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15 results on '"MESH: Orphan Nuclear Receptors"'

1. Insulin Dissociates the Effects of Liver X Receptor on Lipogenesis, Endoplasmic Reticulum Stress, and Inflammation

Author

Rosanne M. Crooke, Jianguo Wang, Xiaowei Sun, Jean-Paul Pais de Barros, Abhiruchi J Mehta, David Masson, Ji Miao, Mary E. Haas, Sudha B. Biddinger, Mark J. Graham, Masanori Aikawa, Division of Endocrinology, Children's Hospital Boston, Harvard Medical School, Harvard Medical School [Boston] (HMS), Isis Pharmaceuticals, IBIS THERAPEUTICS-ISIS Therapeutics, Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Center for Interdisciplinary Cardiovascular Sciences, Harvard Medical School [Boston] (HMS)-Brigham and Women's Hospital [Boston], ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011), Harvard Medical School [Boston] ( HMS ), Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Harvard Medical School [Boston] ( HMS ) -Brigham and Women's Hospital [Boston], and ANR-11-LABX-0021/11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du ( 2011 )

Subjects
0301 basic medicine, medicine.medical_treatment, Lipid-metabolism, Resistance, Biochemistry, Hepatitis, MESH: Hepatitis, MESH: Endoplasmic Reticulum Stress, polycyclic compounds, Insulin, Gene-expression, Phospholipids, Liver X Receptors, Mice, Knockout, biology, MESH : Gene Expression Regulation, Fatty-acid synthesis, food and beverages, Endoplasmic Reticulum Stress, Orphan Nuclear Receptors, Cultured-cells, Lipids, MESH: Gene Expression Regulation, MESH : Endoplasmic Reticulum Stress, Messenger-rna, Liver, MESH: Orphan Nuclear Receptors, Gene Knockdown Techniques, Lipogenesis, Female, lipids (amino acids, peptides, and proteins), Signal Transduction, liver X receptor, medicine.medical_specialty, Lxr-alpha, Mice, Transgenic, digestive system, Phospholipid transfer protein, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Insulin resistance, MESH : Hepatitis, Lysophosphatidylcholine acyltransferase, Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Liver X receptor, Molecular Biology, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Crosses, Genetic, Endoplasmic reticulum, Element-binding protein-1c, MESH : Liver, Cell Biology, medicine.disease, MESH : Orphan Nuclear Receptors, Receptor, Insulin, Mice, Inbred C57BL, Insulin receptor, 030104 developmental biology, Endocrinology, Diabetes Mellitus, Type 2, Gene Expression Regulation, Nuclear receptor, biology.protein, Unfolded protein response, Insulin Resistance, MESH: Liver
Abstract

IF 4.258; International audience; Diabetes is characterized by increased lipogenesis as well as increased endoplasmic reticulum (ER) stress and inflammation. The nuclear hormone receptor liver X receptor (LXR) is induced by insulin and is a key regulator of lipid metabolism. It promotes lipogenesis and cholesterol efflux, but suppresses endoplasmic reticulum stress and inflammation. The goal of these studies was to dissect the effects of insulin on LXR action. We used antisense oligonucleotides to knock down Lxr alpha in mice with hepatocytespecific deletion of the insulin receptor and their controls. We found, surprisingly, that knock-out of the insulin receptor and knockdown of Lxr alpha produced equivalent, non-additive effects on the lipogenic genes. Thus, insulin was unable to induce the lipogenic genes in the absence of Lxr alpha, and LXR alpha was unable to induce the lipogenic genes in the absence of insulin. However, insulin was not required for LXR alpha to modulate the phospholipid profile, or to suppress genes in the ER stress or inflammation pathways. These data show that insulin is required specifically for the lipogenic effects of LXR alpha and that manipulation of the insulin signaling pathway could dissociate the beneficial effects of LXR on cholesterol efflux, inflammation, and ER stress from the negative effects on lipogenesis.

Published
2016
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2. The knock-down of ERCC1 but not of XPF causes multinucleation

Author

Julie Rageul, Frédéric Ezan, Georges Baffet, Sophie Langouët, Christophe Frémin, Signalisation et Réponses aux Agents Infectieux et Chimiques (SeRAIC), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Inserm (Institute of Health and Medical Research), La Ligue contre le cancer, Université de Rennes 1, Région Bretagne, and Université de Rennes (UR)

Subjects
Biochemistry, 0302 clinical medicine, MESH: Endonucleases, Hepatocyte, MESH: Gene Silencing, Excision repair cross-complementing, Liver X Receptors, 0303 health sciences, MESH: Gene Expression Regulation, Neoplastic, Cell cycle, Orphan Nuclear Receptors, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, MESH: Orphan Nuclear Receptors, Gene Knockdown Techniques, 030220 oncology & carcinogenesis, Cell Nucleus Division, XPF, Multinucleation, MESH: Cell Line, Tumor, MESH: Mutation, Xeroderma pigmentosum, DNA repair, Mitosis, Biology, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, Gene Silencing, Molecular Biology, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Cell Biology, Fibroblasts, MESH: Mitosis, Endonucleases, medicine.disease, MESH: Cell Nucleus Division, MESH: Gene Knockdown Techniques, MESH: Fibroblasts, Mutation, MESH: HeLa Cells, Cancer research, ERCC1, MESH: DNA-Binding Proteins, Cytokinesis, HeLa Cells, Nucleotide excision repair
Abstract

International audience; Excision repair cross complementing gene 1 (ERCC1) associated with xeroderma pigmentosum group F (XPF) is a heterodimeric endonuclease historically involved in the excision of bulky helix-distorting DNA lesions during nucleotide excision repair (NER) but also in the repair of DNA interstrand crosslinks. ERCC1 deficient mice show severe growth retardation associated with premature replicative senescence leading to liver failure and death at four weeks of age. In humans, ERCC1 is overexpressed in hepatocellular carcinoma and in the late G1 phase of hepatocyte cell cycle. To investigate whether ERCC1 could be involved in human hepatocyte cell growth and cell cycle progression, we knocked-down ERCC1 expression in the human hepatocellular carcinoma cell line Huh7 by RNA interference. ERCC1 knocked-down cells were delayed in their cell cycle and became multinucleated. This phenotype was rescued by ERCC1 overexpression. Multinucleation was not liver specific since it also occurred in HeLa and in human fibroblasts knocked-down for ERCC1. Multinucleated cells arose after drastic defects leading to flawed metaphase and cytokinesis. Interestingly, multinucleation did not appear after knocking-down other NER enzymes such as XPC and XPF, suggesting that NER deficiency was not responsible for multinucleation. Moreover, XPF mutant human fibroblasts formed multinucleated cells after ERCC1 knock-down but not after XPF knock-down. Therefore our results seem consistent with ERCC1 being involved in multinucleation but not XPF. This work reveals a new role for ERCC1 distinct from its known function in DNA repair, which may be independent of XPF. The role for ERCC1 in mitotic progression may be critical during development, particularly in humans.

Published
2011
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3. PPAR agonists reduce steatosis in oleic acid-overloaded HepaRG cells

Author

Thierry Umbdenstock, Alexandra Rogue, Catherine de la Moureyre-Spire, Sébastien Anthérieu, Aurore Vluggens, Richard J. Weaver, Nancy Claude, André Guillouzo, Foie, métabolismes et cancer, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Biologie Servier, Technologie Servier, Institut de Recherches Servier, This work was supported by the International Research Servier Group (IRIS) and the European Community (Contracts Predict-IV-202222 and MIP-DILI-115336). The MIP-DILI project has received support from the Innovative Medicines Initiative Joint Undertaking, resources of which are composed of financial contribution from the European Union's Seventh Framework Programme (FP7/20072013) and EFPIA companies' in kind contribution. http://www.imi.europa.eu/., Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Cadieu, Muriel

Subjects
MESH: Oxidation-Reduction, Peroxisome Proliferator-Activated Receptors, Drug Evaluation, Preclinical, Receptors, Cytoplasmic and Nuclear, Peroxisome proliferator-activated receptor, MESH: Peroxisome Proliferator-Activated Receptors, Fatty Acids, Nonesterified, Toxicology, PPAR agonist, Muraglitazar, chemistry.chemical_compound, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, MESH: PPAR alpha, Oxazoles, MESH: Fatty Liver, Liver X Receptors, MESH: Lipid Metabolism, chemistry.chemical_classification, 0303 health sciences, MESH: Fatty Acids, Nonesterified, Lipotropic Agents, Fatty liver, MESH: Oxazoles, Orphan Nuclear Receptors, MESH: Gene Expression Regulation, MESH: Glycine, 3. Good health, Liver, MESH: Orphan Nuclear Receptors, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, 030220 oncology & carcinogenesis, Lipogenesis, MESH: Drug Evaluation, Preclinical, Oxidation-Reduction, medicine.drug, MESH: Triglycerides, medicine.medical_specialty, Tesaglitazar, Glycine, Biology, MESH: Receptors, Cytoplasmic and Nuclear, MESH: Lipotropic Agents, Cell Line, 03 medical and health sciences, Internal medicine, medicine, Humans, PPAR alpha, Constitutive Androstane Receptor, Triglycerides, 030304 developmental biology, Pharmacology, MESH: Lipogenesis, MESH: Humans, MESH: Oleic Acid, Troglitazone, Lipid Metabolism, medicine.disease, MESH: Cell Line, Fatty Liver, PPAR gamma, Endocrinology, Gene Expression Regulation, chemistry, MESH: PPAR gamma, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Steatosis, Oleic Acid, MESH: Liver
Abstract

International audience; Although non-alcoholic fatty liver disease (NAFLD) is currently the most common form of chronic liver disease there is no pharmacological agent approved for its treatment. Since peroxisome proliferator-activated receptors (PPARs) are closely associated with hepatic lipid metabolism, they seem to play important roles in NAFLD. However, the effects of PPAR agonists on steatosis that is a common pathology associated with NAFLD, remain largely controversial. In this study, the effects of various PPAR agonists, i.e. fenofibrate, bezafibrate, troglitazone, rosiglitazone, muraglitazar and tesaglitazar on oleic acid-induced steatotic HepaRG cells were investigated after a single 24-hour or 2-week repeat treatment. Lipid vesicles stained by Oil-Red O and triglycerides accumulation caused by oleic acid overload, were decreased, by up to 50%, while fatty acid oxidation was induced after 2-week co-treatment with PPAR agonists. The greatest effects on reduction of steatosis were obtained with the dual PPARα/γ agonist muraglitazar. Such improvement of steatosis was associated with up-regulation of genes related to fatty acid oxidation activity and down-regulation of many genes involved in lipogenesis. Moreover, modulation of expression of some nuclear receptor genes, such as FXR, LXRα and CAR, which are potent actors in the control of lipogenesis, was observed and might explain repression of de novo lipogenesis. CONCLUSION: Altogether, our in vitro data on steatotic HepaRG cells treated with PPAR agonists correlated well with clinical investigations, bringing a proof of concept that drug-induced reversal of steatosis in human can be evaluated in in vitro before conducting long-term and costly in vivo studies in animals and patients.

Published
2014
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4. LXR controls macrophage iron metabolism

Author

Mehdi Daoudi, Gael Bories, Sophie Colin, Bruno Derudas, Bart Staels, Stéphan Haulon, Brigitte Jude, Corinne Copin, Mélanie Fanchon, Loic Belloy, Christophe Zawadzki, Jonathan Vanhoutte, Giulia Chinetti-Gbaguidi, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen du Diabète (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, and Grants from the Région Nord-Pas de Calais/FEDER (CPER N. 1449), the Agence Nationale de la Recherche, France (AlMHA project), the Fondation de France, the Fondation pour la Recherche Médicale, the transatlantic Leducq HDL Network, the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46)

Subjects
Apolipoprotein E, Physiology, Ferroportin, 030204 cardiovascular system & hematology, 0302 clinical medicine, Homeostasis, Macrophage, MESH: Antigens, Differentiation, Myelomonocytic, MESH: Antigens, CD, Cells, Cultured, ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, MESH: Receptors, Cell Surface, 0303 health sciences, MESH: Iron, biology, CD68, Orphan Nuclear Receptors, MESH: Apolipoproteins E, Plaque, Atherosclerotic, Cell biology, Phenotype, Biochemistry, MESH: Orphan Nuclear Receptors, MESH: Homeostasis, MESH: ATP-Binding Cassette Transporters, Cardiology and Cardiovascular Medicine, Mannose Receptor, Mannose receptor, ATP Binding Cassette Transporter 1, MESH: Cells, Cultured, Iron, MESH: Biological Transport, Antigens, Differentiation, Myelomonocytic, Receptors, Cell Surface, In Vitro Techniques, MESH: Phenotype, Article, 03 medical and health sciences, Apolipoproteins E, Antigens, CD, Hepcidin, MESH: Mannose-Binding Lectins, Humans, Lectins, C-Type, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: ATP Binding Cassette Transporter 1, MESH: Plaque, Atherosclerotic, Liver X receptor, 030304 developmental biology, MESH: Humans, Macrophages, MESH: Macrophages, Biological Transport, Mannose-Binding Lectins, Nuclear receptor, biology.protein, ATP-Binding Cassette Transporters, MESH: Lectins, C-Type
Abstract

Rationale: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. Objective: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). Methods and Results: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68 + MR + ) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68 + MR + macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. Conclusions: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.

Published
2013
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5. Liver X receptor activation stimulates iron export in human alternative macrophages

Author

Bories, Gael, Colin, Sophie, Vanhoutte, Jonathan, Derudas, Bruno, Copin, Corinne, Fanchon, Melanie, Daoudi, Mehdi, Belloy, Loic, Haulon, Stephan, Zawadzki, Christophe, Jude, Brigitte, Staels, Bart, Chinetti-Gbaguidi, Giulia, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen de Génomique du Diabète - European Genomic Institute for Diabetes - FR 3508 (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, Grants from the Région Nord-Pas de Calais/FEDER (CPER N. 1449), the Agence Nationale de la Recherche, France (AlMHA project), the Fondation de France, the Fondation pour la Recherche Médicale, the transatlantic Leducq HDL Network, the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46), Institut Européen du Diabète (EGID), and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
MESH: Iron, MESH: Humans, MESH: Biological Transport, MESH: Macrophages, MESH: Phenotype, MESH: Apolipoproteins E, MESH: Orphan Nuclear Receptors, MESH: Homeostasis, MESH: Mannose-Binding Lectins, MESH: ATP-Binding Cassette Transporters, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: ATP Binding Cassette Transporter 1, MESH: Plaque, Atherosclerotic, MESH: Antigens, Differentiation, Myelomonocytic, MESH: Antigens, CD, MESH: Lectins, C-Type, MESH: Receptors, Cell Surface, MESH: Cells, Cultured
Abstract

International audience; RATIONALE: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. OBJECTIVE: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). METHODS AND RESULTS: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. CONCLUSIONS: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.

Published
2013
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6. Bis(monoacylglycero)phosphate accumulation in macrophages induces intracellular cholesterol redistribution, attenuates liver-X receptor/ATP-Binding cassette transporter A1/ATP-binding cassette transporter G1 pathway, and impairs cholesterol efflux

Author

Daria Markina, Michel Lagarde, Asami Makino, Philippe Moulin, Shota Sakai, Etienne Lefai, Toshihide Kobayashi, Maud Arnal-Levron, Shizuya Yamashita, Isabelle Delton-Vandenbroucke, Céline Luquain-Costaz, Michel Guichardant, Vanessa Euthine, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Lipid Biology Laboratory, RIKEN - Institute of Physical and Chemical Research [Japon] (RIKEN), Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine-Osaka University Graduate School of Medicine, This work was supported by grants from INSA-Lyon, Inserm, and RIKEN at Tokyo-Wako, Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Vericel, Evelyne

Subjects
MESH: Lipoproteins, LDL, Gene Expression, ATP-binding cassette transporter, chemistry.chemical_compound, Mice, 0302 clinical medicine, Homeostasis, MESH: Animals, Foam cell, ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, 0303 health sciences, MESH: Lipoproteins, Orphan Nuclear Receptors, Plaque, Atherosclerotic, Cell biology, Lipoproteins, LDL, oxysterol receptors, Biochemistry, MESH: Orphan Nuclear Receptors, MESH: Homeostasis, MESH: ATP-Binding Cassette Transporters, Monoglycerides, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, MESH: Monoglycerides, Intracellular, MESH: Cholesterol, LDL, ATP Binding Cassette Transporter 1, MESH: Gene Expression, MESH: Foam Cells, Lipoproteins, Endosomes, Biology, Cholesterol 7 alpha-hydroxylase, Article, MESH: Lysophospholipids, Cell Line, 03 medical and health sciences, Animals, MESH: Plaque, Atherosclerotic, Liver X receptor, MESH: Mice, 030304 developmental biology, Cholesterol, Macrophages, MESH: Macrophages, Cholesterol, LDL, Sterol, MESH: Cell Line, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, chemistry, MESH: Endosomes, ATP-Binding Cassette Transporters, atherosclerosis, Lysophospholipids, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, 030217 neurology & neurosurgery, Foam Cells
Abstract

Objective— Endosomal signature phospholipid bis(monoacylglycero)phosphate (BMP) has been involved in the regulation of cellular cholesterol homeostasis. Accumulation of BMP is a hallmark of lipid storage disorders and was recently reported as a noticeable feature of oxidized low-density lipoprotein–laden macrophages. This study was designed to delineate the consequences of macrophage BMP accumulation on intracellular cholesterol distribution, metabolism, and efflux and to unravel the underlying molecular mechanisms. Approach and Results— We have developed an experimental design to specifically increase BMP content in RAW 264.7 macrophages. After BMP accumulation, cell cholesterol distribution was markedly altered, despite no change in low-density lipoprotein uptake and hydrolysis, cholesterol esterification, or total cell cholesterol content. The expression of cholesterol-regulated genes sterol regulatory element–binding protein 2 and hydroxymethylglutaryl-coenzyme A reductase was decreased by 40%, indicative of an increase of endoplasmic reticulum–associated cholesterol. Cholesterol delivery to plasma membrane was reduced as evidenced by the 20% decrease of efflux by cyclodextrin. Functionally, BMP accumulation reduced cholesterol efflux to both apolipoprotein A1 and high-density lipoprotein by 40% and correlated with a 40% decrease in mRNA contents of ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, and liver-X receptor α and β. Foam cell formation induced by oxidized low-density lipoprotein exposure was exacerbated in BMP-enriched cells. Conclusions— The present work shows for the first time a strong functional link between BMP and cholesterol-regulating genes involved in both intracellular metabolism and efflux. We propose that accumulation of cellular BMP might contribute to the deregulation of cholesterol homeostasis in atheromatous macrophages.

Published
2013
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7. A systems biology approach to the hepatic role of the oxysterol receptor LXR in the regulation of lipogenesis highlights a cross-talk with PPARα

Author

Stefania Murzilli, Frédéric Lasserre, Jean-Marc A. Lobaccaro, Normand Podechard, Arnaud Polizzi, Justine Bertrand-Michel, Thierry Pineau, Chiara Di Lisio, Alexandra Montagner, Pascal G.P. Martin, Nicolas Loiseau, Hervé Guillou, Simon Ducheix, Simona D'Amore, Aurélien Pommier, ToxAlim (ToxAlim), Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National Polytechnique (Toulouse) (Toulouse INP), Université de Toulouse (UT)-Ecole d'Ingénieurs de Purpan (INP - PURPAN), Université de Toulouse (UT)-Université de Toulouse (UT), Stress, membrane, signalisation, Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Toxicologie Intégrative & Métabolisme (ToxAlim-TIM), Génétique, Reproduction et Développement (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Unité de Nutrition Humaine (UNH), Institut National de la Recherche Agronomique (INRA)-Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université, Laboratory of Lipid Metabolism and Cancer, Consorzio Mario NegriSud, MetaToul Lipidomics, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-MetaboHUB-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Centre de Physiopathologie Toulouse Purpan (CPTP), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INRA-FORMAS France-Sweden cooperative program, Region Midi-Pyrenees, ANR project (Crisalis), Ministere de l'Enseignement Superieur et de la Recherche, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Recherche Agronomique (INRA)-Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Centre National de la Recherche Scientifique (CNRS)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Auvergne - Clermont-Ferrand I (UdA)-Clermont Université-Institut National de la Recherche Agronomique (INRA), Plateau MetaToul-LIPIDOMIQUE = MetaToul-Lipidomics, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul-MetaboHUB, Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées - Toulouse (INSA Toulouse), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique, Reproduction et Développement - Clermont Auvergne (GReD), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne (UCA)-Centre National de la Recherche Scientifique (CNRS), Clermont Université-Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Recherche Agronomique (INRA), Plateau MetaToul-LIPIDOMIQUE, Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaToul, Plateau de lipidomique, Centre de Physiopathologie Toulouse Purpan ex IFR 30 et IFR 150 (CPTP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Le Corre, Morgane, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Ecole d'Ingénieurs de Purpan (INPT - EI Purpan), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut de recherche en santé, environnement et travail (Irset), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-MetaboHUB-MetaToul, Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Ecole Nationale Vétérinaire de Toulouse (ENVT), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Institut National de la Santé et de la Recherche Médicale (INSERM)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université d'Angers (UA)

Subjects
Male, Steatosis, Hydrocarbons, Fluorinated, MESH: Sulfonamides, Peroxisome proliferator-activated receptor, [SDV.GEN] Life Sciences [q-bio]/Genetics, MESH: Protein Isoforms, Ligands, Biochemistry, PPARα, Mice, 0302 clinical medicine, Cytochrome P-450 Enzyme System, Fenofibrate, MESH: Ligands, Protein Isoforms, MESH: Animals, MESH: PPAR alpha, Beta oxidation, Liver X Receptors, Oligonucleotide Array Sequence Analysis, chemistry.chemical_classification, 0303 health sciences, Sulfonamides, Systems Biology, Fatty Acids, General Medicine, Orphan Nuclear Receptors, MESH: Fatty Acids, Liver, MESH: Orphan Nuclear Receptors, 030220 oncology & carcinogenesis, MESH: Systems Biology, Lipogenesis, MESH: Cytochrome P-450 Enzyme System, lipids (amino acids, peptides, and proteins), LXR, Transcriptional Activation, medicine.medical_specialty, Oxysterol, MESH: Mice, Transgenic, MESH: Receptor Cross-Talk, Mice, Transgenic, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Retinoid X receptor, 03 medical and health sciences, Internal medicine, medicine, Animals, PPAR alpha, Cytochrome P450 Family 4, Liver X receptor, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, 030304 developmental biology, MESH: Lipogenesis, [SDV.GEN]Life Sciences [q-bio]/Genetics, Fatty acid, Receptor Cross-Talk, MESH: Fenofibrate, MESH: Male, MESH: Hydrocarbons, Fluorinated, Endocrinology, Nuclear receptor, chemistry, MESH: Oligonucleotide Array Sequence Analysis, MESH: Transcriptional Activation, MESH: Liver
Abstract

International audience; The Liver X Receptors (LXRs) α and β and the Peroxisome Proliferator-Activated Receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids.

Published
2013
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8. Liver X receptor activation stimulates iron export in human alternative macrophages

Author

Bories, Gael, Colin, Sophie, Vanhoutte, Jonathan, Derudas, Bruno, Copin, Corinne, Fanchon, Melanie, Daoudi, Mehdi, Belloy, Loic, Haulon, Stephan, Zawadzki, Christophe, Jude, Brigitte, Staels, Bart, Chinetti-Gbaguidi, Giulia, Derudas, Marie-Hélène, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut Européen du Diabète (EGID), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Université de Lille, Droit et Santé, and Grants from the Région Nord-Pas de Calais/FEDER (CPER N. 1449), the Agence Nationale de la Recherche, France (AlMHA project), the Fondation de France, the Fondation pour la Recherche Médicale, the transatlantic Leducq HDL Network, the 'European Genomic Institute for Diabetes' (EGID, ANR-10-LABX-46)

Subjects
MESH: Iron, MESH: Humans, MESH: Biological Transport, MESH: Macrophages, MESH: Phenotype, MESH: Apolipoproteins E, MESH: Orphan Nuclear Receptors, MESH: Homeostasis, MESH: Mannose-Binding Lectins, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: ATP-Binding Cassette Transporters, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: ATP Binding Cassette Transporter 1, MESH: Plaque, Atherosclerotic, MESH: Antigens, Differentiation, Myelomonocytic, MESH: Antigens, CD, MESH: Lectins, C-Type, MESH: Receptors, Cell Surface, MESH: Cells, Cultured
Abstract

International audience; RATIONALE: In atherosclerotic plaques, iron preferentially accumulates in macrophages where it can exert pro-oxidant activities. OBJECTIVE: The objective of this study was, first, to better characterize the iron distribution and metabolism in macrophage subpopulations in human atherosclerotic plaques and, second, to determine whether iron homeostasis is under the control of nuclear receptors, such as the liver X receptors (LXRs). METHODS AND RESULTS: Here we report that iron depots accumulate in human atherosclerotic plaque areas enriched in CD68 and mannose receptor (MR)-positive (CD68(+)MR(+)) alternative M2 macrophages. In vitro IL-4 polarization of human monocytes into M2 macrophages also resulted in a gene expression profile and phenotype favoring iron accumulation. However, M2 macrophages on iron exposure acquire a phenotype favoring iron release, through a strong increase in ferroportin expression, illustrated by a more avid oxidation of extracellular low-density lipoprotein by iron-loaded M2 macrophages. In line, in human atherosclerotic plaques, CD68(+)MR(+) macrophages accumulate oxidized lipids, which activate LXRα and LXRβ, resulting in the induction of ABCA1, ABCG1, and apolipoprotein E expression. Moreover, in iron-loaded M2 macrophages, LXR activation induces nuclear factor erythroid 2-like 2 expression, thereby increasing ferroportin expression, which, together with a decrease of hepcidin mRNA levels, promotes iron export. CONCLUSIONS: These data identify a role for M2 macrophages in iron handling, a process regulated by LXR activation.

Published
2013
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9. Control of metabolism by nutrient-regulated nuclear receptors acting in the brain

Author

Janne Prawitt, Kadiombo Bantubungi, Bart Staels, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Derudas, Marie-Hélène

Subjects
Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, nuclear receptors, Type 2 diabetes, Disease, MESH: Energy Intake, Bioinformatics, Biochemistry, Energy homeostasis, MESH: Autonomic Nervous System, Mice, 0302 clinical medicine, Endocrinology, MESH: Obesity, MESH: Animals, MESH: PPAR alpha, Adiposity, Liver X Receptors, 0303 health sciences, MESH: Energy Metabolism, Orphan Nuclear Receptors, 3. Good health, MESH: Orphan Nuclear Receptors, Molecular Medicine, MESH: Diabetes Mellitus, Type 2, medicine.medical_specialty, MESH: Rats, brain, MESH: Nuclear Receptor Subfamily 1, Group D, Member 1, Context (language use), Biology, Autonomic Nervous System, 03 medical and health sciences, MESH: Brain, Diabetes mellitus, Internal medicine, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Animals, Humans, PPAR alpha, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Obesity, Liver X receptor, Molecular Biology, energy homeostasis, MESH: Mice, Dyslipidemias, 030304 developmental biology, MESH: Adiposity, MESH: Humans, MESH: Dyslipidemias, Cell Biology, medicine.disease, Rats, PPAR gamma, Diabetes Mellitus, Type 2, Nuclear receptor, MESH: PPAR gamma, Nuclear Receptor Subfamily 1, Group D, Member 1, Energy Intake, Energy Metabolism, 030217 neurology & neurosurgery, Dyslipidemia
Abstract

International audience; Today, we are witnessing a rising incidence of obesity worldwide. This increase is due to a sedentary life style, an increased caloric intake and a decrease in physical activity. Obesity contributes to the appearance of type 2 diabetes, dyslipidemia and cardiovascular complications due to atherosclerosis, and nephropathy. Therefore, the development of new therapeutic strategies may become a necessity. Given the metabolism controlling properties of nuclear receptors in peripheral organs (such as liver, adipose tissues, pancreas) and their implication in various processes underlying metabolic diseases, they constitute interesting therapeutic targets for obesity, dyslipidemia, cardiovascular disease and type 2 diabetes. The recent identification of the central nervous system as a player in the control of peripheral metabolism opens new avenues to our understanding of the pathophysiology of obesity and type 2 diabetes and potential novel ways to treat these diseases. While the metabolic functions of nuclear receptors in peripheral organs have been extensively investigated, little is known about their functions in the brain, in particular with respect to brain control of energy homeostasis. This review provides an overview of the relationships between nuclear receptors in the brain, mainly at the hypothalamic level, and the central regulation of energy homeostasis. In this context, we will particularly focus on the role of PPARα, PPARγ, LXR and Rev-erbα.

Published
2012
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10. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways

Author

Chinetti-Gbaguidi, Giulia, Baron, Morgane, Bouhlel, Mohamed Amine, Vanhoutte, Jonathan, Copin, Corinne, Sebti, Yasmine, Derudas, Bruno, Mayi, Thérèse, Bories, Gael, Tailleux, Anne, Haulon, Stéphane, Zawadzki, Christophe, Jude, Brigitte, Staels, Bart, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hémostase et pathologie cardiovasculaire, and EA2693-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé

Subjects
MESH: Cell Differentiation, MESH: Humans, MESH: Genetic Predisposition to Disease, nuclear receptors, cholesterol, MESH: Macrophages, Atherosclerosis, macrophages, MESH: Leukocytes, Mononuclear, MESH: Cholesterol, MESH: Orphan Nuclear Receptors, MESH: PPAR gamma, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Plaque, Atherosclerotic, MESH: Phagocytosis, MESH: Cells, Cultured
Abstract

International audience; RATIONALE: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype. OBJECTIVE: We previously reported the presence of CD68(+) mannose receptor (MR)(+) M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68(+)MR(+) macrophages is still unknown. METHODS AND RESULTS: Histological analysis revealed that CD68(+)MR(+) macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68(+)MR(-) macrophages. Interleukin (IL)-4-polarized CD68(+)MR(+) macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68(+)MR(+) macrophages. By contrast, CD68(+)MR(+) macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. CONCLUSIONS: These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.

Published
2011
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11. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways

Author

Chinetti-Gbaguidi, Giulia, Baron, Morgane, Bouhlel, Mohamed Amine, Vanhoutte, Jonathan, Copin, Corinne, Sebti, Yasmine, Derudas, Bruno, Mayi, Thérèse, Bories, Gael, Tailleux, Anne, Haulon, Stéphane, Zawadzki, Christophe, Jude, Brigitte, Staels, Bart, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hémostase et pathologie cardiovasculaire, EA2693-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, and Derudas, Marie-Hélène

Subjects
MESH: Cell Differentiation, MESH: Humans, MESH: Genetic Predisposition to Disease, nuclear receptors, cholesterol, MESH: Macrophages, Atherosclerosis, macrophages, MESH: Leukocytes, Mononuclear, MESH: Cholesterol, MESH: Orphan Nuclear Receptors, MESH: PPAR gamma, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Plaque, Atherosclerotic, MESH: Phagocytosis, MESH: Cells, Cultured
Abstract

International audience; RATIONALE: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an "alternative" M2 phenotype. OBJECTIVE: We previously reported the presence of CD68(+) mannose receptor (MR)(+) M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68(+)MR(+) macrophages is still unknown. METHODS AND RESULTS: Histological analysis revealed that CD68(+)MR(+) macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68(+)MR(-) macrophages. Interleukin (IL)-4-polarized CD68(+)MR(+) macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68(+)MR(+) macrophages. By contrast, CD68(+)MR(+) macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. CONCLUSIONS: These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.

Published
2011
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12. Human atherosclerotic plaque alternative macrophages display low cholesterol handling but high phagocytosis because of distinct activities of the PPARγ and LXRα pathways.: Atherosclerotic plaque alternative macrophages

Author

Corinne Copin, Bruno Derudas, Giulia Chinetti-Gbaguidi, Jonathan Vanhoutte, Brigitte Jude, Bart Staels, Gael Bories, Christophe Zawadzki, Stephane Haulon, Anne Tailleux, Yasmine Sebti, Mohamed Amine Bouhlel, Thérèse Hèrvée Mayi, Morgane Baron, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Hémostase et pathologie cardiovasculaire, and EA2693-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé

Subjects
Apolipoprotein E, MESH: Cell Differentiation, Physiology, nuclear receptors, 030204 cardiovascular system & hematology, Article, 03 medical and health sciences, 0302 clinical medicine, MESH: Cholesterol, Phagocytosis, Lipid droplet, Humans, Genetic Predisposition to Disease, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Plaque, Atherosclerotic, Liver X receptor, MESH: Phagocytosis, Cells, Cultured, 030304 developmental biology, Liver X Receptors, 0303 health sciences, MESH: Humans, biology, CD68, MESH: Genetic Predisposition to Disease, Interleukin, cholesterol, MESH: Macrophages, Cell Differentiation, Orphan Nuclear Receptors, Atherosclerosis, Plaque, Atherosclerotic, Cell biology, macrophages, PPAR gamma, MESH: Leukocytes, Mononuclear, Biochemistry, MESH: Orphan Nuclear Receptors, MESH: PPAR gamma, Monocyte differentiation, ABCA1, biology.protein, Leukocytes, Mononuclear, Cardiology and Cardiovascular Medicine, Mannose receptor, MESH: Cells, Cultured
Abstract

Rationale: A crucial step in atherogenesis is the infiltration of the subendothelial space of large arteries by monocytes where they differentiate into macrophages and transform into lipid-loaded foam cells. Macrophages are heterogeneous cells that adapt their response to environmental cytokines. Th1 cytokines promote monocyte differentiation into M1 macrophages, whereas Th2 cytokines trigger an “alternative” M2 phenotype. Objective: We previously reported the presence of CD68 + mannose receptor (MR) + M2 macrophages in human atherosclerotic plaques. However, the function of these plaque CD68 + MR + macrophages is still unknown. Methods and Results: Histological analysis revealed that CD68 + MR + macrophages locate far from the lipid core of the plaque and contain smaller lipid droplets compared to CD68 + MR − macrophages. Interleukin (IL)-4–polarized CD68 + MR + macrophages display a reduced capacity to handle and efflux cellular cholesterol because of low expression levels of the nuclear receptor liver x receptor (LXR)α and its target genes, ABCA1 and apolipoprotein E, attributable to the high 15-lipoxygenase activity in CD68 + MR + macrophages. By contrast, CD68 + MR + macrophages highly express opsonins and receptors involved in phagocytosis, resulting in high phagocytic activity. In M2 macrophages, peroxisome proliferator-activated receptor (PPAR)γ activation enhances the phagocytic but not the cholesterol trafficking pathways. Conclusions: These data identify a distinct macrophage subpopulation with a low susceptibility to become foam cells but high phagocytic activity resulting from different regulatory activities of the PPARγ-LXRα pathways.

Published
2011
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13. Liver X Receptor (LXR) activation negatively regulates visfatin expression in macrophages

Author

Giulia Chinetti-Gbaguidi, Elena Rigamonti, Bart Staels, François Pattou, Thérèse Hèrvée Mayi, Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de chirurgie générale et endocrinienne, Hôpital Claude Huriez [Lille], CHU Lille-CHU Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Thérapie cellulaire du diabète, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, The research leading to these results has received funding from the European Community's 7th Framework Programme (FP7/2007-2013) under grant agreement n° 201608, the 'Nouvelle Societé Française d'Athérosclérose' (to T.H. Mayi) and the 'Fondation Coeur et Artères'., Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), and Derudas, Marie-Hélène

Subjects
nuclear receptors : adipocytokines, Peroxisome proliferator-activated receptor, Gene Expression, Biochemistry, MESH: Down-Regulation, 0302 clinical medicine, Receptor, Nicotinamide Phosphoribosyltransferase, Cells, Cultured, Liver X Receptors, chemistry.chemical_classification, Regulation of gene expression, 0303 health sciences, MESH: Cytokines, MESH: Gene Expression Regulation, Enzymologic, MESH: NAD, Orphan Nuclear Receptors, MESH: Orphan Nuclear Receptors, Cytokines, lipids (amino acids, peptides, and proteins), medicine.symptom, MESH: Cells, Cultured, medicine.medical_specialty, MESH: Gene Expression, Adipose tissue macrophages, Biophysics, Down-Regulation, Inflammation, macrophage, Biology, Gene Expression Regulation, Enzymologic, 03 medical and health sciences, Downregulation and upregulation, Internal medicine, visfatin, medicine, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Liver X receptor, Molecular Biology, 030304 developmental biology, MESH: Humans, Macrophages, MESH: Macrophages, Cell Biology, MESH: Nicotinamide Phosphoribosyltransferase, NAD, PPAR gamma, Endocrinology, chemistry, Nuclear receptor, MESH: PPAR gamma, inflammation, 030217 neurology & neurosurgery
Abstract

International audience; Adipose tissue macrophages (ATM) are the major source of visfatin, a visceral fat adipokine upregulated during obesity. Also known to play a role in B cell differentiation (pre-B cell colony-enhancing factor (PBEF)) and NAD biosynthesis (nicotinamide phosphoribosyl transferase (NAMPT)), visfatin has been suggested to play a role in inflammation. Liver X Receptor (LXR) and Peroxisome Proliferator-Activated Receptor (PPAR)γ are nuclear receptors expressed in macrophages controlling the inflammatory response. Recently, we reported visfatin as a PPARγ target gene in human macrophages. In this study, we examined whether LXR regulates macrophage visfatin expression. Synthetic LXR ligands decreased visfatin gene expression in a LXR-dependent manner in human and murine macrophages. The decrease of visfatin mRNA was paralleled by a decrease of protein secretion. Consequently, a modest and transient decrease of NAD(+) concentration was observed. Interestingly, LXR activation decreased the PPARγ-induced visfatin gene and protein secretion in human macrophages. Our results identify visfatin as a gene oppositely regulated by the LXR and PPARγ pathways in human macrophages.

Published
2011
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14. Regulation of LPCAT3 by LXR

Author

Frédéric Lecerf, Olivier Demeure, Hervé Guillou, Cécile Duby, Simon Ducheix, Colette Désert, Sandrine Lagarrigue, Génétique Animale (GARen), IFR140-Ecole Nationale Supérieure Agronomique de Rennes-AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Ecole Nationale Supérieure Agronomique de Rennes

Subjects
Hydrocarbons, Fluorinated, Response element, MESH: Sulfonamides, Transactivation, 0302 clinical medicine, MESH: 1-Acylglycerophosphocholine O-Acyltransferase, Gene expression, MESH: Animals, database, Liver X Receptors, 0303 health sciences, Sulfonamides, Fatty Acids, MESH: Chickens, 1-Acylglycerophosphocholine O-Acyltransferase, General Medicine, Orphan Nuclear Receptors, Chicken, MESH: Fatty Acids, oxysterol receptors, MESH: Orphan Nuclear Receptors, 030220 oncology & carcinogenesis, lipids (amino acids, peptides, and proteins), LXRE, profiles, alpha, MESH: Cell Line, Tumor, nuclear receptor lxr, In silico, x-receptor, Biology, 03 medical and health sciences, MESH: Gene Expression Profiling, MBOAT5, Cell Line, Tumor, expression, Genetics, Phospholipid homeostasis, Animals, Humans, acyltransferases, Liver X receptor, Gene, 030304 developmental biology, promoter, MESH: Humans, Lipogenesis, Gene Expression Profiling, Molecular biology, gene-expression, MESH: Hydrocarbons, Fluorinated, Gene expression profiling, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, activation, Chickens
Abstract

Chantier qualité GA; In this work we analyzed the transcriptome profiles of chicken hepatoma cells (LMH) in response to T0901317, a pharmacological agonist of the liver X receptor (LXR). Through an in silico search for LXRE (LXR response element) consensus sequences in the promoter of genes whose expression was shown to be sensitive to TO901317, we identified a LXRE in the promoter of the LPCAT3 (lysophosphatidylcholine acyltransferase 3). This motif is highly conserved between species. We further investigated the regulation of this gene and showed that the expression of LPCAT3 was induced both in chicken and human hepatoma cells (LMH and HuH-7, respectively) in response to T0901317. Transactivation and electrophoretic mobility shift assays allowed us to locate a functional LXRE in the chicken LPCAT3 promoter. Altogether these data evidence for the first time that the chicken LPCAT3 gene is a direct target of LXR and therefore suggest a new role for LXR in phospholipid homeostasis.

Published
2010
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15. Liver X receptor alpha regulates fatty acid synthase expression in chicken

Author

Olivier Demeure, Colette Désert, Sirine Assaf, Dominique Hazard, Hervé Guillou, Cécile Duby, Sandrine Lagarrigue, Génétique Animale (GARen), IFR140-Ecole Nationale Supérieure Agronomique de Rennes-AGROCAMPUS OUEST-Institut National de la Recherche Agronomique (INRA), Institut National de la Recherche Agronomique (INRA)-AGROCAMPUS OUEST, and Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Ecole Nationale Supérieure Agronomique de Rennes

Subjects
liver X receptor alpha, Hydrocarbons, Fluorinated, MESH: Sulfonamides, MESH: Amino Acid Sequence, member 3, chemistry.chemical_compound, MESH: Fatty Acid Synthetase Complex, nuclear receptor, MESH: Animals, Cells, Cultured, Liver X Receptors, 0303 health sciences, fatty acid synthase, Sulfonamides, biology, 030302 biochemistry & molecular biology, MESH: Chickens, Liver X receptor alpha, General Medicine, Orphan Nuclear Receptors, Fatty acid synthase, group H, oxysterol receptors, Biochemistry, MESH: Orphan Nuclear Receptors, lipids (amino acids, peptides, and proteins), transcription, nuclear receptor subfamily 1, MESH: Cells, Cultured, chicken, response pathway, Molecular Sequence Data, 03 medical and health sciences, Liver X receptor beta, Animals, Amino Acid Sequence, Liver X receptor, genome, Fatty acid synthesis, lipogenesis, 030304 developmental biology, MESH: Molecular Sequence Data, Liver receptor homolog-1, hepatic lipogenesis, tissue, gene-expression, MESH: Hydrocarbons, Fluorinated, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Nuclear receptor, chemistry, biology.protein, lxr-alpha, Sterol Regulatory Element Binding Protein 1, Animal Science and Zoology, activation, Fatty Acid Synthases, Chickens
Abstract

Chantier qualité GA; Liver X receptor alpha (LXRalpha), also referred to as nuclear receptor subfamily 1, group H, member 3 is a member of the nuclear hormone receptor superfamily, and has recently been shown to act as a master transcription factor governing hepatic lipogenesis in mammals. Liver X receptor alpha directly regulates both the expression of other lipogenic transcription factors and the expression of lipogenic enzymes, thereby enhancing hepatic fatty acid synthesis (FASN). In birds, like in humans, fatty acid synthesis primarily occurs in the liver. Whether LXRalpha is involved in hepatic regulation of lipogenic genes remained to be investigated in this species. Here we show that fatty acid synthase and the expression of other lipogenic genes (sterol regulatory element binding protein 1 and steroyl coenzyme A desaturase 1) are induced in chicken hepatoma cells in response to a pharmacological liver X receptor agonist, T0901317. A detailed analysis of the chicken FASN promoter revealed a functional liver X response element. These data define the chicken FASN gene as a direct target of LXRalpha and further expand the role of LXRalpha as a regulator of lipid metabolism in this species.

Published
2009
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