Véronique Carrière

Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix"), Lutetia Parisorum, Île-de-France, France

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Publications (44)173.37 Total impact

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    ABSTRACT: Background & aims: Reducing post-prandial triglyceridemia may be a promising strategy to lower risk of cardiovascular disorders associated with obesity and type 2 diabetes. In enterocytes, scavenger receptor class B, type 1 (SR-B1, encoded by SCARB1) mediates lipid-micelle sensing to promote assembly and secretion of chylomicrons. The nuclear receptor subfamily 1, group H, members 2 and 3 (also known as liver X receptors or LXRs) regulate genes involved in cholesterol and fatty acid metabolism. We aimed to determine whether intestinal LXRs regulate triglyceride absorption. Methods: C57BL/6J mice were either fed a cholesterol-enriched diet or given synthetic LXR agonists (GW3965 or T0901317). We measured production of chylomicron and localized SR-B1 by immunohistochemistry. Mechanisms of post-prandial triglyceridemia and SR-B1 regulation were studied in Caco-2/TC7 cells incubated with LXR agonists. Results: In mice and in the Caco-2/TC7 cell line, LXR agonists caused localization of intestinal SR-B1 from apical membranes to intracellular organelles and reduced chylomicron secretion. In Caco-2/TC7 cells, LXR agonists reduced SR-B1-dependent lipid micelle-induced Erk phosphorylation. LXR agonists also reduced intracellular trafficking of the apical apolipoprotein B pool towards secretory compartments. LXR reduced levels of SR-B1 in Caco-2/TC7 cells via a post-transcriptional mechanism that involves miRNAs. Conclusion: In Caco-2/TC7 cells and mice, intestinal activation of LXR reduces production of chylomicron by a mechanism dependent on the apical localization of SR-B1.
    Full-text · Article · Nov 2015 · Gastroenterology
  • Frauke Beilstein · Véronique Carrière · Armelle Leturque · Sylvie Demignot
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    ABSTRACT: Cytosolic lipid droplets (LDs) are observed in enterocytes of jejunum during lipid absorption. One important function of the intestine is to secrete chylomicrons, which provide dietary lipids throughout the body, from digested lipids in meals. The current hypothesis is that cytosolic LDs in enterocytes constitute a transient pool of stored lipids that provides lipids during interprandial period while lowering chylomicron production during the post-prandial phase. This smoothens the magnitude of peaks of hypertriglyceridemia. Here, we review the composition and functions of lipids and associated proteins of enterocyte LDs, the known physiological functions of LDs as well as the role of LDs in pathological processes in the context of the intestine.
    No preview · Article · Sep 2015 · Experimental Cell Research

  • No preview · Conference Paper · Sep 2015
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    ABSTRACT: Intestine contributes to energy homeostasis through the absorption, metabolism and transfer of nutrients to the organism. We demonstrated previously that the nuclear receptor HNF-4α controls intestinal epithelium homeostasis and intestinal absorption of dietary lipids. HNF-4γ, the other HNF-4 form highly expressed in intestine, is much less studied. In HNF-4γ knockout mice, we detect an exaggerated insulin peak and an improvement of glucose tolerance during oral but not intraperitoneal glucose tolerance tests, highlighting the involvement of intestine. Moreover, the enteroendocrine L-type cell lineage is modified, as assessed by the increased expression of transcription factors Isl1, Foxa1/2 and Hnf4a, leading to an increase of both GLP-1-positive cells and basal and stimulated GLP-1 plasma levels, potentiating the glucose-stimulated insulin secretion. Using the GLP-1 antagonist exendin 9-39, we demonstrate a direct effect of GLP-1 on the improved glucose tolerance. GLP-1 exerts a trophic effect on pancreatic β-cells and we report an increase of the β-cell fraction correlated with an augmented number of proliferative islet cells and with resistance to streptozotocin-induced diabetes. In conclusion, the loss of HNF-4γ improves glucose homeostasis, through a modulation of the enteroendocrine cell lineage. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    No preview · Article · Mar 2015 · Diabetes
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    ABSTRACT: Introduction Les désordres métaboliques comme le diabète, l’obésité et le syndrome métabolique sont des préoccupations majeures de santé publique. Malgré sa contribution à l’homéostasie énergétique par sa fonction d’absorption des nutriments, l’intestin a reçu peu d’attention concernant son rôle potentiel dans ces pathologies comparé au foie, muscles et tissu adipeux. Deux formes du récepteur nucléaire HNF-4, alpha et gamma, sont fortement exprimés dans l’épithélium intestinal. Nous avons démontré précédemment que HNF-4alpha contrôle l’homéostasie de l’épithélium intestinal et l’absorption des lipides alimentaires par l’intestin. Contrairement à la forme alpha, HNF-4gamma a été peu étudié. Notre objectif est de déterminer son rôle physiologique. Matériels et méthodes Nous avons utilisé un modèle murin d’invalidation totale et constitutive de HNF-4gamma présentant un gain de poids significatif dès 4 mois suggérant une perturbation métabolique. Résultats La perte d’expression de HNF-4gamma entraîne une augmentation de la tolérance au glucose et une hyperinsulinémie lors d’un test oral au glucose mais pas lors d’un test intrapéritonéal, démontrant la part intestinale du phénotype observé. Grâce à un antagoniste du GLP-1, l’exendine 9, nous avons montré que le GLP-1, une entérohormone incrétine, est directement impliquée dans cet effet. De plus, l’invalidation de HNF-4gamma entraîne une augmentation du nombre de cellules exprimant le GLP-1 dans le jéjunum et le côlon (×1,7) ainsi que la quantité plasmatique basal et en réponse au glucose de GLP-1. L’analyse morphologique du pancréas et fonctionnelle sur îlots de Langherans isolés montre que la perte d’expression de HNF-4gamma entraîne une augmentation du nombre d’îlots moyens et larges (respectivement ×1,5 et ×1,8) ainsi que de leurs contenus en insuline (×1,7) sans que leurs capacités sécrétoires soit affectées. Conclusion Nous démontrons pour la première fois un rôle spécifique de HNF-4gamma dans le contrôle de l’homéostasie glucidique soulignant l’implication de l’intestin dans le contrôle de la balance énergétique.
    No preview · Article · Mar 2014 · Diabetes & Metabolism
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    ABSTRACT: Enterocytes, the intestinal absorptive cells, have to deal with massive alimentary lipids upon food consumption. They orchestrate complex lipid trafficking events that lead to the secretion of triglyceride-rich lipoproteins and/or the intracellular transient storage of lipids as lipid droplets (LDs). LDs originate from the endoplasmic reticulum (ER) membrane and are mainly composed of a triglyceride (TG) and cholesterol-ester core surrounded by a phospholipid and cholesterol monolayer and specific coat proteins. The pivotal role of LDs in cellular lipid homeostasis is clearly established but processes regulating LD dynamics in enterocytes are poorly decrypted. Here we show that delivery of alimentary lipid micelles to polarized human enterocytes induces an immediate autophagic response, accompanied by phosphatidylinositol-3-phosphate appearance at the ER membrane. We observed a specific and rapid capture of newly synthesized LD at the ER membrane by nascent autophagosomal structures. By combining pharmacological and genetic approaches, we demonstrate that autophagy is a key player in TG targeting to lysosomes. Our results highlight the yet unraveled role of autophagy in the regulation of TG distribution, trafficking and turnover in human enterocytes.
    Full-text · Article · Oct 2013 · Molecular biology of the cell
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    ABSTRACT: L’hypertriglycéridémie postprandiale est un facteur de risque des maladies cardiovasculaires. L’intestin de part son rôle dans l’absorption des lipides alimentaires participe à la sécrétion des lipoprotéines riches en triglycérides (LRT) et contribue à l’augmentation du taux plasmatique de triglycérides en période postprandiale. L’étude des mécanismes moléculaires impliqués dans la sécrétion intestinale des LRT permettra l’identification de nouvelles cibles thérapeutiques pour le traitement des maladies métaboliques. La détection des lipides alimentaires par les cellules intestinales constitue un nouveau mécanisme pouvant moduler la sécrétion des LRT. Alors que de nombreuses études relatent l’importance des cellules entéroendocrines dans la détection des lipides alimentaires, plusieurs données suggèrent l’implication des entérocytes, les cellules absorbantes de l’intestin dans ce processus. Des travaux récents rapportant le rôle du récepteur scavenger SR-BI dans la détection des lipides alimentaires apportés sous leur forme physiologique de micelles lipidiques seront présentés.
    No preview · Article · Dec 2012 · Cahiers de Nutrition et de Diététique
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    ABSTRACT: Rationale: Signal initiation by the high-density lipoprotein (HDL) receptor scavenger receptor class B, type I (SR-BI), which is important to actions of HDL on endothelium and other processes, requires cholesterol efflux and the C-terminal transmembrane domain. The C-terminal transmembrane domain uniquely interacts with plasma membrane (PM) cholesterol. Objective: The molecular basis and functional significance of SR-BI interaction with PM cholesterol are unknown. We tested the hypotheses that the interaction is required for SR-BI signaling, and that it enables SR-BI to serve as a PM cholesterol sensor. Methods and results: In studies performed in COS-M6 cells, mutation of a highly conserved C-terminal transmembrane domain glutamine to alanine (SR-BI-Q445A) decreased PM cholesterol interaction with the receptor by 71% without altering HDL binding or cholesterol uptake or efflux, and it yielded a receptor incapable of HDL-induced signaling. Signaling prompted by cholesterol efflux to methyl-β-cyclodextrin also was prevented, indicating that PM cholesterol interaction with the receptor enables it to serve as a PM cholesterol sensor. Using SR-BI-Q445A, we further demonstrated that PM cholesterol sensing by SR-BI does not influence SR-BI-mediated reverse cholesterol transport to the liver in mice. However, the PM cholesterol sensing does underlie apolipoprotein B intracellular trafficking in response to postprandial micelles or methyl-β-cyclodextrin in cultured enterocytes, and it is required for HDL activation of endothelial NO synthase and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo. Conclusions: Through interaction with PM cholesterol, SR-BI serves as a PM cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells.
    Full-text · Article · Sep 2012 · Circulation Research
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    ABSTRACT: Post-prandial hypertriglyceridemia is a risk factor for metabolic diseases. The intestine, through its role in alimentary lipid absorption, participates in the secretion of lipoprotein rich-triglycerides (TRL) and contributes to the increase in plasma triglyceride levels during the postprandial state. Understanding the molecular mechanisms involved in the secretion of intestinal TRL would allow the identification of new drug targets for treatment of metabolic diseases. The sensing of lipids by intestinal cells represents a promising mechanism allowing the modulation of TRL secretion. While many studies show the importance of enteroendocrine cells in the detection of alimentary lipids, several evidence suggest also the implication of enterocytes, the absorptive intestinal cells, in this process. Recent experimental results on the role of the scavenger receptor SR-BI in the detection of dietary lipids, supplied in their physiological form of postprandial lipid micelles, are reviewed.
    No preview · Article · Jul 2012 · OCL - Oleagineux Corps Gras Lipides
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    ABSTRACT: With an excessive postprandial accumulation of intestine-derived, triglyceride-rich lipoproteins being a risk factor of cardiovascular diseases, it is essential to characterize the mechanisms controlling the intestinal absorption of dietary lipids. Our aim was to investigate the role of the transcription factor hepatocyte nuclear factor (HNF)-4α in this process. We used transgenic mice with a specific and inducible intestinal knockout of Hnf-4α gene. One hour after a lipid bolus, in the presence of the lipase inhibitor tyloxapol, lower amounts of triglycerides were found in both plasma and intestinal epithelium of the intestine-specific Hnf-4α knockout (Hnf-4α(intΔ)) mice compared with the Hnf-4α(loxP/loxP) control mice. These discrepancies were due to a net decrease of the intestinal uptake of fatty acid in Hnf-4α(intΔ) mice compared with Hnf-4α(loxP/loxP) mice, as assessed by the amount of radioactivity that was recovered in intestine and plasma after gavage with labeled triolein or oleic acid, or in intestinal epithelial cells isolated from jejunum after a supply of labeled oleic acid-containing micelles. This decreased fatty acid uptake was associated with significant lower levels of the fatty acid transport protein-4 mRNA and protein along the intestinal tract and with a lower acyl-CoA synthetase activity in Hnf-4α(intΔ) mice compared with the control mice. We conclude that the transcription factor HNF-4α is a key factor of the intestinal absorption of dietary lipids, which controls this process as early as in the initial step of fatty acid uptake by enterocytes.
    Preview · Article · Mar 2012 · AJP Gastrointestinal and Liver Physiology
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    ABSTRACT: As arginine plays a key role in the regulation of liver ureagenesis, we hypothesised that a modulation of enzymes involved in arginine metabolism within the intestine contributes to the regulation of N homeostasis according to protein supply. Our aim was to study the influence of variations in protein or amino acid (AA) supply on intestinal arginase, glutaminase, ornithine aminotransferase (OAT), argininosuccinate lyase and argininosuccinate synthetase. We evaluated in vivo in rats the responses of these enzymes to short-term (ST, 16 h) and long-term (LT, 15 d) variations in dietary protein (10, 17 or 25 % protein diet). In addition, in order to test whether these responses could involve a direct action of AA on the gene expression and activity of these enzymes, Caco-2/TC7 cells were cultured for 3 d with increasing AA concentrations. In vivo, in the ST, both high- and low-protein diets increased arginase activity in the intestinal mucosa (ST25 %: 46 (sem 2) μmol/g per min and ST10 %: 46 (sem 2) μmol/g per min v. ST17 %: 36 (sem 3) μmol/g per min, P < 0.05). In the LT, OAT expression was increased in the LT10 % group (+277 %, P < 0.05) compared with the LT17 % group. Caco-2/TC7 cells showed inverse relationships between AA supply and arginase (P = 0.058) and OAT (P = 0.035) expressions. The present study demonstrates the regulation of intestinal arginase and OAT expressions in response to protein supply. Our in vitro experiments further indicate a direct AA-induced regulation of the mRNA abundance of these enzymes. In situations of limited protein supply, this regulation would increase intestinal arginine catabolism and, possibly via a decrease in arginine portal release, decrease hepatic AA oxidation, thus promoting N sparing.
    Full-text · Article · Jul 2011 · The British journal of nutrition

  • No preview · Article · Jun 2011 · Atherosclerosis Supplements
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    ABSTRACT: The intestine is responsible for absorbing dietary lipids and delivering them to the organism as triglyceride-rich lipoproteins (TRL). It is important to determine how this process is regulated in enterocytes, the absorptive cells of the intestine, as prolonged postprandial hypertriglyceridemia is a known risk factor for atherosclerosis. During the postprandial period, dietary lipids, mostly triglycerides (TG) hydrolyzed by pancreatic enzymes, are combined with bile products and reach the apical membrane of enterocytes as postprandial micelles (PPM). Our aim was to determine whether these micelles induce, in enterocytes, specific early cell signaling events that could control the processes leading to TRL secretion. The effects of supplying PPM to the apex of Caco-2/TC7 enterocytes were analyzed. Micelles devoid of TG hydrolysis products, like those present in the intestinal lumen in the interprandial period, were used as controls. The apical delivery of PPM specifically induced a number of cellular events that are not induced by interprandial micelles. These early events included the trafficking of apolipoprotein B, a structural component of TRL, from apical towards secretory domains, and the rapid, dose-dependent activation of ERK and p38MAPK. PPM supply induced the scavenger receptor SR-BI/CLA-1 to cluster at the apical brush border membrane and to move from non-raft to raft domains. Competition, inhibition or knockdown of SR-BI/CLA-1 impaired the PPM-dependent apoB trafficking and ERK activation. These results are the first evidence that enterocytes specifically sense postprandial dietary lipid-containing micelles. SR-BI/CLA-1 is involved in this process and could be a target for further study with a view to modifying intestinal TRL secretion early in the control pathway.
    Full-text · Article · Feb 2009 · PLoS ONE

  • No preview · Article · Jan 2009 · PLoS ONE
  • G. Ventura · C. Moinard · V. Carrière · J. Chambaz · L. Cynober · J. De Bandt

    No preview · Article · Dec 2008 · Clinical Nutrition Supplements
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    ABSTRACT: Intestine contributes to lipid homeostasis through the absorption of dietary lipids, which reach the apical pole of enterocytes as micelles. The present study aimed to identify the specific impact of these dietary lipid-containing micelles on gene expression in enterocytes. We analyzed, by microarray, the modulation of gene expression in Caco-2/TC7 cells in response to different lipid supply conditions that reproduced either the permanent presence of albumin-bound lipids at the basal pole of enterocytes or the physiological delivery, at the apical pole, of lipid micelles, which differ in their composition during the interprandial (IPM) or the postprandial (PPM) state. These different conditions led to distinct gene expression profiles. We observed that, contrary to lipids supplied at the basal pole, apical lipid micelles modulated a large number of genes. Moreover, compared with the apical supply of IPM, PPM specifically impacted 46 genes from three major cell function categories: signal transduction, lipid metabolism, and cell adhesion/architecture. Results from this first large-scale analysis underline the importance of the mode and polarity of lipid delivery on enterocyte gene expression. They demonstrate specific and coordinated transcriptional effects of dietary lipid-containing micelles that could impact the structure and polarization of enterocytes and their functions in nutrient transfer.
    Full-text · Article · Sep 2008 · AJP Gastrointestinal and Liver Physiology
  • G. Ventura · C. Moinard · V. Carrière · J. Chambaz · L. Cynober · J. De Bandt
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    ABSTRACT: Introduction et but de l’étude Le flux portal d’Arginine (Arg) est un élément clé de la régulation de l’uréogenèse hépatique. L’intestin est l’organe qui contrôle la disponibilité de l’Arg apportée par voie digestive. Cela dépendrait d’une modulation de l’expression de différentes enzymes (arginase, glutaminase, ornithine ami-notransférase (OAT) et argininosuccinate lyase (ASL) et synthétase (ASS)) par les apports en protéines de la ration alimentaire. Le but de ce travail a été d’étudier l’influence d’apports croissants en acides aminés (AA) sur l’expression de ces enzymes dans un modèle de cellules intestinales, les cellules Caco-2/TC7. Matériel et méthodes Des cellules Caco-2/TC7 ont été cultivées sur filtre semi-perméable pendant 15 jours en milieu standard puis ont été réparties en 4 groupes (n=3). Les cellules ont alors été exposées pendant 3 jours à différents milieux dépourvu d’AA (0), ou contenant des concentrations croissantes en AA, correspondant à une (1X), deux (2X) et quatre (4X) fois les concentrations physiologiques plasmatiques post-prandiales. Les ARNm codant pour les enzymes d’intérêt ont été quantifiés par PCR en temps réel. Les résultats ont été analysés par régression linéaire (test de Student sur la pente). Résultats Il existe une relation inverse entre les apports en AA et l’expression de la glutaminase (p= 0,028), de l’OAT (p= 0,035), de l’ASS (p= 0,028) et de l’arginase (p= 0,058). Conclusions Cette étude montre pour la première fois un effet direct des AA sur la régulation au niveau transcriptionnel des enzymes du carrefour intestinal de l’arginine en fonction de l’apport Tableau 1Les niveaux d’expression des différentes enzymes, rapportées à la quantité d’ARNr 18SView Within Article azoté. Cette régulation permettrait ainsi, dans des situations de faibles apports azotés, de favoriser la synthèse intestinale de citrulline et par conséquent la néosynthèse rénale d’Arg. Lors d’apports azotés plus importants, cela favoriserait le passage de l’Arg absorbée dans le système porte et donc une stimulation adaptée de l’uréoge-nèse hépatique.
    No preview · Article · Nov 2007 · Nutrition Clinique et Métabolisme
  • O. Béaslas · V. Carrière · F. Delers · M. Rousset · J. Chambaz

    No preview · Article · May 2006 · Gastroentérologie Clinique et Biologique
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    ABSTRACT: Glucose-6-phosphatase (G6Pase) catalyzes the release of glucose from glucose 6-phosphate. This enzyme was mainly studied in the liver, but while detected in the small intestine little is known about the regulation of its intestinal expression. This study describes the mechanisms of the glucose-dependent regulation of G6Pase expression in intestinal cells. Results obtained in vivo and in Caco-2/TC7 enterocytes showed that glucose increases the G6Pase mRNA level. In Caco-2/TC7 cells, glucose stabilized G6Pase mRNA and activated the transcription of the gene, meaning that glucose-dependent G6Pase expression involved both transcriptional and post-transcriptional mechanisms. Reporter-gene studies showed that, although the -299/+57 region of the human G6Pase promoter was sufficient to trigger the glucose response in the hepatoma cell line HepG2, the -1157/-1133 fragment was required for maximal activation of glucose-6-phosphatase gene transcription in Caco-2/TC7 cells. This fragment binds the aryl receptor nuclear translocator (ARNT), cAMP-responsive element-binding protein, and upstream stimulatory factor transcription factors. The DNA binding activity of these transcription factors was increased in nuclear extracts of differentiated cells from the intestinal villus of mice fed sugar-rich diets as compared with mice fed a no-sugar diet. A direct implication of ARNT in the activation of G6Pase gene transcription by glucose has been observed in Caco-2/TC7 cells using RNA interference experiments. These results support a physiological role for G6Pase in the control of nutrient absorption in the small intestine.
    Full-text · Article · Jun 2005 · Journal of Biological Chemistry
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    ABSTRACT: Apolipoprotein (apo) A-IV, a component of triglyceride-rich lipoproteins secreted by the small intestine, has been shown to play an important role in the control of lipid homeostasis. Numerous studies have described the induction of apoA-IV gene expression by lipids, but the molecular mechanisms involved in this process remain unknown. In this study, we have demonstrated that a lipid bolus induced transcription of the apoA-IV gene in transgenic mice and that the regulatory region of the apoA-IV gene, composed of the apoC-III enhancer and the apoA-IV promoter (eC3-A4), was responsible for this induction. In enterocyte Caco-2/TC7 cells, a permanent supply of lipids at the basal pole induced expression of the apoA-IV gene both at the transcriptional level and through mRNA stabilization. ApoA-IV gene transcription and protein secretion were further induced by an apical supply of complex lipid micelles mimicking the composition of duodenal micelles, and this effect was not reproduced by apical delivery of different combinations of micelle components. Only induction of the apoA-IV gene by lipid micelles involved the participation of hepatic nuclear factor (HNF)-4, as demonstrated using a dominant negative form of this transcription factor. Accordingly, lipid micelles increased the DNA binding activity of HNF-4 on the eC3-A4 region. These results emphasize the importance of physiological delivery of dietary lipids on apoA-IV gene expression and the implication of HNF-4 in this regulation.
    No preview · Article · Mar 2005 · Journal of Biological Chemistry

Publication Stats

946 Citations
173.37 Total Impact Points

Institutions

  • 2015
    • Hôpital La Pitié Salpêtrière (Groupe Hospitalier "La Pitié Salpêtrière - Charles Foix")
      Lutetia Parisorum, Île-de-France, France
  • 1996-2015
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • Université de Rennes 1
      Roazhon, Brittany, France
  • 2001-2013
    • Pierre and Marie Curie University - Paris 6
      • Centre de recherche des Cordeliers - UMR_S 872
      Lutetia Parisorum, Île-de-France, France
  • 2007
    • Institut des Systèmes Complexes, Paris Île-de-France
      Lutetia Parisorum, Île-de-France, France
  • 2003
    • UPMC
      Pittsburgh, Pennsylvania, United States
  • 1992
    • Unité Inserm U1077
      Caen, Lower Normandy, France