Alain Grynberg

Université Paris 13 Nord, Île-de-France, France

Are you Alain Grynberg?

Claim your profile

Publications (116)343.34 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The preservation of a constant pool of free cholesterol (FC) is critical to ensure several functions of cardiomyocytes. We investigated the impact of the membrane incorporation of arachidonic acid (C20:4 ω6, AA) or docosahexaenoic acid (C22:6 ω3, DHA) as ω6 or ω3 polyunsaturated fatty acids (PUFAs) on cholesterol homeostasis in primary cultures of neonatal rat cardiac myocytes. We measured significant alterations to the phospholipid FA profiles, which had markedly different ω6/ω3 ratios between the AA and DHA cells (13 vs. 1). The AA cells showed a 2.7-fold lower cholesterol biosynthesis than the DHA cells. Overall, the AA cells showed 2-fold lower FC masses and 2-fold higher cholesteryl ester masses than the DHA cells. The AA cells had a lower FC to phospholipid ratio and higher triglyceride levels than the DHA cells. Moreover, the AA cells showed a 40% decrease in ATP binding cassette transporter A1 (ABCA1)-mediated and a 19% decrease in ABCG1-mediated cholesterol efflux than the DHA cells. The differences in cholesterol efflux pathways induced by AA or DHA incorporation were not caused by variations in ABCs transporter expression and were reduced when ABCs transporters were overexpressed by exposure to LXR/RXR agonists. These results show that AA incorporation into cardiomyocyte membranes decreased the FC turnover by markedly decreasing the endogenous cholesterol synthesis and by decreasing the ABCA1- and ABCG1-cholesterol efflux pathways, whereas DHA had the opposite effects. We propose that these observations may partially contribute to the beneficial effects on the heart of a diet containing a high ω3/ω6 PUFA ratio.
    No preview · Article · Jul 2014 · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
  • [Show abstract] [Hide abstract]
    ABSTRACT: Purpose: To study, in high-fructose-fed rats, the effect of a dietary enrichment in omega-3 polyunsaturated fatty acids (n-3 PUFA) on the expression of genes involved in lipid metabolism and cardiovascular function. Methods: Twenty-eight male "Wistar Han" rats received for 8 weeks, either a standard chow food or an isocaloric 67% fructose diet enriched or not in alpha-linolenic acid (ALA) or in docosahexaenoic (DHA) and eicosapentaenoic acids (EPA) mix (DHA/EPA). After sacrifice, blood was withdrawn for biochemical analyses; heart, periepididymal adipose tissue and liver were collected and analyzed for the expression of 22 genes by real-time PCR. Results: Fructose intake resulted in an increase in liver weight and triglyceride content, plasma triglyceride and cholesterol concentrations, although no difference in glucose and insulin. In the liver, lipogenesis was promoted as illustrated by an increase in stearoyl-CoA desaturase and fatty acid synthase (Fasn) together with a decrease in PPAR gamma, delta and PPAR gamma coactivator 1 alpha (PGC1 alpha) expression. In the heart, Fasn and PPAR delta expression were increased. The addition of ALA or DHA/EPA into the diet resulted in a protection against fructose effects except for the decreased expression of PPARs in the liver that was not counterbalanced by n-3 PUFA suggesting that n-3 PUFA and fructose act independently on the expression of PPARs and PGC1 alpha. Conclusions: In liver, but not in heart, the fructose-enriched diet induces an early tissue-specific reduction in PPAR gamma and delta expression, which is insensitive to n-3 PUFA intake and dissociated from lipogenesis.
    No preview · Article · Dec 2012 · European Journal of Nutrition
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although cholesterol-rich microdomains are highly involved in the functions of cardiomyocytes, the cholesterol homeostasis is largely unknown in these cells. We developed experimental procedures to assess cholesterol synthesis, cholesterol masses and cholesterol efflux from primary cultures of cardiac myocytes obtained from 2 to 4 days old Wistar rats. We first observed that cardiomyocytes poorly internalized exogenously supplied native or modified LDL and that free cholesterol (FC) efflux to free apolipoprotein AI (apo AI) and to HDL was mediated by ATP binding cassette transporter A1 (ABCA1) and likely by ATP binding cassette transporter G1 (ABCG1), respectively, which are both upregulated by liver X receptor/retinoid X receptor (LXR/RXR) activation. We then investigated the consequences of cholesterol synthesis inhibition on cholesterol homeostasis using an HMGCoA reductase inhibitor (pravastatin, 90% effective concentration (EC90): 0.11 mM, 18 h). We observed no impact of cholesterol synthesis inhibition on the FC or cholesteryl ester (CE) masses. Consistently with no FC mass changes, pravastatin treatment had no notable impact on LDL receptors mRNA expression or on the capacity of cardiomyocytes to uptake radiolabeled LDL. Conversely, pravastatin treatment induced a significant decrease of cholesterol efflux to both apo AI and HDL whereas the passive aqueous diffusion remained unchanged. The cholesterol efflux pathway reductions induced by cholesterol synthesis inhibition were not caused by a reduction of ABC transporter expression (mRNA or protein). These results show that cardiac myocytes down-regulate active cholesterol efflux processes when endogenous cholesterol synthesis is inhibited, allowing them to preserve cholesterol homeostasis.
    No preview · Article · Jun 2012 · Journal of Molecular and Cellular Cardiology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Consumption of trans fatty acids (TFA) increase cardiovascular risk more than do saturated FA, but the mechanisms explaining their atherogenicity are still unclear. We investigated the impact of membrane incorporation of TFA on cholesterol efflux by exposing J774 mouse macrophages or human monocyte-derived macrophages (HMDM) to media enriched or not (standard medium) with industrially produced elaidic (trans-9 18:1) acid, naturally produced vaccenic (trans-11 18:1) acid (34 h, 70 μM) or palmitic acid. In J774 macrophages, elaidic and palmitic acid, but not vaccenic acid, reduced ABCA1-mediated efflux by ~23% without affecting aqueous diffusion, SR-BI or ABCG1-mediated pathways, and this effect was maintained in cholesterol-loaded cells. The impact of elaidic acid on the ABCA1 pathway was weaker in cholesterol-normal HMDM, but elaidic acid induced a strong reduction of ABCA1-mediated efflux in cholesterol-loaded cells (-36%). In J774 cells, the FA supplies had no impact on cellular free cholesterol or cholesteryl ester masses, the abundance of ABCA1 mRNA or the total and plasma membrane ABCA1 protein content. Conversely, TFA or palmitic acid incorporation induced strong modifications of the membrane FA composition with a decrease in the ratio of (cis-monounsaturated FA+polyunsaturated FA):(saturated FA+TFA), with elaidic and vaccenic acids representing each 20% and 13% of the total FA composition, respectively. Moreover, we demonstrated that cellular ATP was required for the effect of elaidic acid, suggesting that it contributes to atherogenesis by impairing ABCA1-mediated cholesterol efflux in macrophages, likely by decreasing the membrane fluidity, which could thereby reduce ATPase activity and the function of the transporter.
    No preview · Article · Oct 2011 · Biochimica et Biophysica Acta

  • No preview · Article · Jun 2011

  • No preview · Article · Jun 2011 · Atherosclerosis Supplements
  • [Show abstract] [Hide abstract]
    ABSTRACT: The aim of this study was to evaluate the effects of dietary pure eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) on the physiology of the heart in normoxic conditions and during postischemic reperfusion. These effects were compared with those of dietary n-6 polyunsaturated fatty acids (PUFA). Rats were fed a diet containing either sunflower seed oil (75 g x kg(-1), SSO group), or a mixture of EPA (20:5 n-3) ethyl ester and SSO (10:90, EPA group), or a mixture of DHA (22:6 n-3) ethyl ester and SSO (10:90, DHA group), or a mixture of EPA + DHA ethyl esters and SSO (4.2:5.8:90, e+D group) for 6 weeks. The hearts were then perfused according to the working mode. The perfusion was maintained either in normoxic conditions or stopped for 17 min (global zero-flow ischemia) and restored for 33 min (reperfusion). The aortic and coronary flows, aortic developed pressure, and electrocardiogram were continuously monitored. When rats were fed a diet containing either EPA and (or) DHA, the n-6/n-3 PUFA ratio of cardiac phospholipids decreased. The proportion of arachidonic acid was reduced more with DHA than dietary EPA. In the EPA group, the percentage of DHA was lower than in the DHA group, but the percentage of EPA and docosapentaenoic acid (22:5 n-3) was higher. These changes in membrane fatty acid composition altered the cardiac function. In normoxic conditions, the coronary flow was higher in the SSO group than in the DHA and EPA groups. The heart rate was lower in the DHA and e+D groups than in the EPA and SSO groups. The aortic flow, cardiac output, and aortic developed pressure were not affected. During postischemic reperfusion, the recovery of aortic flow, coronary flow, and aortic developed pressure was similar in the four groups. A slightly improved recovery of cardiac function was noticed in the EPA group, but the difference was not significant. Feeding rats 5% fish oil + 5% SSO instead of 10% SSO for 8 weeks increased the incorporation of EPA in cardiac phospholipids and favored the recovery (+120%) of aortic flow during postischemic reperfusion. In conclusion, the beneficial effect of dietary fish oil on the recovery of cardiac pump activity during reperfusion was not observed with DHA or EPA alone. It appears to be positively related to the accumulation of EPA in membrane phospholipids. The dietary conditions favouring EPA accumulation remain to be determined.
    No preview · Article · Feb 2011 · Canadian Journal of Physiology and Pharmacology
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dietary supplements in polyunsaturated fatty acids (PUFA), particularly omega-3, are well known for their beneficial effects in preventing cardiovascular diseases (CVD). The aim of this study was to determine the role of PUFA on the modulation of apoptosis induced by hypochlorous acidoxidized LDL (HOCl-oxLDL) in U937 cells. We tested the effect of monocyte cell line U937 supplementation with eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (ARA) or oleic acid (OA) on the modulation of HOCl-oxLDL-induced apoptosis. First, we showed the incorporation of fatty acids in the cellular membrane in U937 cells. Then, we showed that both EPA and ARA exerted a pro-apoptotic effect through the intrinsic mitochondrial apoptotic pathway including the dissipation of mitochondrial membrane potential followed by cardiolipin depletion, the downstream activation of caspase-3 and the increase in DNA fragmentation. The pro-apoptotic effect of EPA or ARA was completely blocked in U937/Bcl-2 cells. A new mechanism of dietary supplements in PUFA with likely consequences in apoptosis could be suggested through the mitochondrial pathway in monocytes.
    No preview · Article · Feb 2011 · Journal of atherosclerosis and thrombosis
  • [Show abstract] [Hide abstract]
    ABSTRACT: Trimetazidine (TMZ), a partial inhibitor of fatty acid oxidation, has been effective in treating chronic angina, but its effects on the development of post-myocardial infarction (MI) left ventricular remodeling are not defined. In this study, we tested whether chronic pre-MI administration of TMZ would be beneficial during and after acute MI. Two-hundred male Wistar rats were studied in four groups: sham + TMZ diet (n = 20), sham + control diet (n = 20), MI + TMZ diet (n = 80), and MI + control diet (n = 80) splitted into one short-term and one long-term experiments. Sham surgery consisted of a thoracotomy without coronary ligation. MI was induced by coronary occlusion followed by reperfusion. Left ventricle (LV) function and remodeling were assessed by serial echocardiography throughout a 24-week post-MI period. LV remodeling was also assessed by quantitative histological analysis of post-MI scar formation at 24 weeks post-MI. During the short-term experiment, 10/80 rats died after MI, with no difference between groups (MI + control = 7/40, MI + TMZ = 3/40, P = 0.3). In the long-term experiment, the deaths occurred irregularly over the 24 weeks with no difference between groups (MI + control = 16% mortality, MI + TMZ = 17%, P = 0.8). There was no difference between groups as regard to LV ejection fraction (MI + control = 36 +/- 13%, MI + TMZ = 35 +/- 13%, P = 0.6). In this experimental model, TMZ had no effects on the post-MI occurrence of LV dysfunction or remodeling. Further investigations are warranted to assess whether the partial inhibition of fatty acid oxidation may limit the ability of the heart to respond to acute severe stress.
    No preview · Article · Aug 2010 · Fundamental and Clinical Pharmacology
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A great number of milk-derived peptides have been shown to exhibit angiotensin converting enzyme (ACE) inhibitory properties and thus potential utility in the regulation of blood pressure. The present work aimed to investigate the effects of 2 milk trypsin hydrolysates from alpha(S1)- and alpha(S2)-casein (CH1 and CH2, respectively) on ACE activity evaluated in human umbilical vein endothelial cells (HUVEC) in vitro, rat aortic tissues ex vivo, and renovascular hypertensive rat in vivo. Incubation of HUVEC and rat aortic tissues with CH1 or CH2 induced a concentration-dependent inhibition of hydrolysis of the ACE substrate hippuryl-histidyl-leucine (HHL), the hydrolysates being much less potent than perindopril (an ACE inhibitor). However, in contrast to perindopril, CH1 and CH2 failed to modify angiotensin I-induced aortic ring vasoconstriction. The HPLC profiles of rat plasma after intragastric administration were variable among individuals but none of the observed peaks corresponded to peptides comprising CH1 or CH2 or to fragments of these peptides. During 4 wk of cardiovascular monitoring, in hydrolysate-fed renovascular hypertensive rats, systolic blood pressure weakly decreased compared with the control group. However, the CH1-fed hypertensive rats exhibited a decrease of heart rate during the nocturnal period of activity. To conclude, our results show that CH1 and CH2 inhibited ACE activity in HUVEC and rat aortic tissue but failed to antagonize the aortic-constricting effects of the natural agonist angiotensin I. Moreover, we demonstrated that CH1, to a greater extent than CH2, can slightly affect cardiovascular parameters although the ingested bioactive peptides could not be detected in the blood.
    Full-text · Article · Jul 2010 · Journal of Dairy Science
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Metabolic programming and metabolic imprinting describe early life events, which impact upon on later physiological outcomes. Despite the increasing numbers of papers and studies, the distinction between metabolic programming and metabolic imprinting remains confusing. The former can be defined as a dynamic process whose effects are dependent upon a critical window(s) while the latter can be more strictly associated with imprinting at the genomic level. The clinical end points associated with these phenomena can sometimes be mechanistically explicable in terms of gene expression mediated by epigenetics. The predictivity of outcomes depends on determining if there is causality or association in the context of both early dietary exposure and future health parameters. The use of biomarkers is a key aspect of determining the predictability of later outcome, and the strengths of particular types of biomarkers need to be determined. It has become clear that several important health endpoints are impacted upon by metabolic programming/imprinting. These include the link between perinatal nutrition, nutritional epigenetics and programming at an early developmental stage and its link to a range of future health risks such as CVD and diabetes. In some cases, the evidence base remains patchy and associative, while in others, a more direct causality between early nutrition and later health is clear. In addition, it is also essential to acknowledge the communication to consumers, industry, health care providers, policy-making bodies as well as to the scientific community. In this way, both programming and, eventually, reprogramming can become effective tools to improve health through dietary intervention at specific developmental points.
    Full-text · Article · Jul 2010 · The British journal of nutrition

  • No preview · Article · Jun 2010 · Atherosclerosis Supplements
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Olive oil and fish oils are known to possess beneficial properties for human health. We investigated whether different oils and fatty acids alone were able to decrease oxidative stress induced on corneal cells. In our in vivo study, rats were fed with marine oils rich in polyunsaturated fatty acids (PUFA) or refined olive oil during 28 days. At the end of the protocol, corneas were analysed for their fatty acids composition to study the incorporation of fatty acids in cell membranes. In our in vitro study, a human corneal cell line was incubated with marine oils or refined olive oil and subjected to oxidative stress (tBHP 50 muM, 1 hour). Effects on reactive oxygen species generation, mitochondria and caveolin-1 expression were studied using microcytofluorometry, flow cytometry and confocal microscopy. Our results indicate that dietary oils changed the fatty acids composition of corneal cell membranes. According to our results, PUFA-rich oils and refined olive oil (free of antioxidants) blocked reactive oxygen species production. Oleic acid, the major fatty acid of olive oil, also decreased oxidative stress. Moreover, oleic acid modified caveolin-1 expression. Antioxidant properties of oleic acid could be due to disruption of membrane microdomains such as caveolae. Oleic acid, a potential potent modulator of oxidative stress, could be added to PUFA-rich oils to prevent oxidative stress-linked corneal pathology.
    Full-text · Article · Nov 2009 · Nutrition & Metabolism
  • [Show abstract] [Hide abstract]
    ABSTRACT: Since android overweight/obesity and insulin resistance are independent risk factors for cardiovascular disease, we investigated their impact on basal and postprandial scavenger receptor BI (SR-BI) and ATP binding cassette transporter A1 (ABCA1)-mediated serum cholesterol efflux. Twelve android overweight to obese and 9 normal weight controls women underwent body composition analysis by dual energy X-ray absorptiometry, a euglycemic hyperinsulinemic clamp, and an oral fat load with blood sampling at initial time (T0), 4h (T4) and 10h (T10) after the fat load. Serum lipids and HDL-parameters, capacities of serum to promote cholesterol efflux from SR-BI expressing Fu5AH hepatoma cells or from ABCA1-expressing J774 macrophages and to abilities of serum to induce a net removal of cholesterol from macrophage foam cells were measured at T0, T4 and T10. Sera from overweight/obese exhibited moderately decreased SR-BI-mediated cholesterol efflux capacities, in accordance with reduced HDL concentrations, but importantly increased ABCA1-mediated cholesterol efflux and increased cholesterol extraction capacities over the postprandial period, partly related to higher prebeta-HDL concentrations. In multiple regression analyses, android obesity-related parameters and HDL-PL or prebeta-HDL levels remained the only independent correlates for SR-BI or ABCA1-dependent fractional cholesterol efflux while only prebeta-HDL levels remained correlated to cholesterol extraction capacities. Our results suggest that android overweight/obesity may not result in an impaired cholesterol efflux capacity.
    No preview · Article · Sep 2009 · Atherosclerosis
  • M Nowak · A Lucas · K Sayegrih · S Tardivel · S Vicca · A Grynberg · B Lacour

    No preview · Article · Jun 2009 · Atherosclerosis Supplements
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This study was designed to evaluate the effects of individual dietary long-chain n-3 polyunsaturated fatty acids (LCPUFA) on hypertension and cardiac consecutive disorders in spontaneously hypertensive rats (SHR) as compared to Wistar-Kyoto rats (WKY). Rats were fed for 2 months an eicosapentaenoic (EPA)- or docosahexaenoic acid (DHA)-rich diet (240 mg/day) or an n-3 PUFA-free diet. Male SHR (n=6), implanted with cardiovascular telemetry devices, were housed in individual cages for continuous measurements of cardiovascular parameters (blood pressure (BP) and heart rate (HR)) during either activity or rest periods, ECG were recorded during the quiet period. The n-6 PUFA upstream of arachidonic acid was affected in SHR tissues. The cardiac phospholipid fatty acid profile was significantly affected by dietary DHA supply, and EPA in a very lower extent, since DHA only was incorporated in the membranes instead of n-6 PUFAs. Endothelium n-6 PUFA content increased in all SHR groups. Compared to WKY, linoleic acid content decreased in both studied tissues. Cardiac noradrenalin decreased while the adrenal catecholamine stores decreased in SHR as compared to WKY. Both n-3 PUFA supply induced a decrease of adrenal catecholamine stores. Nevertheless after 6 weeks, DHA but not EPA induced a lowering-blood pressure effect and shortened the QT interval in SHR, most probably through its tissue enrichment and a specific effect on adrenergic function. Dietary DHA supply retards blood pressure development and has cardioprotective effect. These findings, showing the cardioprotective effects of DHA in living animals, were obtained in SHR, but may relate to essential hypertension in humans.
    Full-text · Article · Jun 2009 · Prostaglandins Leukotrienes and Essential Fatty Acids

  • No preview · Article · Jun 2009 · Atherosclerosis Supplements
  • N Attia · N Fournier · B Vedie · M Cambillau · A Grynberg · J-L Paul · B Guerci

    No preview · Article · Jun 2009 · Atherosclerosis Supplements
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: Previous work showed that the functional cardiac effect of dietary alpha-linolenic acid (ALA) in rats requires a long feeding period (6 months), although a docosahexaenoic (DHA) acid-supply affects cardiac adrenergic response after 2 months. However, the total cardiac membrane n-3 polyunsaturated fatty acid (PUFA) composition remained unchanged after 2 months. This delay could be due to a specific reorganization of the different subcellular membrane PUFA profiles. This study was designed to investigate the evolution between 2 and 6 months of diet duration of the fatty acid profile in sarcolemmal (SL), mitochondrial (MI), nuclear (NU) and sarcoplasmic reticulum (SR) membrane fractions. Methods: Male Wistar rats were randomly assigned to 3 dietary groups (n = 10/diet/period), either n-3 PUFA-free diet (CTL), or ALA or DHA-rich diets. After 2 or 6 months, the subcellular cardiac membrane fractions were separated by differential centrifugations and sucrose gradients. Each membrane profile was analysed by gas chromatography (GC) after lipid extraction. Results: As expected the n-3 PUFA-rich diets incorporated n-3 PUFA instead of n-6 PUFA in all the subcellular fractions, which also exhibited individual specificities. The diet duration increased SFA and decreased PUFA in SL, whereas NU remained constant. The SR and MI enriched in n-3 PUFA exhibited a decreased DHA level with ageing in the DHA and CTL groups. Conversely, the n-3 PUFA level remained unchanged in the ALA group, due to a significant increase in docosapentaenoic acid (DPA). N-3 PUFA rich diets lead to a better PUFA profile in all the fractions and significantly prevent the profile modifications induced by ageing. Conclusion: With the ALA diet the n-3 PUFA content, particularly in SR and SL kept increasing between 2 and 6 months, which may partly account for the delay to achieve the modification of adrenergic response.
    Full-text · Article · Mar 2009 · Nutrition & Metabolism
  • Source

    Full-text · Article · Mar 2009 · Archives of Cardiovascular Diseases

Publication Stats

2k Citations
343.34 Total Impact Points


  • 2011-2014
    • Université Paris 13 Nord
      Île-de-France, France
  • 2003-2012
    • Université Paris-Sud 11
      • Faculty of Pharmaceutical Sciences
      Lutetia Parisorum, Île-de-France, France
  • 1988-2010
    • French National Institute for Agricultural Research
      • Centre des Sciences du Goût et de l’Alimentation (CSGA)
      Lutetia Parisorum, Île-de-France, France
  • 2001-2003
    • University of Iceland
      • Institute of Science
      Reykjavík, Capital Region, Iceland
    • Observatoire de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2002
    • Iris Pharma
      La Gaude, Provence-Alpes-Côte d'Azur, France
  • 1993
    • Goethe-Universität Frankfurt am Main
      Frankfurt, Hesse, Germany
  • 1991
    • Hebrew University of Jerusalem
      Yerushalayim, Jerusalem District, Israel
  • 1989
    • Shaare Zedek Medical Center
      • Department of Medicine
      Yerushalayim, Jerusalem, Israel