Knockdown expression and hepatic deficiency reveal an atheroprotective role for SR-BI in liver and peripheral tissues.

Scavenger receptor SR-BI has been implicated in HDL-dependent atheroprotective mechanisms. We report the generation of an SR-BI conditional knockout mouse model in which SR-BI gene targeting by loxP site insertion produced a hypomorphic allele (hypomSR-BI). Attenuated SR-BI expression in hypomSR-BI mice resulted in 2-fold elevation in plasma total cholesterol (TC) levels.

Transcription factor sterol regulatory element binding protein 2 regulates scavenger receptor Cla-1 gene expression.

Objective: The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested that Cla-1 gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whether Cla-1 is a target gene of the sterol regulatory element binding protein (SREBP) transcription factor family.

Micronized fenofibrate normalizes the enhanced lipidemic response to a fat load in patients with type 2 diabetes and optimal glucose control.

This study evaluated the postprandial (PP) response to an oral fat load in 28 male patients with type 2 diabetes (mean HbA1c of 5.1%), all receiving metformin and performing physical exercise, compared with healthy subjects. The effects of micronized fenofibrate (200 mg once daily) on triglycerides (TG) and retinyl palmitate (RP) responses, lipoprotein mass concentrations, post-heparin lipase activities and coagulation factors were investigated after a 16-week double-blind, placebo-controlled period.

A novel cholesteryl ester transfer protein promoter polymorphism (-971G/A) associated with plasma high-density lipoprotein cholesterol levels. Interaction with the TaqIB and -629C/A polymorphisms.

The plasma cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport (RCT) by mediating the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to atherogenic ApoB-containing lipoproteins, including VLDL, IDL and LDL. We describe a new polymorphism located at position -971 in the human CETP gene promoter, which corresponds to a G/A substitution at a potential AvaI restriction site. The relationship between the -971G/A polymorphism, plasma lipid parameters and plasma CETP concentration was evaluated in the Etude Cas-Témoins de l'Infarctus du Myocarde (control-myocardial infarction cases) cohort, and revealed that the -971G/A polymorphism (A allele frequency: 0.

Functional analysis of the chimpanzee and human apo(a) promoter sequences: identification of sequence variations responsible for elevated transcriptional activity in chimpanzee.

Lp(a) concentrations vary considerably among individuals and are primarily determined by the apo(a) gene locus. We have previously shown that mean plasma Lp(a) levels in the chimpanzee are significantly higher than those observed in humans (Doucet, C., Huby, T.

Autosomal dominant type IIa hypercholesterolemia: evaluation of the respective contributions of LDLR and APOB gene defects as well as a third major group of defects.

Autosomal dominant type IIa hypercholesterolaemia (ADH) is characterised by an elevation of total plasma cholesterol associated with increased LDL particles. Numerous different molecular defects have been identified in the LDL receptor (LDLR) and few specific mutations in the apolipoprotein B (APOB) gene resulting in familial hypercholesterolaemia and familial defective apoB-100 respectively. To estimate the respective contribution of LDLR, APOB and other gene defects in this disease, we studied 33 well characterised French families diagnosed over at least three generations with ADH through the candidate gene approach.

New functional promoter polymorphism, CETP/-629, in cholesteryl ester transfer protein (CETP) gene related to CETP mass and high density lipoprotein cholesterol levels: role of Sp1/Sp3 in transcriptional regulation.

A new polymorphism located at position -629 (CETP/-629A/C) in the promoter of the cholesteryl ester transfer protein (CETP) gene is described. The -629A allele was associated with lower CETP mass (P<0. 0001) and higher high density lipoprotein cholesterol (P<0.

The promoter of human tissue factor pathway inhibitor gene: identification of potential regulatory elements.

Tissue factor pathway inhibitor is the major potent physiologic inhibitor of tissue factor-induced coagulation. Several potential binding sites for transcription factors have been described in the 750 bp of the 5' flanking region of the human tissue factor pathway inhibitor gene reported earlier. To identify elements that regulate the expression of tissue factor pathway inhibitor in endothelial, hepatocyte, and monocyte cells, the sequence of an additional 770 bp of tissue factor pathway inhibitor was determined.

Adenovirus-mediated overexpression of tissue inhibitor of metalloproteinase-1 reduces atherosclerotic lesions in apolipoprotein E-deficient mice.

Background: To define the role of metalloproteinases (MMPs) in the development of lipid-rich atherosclerotic lesions in relation to the balance between proteolytic and antiproteolytic activities, we investigated the impact of adenovirus-mediated elevation in the circulating levels of human tissue inhibitor of MMP (TIMP-1) in atherosclerosis-susceptible apolipoprotein E-deficient (apoE(-/-)) mice.

Methods And Results: Infusion of apoE(-/-) mice fed a lipid-rich diet with rAd.RSV.

Tissue factor pathway inhibitor is expressed by human monocyte-derived macrophages : relationship to tissue factor induction by cholesterol and oxidized LDL.

Lipid-laden macrophages express tissue factor (TF), which may activate the extrinsic coagulation pathway on rupture of the atherosclerotic plaque. Tissue factor pathway inhibitor (TFPI) is a major regulator of TF-induced coagulation. We evaluated the possibility that monocyte-derived macrophages express this protein, thereby contributing to regulation of TF activity (TFact).

Inhibition of LPL expression in human monocyte-derived macrophages is dependent on LDL oxidation state: a key role for lysophosphatidylcholine.

The regulation of macrophage lipoprotein lipase (LPL) secretion and mRNA expression by atherogenic lipoproteins is of critical relevance to foam cell formation. LPL is present in arterial lesions and constitutes a bridging ligand between lipoproteins, proteoglycans, and cell receptors, thus favoring macrophage lipoprotein uptake and lipid accumulation. We investigated the effects of native and of oxidized lipoproteins on the expression of LPL in an in vitro human monocyte-macrophage system.

Familial lecithin:cholesterol acyltransferase deficiency: molecular analysis of a compound heterozygote: LCAT (Arg147 --> Trp) and LCAT (Tyr171 --> Stop).

Lecithin:cholesterol acyltransferase (LCAT) is responsible for the formation of the majority of plasma cholesteryl esters. Familial LCAT deficiency is associated with corneal opacity, anemia and proteinurea and typically results in renal failure in the 4-5th decade; this syndrome is equally characterized by the quasi-absence of plasma LCAT activity with variable enzyme mass and very low levels of plasma cholesteryl esters. In this study, we report detailed analyses of plasma lipids and lipoprotein profile in two sisters (CM and ML) presenting classical homozygous LCAT-deficiency; the younger sibling (CM) had proteinurea from an early age whereas the older sister (ML) has never exhibited renal dysfunction.

Impact of a combination of a calcium antagonist and a beta-blocker on cell- and copper-mediated oxidation of LDL and on the accumulation and efflux of cholesterol in human macrophages and murine J774 cells.

Calcium antagonists and beta-blockers may retard or inhibit atherogenesis. In the absence of data pertaining to the potential cardioprotective action of an association of such agents, we have investigated the impact of nifedipine and atenolol, alone or in combination, on the capacity of monocyte-macrophages (ex vivo) and copper ions (in vitro) to oxidize LDL and on intracellular metabolism and efflux of free and esterified forms of cholesterol in human macrophages and foam cells. At concentrations up to 100 micromol/L, atenolol had no effect on the oxidative resistance of LDL; on the contrary, nifedipine displayed a significant dose-dependent capacity to protect LDL during copper-mediated oxidation (100 micromol/L; P<.

Effect of gemfibrozil on the concentration and composition of very low density and low density lipoprotein subfractions in hypertriglyceridemic patients.

The effect of gemfibrozil treatment on very low (VLDL) and low (LDL) density lipoprotein subfractions has been investigated in 9 moderate hypertriglyceridemic (HTG) patients (triglyceride (TG) levels 237-426 mg/dl). Three VLDL subfractions, VLDL1 (Sf 175-400), VLDL2 (Sf 100-175) and VLDL3 (Sf 20-100) and 4 LDL subspecies, LDL1 (1.023-1.

Postprandial amplification of lipoprotein abnormalities in controlled type II diabetic subjects: relationship to postprandial lipemia and C-peptide/glucagon levels.

Lipoprotein abnormalities, mainly high very-low-density lipoprotein (VLDL) and low high-density lipoprotein (HDL) levels, increase the risk of coronary heart disease (CHD) in type II diabetic patients. To investigate the relationship between these lipoprotein abnormalities and the postprandial (PP) lipid-clearing capacity, triglyceride (TG) and hormonal levels were determined hourly up to the 4th hour after a mixed meal containing 32.5 g lipids/m2 body surface in 14 treated non-obese type II diabetic patients with adequate nutritional and glycemic control (hemoglobin A1C [HbA1C] < 7%) and in 12 healthy subjects matched for age, sex, and body mass index (BMI).

Genetic and phenotypic heterogeneity in familial lecithin: cholesterol acyltransferase (LCAT) deficiency. Six newly identified defective alleles further contribute to the structural heterogeneity in this disease.

The presence of lecithin:cholesterol acyltransferase (LCAT) deficiency in six probands from five families originating from four different countries was confirmed by the absence or near absence of LCAT activity. Also, other invariate symptoms of LCAT deficiency, a significant increase of unesterified cholesterol in plasma lipoproteins and the reduction of plasma HDL-cholesterol to levels below one-tenth of normal, were present in all probands. In the probands from two families, no mass was detectable, while in others reduced amounts of LCAT mass indicated the presence of a functionally inactive protein.

A multicenter comparison of the effects of simvastatin and fenofibrate therapy in severe primary hypercholesterolemia, with particular emphasis on lipoproteins defined by their apolipoprotein composition.

This multicenter, double-blind, randomized study was designed to compare the effects of simvastatin (20 mg/d and 40 mg/d) and fenofibrate (400 mg/d) on plasma lipids, lipoproteins, apolipoproteins (apo), and lipoprotein particles defined by their apo composition (Lp A-I, Lp A-II:A-I, Lp E:B, Lp C-III:B) in primary hypercholesterolemia. After 6 and 10 weeks of therapy, both drugs lowered plasma cholesterol, low-density lipoprotein (LDL) cholesterol, and apo B. The effect on LDL and apo B was significantly more pronounced for simvastatin (P = .

Lipoprotein particle analysis comparing simvastatin and fenofibrate.

This study compares the effects of fenofibrate and simvastatin in primary hypercholesterolemia, with particular regard to lipoprotein particles, as defined by their apolipoprotein composition: LpAI, LpAII: AI, LpE:B, LpCIII:B. This was a double-blind study in which patients were randomized to 2 groups, one receiving simvastatin 20 mg once daily and the other receiving fenofibrate 200 mg b.i.

[Determination of lipoprotein Lp(a). A semi-automatic immuno-turbidimetric method].

A sensitive, accurate, semiautomatic immunoturbidimetric assay for determining Lp(a) levels using a Hitachi 705 apparatus is described. A polyclonal antibody against anti-Lp(a) produced by Immuno-france is used. Studies proved that this test is reliable and that results are well correlated with those obtained by immunonephelometry.

[The efficacy and tolerance of simvastatin and fenofibrate in primary hypercholesterolemia].

The effects of simvastatin and fenofibrate on blood lipids and the side-effects of these two drugs were compared in a double-blind trial involving 184 adults with primary hypercholesterolemia (total cholesterol levels: 3.87 +/- 1.02 g/l in the simvastatin group, 3.

Fluidity changes and chemical composition of lipoproteins in type IIa hyperlipoproteinemia.

The chemical composition and the physical properties of lipoproteins (VLDL, LDL and HDL) were studied in two groups of patients: 14 healthy normolipidemic subjects and 15 type IIa familial hypercholesterolemic patients. The steady-state fluorescence anisotropy rs was estimated in lipoproteins by the fluorescence depolarization of two fluorescent probes: the DPH (1,6-diphenyl-1,3,5-hexatriene) and the TMA-DPH (1,4-trimethylammonium phenyl-6-1,3,5-hexatriene). A structured order parameter S was calculated from the DPH fluorescence anisotropy.

Plasma lipids, lipoproteins and apolipoproteins in two kindreds of hypobetalipoproteinemia.

Plasma lipids and apolipoproteins were quantified in two kindreds of hypobetalipoproteinemia. All affected members were asymptomatic but showed a decrease of 75% in apolipoprotein B and of 69% in LDL-cholesterol. There were no major changes in apo A-I and A-II but all affected family members had reduced levels of apo C-II (by 58%) and C-III (by 59%) without significant decrease in apo C-I and no specific decrease of apo C-III1.

Comparative study of the precipitation of low density lipoproteins by aortic proteodermatan sulphate and heparin.

The aortic proteoglycans and heparin were shown to form insoluble complexes with human low density lipoproteins (LDL). The effect of temperature, polyethylene glycol and ionic strength on the formation of complexes between porcine aortic proteodermatan sulphate (PDS) and LDL has been studied by laser nephelometry and comparisons made with heparin LDL complexes. Turbidity was a nonlinear function of the quantity of LDL precipitated by PDS.

Efficacy and safety of simvastatin (alone or in association with cholestyramine). A 1-year study in 66 patients with type II hyperlipoproteinaemia.

The effects and safety of simvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, were investigated alone or in association with cholestyramine in 66 patients with hypercholesterolaemia, in a 1-year study. In type IIa hypercholesterolaemia (41 patients), the association was more effective than simvastatin used alone in lowering total cholesterol (37% vs 29%) and LDL-cholesterol (45% vs 37%). In type IIb hypercholesterolaemia (23 patients), the association simvastatin-cholestyramine did not appear more effective than simvastatin used alone.

[Use of 6 serum pools in standardization of the determination of apolipoproteins AI and B in the human serum].

The proliferation of commercial immunoassays for the determination of apolipoproteins AI and B as parameters of risk for coronary heart disease and the discordance between the values obtained with the systems have made more urgent than ever the need for standardization of these assays. The authors report here the results of a collaborative study on the standardization of the values between the "Comité Française de Coordination des Recherches sur l'Athérosclérose et le Cholestérol (ARCOL)" and 13 Companies providing 15 different analytical systems. The results show that standardized measurements are not possible using a "consensus international standard" and that the major problem is related to the enormous variability of the analytical systems.