Measurement of lipoprotein particles.
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Antibodies, Monoclonal↗
Biomedical subjects
J C Fruchart
Publications and source records attributed to J C Fruchart.
Post-statin approaches to hyperlipidaemia.
The advent of statins has virtually resolved the treatment of a majority of essential hypercholesterolaemic patients. Nevertheless, other abnormalities in lipoprotein metabolism, including such lipoprotein disturbances as hypertriglyceridaemia, mixed hyperlipidaemia, accumulation of small dense low density lipoprotein (LDL), high levels of lipoprotein (a) (Lp[a]) and hypo-HDL-cholesterolaemia, although also highly atherogenic, are not as efficiently treated as essential hypercholesterolaemia. Pharmaceutical companies are improving new molecules directed against old targets (PPARalpha: fibrates) or creating original molecules directed against new targets (acyl CoA:cholesterol acyltransferase (ACAT), microsomal triglyceride transfer protein (MTP), retinoid X receptor (RXR)). Of the multitude of ACAT inhibitors, only a few have reached preliminary clinical studies: e.g., F-1394, Sch48461 and CI-1011. They reduce LDL-cholesterol and atherosclerosis development in animals, partly by directly inhibiting cholesteryl ester formation in the artery wall. BW-USC-148 is a fibric acid derivative with ACAT-inhibiting activity. The hypocholesterolaemic activity for this novel ureido fibrate analogue was found to be over 100-fold greater than that of any 'second generation' fibrate in cholesterol-fed rats, mainly through its fibrate activity (PPARalpha activation) but not its ACAT activity. Targretin (LGD1069), a member of the rexinoid family (RXR activator), was shown to decrease triglyceridaemia and to increase HDL levels in hypertriglyceridaemic rats. Microsomal triglyceride transfer protein inhibitors are potent inhibitors of the synthesis of all the atherogenic apolipoprotein B-containing particles and are under development, but in vivo data are not yet available in literature. Vitamin E, an old molecule, should be used in the near future as a potent anti-atherosclerotic treatment due to its anti-oxidant power. Results of preliminary gene therapy studies of homozygous familial hypercholesterolaemic patients and of hypo-HDL-cholesterolaemia in animals are promising but do not show hope for significant clinical use in the near future. The improvement in the understanding of the molecular mechanisms of dyslipoproteinaemia and atherosclerosis development, taken together with new strategies in drug design and drug synthesis, has led to the discovery of potent normolipidaemic drugs.
Journal Article↗
[Reverse cholesterol transport and use of transgenic mice and rabbits to reveal candidate genes for protection against atherosclerosis].
Atherosclerosis is the leading cause of death in industrial societies. In France, 215 men out of 100,000 aged from 25 to 64 years old suffered of a myocardial infarction in 1992 and due to this disease 67 men out of 100,000 died. Hypercholesterolemia corresponding to a high LDL cholesterol level is an important risk factor of myocardial infarction. Nevertheless a low cholesterol level in the HDL fraction (frequently associated with an increase in triglycerides concentrations) is a common abnormality found in patients with confirmed coronary artery disease. Therefore, besides tentatives to reduce triglycerides and LDL cholesterol levels, a therapeutical strategy consists in increasing the serum HDL cholesterol concentration in order to improve the "reverse cholesterol transport". Apo A-I is the major protein of HDL. Studies in mice and rabbits transgenic for human apo A-I showed that overexpression of this protein in these animals resulted in an increase in the HDL cholesterol level. The serum of these animals contents a high concentration of particles containing human apo A-I but not mouse apo A-II (LpA-I) and presents a higher ability to induce cellular cholesterol efflux than the serum of the control mice. These alterations result in a reduction of atherosclerosis development when these animals are submitted to a cholesterol rich diet. Lecithin cholesterol acyl-transferase (LCAT) is a major enzyme in the metabolic cascade leading to the return of cholesterol to the liver. The metabolic role of LCAT is to esterify the free cholesterol of native HDL. Native HDL acquire free cholesterol during the transfer of cholesterol from the cell membrane to the particle during the cellular cholesterol efflux, which is the first step of the "reverse cholesterol transport". Mice and rabbits transgenic for human LCAT have higher HDL-cholesterol levels. Transgenic rabbits but not transgenic mice are protected against diet induced atherosclerosis development. Nevertheless, cholesterol fed mice which are transgenic for both human LCAT and simian cholesteryl ester transfer (CETP) protein do not develop atherosclerosis. This data indicates that over production of LCAT reduces atherosclerosis when CETP is naturally (rabbit) or artificially (CETP transgenic mice) expressed in the animals. Tentatives of gene therapy in mice induced by adenovirus-mediated transfer of human apo A-I and LCAT genes also increased circulating apo A-I and LCAT. Therefore apo A-I and LCAT are two potential targets for gene therapy in patients with atherosclerosis associated with a low HDL cholesterol level.
Adult↗
Inhibitory effects of specific apolipoprotein C-III isoforms on the binding of triglyceride-rich lipoproteins to the lipolysis-stimulated receptor.
ApoC-III overexpression in mice results in severe hypertriglyceridemia due primarily to a delay in the clearance of triglyceride-rich lipoproteins. We have, in primary cultures of rat hepatocytes, characterized a lipolysis-stimulated receptor (LSR). The apparent number of LSR that are available on rat liver plasma membranes is negatively correlated with plasma triglyceride concentrations measured in the fed state. We therefore proposed that the primary physiological role of the LSR is to contribute to the cellular uptake of triglyceride-rich lipoproteins. We have now tested the effect of apoC-III on the binding of triglyceride-rich lipoproteins to LSR. Supplementation of 125I-very low density lipoprotein (VLDL) with apoC-III inhibited the LSR-mediated binding, internalization, and degradation of 125I-VLDL in primary cultures of rat hepatocytes. Studies using isolated rat liver plasma membranes showed that enrichment of human VLDL and chylomicrons with synthetic or purified human apoC-III decreased their binding to the LSR by about 40%. Supplementation of triglyceride-rich lipoproteins under the same conditions with human apoC-II had no such inhibitory effect, despite the fact that this apoprotein bound as efficiently as apoC-III to these particles. Preincubation of LDL with apoC-III did not modify its binding to LSR. Partitioning studies using 125I-apoC-III showed that this lack of effect was due to apoC-III's inability to efficiently associate with LDL. Purified human apoC-III1 was as efficient as the synthetic nonsialylated form of apoC-III in inhibiting binding of VLDL to LSR. However, despite a 2-fold greater binding of apoC-III2 to VLDL, this isoform was a less efficient inhibitor of the binding of VLDL to LSR than apoC-III1 or nonsialylated apoC-III. Desialylation of apoC-III2 by treatment with neuraminidase increased the inhibition of VLDL binding to LSR to a level similar to that observed with apoC-III1 and nonsialylated apoC-III. We propose that apoC-III regulates in part the rate of removal of triglyceride-rich particles by inhibiting their binding to the LSR, and that the level of inhibition is determined by the degree of apoC-III sialylation.
Animals↗
Endothelial derived vasorelaxation is impaired in human APO A-I transgenic rabbits.
Endothelium-derived relaxing factor (nitric oxide: NO) may provide an endogenous defence against atherosclerosis which impairs endothelium-dependent vascular relaxation. Atherosclerosis development is inhibited in cholesterol fed human apo A-I transgenic rabbits (Duverger, N., Circulation, 1996, 94, 713-717). We investigated if endothelium-dependent vascular relaxation is modified in human apo A-I transgenic rabbits by testing in vitro endothelium-dependent receptor-dependent vascular relaxation to acetylcholine and endothelium-dependent receptor-independent vascular relaxation to A23187 of abdominal aorta, precontracted with phenylephrine, in human apo A-I transgenic rabbits (n=4) versus non transgenic littermates (n=4). Endothelium-independent vascular relaxation was investigated with sodium nitroprusside. Vascular precontraction to phenylephrine was significantly increased in human apo A-I transgenic rabbits (p<0.05) while endothelium-independent vascular relaxation to nitroprusside was similar between human apo A-I transgenic rabbits and control rabbits. Endothelium-dependent receptor-dependent and receptor-independent vascular relaxations were reduced in human apo A-I transgenic rabbits (p<0.05). Maximum endothelium-dependent receptor-dependent vascular relaxation was negatively correlated with HDL-cholesterol and total apo A-I (rabbit+ human) plasma levels (r=0.87 and 0.86, p=0.01, respectively) but not with atherogenic plasma lipid (VLDL-cholesterol, LDL-cholesterol, VLDL+LDL cholesterol, triglycerides, apolipoprotein B) levels. These results suggest that the transgenesis of human apo A-I in rabbits impairs signal transduction of endothelial NO synthesis.
Acetylcholine↗
High-density-lipoprotein subfraction 3 interaction with glycosylphosphatidylinositol-anchored proteins.
To elucidate further the binding of high-density-lipoprotein subfraction 3 (HDL3) to cells, the involvement of glycosylphosphatidylinositol-anchored proteins (GPI-proteins) was studied. Treatment of cultured cells, such as fibroblasts or SK-MES-1 cells, with a phosphatidylinositol-specific phospholipase C (PI-PLC) significantly decreases specific HDL3 binding. Moreover, PI-PLC treatment of cultured cells or cellular plasma membrane fractions results in releasing proteins. These proteins have a soluble form and can also bind HDL3, as revealed by ligand blotting experiments with HDL3. In order to obtain enriched GPI-proteins, we used a detergent-free purification method to prepare a caveolar membrane fraction. In the caveolar fraction, we obtained, by ligand blotting experiments, the enrichment of two HDL3-binding proteins with molecular masses of 120 and 80 kDa. These proteins were also revealed in a plasma membrane preparation with two other proteins, with molecular masses of 150 and 104 kDa, and were sensitive to PI-PLC treatment. Electron microscopy also showed the binding of Au-labelled HDL3 inside the caveolar membrane invaginations. In SK-MES-1 cells, HDL3 are internalized into a particular structure, resulting in the accumulation and concentration of such specific membrane domains. To sum up, a demonstration has been made of the implication of GPI-proteins as well as caveolae in the binding of HDL3 to cells.
Biological Transport↗
Alterations in lipoprotein metabolism in peroxisome proliferator-activated receptor alpha-deficient mice.
The peroxisome proliferator-activated receptor-alpha (PPARalpha) controls gene expression in response to a diverse class of compounds collectively referred to as peroxisome proliferators. Whereas most known peroxisome proliferators are of exogenous origin and include hypolipidemic drugs and other industrial chemicals, several endogenous PPARalpha activators have been identified such as fatty acids and steroids. The latter finding and the fact that PPARalpha modulates target genes encoding enzymes involved in lipid metabolism suggest a role for PPARalpha in lipid metabolism. This was investigated in the PPARalpha-deficient mouse model. Basal levels of total serum cholesterol, high density lipoprotein cholesterol, hepatic apolipoprotein A-I mRNA, and serum apolipoprotein A-I in PPARalpha-deficient mice are significantly higher compared with wild-type controls. Treatment with the fibrate Wy 14,643 decreased apoA-I serum levels and hepatic mRNA levels in wild-type mice, whereas no effect was detected in the PPARalpha-deficient mice. Administration of the fibrate Wy 14,643 to wild-type mice results in marked depression of hepatic apolipoprotein C-III mRNA and serum triglycerides compared with untreated controls. In contrast, PPARalpha-deficient mice were unaffected by Wy 14,643 treatment. These studies demonstrate that PPARalpha modulates basal levels of serum cholesterol, in particular high density lipoprotein cholesterol, and establish that fibrate-induced modulation in hepatic apolipoprotein A-I, C-III mRNA, and serum triglycerides observed in wild-type mice is mediated by PPARalpha.
Animals↗
Transcriptional regulation of apolipoprotein A-I gene expression by the nuclear receptor RORalpha.
Since elevated concentrations of plasma high density lipoprotein (HDL) and its major apolipoprotein (apo), apoA-I, confer protection against atherosclerosis, considerable research efforts have focussed on the identification of factors regulating apoA-I gene expression in an attempt to increase its production. Nuclear receptors are interesting candidates because they are transcription factors whose activity is ligand-dependent. In the present study we identified the orphan receptor RORalpha1 as an activator of apoA-I gene transcription. In apoA-I-expressing intestinal Caco-2 cells, overexpression of the RORalpha1, but not the RORalpha2 or RORalpha3 isoforms, increased rat apoA-I gene transcription. Deletion and site-directed mutagenesis experiments identified a functional ROR-responsive element (RORE) in the rat and mouse apoA-I gene promoters, which overlaps with the TATA box. Gel shift experiments indicated that this RORE binds the RORalpha1 isoform, but not the RORalpha2 or RORalpha3 isoforms. Furthermore, compared with wild type mice, apoA-I mRNA levels were significantly lower in small intestines of staggerer mice homozygous for a deletion in the RORalpha gene. In addition, reverse transcriptase-polymerase chain reaction analysis revealed the expression of RORalpha in small intestinal epithelium and in Caco-2 cells. These data indicate a novel, physiological role for RORalpha1 in the regulation of genes involved in lipid and lipoprotein metabolism and possibly in the development of metabolic diseases, such as atherosclerosis.
Animals↗
HDL3 binds to glycosylphosphatidylinositol-anchored proteins to activate signalling pathways.
Previous studies have indicated that in HepG2 cells HDL3-signalling involves glycosylphosphatidylinositol (GPI) anchored proteins. HDL3-binding to HepG2 cells was found to be enhanced by cellular preincubation with PI-PLC inhibitors and sensitive to a cellular preincubation with exogenous PI-PLC, suggesting that HDL3 binds directly on GPI-anchored proteins to initiate signaling. Moreover HDL3-binding was found to be partly inhibited by antibodies against the HDL-binding protein (AbHBP). HDL3, when binding to HepG2 cells, promoted the release in the culture medium of a 110 kDa protein that binds AbHBP, while a cellular preincubation with antibodies against the inositol-phosphoglycan (IPG) moiety of GPI-anchor (AbIPG), used to block lipolytic cleavage of the GPI-anchor, inhibits HDL3-induced release of the 110 kDa protein in the culture medium. In [3H]-PC prelabeled HepG2 cells, AbHBP were found to stimulate PC-hydrolysis and DAG generation within 5 min as did HDL3 stimulation. Cellular preincubation with AbIPG was found to inhibit only the HDL3-signal and not the AbHBP-signal, while a prior cellular pretreatment with PI-PLC from Bacillus cereus was found to inhibit the HDL3-and AbHBP-signal. Moreover cellular preincubation with AbHBP for 1 h at 37 degrees C was found to inhibit HDL3-signalling pathways. Our results suggest that in HepG2 cells a 110 kDa protein, which could be HBP, can be anchored to the membrane via GPI, and can function in HDL3-signalling pathways as binding sites.
Antibodies↗
The organization, promoter analysis, and expression of the human PPARgamma gene.
PPARgamma is a member of the PPAR subfamily of nuclear receptors. In this work, the structure of the human PPARgamma cDNA and gene was determined, and its promoters and tissue-specific expression were functionally characterized. Similar to the mouse, two PPAR isoforms, PPARgamma1 and PPARgamma2, were detected in man. The relative expression of human PPARgamma was studied by a newly developed and sensitive reverse transcriptase-competitive polymerase chain reaction method, which allowed us to distinguish between PPARgamma1 and gamma2 mRNA. In all tissues analyzed, PPARgamma2 was much less abundant than PPARgamma1. Adipose tissue and large intestine have the highest levels of PPARgamma mRNA; kidney, liver, and small intestine have intermediate levels; whereas PPARgamma is barely detectable in muscle. This high level expression of PPARgamma in colon warrants further study in view of the well established role of fatty acid and arachidonic acid derivatives in colonic disease. Similarly as mouse PPARgammas, the human PPARgammas are activated by thiazolidinediones and prostaglandin J and bind with high affinity to a PPRE. The human PPARgamma gene has nine exons and extends over more than 100 kilobases of genomic DNA. Alternate transcription start sites and alternate splicing generate the PPARgamma1 and PPARgamma2 mRNAs, which differ at their 5'-ends. PPARgamma1 is encoded by eight exons, and PPARgamma2 is encoded by seven exons. The 5'-untranslated sequence of PPARgamma1 is comprised of exons A1 and A2, whereas that of PPARgamma2 plus the additional PPARgamma2-specific N-terminal amino acids are encoded by exon B, located between exons A2 and A1. The remaining six exons, termed 1 to 6, are common to the PPARgamma1 and gamma2. Knowledge of the gene structure will allow screening for PPARgamma mutations in humans with metabolic disorders, whereas knowledge of its expression pattern and factors regulating its expression could be of major importance in understanding its biology.
3T3 Cells↗
HDL3-signalling in HepG2 cells involves glycosyl-phosphatidylinositol-anchored proteins.
In [3H]phosphatidylcholine (PC) prelabelled HepG2 cells, HDL3 stimulates a biphasic increase in 1.2-diacylglycerol (DAG). The early phase is mediated in part by a phospholipase C which is inhibited by 10 microM D 609, RHC-80267 or U-73122 and less by 100 microM propranolol. A phospholipase D is more likely involved in the late phase, as the DAG peak lags behind phosphatidic acid rise and is blocked by 100 microM propranolol. Cellular preincubation with 200 microg/ml antibodies against the inositolphosphoglycan (IPG) moiety of the GPI-anchor (Ab(IPG)), or depletion in GPI-anchored proteins by cellular pretreatment with 0.5 U/ml PI-PLC, 1 mM insulin and 2 HU/ml streptolysin-O, or depletion in membrane cholesterol content by filipin (5 microg/ml), digitonin (5 microg/ml) and cholesterol oxidase (0.5 U/ml) decreases the HDL3-signal, suggesting the involvement of a lipolytic cleavage of GPI-anchored proteins. Inhibition of proteases by 1 mM leupeptin/PMSF improves the response time to HDL3, with a DAG peak at 2-3 min. In the presence of protease-inhibitors, HDL3 releases in the culture medium several proteins with a residual IPG that binds Ab(IPG) after SDS-PAGE analysis and immunoblotting. HDL3-signalling pathways comprise tyrosine kinases, as preincubation with 100 microg/ml genistein or tyrphostin inhibits the HDL3-signal. HDL3 activates PC hydrolysis through a multistep pathway involving the cleavage of GPI-anchored proteins.
Antibodies↗
Cholesterol efflux, lecithin-cholesterol acyltransferase activity, and pre-beta particle formation by serum from human apolipoprotein A-I and apolipoprotein A-I/apolipoprotein A-II transgenic mice consistent with the latter being less effective for reverse cholesterol transport.
Studies assessing fatty streak formation in mice have revealed that human apolipoprotein A-I (apoAI) transgenic mice (TgAI) have 15-fold less atherosclerosis susceptibility than combined human apolipoprotein A-I/human apolipoprotein A-II (apoAI:AII) transgenics (TgAI:AII) and 40-fold less than nontransgenic control mice. In order to examine the biochemical mechanisms underlying those in vivo observations, we have compared in vitro properties of serum from the different groups of animals for participation in cholesterol efflux, LCAT activation, and pre-beta particle formation. Analysis of cholesterol efflux from both Fu5AH hepatoma and Ob1771 adipose cells revealed serum from the TgAI to be the most efficient in promoting efflux. The two-dimensional electrophoresis of mouse serum shows that control mice have exclusively apoAI in alpha particles. TgAI and TgAI:AII mice have 30 and 38% of total apoAI in particles with pre-beta electrophoretic mobility, respectively. The distribution of cell-derived cholesterol between these apoAI-containing lipoprotein subspecies after 1 and 60 min of incubation with Fu5AH hepatoma cells was examined. This revealed after a 1 min incubation 66 +/- 8 and 83 +/- 9% of the counts in particles with pre-beta mobility for TgAI and TgAI:AII mice, respectively; while after 60 min of incubation, only 6 +/- 2% of counts remained in pre-beta particles from the TgAI and 30 +/- 3% for the TgAI:AII. This suggests faster movement of cholesterol from pre-beta to alpha particles in plasma from the TgAI. Consistent with this is the observation that LCAT activity with both exogenous and endogenous substrate increased in the TgAI versus the TgAI:AII mice. The previously observed decrease in fatty streak formation in the TgAI versus the TgAI:AII and control mice is consistent with the in vitro studies presented here and suggests that HDL containing human apoAI is a more effective participant in the postulated early steps in reverse cholesterol transport than HDL containing both human apoAI and human apoAII, and/or murine HDL.
Animals↗
Distribution of apolipoprotein E between apo B- and non apo B-containing lipoproteins according to apo E phenotype.
Apolipoprotein E (apo E) is a component of all the classes of lipoproteins and can be distributed among apo B- (LpB) and non apo B-containing lipoproteins (Lp-non-B). Using a new electroimmunoassay kit, plasma apo E, apo E in Lp-non-B (apo E-Lp-non-B) and apo E in LpB (apo E-LpB) levels were measured in healthy control subjects (n=481) from 3 centers participating in the ECTIM study (Etude Cas-Témoins sur l'Infarctus du Myocarde), a population-based study on myocardial infarction. The distribution of apo E among lipoproteins was analyzed according to the apo E phenotype after adjustment for center, body mass index, tobacco use, alcohol consumption and triglycerides. Apo E was higher (average excess: + 0.32; P < 0.0001) and lower (average excess: -0.12; P < 0.0001) in subjects carrying the allele epsilon2 and the allele epsilon4 respectively, than in apo E3/3 subjects. These differences are the consequence of variations in apo E-Lp-non-B which clearly differed between the groups classified according to their apo E phenotype (P < 0.0001). The average excess of apo E Lp non-B compared to apo E3/3 subjects was + 0.43 (P < 0.0001) and -0.22 (P < 0.0001) for the epsilon2 and epsilon4 alleles respectively. Apo E-LpB was lower in subjects carrying the epsilon2 allele (P < 0.02) while the presence of the epsilon4 allele did not modify this parameter. The proportion of apo E within HDL was clearly higher and lower in subjects carrying apo E2 and apo E4 respectively than in apo E3/3 subjects. Although triglyceride levels were dependent on the apo E phenotype, the adjustment of the proportion of apo E in HDL for triglycerides hardly modified the results. For the first time, these results, using direct measurements on a large number of subjects, confirm the greater preference of apo E4 over apo E2 for LpB and vice versa for Lp-non-B. They also show a greater affinity of apo E2 for HDL compared to apo E3. This high affinity of apo E2 for HDL could be due to the formation of the apo E-A-II complex. These results indicate that apo E phenotype modulates the distribution of apo E among lipoproteins and suggest differences in lipoprotein metabolism between apo E2, apo E3 and apo E4.
Adult↗
Effect of smoking cessation on lipoprotein A-I and lipoprotein A-I:A-II levels.
Cigarette smoking is associated with low plasma high-density lipoprotein cholesterol (HDL-C) and apolipoprotein (apo) A-I levels, which may explain, in part, its deleterious effects on coronary heart disease (CHD). In a group of ex-smokers, we assessed the influence of smoking cessation on apo A-I particle levels. Plasma lipid, apolipoprotein, and lipoparticle concentrations of 58 subjects who had completely stopped smoking (ex-smokers) were compared with those of 37 subjects who had continued smoking (smokers) before and after a smoking cessation counseling program. Nutritional intake was recorded before and after the program to adjust for potential interaction with plasma lipid variables. Smokers and ex-smokers were similar in gender distribution, age, body mass index (BMI), social status, and nutrient intake. There were significantly greater increases in total cholesterol (P < .04), HDL-C (P < .005), HDL2-C (P < .008), and lipoprotein (Lp) A-I:A-II (P < .04) in ex-smokers than in smokers. After smoking cessation, ex-smokers consumed more vegetable protein (P < .02) and polysaccharides (P < .04) and had higher plasma levels of HDL-C (P < .0004), apo A-I (P < .001), Lp A-I (P < .007), and Lp A-I:A-II (P < .01) than smokers. Adjustments on nutritional variables did not show any additional difference between ex-smokers and smokers, suggesting that smoking per se effects Lp A-I and Lp A-I:A-II levels. In conclusion, HDL particles including Lp A-I and Lp A-I:A-II are higher in ex-smokers than in smokers.
Adult↗
Fish-eye disease: structural and in vivo metabolic abnormalities of high-density lipoproteins.
Fish-eye disease (FED) in humans is characterized by corneal opacities and markedly decreased plasma concentrations of high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) AI, and apo All, but no tendency to precocious atherosclerosis is present. To elucidate this paradox, the structure of HDL, the potential of serum to promote cholesterol efflux from cultured cells, and the in vivo metabolism of HDL were examined in a 53-year-old woman with a FED syndrome in association with a markedly decreased lecithin:cholesterol acyltransferase (LCAT) activity in HDL due to a mutation of the LCAT gene (Arg158 --> Cys). HDLs isolated by ultracentrifugation were small and enriched in unesterified cholesterol and phospholipids at the expense of cholesteryl esters and proteins. The apolipoprotein content showed an enrichment in apo E and apo AIV, whereas apo AI and apo All were dramatically reduced. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting using specific antibodies showed that the apo E was free or covalently bound to apo All. These particles analyzed by electron microscopy were small and round lipoproteins with a size similar to the smallest fraction of normal HDL3. The potential capacity of the serum to promote efflux from the cells was approximately 40% of control serum levels, but FED HDLs were as efficient as control HDLs in promoting cholesterol efflux from cells. To assess the metabolism of HDL apolipoproteins, in vivo apolipoprotein kinetic studies were performed using endogenous labeling techniques in the patient with FED and three control subjects. All subjects were administered D3-labeled leucine by primed constant infusion for up to 10 hours. The fractional synthetic rates (FSRs) of apo AI and apo All in the patient were 0.674 and 0.594 per day, clearly higher than in controls, 0.210 +/- 0.053 and 0.148 +/- 0.014 per day for apo AI and apo All, respectively. Apo AI and apo All production rates in the patient with FED were normal, 11.32 and 2.62 mg/kg x d, respectively, as compared with those in normal subjects, 11.45 +/- 1.23 and 2.68 +/- 0.17 mg/kg x d. These data established that hypoalphalipoproteinemia in FED was caused by marked hypercatabolism of apo AI and apo All. This hypercatabolism could be the consequence of structural abnormalities due to the selective LCAT deficiency. In conclusion, two steps of reverse cholesterol transport, cholesterol efflux and apo-HDL metabolism, appeared particularly efficient. This efficiency could participate in the absence of premature atherosclerosis in FED patients as regards the low HDL level.
Adult↗
Effect of pravastatin on angiographic restenosis after coronary balloon angioplasty. The PREDICT Trial Investigators. Prevention of Restenosis by Elisor after Transluminal Coronary Angioplasty.
OBJECTIVES: This study sought to determine whether pravastatin affects clinical or angiographic restenosis after coronary balloon angioplasty. BACKGROUND: Experimental data and preliminary clinical studies suggest that lipid-lowering drugs might have a beneficial effect on restenosis after coronary angioplasty. METHODS: In a multicenter, randomized, double-blind trial, 695 patients were randomized to receive pravastatin (40 mg/day) or placebo for 6 months after successful balloon angioplasty. All patients received aspirin (100 mg/day). The primary angiographic end point was minimal lumen diameter (MLD) at follow-up, assessed by quantitative coronary angiography. A sample size of 313 patients per group was required to demonstrate a difference of 0.13 mm in MLD between groups (allowing for a two-tailed alpha error of 0.05 and a beta error of 0.20). To allow for incomplete angiographic follow-up (estimated lost to follow-up rate of 10%), 690 randomized patients were required. Secondary end points were angiographic restenosis rate (restenosis assessed as a categoric variable, > 50% stenosis) and clinical events (death, myocardial infarction, target vessel revascularization). RESULTS: At baseline, clinical, demographic, angiographic and lipid variables did not differ significantly between groups. In patients treated with pravastatin, there was a significant reduction in total and low density lipoprotein cholesterol and triglyceride levels and a significant increase in high density lipoprotein cholesterol levels. At follow-up the MLD (mean +/- SD) was 1.47 +/- 0.62 mm in the placebo group and 1.54 +/- 0.66 mm in the pravastatin group (p = 0.21). Similarly, late loss and net gain did not differ significantly between groups. The restenosis rate (recurrence > 50% stenosis) was 43.8% in the placebo group and 39.2% in the pravastatin group (p = 0.26). Clinical restenosis did not differ significantly between groups. CONCLUSIONS: Although pravastatin has documented efficacy in reducing clinical events and angiographic disease progression in patients with coronary atherosclerosis, this study shows that it has no effect on angiographic outcome at the target site 6 months after coronary angioplasty.
Adult↗
Adrenocorticotrophic hormone lowers serum Lp(a) and LDL cholesterol concentrations in hemodialysis patients.
Previously, we have shown that short-term administration of adrenocorticotrophic hormone (ACTH) results in reduced concentrations of apolipoprotein B-containing lipoproteins, including lipoprotein(a), and reduced activities of hepatic lipase. These effects were observed in steroid-treated patients suffering from iatrogenic ACTH deficiency and in healthy individuals. The direct nature of the influence of ACTH on hepatic lipoprotein metabolism was confirmed by in vitro experiments. The aim of the present investigation was to study the effects of ACTH treatment on uremic patients, who exhibit disturbed lipoprotein pattern due to the slow removal of triglyceride-rich lipoproteins and who probably are ACTH resistant. Eight patients on chronic hemodialysis were studied. After one intramuscular injection of Synacthen Depot (a synthetic ACTH1-24 preparation from Ciba Geigy AG, Basel, Switzerland) 1 mg, the only change noted was a significant reduction of 26% in median lipoprotein(a) concentration. After five injections, a further decrease (65%) was found in the lipoprotein(a) concentration. Also, reductions in median concentrations of total cholesterol, low density lipoprotein cholesterol and apolipoprotein B were observed. The magnitude of these changes was 15 to 30%. In contrast to previously studied groups, no changes were observed regarding triglyceride metabolism. Significantly increased median concentration of apolipoprotein CIII was found. However, the excess apolipoprotein CIII was confined to the fraction that was not associated with apolipoprotein B. Thus, administration of ACTH to uremic patients improved their atherogenic lipoprotein profile, a fact that may have future therapeutic implications. In comparison to previously studied groups, the uremic patients responded rather slowly and not at all regarding triglyceride metabolism.
Adrenocorticotropic Hormone↗
Relationship between low-density lipoprotein size and apolipoprotein A-I-containing particles: the ECTIM study.
It is now established that small dense low-density lipoproteins (LDLs) are more common among patients with coronary heart disease than among control individuals. Small LDL size is also associated with a high-risk profile, including increased levels of triglycerides and decreased high-density lipoprotein (HDL)-cholesterol. Furthermore, some human HDL particles contain both apolipoprotein (apo) A-I and apoA-II (LpA-I:A-II) while others contain apoA-I but are devoid of apoA-II (LpA-I). We have investigated the relationship between LDL size, measured by non-denaturing gradient-gel electrophoresis, and HDL parameters, particularly LpA-I and LpA-I:A-II levels, in healthy control subjects (n = 408). LDL size was positively and significantly correlated with HDL-cholesterol (r = 0.43), apoA-I (r = 0.32) and LpA-I (r = 0.29), whereas no correlation was observed with apoA-II and LpA-I:A-II. The determination of the mean apoA-I and LpA-I in the quintiles of LDL size distribution revealed a progressive increase in apoA-I and LpoA-I from the first quintile (small LDLs), 137 and 42 mg dL-1 respectively, to the fifth quintile (large LDLs), 161 and 54 mg dL-1 respectively. Conversely, no evolution of apoA-II and LpA-I:A-II was observed. Multivariate analysis showed that not only triglycerides, but also HDL-cholesterol, apoA-I and LpA-I, are determinants of LDL size, depending on the model used. Thus, part of the variation in size of LDLs is associated with the metabolism of HDL independently of that of triglycerides. Thus, a low concentration of LpA-I combined with the presence of small LDLs could contribute to the high-risk profile observed in subjects with small LDLs.
Adult↗