homeostasis. SR-BI is found in the liver, where its expression is regulated by estrogen, dietar

Protective effect of oleuropein, an olive oil biophenol, on low density lipoprotein oxidizability in rabbits

Abstract: On the basis of the results obtained with pilot studies conducted in vitro on human low density lipoprotein (LDL) and on cell cultures (Caco-2), which had indicated the ability of certain molecules present in olive oil to inhibit prooxidative processes, an in vivo study was made of laboratory rabbits fed special diets. Three different diets were prepared: a standard diet for rabbits (diet A), a standard diet for rabbits modified by the addition of 10% (w/w) extra virgin olive oil (diet B), a modified standard diet for rabbits (diet C) differing from diet B only in the addition of 7 mg kg−1 of oleuropein. A series of biochemical parameters was therefore identified, both in the rabbit plasma and the related isolated LDL, before and after Cu-induced oxidation. The following, in particular, were selected: (i) biophenols, vitamins E and C, uric acid, and total, free, and ester cholesterol in the plasma; (ii) proteins, triglycerides, phospholipids, and total, free, and ester cholesterol in the native LDL (for the latter, the dimensions were also measured); (iii) lipid hydroperoxides, aldehydes, conjugated dienes, and relative electrophoretic mobility (REM) in the oxidized LDL (ox-LDL). In an attempt to summarize the results obtained, it can be said that this investigation has not only verified the antioxidant efficacy of extra virgin olive oil biophenols and, in particular, of oleuropein, but has also revealed a series of thus far unknown effects of the latter on the plasmatic lipid situation. In fact, the addition of oleuropein in diet C increased the ability of LDL to resist oxidation (less conjugated diene formation) and, at the same time, reduced the plasmatic levels of total, free, and ester cholesterol (−15, −12, and −17%, respectively), giving rise to a redistribution of the lipidic components of LDL (greater phospholipid and cholesterol amounts) with an indirect effect on their dimesions (bigger by about 12%).

Increased LDL Cholesterol and Atherosclerosis in LDL Receptor–Deficient Mice With Attenuated Expression of Scavenger Receptor B1

Abstract: —Scavenger receptor BI (SR-BI) is a multiligand cell-surface receptor that plays a central role in high density lipoprotein homeostasis in rodents. To investigate a role for SR-BI in athero...