Natalie Fournier | Paris Sud XI University (original) (raw)
Papers by Natalie Fournier
Atherosclerosis Supplements, 2007
Annales de biologie clinique
Lipoprotein transport genes have been used to make either transgenic or knockout mice with altere... more Lipoprotein transport genes have been used to make either transgenic or knockout mice with altered lipoprotein levels and metabolism. These models have provided information in at least three major issues. First, transgenic mice allow to study gene expression regulation. This approach has been helpful in identifying tissue specific expression of two clusters of apolipoprotein genes apo E/CI/CII and apo AI/CIII/AIV. Another example is the identification of a cis-acting region controlling transcription of the CETP gene in response to diet. Second, transgenic mice model provides relevant insights into lipoprotein metabolism: the structural role of human apo AII, the effect of apo AI on HDL subfractions distribution, the contribution of apo CIII to hypertriglyceridemia, and by contrast of apo E in the clearance of atherogenic TG rich lipoproteins, the role of CETP in the balance of LDL and HDL concentration and distribution. Finally, certain strains of mice under specific conditions of diet develop atherosclerotic lesions which have been shown to be reduced in human apo AI transgenic animals. However, the best mouse model for further investigation of human atherosclerosis seems to be apo E knockout mice.
Atherosclerosis Supplements, 2010
Atherosclerosis Supplements, 2001
The Journal of Lipid Research, 2010
This article is available online at http://www.jlr.org
Clinica Chimica Acta, 1995
Hyperglycaemia in diabetic patients results in non-enzymatic glycation of plasma proteins, includ... more Hyperglycaemia in diabetic patients results in non-enzymatic glycation of plasma proteins, including lipoproteins such as high-density lipoproteins (HDL). We studied the effects of in vitro HDL glycation on the activity of lecithin-cholesterol acyl transferase (LCAT), a key enzyme in HDL plasma metabolism. LCAT was prepared from non-diabetic subjects and HDL by sequential density ultracentrifugation (in the density range of 1.063-1.21 g/ml) from both diabetic and non-diabetic patients. HDL from non-diabetic patients were glycated in vitro by incubating lipoproteins with 100 mmol/l glucose for various times at 37°C with sodium cyanoborohydride as reducing agent. Glycation of HDL protein was quantified by measuring the percentage of derived amino acid residues using the TNBS assay. Kinetic parameters of LCAT were first determined using native HDL from non-diabetic patients and in vitro glycated HDL. With native HDL, K m and lima x were 51.1 4-4.2 #mol/1 (n = 8) and 12.9 4-2.4 nmol/ml/h (n = 8), respectively. Enzyme reactivity, calculated as the Vmax/K m ratio, was 0.25 ± 0.04 h -~ (n = 8). In the case of moderate glycation (derived residues < 30%; n = 19) a significant increase in both Km (18.2 4-3.4%; mean ± S.D.) and V~x (9.3 4-2.4%) was observed. In contrast, with a high level of glycation (derived residues > 30%; n = 8), both parameters fell (Kin, 25 ± 6.3%; V~x, 34.1 ± 3.3%). In addition, whatever the level of glycation, enzyme reactivity was lower in the presence of in vitro glycated HDL. This decrease in LCAT reactivity was not due to a peroxidative process nor to an alteration of the protein and lipid composition of in vitro glycated HDL. It could, however, be explained by glycation of lysine residues in apolipoprotein A-I, which is the most potent activator of LCAT. In a second * Corresponding author.
Biochemistry, 2001
Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cho... more Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without degradation of the HDL particle. In addition, SR-BI stimulates the bi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC from plasma HDL. SR-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanced sensitivity of membrane cholesterol to extracellular cholesterol oxidase. In contrast, CD36, a closely related class B scavenger receptor, has none of these activities despite binding HDL with high affinity. In the present study, analyses of chimeric SR-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activities related to HDL CE selective uptake, bi-directional FC flux, and the alteration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI. The N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma membrane. The C-terminal tail of SR-BI is dispensable for activity as well for targeting to the plasma membrane. Thus, multiple distinct functional activities are localized to the SR-BI extracellular domain.
Atherosclerosis, 2012
To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspeci... more To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway. The capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0-8 h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10 mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10 mg/d) in 16 patients displaying low HDL-C levels (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;40 mg/dl). The larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner. CETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.
Atherosclerosis, 1999
Poster session: lntracellular trqfficking and assembly of lipoproteins/reverse cholesterol transp... more Poster session: lntracellular trqfficking and assembly of lipoproteins/reverse cholesterol transport primary lipid abnormality is hypertriglyceridemia. In this 6 week (w), multicenter, double-blind, parallel study, 196 patients with triglycerides (TG) of 300 mg/dL (3.41 mmol/L) to 900 mg/dL (10.22 mmol/L) and LDL-C > 75 mg/dL ( 1.94 mmol/L) were randomized to placebo, S 20, 40 or 80 mg/day for 6 w. The baseline (BL, mg/dL) and mean % change (CH; median for TG and VLDL-C) from BL to w 6 for the major lipids and lipoproteins were:
Arteriosclerosis, Thrombosis, and Vascular Biology, 1997
The relationships of cell cholesterol efflux to HDL phospholipid (PL) content and composition in ... more The relationships of cell cholesterol efflux to HDL phospholipid (PL) content and composition in human serum were analyzed in two groups of subjects selected on the basis of their HDL cholesterol (HDL-C) levels: a norm-HDL group (1.10 mmol/L &amp;lt; HDL-C &amp;lt; 1.50 mmol/L) and a high-HDL group (HDL-C &amp;gt; 1.75 mmol/L). In the high-HDL group, the relative fractional efflux was significantly higher than in the norm-HDL group, and in both groups, fractional efflux was correlated with a number of lipoprotein parameters, the best correlation and the only one that remained significant after multivariate analysis being with HDL phospholipid (HDL-PL). Analysis of the HDL-PL subclasses revealed that HDL in the high-HDL sera was enriched with phosphatidylethanolamine (HDL-PE) and relatively deficient in sphingomyelin (HDL-SM) compared with norm-HDL sera. Moreover, the fractional efflux values in the high-HDL group were negatively correlated with the proportion of HDL-PE (r = -.64, P &amp;lt; .0001) and positively correlated with the proportion of HDL-SM (r = .43, P &amp;lt; .01). Thus, this study provides evidence that HDL-PL concentration can be used to predict the capacity of serum to accept cellular cholesterol. Among the differences described between norm-HDL and high-HDL sera, the variability in PE to SM ratio might reflect changes in serum cholesterol acceptors that modulate the first step of reverse cholesterol transport.
Atherosclerosis, Aug 31, 2001
The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. Th... more The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. The aim of the present study was to analyze and interpret the relationships between triglycerides (TG), HDL-related parameters and serum cholesterol efflux potential in an asymptomatic population including both normo-and hyperlipidemic individuals. In a large sample (n= 1143) of this population, there was a negative correlation between TG and HDL-cholesterol (HDL-C) (r= −0.49, P B0.0001) whereas the negative correlation between TG and HDL-phospholipid (HDL-PL) (r= −0.29, P B 0.0001) was weaker, leading to a strong positive correlation between TG and HDL-PL/C ratio (r= 0.58, PB 0.0001). Thus, increased TG concentrations were associated with an enrichment of HDL with PL. Since we have demonstrated previously that HDL-PL is the major determinant for cholesterol efflux potential from Fu5AH rat hepatoma cells, we determined the effect of the variations in HDL lipid composition on the cholesterol efflux capacity in a subsample of 198 subjects. Compared with normolipidemic subjects (NLP) (TG 51.7 mmol/l; LDL-C54.1 mmol/l, n=58), hypertriglyceridemic subjects (HTG) (TG \1.7 mmol/l, n= 63) exhibited lower HDL-C levels (1.08 9 0.21 vs. 1.25 9 0.32, P= 0.0003) whereas they showed similar HDL-PL concentrations (1.25 90.21 vs. 1.25 92.7) and, thus, higher HDL-PL/C ratio (1.17 9 0.15 vs. 1.02 90.14, P = 0.0001). The relative efflux capacity of serum measured in the Fu5AH system (5% serum, 4 h incubation at 37°C) was on average identical in the HTG and NLP groups. Thus, this study provides evidence that despite decreased HDL concentrations, as determined routinely by the HDL-C assay, some HTG subjects maintained serum cholesterol efflux capacity thanks to the enrichment of HDL with PL.
Atherosclerosis Supplements, 2006
We studied the size distribution assessed by polyacrilamide gradient gel electrophoresis, of HDL ... more We studied the size distribution assessed by polyacrilamide gradient gel electrophoresis, of HDL isolated from the plasma of 47 children with T2DM, 16 obese children with IGT, 43 with obesity and normal glucose tolerance, and 39 lean controls.
Atherosclerosis Supplements, 2011
Background: Distinct subpopulations of macrophages have been identified in the human arterial int... more Background: Distinct subpopulations of macrophages have been identified in the human arterial intima, with varying effects on the development of atherosclerosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are hematopoietic growth factors that regulate the generation and function of monocyte-derived macrophages. Methods: A gene expression profile related to cholesterol uptake and efflux, and the cholesterol contents were analyzed in cultured human macrophages differentiated with either GM-or M-CSF, and after pre-exposure to acetylated LDL in the absence or presence of cholesterol acceptors. Results: Macrophages differentiated with M-CSF expressed higher mRNA levels of CD36 and SR-AI, the two scavenger receptors for modified LDL. This correlated with a greater ability of macrophages to accumulate cholesteryl esters in response to incubation with acetylated LDL. Macrophages differentiated with GM-CSF, again, showed higher expression of SR-BI and ABCG1 mRNA, two receptors capable of mediating cholesterol efflux. However, such divergent gene expression profile favoring a pro-atherogenic role for M-CSF, rather than for GM-CSF, was attenuated in the foam cell phenotype. Furthermore, HDL-2 and human blood plasma induced similar degrees of cholesterol efflux in both types of macrophages. Conclusions: A protective compensatory upregulation of some components of the cholesterol efflux machinery was observed in the M-CSF-subtype of macrophages upon foam cell formation. Thus, the gene profile of human macrophages is influenced, in addition to growth factors, also by the relative availability of modified LDL particles and of HDL particles. Ultimately, the composite effect of growth factors and lipoproteins determine cholesterol balance of the macrophages.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016
A diet rich in n-3/n-6 polyunsaturated fatty acids (PUFAs) is cardioprotective. Dietary PUFAs aff... more A diet rich in n-3/n-6 polyunsaturated fatty acids (PUFAs) is cardioprotective. Dietary PUFAs affect the cellular phospholipids composition, which may influence the function of membrane proteins. We investigated the impact of the membrane incorporation of several PUFAs on ABCA1-mediated cholesterol efflux, a key antiatherogenic pathway. Arachidonic acid (AA) (C20:4 n-6) and docosahexaenoic acid (DHA) (C22:6 n-3) decreased or increased cholesterol efflux from J774 mouse macrophages, respectively, whereas they had no effect on efflux from human monocyte-derived macrophages (HMDM). Importantly, eicosapentaenoic acid (EPA) (C20:5 n-3) induced a dose-dependent reduction of ABCA1 functionality in both cellular models (-28% for 70μM of EPA in HMDM), without any alterations in ABCA1 expression. These results show that PUFA membrane incorporation does not have the same consequences on cholesterol efflux from mouse and human macrophages. The EPA-treated HMDM exhibited strong phospholipid composition changes, with high levels of both EPA and its elongation product docosapentaenoic acid (DPA) (C22:5 n-3), which is associated with a decreased level of AA. In HMDM, EPA reduced the ATPase activity of the membrane transporter. Moreover, the activation of adenylate cyclase by forskolin and the inhibition of cAMP phosphodiesterase by isobutylmethylxanthine restored ABCA1 cholesterol efflux in EPA-treated human macrophages. In conclusion, EPA membrane incorporation reduces ABCA1 functionality in mouse macrophages as well as in primary human macrophages and this effect seems to be PKA-dependent in human macrophages.
Atherosclerosis Supplements, 2009
Atherosclerosis Supplements, 2007
Annales de biologie clinique
Lipoprotein transport genes have been used to make either transgenic or knockout mice with altere... more Lipoprotein transport genes have been used to make either transgenic or knockout mice with altered lipoprotein levels and metabolism. These models have provided information in at least three major issues. First, transgenic mice allow to study gene expression regulation. This approach has been helpful in identifying tissue specific expression of two clusters of apolipoprotein genes apo E/CI/CII and apo AI/CIII/AIV. Another example is the identification of a cis-acting region controlling transcription of the CETP gene in response to diet. Second, transgenic mice model provides relevant insights into lipoprotein metabolism: the structural role of human apo AII, the effect of apo AI on HDL subfractions distribution, the contribution of apo CIII to hypertriglyceridemia, and by contrast of apo E in the clearance of atherogenic TG rich lipoproteins, the role of CETP in the balance of LDL and HDL concentration and distribution. Finally, certain strains of mice under specific conditions of diet develop atherosclerotic lesions which have been shown to be reduced in human apo AI transgenic animals. However, the best mouse model for further investigation of human atherosclerosis seems to be apo E knockout mice.
Atherosclerosis Supplements, 2010
Atherosclerosis Supplements, 2001
The Journal of Lipid Research, 2010
This article is available online at http://www.jlr.org
Clinica Chimica Acta, 1995
Hyperglycaemia in diabetic patients results in non-enzymatic glycation of plasma proteins, includ... more Hyperglycaemia in diabetic patients results in non-enzymatic glycation of plasma proteins, including lipoproteins such as high-density lipoproteins (HDL). We studied the effects of in vitro HDL glycation on the activity of lecithin-cholesterol acyl transferase (LCAT), a key enzyme in HDL plasma metabolism. LCAT was prepared from non-diabetic subjects and HDL by sequential density ultracentrifugation (in the density range of 1.063-1.21 g/ml) from both diabetic and non-diabetic patients. HDL from non-diabetic patients were glycated in vitro by incubating lipoproteins with 100 mmol/l glucose for various times at 37°C with sodium cyanoborohydride as reducing agent. Glycation of HDL protein was quantified by measuring the percentage of derived amino acid residues using the TNBS assay. Kinetic parameters of LCAT were first determined using native HDL from non-diabetic patients and in vitro glycated HDL. With native HDL, K m and lima x were 51.1 4-4.2 #mol/1 (n = 8) and 12.9 4-2.4 nmol/ml/h (n = 8), respectively. Enzyme reactivity, calculated as the Vmax/K m ratio, was 0.25 ± 0.04 h -~ (n = 8). In the case of moderate glycation (derived residues < 30%; n = 19) a significant increase in both Km (18.2 4-3.4%; mean ± S.D.) and V~x (9.3 4-2.4%) was observed. In contrast, with a high level of glycation (derived residues > 30%; n = 8), both parameters fell (Kin, 25 ± 6.3%; V~x, 34.1 ± 3.3%). In addition, whatever the level of glycation, enzyme reactivity was lower in the presence of in vitro glycated HDL. This decrease in LCAT reactivity was not due to a peroxidative process nor to an alteration of the protein and lipid composition of in vitro glycated HDL. It could, however, be explained by glycation of lysine residues in apolipoprotein A-I, which is the most potent activator of LCAT. In a second * Corresponding author.
Biochemistry, 2001
Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cho... more Scavenger receptor BI (SR-BI) mediates the selective uptake of high-density lipoprotein (HDL) cholesteryl ester (CE), a process by which HDL CE is taken into the cell without degradation of the HDL particle. In addition, SR-BI stimulates the bi-directional flux of free cholesterol (FC) between cells and lipoproteins, an activity that may be responsible for net cholesterol efflux from peripheral cells as well as the rapid hepatic clearance of FC from plasma HDL. SR-BI also increases cellular cholesterol mass and alters cholesterol distribution in plasma membrane domains as judged by the enhanced sensitivity of membrane cholesterol to extracellular cholesterol oxidase. In contrast, CD36, a closely related class B scavenger receptor, has none of these activities despite binding HDL with high affinity. In the present study, analyses of chimeric SR-BI/CD36 receptors and domain-deleted SR-BI have been used to test the various domains of SR-BI for functional activities related to HDL CE selective uptake, bi-directional FC flux, and the alteration of membrane cholesterol mass and distribution. The results show that each of these activities localizes to the extracellular domain of SR-BI. The N-terminal cytoplasmic tail and transmembrane domains appear to play no role in these activities other than targeting the receptor to the plasma membrane. The C-terminal tail of SR-BI is dispensable for activity as well for targeting to the plasma membrane. Thus, multiple distinct functional activities are localized to the SR-BI extracellular domain.
Atherosclerosis, 2012
To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspeci... more To evaluate the impact of CETP inhibition on the capacity of individual postprandial HDL subspecies to promote key steps of the reverse cholesterol transport pathway. The capacity of HDL particles to mediate cellular free cholesterol efflux and selective hepatic uptake of cholesteryl esters was evaluated throughout postprandial phase (0-8 h) following consumption of a standardised mixed meal before and after treatment for 6 weeks with atorvastatin alone (10 mg/d) and subsequently with combination torcetrapib/atorvastatin (60/10 mg/d) in 16 patients displaying low HDL-C levels (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;40 mg/dl). The larger HDL2b and HDL2a subfraction displayed a superior capacity to mediate cellular free cholesterol efflux via both SR-BI and ABCG1-dependent pathways than smaller HDL3 subspecies. CETP inhibition specifically enhanced the capacity of HDL2b subfraction for both SR-BI and ABCG1 dependent efflux. However, only the SR-BI-dependent efflux to HDL2b subspecies can be further enhanced during postprandial lipemia following CETP inhibition. Concomitantly, postprandial lipemia was associated with a reduced capacity of total HDL particles to deliver cholesteryl esters to hepatic cells in a drug independent manner. CETP inhibition specifically improves postprandial SR-BI and ABCG1-dependent efflux to larger HDL2b subspecies. In addition, CETP inhibition improves HDL-CE delivery to hepatic cells and maintains an efficient direct return of cholesteryl esters to the liver during postprandial lipemia.
Atherosclerosis, 1999
Poster session: lntracellular trqfficking and assembly of lipoproteins/reverse cholesterol transp... more Poster session: lntracellular trqfficking and assembly of lipoproteins/reverse cholesterol transport primary lipid abnormality is hypertriglyceridemia. In this 6 week (w), multicenter, double-blind, parallel study, 196 patients with triglycerides (TG) of 300 mg/dL (3.41 mmol/L) to 900 mg/dL (10.22 mmol/L) and LDL-C > 75 mg/dL ( 1.94 mmol/L) were randomized to placebo, S 20, 40 or 80 mg/day for 6 w. The baseline (BL, mg/dL) and mean % change (CH; median for TG and VLDL-C) from BL to w 6 for the major lipids and lipoproteins were:
Arteriosclerosis, Thrombosis, and Vascular Biology, 1997
The relationships of cell cholesterol efflux to HDL phospholipid (PL) content and composition in ... more The relationships of cell cholesterol efflux to HDL phospholipid (PL) content and composition in human serum were analyzed in two groups of subjects selected on the basis of their HDL cholesterol (HDL-C) levels: a norm-HDL group (1.10 mmol/L &amp;lt; HDL-C &amp;lt; 1.50 mmol/L) and a high-HDL group (HDL-C &amp;gt; 1.75 mmol/L). In the high-HDL group, the relative fractional efflux was significantly higher than in the norm-HDL group, and in both groups, fractional efflux was correlated with a number of lipoprotein parameters, the best correlation and the only one that remained significant after multivariate analysis being with HDL phospholipid (HDL-PL). Analysis of the HDL-PL subclasses revealed that HDL in the high-HDL sera was enriched with phosphatidylethanolamine (HDL-PE) and relatively deficient in sphingomyelin (HDL-SM) compared with norm-HDL sera. Moreover, the fractional efflux values in the high-HDL group were negatively correlated with the proportion of HDL-PE (r = -.64, P &amp;lt; .0001) and positively correlated with the proportion of HDL-SM (r = .43, P &amp;lt; .01). Thus, this study provides evidence that HDL-PL concentration can be used to predict the capacity of serum to accept cellular cholesterol. Among the differences described between norm-HDL and high-HDL sera, the variability in PE to SM ratio might reflect changes in serum cholesterol acceptors that modulate the first step of reverse cholesterol transport.
Atherosclerosis, Aug 31, 2001
The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. Th... more The high triglyceride/low HDL-cholesterol trait is a common finding in the general population. The aim of the present study was to analyze and interpret the relationships between triglycerides (TG), HDL-related parameters and serum cholesterol efflux potential in an asymptomatic population including both normo-and hyperlipidemic individuals. In a large sample (n= 1143) of this population, there was a negative correlation between TG and HDL-cholesterol (HDL-C) (r= −0.49, P B0.0001) whereas the negative correlation between TG and HDL-phospholipid (HDL-PL) (r= −0.29, P B 0.0001) was weaker, leading to a strong positive correlation between TG and HDL-PL/C ratio (r= 0.58, PB 0.0001). Thus, increased TG concentrations were associated with an enrichment of HDL with PL. Since we have demonstrated previously that HDL-PL is the major determinant for cholesterol efflux potential from Fu5AH rat hepatoma cells, we determined the effect of the variations in HDL lipid composition on the cholesterol efflux capacity in a subsample of 198 subjects. Compared with normolipidemic subjects (NLP) (TG 51.7 mmol/l; LDL-C54.1 mmol/l, n=58), hypertriglyceridemic subjects (HTG) (TG \1.7 mmol/l, n= 63) exhibited lower HDL-C levels (1.08 9 0.21 vs. 1.25 9 0.32, P= 0.0003) whereas they showed similar HDL-PL concentrations (1.25 90.21 vs. 1.25 92.7) and, thus, higher HDL-PL/C ratio (1.17 9 0.15 vs. 1.02 90.14, P = 0.0001). The relative efflux capacity of serum measured in the Fu5AH system (5% serum, 4 h incubation at 37°C) was on average identical in the HTG and NLP groups. Thus, this study provides evidence that despite decreased HDL concentrations, as determined routinely by the HDL-C assay, some HTG subjects maintained serum cholesterol efflux capacity thanks to the enrichment of HDL with PL.
Atherosclerosis Supplements, 2006
We studied the size distribution assessed by polyacrilamide gradient gel electrophoresis, of HDL ... more We studied the size distribution assessed by polyacrilamide gradient gel electrophoresis, of HDL isolated from the plasma of 47 children with T2DM, 16 obese children with IGT, 43 with obesity and normal glucose tolerance, and 39 lean controls.
Atherosclerosis Supplements, 2011
Background: Distinct subpopulations of macrophages have been identified in the human arterial int... more Background: Distinct subpopulations of macrophages have been identified in the human arterial intima, with varying effects on the development of atherosclerosis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage colony-stimulating factor (M-CSF) are hematopoietic growth factors that regulate the generation and function of monocyte-derived macrophages. Methods: A gene expression profile related to cholesterol uptake and efflux, and the cholesterol contents were analyzed in cultured human macrophages differentiated with either GM-or M-CSF, and after pre-exposure to acetylated LDL in the absence or presence of cholesterol acceptors. Results: Macrophages differentiated with M-CSF expressed higher mRNA levels of CD36 and SR-AI, the two scavenger receptors for modified LDL. This correlated with a greater ability of macrophages to accumulate cholesteryl esters in response to incubation with acetylated LDL. Macrophages differentiated with GM-CSF, again, showed higher expression of SR-BI and ABCG1 mRNA, two receptors capable of mediating cholesterol efflux. However, such divergent gene expression profile favoring a pro-atherogenic role for M-CSF, rather than for GM-CSF, was attenuated in the foam cell phenotype. Furthermore, HDL-2 and human blood plasma induced similar degrees of cholesterol efflux in both types of macrophages. Conclusions: A protective compensatory upregulation of some components of the cholesterol efflux machinery was observed in the M-CSF-subtype of macrophages upon foam cell formation. Thus, the gene profile of human macrophages is influenced, in addition to growth factors, also by the relative availability of modified LDL particles and of HDL particles. Ultimately, the composite effect of growth factors and lipoproteins determine cholesterol balance of the macrophages.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2016
A diet rich in n-3/n-6 polyunsaturated fatty acids (PUFAs) is cardioprotective. Dietary PUFAs aff... more A diet rich in n-3/n-6 polyunsaturated fatty acids (PUFAs) is cardioprotective. Dietary PUFAs affect the cellular phospholipids composition, which may influence the function of membrane proteins. We investigated the impact of the membrane incorporation of several PUFAs on ABCA1-mediated cholesterol efflux, a key antiatherogenic pathway. Arachidonic acid (AA) (C20:4 n-6) and docosahexaenoic acid (DHA) (C22:6 n-3) decreased or increased cholesterol efflux from J774 mouse macrophages, respectively, whereas they had no effect on efflux from human monocyte-derived macrophages (HMDM). Importantly, eicosapentaenoic acid (EPA) (C20:5 n-3) induced a dose-dependent reduction of ABCA1 functionality in both cellular models (-28% for 70μM of EPA in HMDM), without any alterations in ABCA1 expression. These results show that PUFA membrane incorporation does not have the same consequences on cholesterol efflux from mouse and human macrophages. The EPA-treated HMDM exhibited strong phospholipid composition changes, with high levels of both EPA and its elongation product docosapentaenoic acid (DPA) (C22:5 n-3), which is associated with a decreased level of AA. In HMDM, EPA reduced the ATPase activity of the membrane transporter. Moreover, the activation of adenylate cyclase by forskolin and the inhibition of cAMP phosphodiesterase by isobutylmethylxanthine restored ABCA1 cholesterol efflux in EPA-treated human macrophages. In conclusion, EPA membrane incorporation reduces ABCA1 functionality in mouse macrophages as well as in primary human macrophages and this effect seems to be PKA-dependent in human macrophages.
Atherosclerosis Supplements, 2009