Béatrice Desvergne

Publications of Béatrice Desvergne

• Protective role of peroxisome proliferator-activated receptor-β/δ in septic shock.

  Authors: Amar Kapoor, Yasunori Shintani, Massimo Collino, Marcin F Osuchowski, Daniel Busch, Nimesh S A Patel, Bruno Sepodes, Sara Castiglia, Roberto Fantozzi, David Bishop-Bailey, Helder Mota-Filipe, Muhammad M Yaqoob, Ken Suzuki, Soheyl Bahrami, Béatrice Desvergne, Jane A Mitchell, Christoph Thiemermann

  American journal of respiratory and critical care medicine. 12/2010; 182(12):1506-15.

  Peroxisome proliferator-activated receptor (PPAR)-β/δ is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-β/δ in sepsis is unknown. WePeroxisome proliferator-activated receptor (PPAR)-β/δ is a transcription factor that belongs to the PPAR nuclear hormone receptor family, but the role of PPAR-β/δ in sepsis is unknown. We investigated the role of PPAR-β/δ in murine models of LPS-induced organ injury and dysfunction and cecal ligation and puncture (CLP)-induced polymicrobial sepsis. Wild-type (WT) and PPAR-β/δ knockout (KO) mice and C57BL/6 mice were subjected to LPS for 16 hours. C57BL/6 mice received the PPAR-β/δ agonist GW0742 (0.03 mg/kg intravenously, 1 h after LPS) or GW0742 plus the PPAR-β/δ antagonist GSK0660 (0.1 mg/kg intravenously, 30 min before LPS). CD-1 mice subjected to CLP received GW0742 or GW0742 plus GSK0660. In PPAR-β/δ KO mice, endotoxemia exacerbated organ injury and dysfunction (cardiac, renal, and hepatic) and inflammation (lung) compared with WT mice. In C57BL/6 mice subjected to endotoxemia, GW0742 significantly (1) attenuated organ (cardiac and renal) dysfunction and inflammation (lung); (2) increased the phosphorylation of Akt and glycogen synthase kinase (GSK)-3β; (3) attenuated the increase in extracellular signal-regulated kinase (ERK)1/2 and signal transducer and activator of transcription (STAT)-3 phosphorylation; and (4) attenuated the activation of nuclear factor (NF)-κB and the expression of inducible nitric oxide synthase (iNOS). In CD-1 mice subjected to CLP, GW0742 improved 10-day survival. All the observed beneficial effects of GW0742 were attenuated by the PPAR-β/δ antagonist GSK0660. PPAR-β/δ protects against multiple organ injury and dysfunction, and inflammation caused by endotoxic shock and improves survival in polymicrobial sepsis by a mechanism that may involve activation of Akt and inhibition of GSK-3β and NF-κB.

• Endocrine disruptors: from endocrine to metabolic disruption.

  Authors: Cristina Casals-Casas, Béatrice Desvergne

  Annual review of physiology. 11/2010; 73:135-62.

  Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides,Synthetic chemicals currently used in a variety of industrial and agricultural applications are leading to widespread contamination of the environment. Even though the intended uses of pesticides, plasticizers, antimicrobials, and flame retardants are beneficial, effects on human health are a global concern. These so-called endocrine-disrupting chemicals (EDCs) can disrupt hormonal balance and result in developmental and reproductive abnormalities. New in vitro, in vivo, and epidemiological studies link human EDC exposure with obesity, metabolic syndrome, and type 2 diabetes. Here we review the main chemical compounds that may contribute to metabolic disruption. We then present their demonstrated or suggested mechanisms of action with respect to nuclear receptor signaling. Finally, we discuss the difficulties of fairly assessing the risks linked to EDC exposure, including developmental exposure, problems of high- and low-dose exposure, and the complexity of current chemical environments.

• PPARgamma in placental angiogenesis.

  Authors: Karim Nadra, Laure Quignodon, Chiara Sardella, Elisabeth Joye, Antonio Mucciolo, Roman Chrast, Béatrice Desvergne

  Endocrinology. 10/2010; 151(10):4969-81.

  Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in diverse biological processes including adipocyte differentiation, glucose homeostasis, and inflammatoryPeroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor involved in diverse biological processes including adipocyte differentiation, glucose homeostasis, and inflammatory responses. Analyses of PPARγ knockout animals have been so far preempted by the early embryonic death of PPARγ-/- embryos as a consequence of the severe alteration of their placental vasculature. Using Sox2Cre/PPARγL2/L2 mice, we obtained fully viable PPARγ-null mice through specific and total epiblastic gene deletion, thereby demonstrating that the placental defect is the unique cause of PPARγ-/- embryonic lethality. The vasculature defects observed in PPARγ-/- placentas at embryonic d 9.5 correlated with an unsettled balance of pro- and antiangiogenic factors as demonstrated by increased levels of proliferin (Prl2c2, PLF) and decreased levels of proliferin-related protein (Prl7d1, PRP), respectively. To analyze the role of PPARγ in the later stage of placental development, when its expression peaks, we treated pregnant wild-type mice with the PPARγ agonist rosiglitazone. This treatment resulted in a disorganization of the placental layers and an altered placental microvasculature, accompanied by the decreased expression of proangiogenic genes such as Prl2c2, vascular endothelial growth factor, and Pecam1. Together our data demonstrate that PPARγ plays a pivotal role in controlling placental vascular proliferation and contributes to its termination in late pregnancy.

• Peroxisome proliferator-activated receptor gamma activation is required for maintenance of innate antimicrobial immunity in the colon.

  Authors: Laurent Peyrin-Biroulet, Julia Beisner, Guoxing Wang, Sabine Nuding, Sajit Thottathil Oommen, Denise Kelly, Erika Parmentier-Decrucq, Rodrigue Dessein, Emilie Merour, Philipe Chavatte, Teddy Grandjean, Aude Bressenot, Pierre Desreumaux, Jean-Frédéric Colombel, Béatrice Desvergne, Eduard F Stange, Jan Wehkamp, Mathias Chamaillard

  Proceedings of the National Academy of Sciences of the United States of America. 05/2010; 107(19):8772-7.

  Crohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gammaCrohn's disease (CD), a major form of human inflammatory bowel disease, is characterized by primary immunodeficiencies. The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) is essential for intestinal homeostasis in response to both dietary- and microbiota-derived signals. Its role in host defense remains unknown, however. We show that PPARgamma functions as an antimicrobial factor by maintaining constitutive epithelial expression of a subset of beta-defensin in the colon, which includes mDefB10 in mice and DEFB1 in humans. Colonic mucosa of Ppargamma mutant animals shows defective killing of several major components of the intestinal microbiota, including Candida albicans, Bacteroides fragilis, Enterococcus faecalis, and Escherichia coli. Neutralization of the colicidal activity using an anti-mDefB10 blocking antibody was effective in a PPARgamma-dependent manner. A functional promoter variant that is required for DEFB1 expression confers strong protection against Crohn's colitis and ileocolitis (odds ratio, 0.559; P = 0.018). Consistently, colonic involvement in CD is specifically linked to reduced expression of DEFB1 independent of inflammation. These findings support the development of PPARgamma-targeting therapeutic and/or nutritional approaches to prevent colonic inflammation by restoring antimicrobial immunity in CD.

• The pollutant diethylhexyl phthalate regulates hepatic energy metabolism via species-specific PPARalpha-dependent mechanisms.

  Authors: Jérôme N Feige, Alan Gerber, Cristina Casals-Casas, Qian Yang, Carine Winkler, Elodie Bedu, Manuel Bueno, Laurent Gelman, Johan Auwerx, Frank J Gonzalez, Béatrice Desvergne

  Environmental health perspectives. 02/2010; 118(2):234-41.

  The modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrialThe modulation of energetic homeostasis by pollutants has recently emerged as a potential contributor to the onset of metabolic disorders. Diethylhexyl phthalate (DEHP) is a widely used industrial plasticizer to which humans are widely exposed. Phthalates can activate the three peroxisome proliferator-activated receptor (PPAR) isotypes on cellular models and induce peroxisome proliferation in rodents. In this study, we aimed to evaluate the systemic and metabolic consequences of DEHP exposure that have remained so far unexplored and to characterize the underlying molecular mechanisms of action. As a proof of concept and mechanism, genetically engineered mouse models of PPARs were exposed to high doses of DEHP, followed by metabolic and molecular analyses. DEHP-treated mice were protected from diet-induced obesity via PPARalpha-dependent activation of hepatic fatty acid catabolism, whereas the activity of neither PPARbeta nor PPARgamma was affected. However, the lean phenotype observed in response to DEHP in wild-type mice was surprisingly abolished in PPARalpha-humanized mice. These species differences are associated with a different pattern of coregulator recruitment. These results demonstrate that DEHP exerts species-specific metabolic actions that rely to a large extent on PPARalpha signaling and highlight the metabolic importance of the species-specific activation of PPARalpha by xenobiotic compounds.

• The PPARbeta/delta agonist GW0742 relaxes pulmonary vessels and limits right heart hypertrophy in rats with hypoxia-induced pulmonary hypertension.

  Authors: Louise S Harrington, Laura Moreno, Anna Reed, Stephen J Wort, Béatrice Desvergne, Christopher Garland, Lan Zhao, Jane A Mitchell

  PloS one. 01/2010; 5(3):e9526.

  Pulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated withPulmonary vascular diseases are increasingly recognised as important clinical conditions. Pulmonary hypertension associated with a range of aetiologies is difficult to treat and associated with progressive morbidity and mortality. Current therapies for pulmonary hypertension include phosphodiesterase type 5 inhibitors, endothelin receptor antagonists, or prostacyclin mimetics. However, none of these provide a cure and the clinical benefits of these drugs individually decline over time. There is, therefore, an urgent need to identify new treatment strategies for pulmonary hypertension. Here we show that the PPARbeta/delta agonist GW0742 induces vasorelaxation in systemic and pulmonary vessels. Using tissue from genetically modified mice, we show that the dilator effects of GW0742 are independent of the target receptor PPARbeta/delta or cell surface prostacyclin (IP) receptors. In aortic tissue, vascular relaxant effects of GW0742 were not associated with increases in cGMP, cAMP or hyperpolarisation, but were attributed to inhibition of RhoA activity. In a rat model of hypoxia-induced pulmonary hypertension, daily oral dosing of animals with GW0742 (30 mg/kg) for 3 weeks significantly reduced the associated right heart hypertrophy and right ventricular systolic pressure. GW0742 had no effect on vascular remodelling induced by hypoxia in this model. These observations are the first to show a therapeutic benefit of 'PPARbeta/delta' agonists in experimental pulmonary arterial hypertension and provide pre-clinical evidence to favour clinical trials in man.

• PPAR{beta}/{delta} Agonists Modulate Platelet Function via a Mechanism Involving PPAR Receptors and Specific Association/Repression of PKC{alpha}

  Authors: Ferhana Y Ali, Matthew G Hall, Béatrice Desvergne, Timothy D Warner, Jane A Mitchell

  Arteriosclerosis, thrombosis, and vascular biology. 09/2009;

  OBJECTIVE: Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a nuclear receptor found in platelets. PPARbeta/delta agonists acutely inhibit platelet function within a fewOBJECTIVE: Peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) is a nuclear receptor found in platelets. PPARbeta/delta agonists acutely inhibit platelet function within a few minutes of addition. As platelets are anucleated, the effects of PPARbeta/delta agonists on platelets must be nongenomic. Currently, the particular role of PPARbeta/delta receptors and their intracellular signaling pathways in platelets are not known. METHODS AND RESULTS: We have used mice lacking PPARbeta/delta (PPARbeta/delta(-/-)) to show the effects of the PPARbeta/delta agonist GW501516 on platelet adhesion and cAMP levels are mediated specifically by PPARbeta/delta, however GW501516 had no PPARbeta/delta-specific effect on platelet aggregation. Studies in human platelets showed that PKCalpha, which can mediate platelet activation, was bound and repressed by PPARbeta/delta after platelets were treated with GW501516. CONCLUSIONS: These data provide evidence of a novel mechanism by which PPAR receptors influence platelet activity and thereby thrombotic risk.

• PPAR-mediated activity of phthalates: A link to the obesity epidemic?

  Authors: Béatrice Desvergne, Jérôme N Feige, Cristina Casals-Casas

  Molecular and cellular endocrinology. 06/2009; 304(1-2):43-8.

  The endocrine disruption hypothesis asserts that exposure to small amounts of some chemicals in the environment may interfere with the endocrine system and lead to harmful effects in wildlife andThe endocrine disruption hypothesis asserts that exposure to small amounts of some chemicals in the environment may interfere with the endocrine system and lead to harmful effects in wildlife and humans. Many of these chemicals may interact with members of the nuclear receptor superfamily. Peroxisome proliferator-activated receptors (PPARs) are such candidate members, which interact with many different endogenous and exogenous lipophilic compounds. More particularly, the roles of PPARs in lipid and carbohydrate metabolism raise the question of their activation by a sub-class of pollutants, tentatively named "metabolic disrupters". Phthalates are abundant environmental micro-pollutants in Europe and North America and may belong to this class. Mono-ethyl-hexyl-phthalate (MEHP), a metabolite of the widespread plasticizer di-ethyl-hexyl-phthalate (DEHP), has been found in exposed organisms and interacts with all three PPARs. A thorough analysis of its interactions with PPARgamma identified MEHP as a selective PPARgamma modulator, and thus a possible contributor to the obesity epidemic.

• PPARdelta/beta: the lobbyist switching macrophage allegiance in favor of metabolism.

  Authors: Béatrice Desvergne

  Cell metabolism. 06/2008; 7(6):467-9.

  Macrophages, which belong to the immune system, are increasingly being recognized for their contribution to metabolic regulation. In two studies by Kang et al. (2008) and Odegaard et al. (2008) inMacrophages, which belong to the immune system, are increasingly being recognized for their contribution to metabolic regulation. In two studies by Kang et al. (2008) and Odegaard et al. (2008) in this issue of Cell Metabolism, we learn that alternative activation (M2a) of resident macrophages in liver and adipose tissue depends highly on PPARdelta/beta activity, leading to improved fatty acid metabolism and insulin sensitivity.

• Peroxisome Proliferator-Activated Receptor beta/delta in the Brain: Facts and Hypothesis.

  Authors: M. G. Hall, Laure Quignodon, Béatrice Desvergne

  PPAR research. 02/2008; 2008:780452.

  peroxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressedperoxisome proliferator-activated receptors (PPARs) are nuclear receptors acting as lipid sensors. Besides its metabolic activity in peripheral organs, the PPAR beta/delta isotype is highly expressed in the brain and its deletion in mice induces a brain developmental defect. Nevertheless, exploration of PPARbeta action in the central nervous system remains sketchy. The lipid content alteration observed in PPARbeta null brains and the positive action of PPARbeta agonists on oligodendrocyte differentiation, a process characterized by lipid accumulation, suggest that PPARbeta acts on the fatty acids and/or cholesterol metabolisms in the brain. PPARbeta could also regulate central inflammation and antioxidant mechanisms in the damaged brain. Even if not fully understood, the neuroprotective effect of PPARbeta agonists highlights their potential benefit to treat various acute or chronic neurological disorders. In this perspective, we need to better understand the basic function of PPARbeta in the brain. This review proposes different leads for future researches.

• Stage-specific integration of maternal and embryonic peroxisome proliferator-activated receptor delta signaling is critical to pregnancy success.

  Authors: Haibin Wang, Huirong Xie, Xiaofei Sun, Susanne Tranguch, Hao Zhang, Xiangxu Jia, Dingzhi Wang, Sanjoy K Das, Béatrice Desvergne, Walter Wahli, Raymond N DuBois, Sudhansu K Dey

  The Journal of biological chemistry. 01/2008; 282(52):37770-82.

  Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation,Successful pregnancy depends on well coordinated developmental events involving both maternal and embryonic components. Although a host of signaling pathways participate in implantation, decidualization, and placentation, whether there is a common molecular link that coordinates these processes remains unknown. By exploiting genetic, molecular, pharmacological, and physiological approaches, we show here that the nuclear transcription factor peroxisome proliferator-activated receptor (PPAR) delta plays a central role at various stages of pregnancy, whereas maternal PPARdelta is critical to implantation and decidualization, and embryonic PPARdelta is vital for placentation. Using trophoblast stem cells, we further elucidate that a reciprocal relationship between PPARdelta-AKT and leukemia inhibitory factor-STAT3 signaling pathways serves as a cell lineage sensor to direct trophoblast cell fates during placentation. This novel finding of stage-specific integration of maternal and embryonic PPARdelta signaling provides evidence that PPARdelta is a molecular link that coordinates implantation, decidualization, and placentation crucial to pregnancy success. This study is clinically relevant because deferral of on time implantation leads to spontaneous pregnancy loss, and defective trophoblast invasion is one cause of preeclampsia in humans.

• Adipose tissue integrity as a prerequisite for systemic energy balance: a critical role for peroxisome proliferator-activated receptor gamma.

  Authors: Silvia I Anghel, Elodie Bedu, Celine Delucinge-Vivier, Patrick Descombes, Béatrice Desvergne, Walter Wahli

  The Journal of biological chemistry. 11/2007; 282(41):29946-57.

  Peroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated withPeroxisome proliferator-activated receptor gamma (PPARgamma) is an essential regulator of adipocyte differentiation, maintenance, and survival. Deregulations of its functions are associated with metabolic diseases. We show here that deletion of one PPARgamma allele not only affected lipid storage but, more surprisingly, also the expression of genes involved in glucose uptake and utilization, the pentose phosphate pathway, fatty acid synthesis, lipolysis, and glycerol export as well as in IR/IGF-1 signaling. These deregulations led to reduced circulating adiponectin levels and an energy crisis in the WAT, reflected in a decrease to nearly half of its intracellular ATP content. In addition, there was a decrease in the metabolic rate and physical activity of the PPARgamma(+/-) mice, which was abolished by thiazolidinedione treatment, thereby linking regulation of the metabolic rate and physical activity to PPARgamma. It is likely that the PPARgamma(+/-) phenotype was due to the observed WAT dysfunction, since the gene expression profiles associated with metabolic pathways were not affected either in the liver or the skeletal muscle. These findings highlight novel roles of PPARgamma in the adipose tissue and underscore the multifaceted action of this receptor in the functional fine tuning of a tissue that is crucial for maintaining the organism in good health.

• Molecular basis of selective PPARgamma modulation for the treatment of Type 2 diabetes.

  Authors: Laurent Gelman, Jérôme N Feige, Béatrice Desvergne

  Biochimica et biophysica acta. 09/2007; 1771(8):1094-107.

  Peroxisome proliferator-activated receptors (PPARs) (alpha, beta/delta and gamma) are lipid sensors capable of adapting gene expression to integrate various lipid signals. As such, PPARs are alsoPeroxisome proliferator-activated receptors (PPARs) (alpha, beta/delta and gamma) are lipid sensors capable of adapting gene expression to integrate various lipid signals. As such, PPARs are also very important pharmaceutical targets, and specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders. In particular, compounds of the class of the thiazolinediones (TZDs) are PPARgamma agonists and potent insulin-sensitizers. The specific but still broad expression patterns of PPARgamma, as well as its implication in numerous pathways, constitutes also a disadvantage regarding drug administration, since this potentially increases the chance to generate side-effects through the activation of the receptor in tissues or cells not affected by the disease. Actually, numerous side effects associated with the administration of TZDs have been reported. Today, a new generation of PPARgamma modulators is being actively developed to activate the receptor more specifically, in a cell and time-dependent manner, in order to induce a specific subset of target genes only and modulate a restricted number of metabolic pathways. We will discuss here why and how the development of such selective PPARgamma modulators is possible, and summarize the results obtained with the published molecules.

• PPARs special issue: anchoring the present to explore the future.

  Authors: Béatrice Desvergne

  Biochimica et biophysica acta. 09/2007; 1771(8):913-4.

• The endocrine disruptor monoethyl-hexyl-phthalate is a selective peroxisome proliferator-activated receptor gamma modulator that promotes adipogenesis.

  Authors: Jérôme N Feige, Laurent Gelman, Daniel Rossi, Vincent Zoete, Raphaël Métivier, Cicerone Tudor, Silvia I Anghel, Aurélien Grosdidier, Caroline Lathion, Yves Engelborghs, Olivier Michielin, Walter Wahli, Béatrice Desvergne

  The Journal of biological chemistry. 07/2007; 282(26):19152-66.

  The ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition ofThe ability of pollutants to affect human health is a major concern, justified by the wide demonstration that reproductive functions are altered by endocrine disrupting chemicals. The definition of endocrine disruption is today extended to broader endocrine regulations, and includes activation of metabolic sensors, such as the peroxisome proliferator-activated receptors (PPARs). Toxicology approaches have demonstrated that phthalate plasticizers can directly influence PPAR activity. What is now missing is a detailed molecular understanding of the fundamental basis of endocrine disrupting chemical interference with PPAR signaling. We thus performed structural and functional analyses that demonstrate how monoethyl-hexyl-phthalate (MEHP) directly activates PPARgamma and promotes adipogenesis, albeit to a lower extent than the full agonist rosiglitazone. Importantly, we demonstrate that MEHP induces a selective activation of different PPARgamma target genes. Chromatin immunoprecipitation and fluorescence microscopy in living cells reveal that this selective activity correlates with the recruitment of a specific subset of PPARgamma coregulators that includes Med1 and PGC-1alpha, but not p300 and SRC-1. These results highlight some key mechanisms in metabolic disruption but are also instrumental in the context of selective PPAR modulation, a promising field for new therapeutic development based on PPAR modulation.

• IL-13 induces expression of CD36 in human monocytes through PPARgamma activation.

  Authors: Antoine Berry, Patricia Balard, Agnès Coste, David Olagnier, Céline Lagane, Hélène Authier, Françoise Benoit-Vical, Jean-Claude Lepert, Jean-Paul Séguéla, Jean-François Magnaval, Pierre Chambon, Daniel Metzger, Béatrice Desvergne, Walter Wahli, Johan Auwerx, Bernard Pipy

  European journal of immunology. 07/2007; 37(6):1642-52.

  The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure toThe class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)gamma pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARgamma pathway was demonstrated using transfection of a PPARgamma expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARgamma, and in peritoneal macrophages from PPARgamma-conditional null mice. We also show that CD36 induction by IL-13 via PPARgamma is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-Delta12,14-prostaglandin J2, an endogenous PPARgamma ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARgamma are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARgamma in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARgamma ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.

• MRI monitoring of focal cerebral ischemia in peroxisome proliferator-activated receptor (PPAR)-deficient mice.

  Authors: Jean-Baptiste Pialat, Tae-Hee Cho, Olivier Beuf, Elisabeth Joye, Samir Moucharrafie, Samir Moucharaffie, Jean-Baptiste Langlois, Chantal Nemoz, Marc Janier, Yves Berthezene, Norbert Nighoghossian, Béatrice Desvergne, Marlène Wiart

  NMR in biomedicine. 06/2007; 20(3):335-42.

  Peroxisome proliferator-activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they arePeroxisome proliferator-activated receptors (PPARs) are a potential target for neuroprotection in focal ischemic stroke. These nuclear receptors have major effects in lipid metabolism, but they are also involved in inflammatory processes. Three PPAR isotypes have been identified: alpha, beta (or delta) and gamma. The development of PPAR transgenic mice offers a promising tool for prospective therapeutic studies. This study used MRI to assess the role of PPARalpha and PPARbeta in the development of stroke. Permanent middle cerebral artery occlusion induced focal ischemia in wild-type, PPARalpha-null mice and PPARbeta-null mice. T(2)-weighted MRI was performed with a 7 T MRI scan on day 0, 1, 3, 7 and 14 to monitor lesion growth in the various genotypes. General Linear Model statistical analysis found a significant difference in lesion volume between wild-type and PPAR-null mice for both alpha and beta isotypes. These data validate high-resolution MRI for monitoring cerebral ischemic lesions, and confirm the neuroprotective role of PPARalpha and PPARbeta in the brain.

• Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes.

  Authors: Arup Kumar Indra, Eduardo Castaneda, Maria Cristina Antal, Ming Jiang, Nadia Messaddeq, Xiangjun Meng, Christiane V Loehr, Patricio Gariglio, Shigeaki Kato, Walter Wahli, Béatrice Desvergne, Daniel Metzger, Pierre Chambon

  The Journal of investigative dermatology. 06/2007; 127(5):1250-60.

  Retinoid-X-receptor alpha (RXRalpha), a member of the nuclear receptor (NR) superfamily, is a ligand-dependent transcriptional regulatory factor. It plays a crucial role in NR signalling throughRetinoid-X-receptor alpha (RXRalpha), a member of the nuclear receptor (NR) superfamily, is a ligand-dependent transcriptional regulatory factor. It plays a crucial role in NR signalling through heterodimerization with some 15 NRs. We investigated the role of RXRalpha and its partners on mouse skin tumor formation and malignant progression upon topical DMBA/TPA treatment. In mutants selectively ablated for RXRalpha in keratinocytes, epidermal tumors increased in size and number, and frequently progressed to carcinomas. As keratinocyte-selective peroxisome proliferator-activated receptor gamma (PPARgamma) ablation had similar effects, RXRalpha/PPARgamma heterodimers most probably mediate epidermal tumor suppression. Keratinocyte-selective RXRalpha-null and vitamin-D-receptor null mice also exhibited more numerous dermal melanocytic growths (nevi) than control mice, but only nevi from RXRalpha mutant mice progressed to invasive human-melanoma-like tumors. Distinct RXRalpha-mediated molecular events appear therefore to be involved, in keratinocytes, in cell-autonomous suppression of epidermal tumorigenesis and malignant progression, and in non-cell-autonomous suppression of nevi formation and progression. Our study emphasizes the crucial role of keratinocytes in chemically induced epidermal and melanocytic tumorigenesis, and raises the possibility that they could play a similar role in UV-induced tumorigenesis, notably in nevi formation and progression to melanoma.

• Combined simulation and mutagenesis analyses reveal the involvement of key residues for peroxisome proliferator-activated receptor alpha helix 12 dynamic behavior.

  Authors: Liliane Michalik, Vincent Zoete, Grigorios Krey, Aurélien Grosdidier, Laurent Gelman, Pierre Chodanowski, Jérôme N Feige, Béatrice Desvergne, Walter Wahli, Olivier Michielin

  The Journal of biological chemistry. 04/2007; 282(13):9666-77.

  The dynamic properties of helix 12 in the ligand binding domain of nuclear receptors are a major determinant of AF-2 domain activity. We investigated the molecular and structural basis of helix 12The dynamic properties of helix 12 in the ligand binding domain of nuclear receptors are a major determinant of AF-2 domain activity. We investigated the molecular and structural basis of helix 12 mobility, as well as the involvement of individual residues with regard to peroxisome proliferator-activated receptor alpha (PPARalpha) constitutive and ligand-dependent transcriptional activity. Functional assays of the activity of PPARalpha helix 12 mutants were combined with free energy molecular dynamics simulations. The agreement between the results from these approaches allows us to make robust claims concerning the mechanisms that govern helix 12 functions. Our data support a model in which PPARalpha helix 12 transiently adopts a relatively stable active conformation even in the absence of a ligand. This conformation provides the interface for the recruitment of a coactivator and results in constitutive activity. The receptor agonists stabilize this conformation and increase PPARalpha transcription activation potential. Finally, we disclose important functions of residues in PPARalpha AF-2, which determine the positioning of helix 12 in the active conformation in the absence of a ligand. Substitution of these residues suppresses PPARalpha constitutive activity, without changing PPARalpha ligand-dependent activation potential.

• Association with coregulators is the major determinant governing peroxisome proliferator-activated receptor mobility in living cells.

  Authors: Cicerone Tudor, Jérôme N Feige, Harikishore Pingali, Vidya Bhushan Lohray, Walter Wahli, Béatrice Desvergne, Yves Engelborghs, Laurent Gelman

  The Journal of biological chemistry. 03/2007; 282(7):4417-26.

  The nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisomeThe nucleus is an extremely dynamic compartment, and protein mobility represents a key factor in transcriptional regulation. We showed in a previous study that the diffusion of peroxisome proliferator-activated receptors (PPARs), a family of nuclear receptors regulating major cellular and metabolic functions, is modulated by ligand binding. In this study, we combine fluorescence correlation spectroscopy, dual color fluorescence cross-correlation microscopy, and fluorescence resonance energy transfer to dissect the molecular mechanisms controlling PPAR mobility and transcriptional activity in living cells. First, we bring new evidence that in vivo a high percentage of PPARs and retinoid X receptors is associated even in the absence of ligand. Second, we demonstrate that coregulator recruitment (and not DNA binding) plays a crucial role in receptor mobility, suggesting that transcriptional complexes are formed prior to promoter binding. In addition, association with coactivators in the absence of a ligand in living cells, both through the N-terminal AB domain and the AF-2 function of the ligand binding domain, provides a molecular basis to explain PPAR constitutive activity.