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1. Elevated serum ceramides are linked with obesity-associated gut dysbiosis and impaired glucose metabolism

Author

Maria Carlota Dao, Edi Prifti, Judith Aron-Wisnewsky, Eugeni Belda, Salwa W. Rizkalla, Brandon D. Kayser, Karine Clément, Isabelle Dugail, Jean-Daniel Zucker, Marie Lhomme, Anatol Kontush, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Service de Nutrition [CHU Pitié-Salpétrière], Institut E3M [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Service de nutrition [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]

Subjects
Male, [SDV]Life Sciences [q-bio], Endocrinology, Diabetes and Metabolism, Clinical Biochemistry, Gut flora, 01 natural sciences, Biochemistry, chemistry.chemical_compound, Endotoxin, Tandem Mass Spectrometry, Glucose homeostasis, Chromatography, High Pressure Liquid, 2. Zero hunger, Glucose metabolism, 0303 health sciences, biology, Methanobrevibacter smithii, Middle Aged, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, 3. Good health, Female, Adult, Ceramide, medicine.medical_specialty, Diabetes risk, Ceramides, Article, 03 medical and health sciences, Insulin resistance, Internal medicine, medicine, Humans, Metabolomics, Obesity, Microbiome, Retrospective Studies, 030304 developmental biology, Sphingolipids, 010401 analytical chemistry, Lipid metabolism, biology.organism_classification, medicine.disease, Gastrointestinal Microbiome, 0104 chemical sciences, Cross-Sectional Studies, Glucose, Endocrinology, chemistry, Dysbiosis, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; INTRODUCTION:Low gut microbiome richness is associated with dyslipidemia and insulin resistance, and ceramides and other sphingolipids are implicated in the development of diabetes.OBJECTIVES:Determine whether circulating sphingolipids, particularly ceramides, are associated with alterations in the gut microbiome among obese patients with increased diabetes risk.METHODS:This was a cross-sectional and longitudinal retrospective analysis of a dietary/weight loss intervention. Fasted serum was collected from 49 participants (41 women) and analyzed by HPLC-MS/MS to quantify 45 sphingolipids. Shotgun metagenomic sequencing of stool was performed to profile the gut microbiome.RESULTS:Confirming the link to deteriorated glucose homeostasis, serum ceramides were positively correlated with fasting glucose, but inversely correlated with fasting and OGTT-derived measures of insulin sensitivity and β-cell function. Significant associations with gut dysbiosis were demonstrated, with SM and ceramides being inversely correlated with gene richness. Ceramides with fatty acid chain lengths of 20-24 carbons were the most associated with low richness. Diet-induced weight loss, which improved gene richness, decreased most sphingolipids. Thirty-one MGS, mostly corresponding to unidentified bacteria species, were inversely correlated with ceramides, including a number of Bifidobacterium and Methanobrevibacter smithii. Higher ceramide levels were also associated with increased metagenomic modules for lipopolysaccharide synthesis and flagellan synthesis, two pathogen-associated molecular patterns, and decreased enrichment of genes involved in methanogenesis and bile acid metabolism.CONCLUSION:This study identifies an association between gut microbiota richness, ceramides, and diabetes risk in overweight/obese humans, and suggests that the gut microbiota may contribute to dysregulation of lipid metabolism in metabolic disorders.

Published
2019
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2. PCSK9 inhibition, atherosclerotic cardiovascular disease, and health economics: Challenges at the crossroads

Author

Jane K Stock, M. John Chapman, Lieven Annemans, University College Ghent, Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Gestionnaire, Hal Sorbonne Université, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Endocrinology, Diabetes and Metabolism, 030204 cardiovascular system & hematology, MESH: Atherosclerosis, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Health care, Medicine, 030212 general & internal medicine, Enzyme Inhibitors, [SHS.ECO] Humanities and Social Sciences/Economics and Finance, PCSK9 Inhibitors, Nutrition and Dietetics, Atherosclerotic cardiovascular disease, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Disease trajectory, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Innovative pharmacotherapeutics, Models, Economic, PCSK9 inhibitors, MESH: Enzyme Inhibitors, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine, medicine.drug, MESH: Cholesterol, LDL, medicine.medical_specialty, Statin, medicine.drug_class, JEL: I - Health, Education, and Welfare/I.I1 - Health/I.I1.I18 - Government Policy • Regulation • Public Health, 03 medical and health sciences, Ezetimibe, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal Medicine, Humans, Low-density lipoprotein cholesterol, Intensive care medicine, MESH: Models, Economic, Health economics, MESH: Humans, business.industry, PCSK9, Health economic modeling, Cholesterol, LDL, Atherosclerosis, MESH: Proprotein Convertase 9, Quality-adjusted life year, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

International audience; Background: Improved survival after a cardiovascular event has led to an expanding patient population at very high risk of recurrent events. Reduction in low-density lipoprotein cholesterol, and thus implicitly non-high-density lipoprotein cholesterol, to guideline-recommended goals is a key tenet of secondary prevention. Yet, standard-of-care treatment with statin (with or without ezetimibe) often leaves a high risk of preventable cardiovascular events. Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9), highly efficacious lipid-lowering treatments that confer reduction in cardiovascular events and death, clearly have a role in the personalized management of these very-high-risk patients. Given budget constraints, however, their integration into the health care pathway merits health economic considerations. Consequently, it is important to identify challenges at the crossroads of the clinical and economic dimensions.Findings and conclusion: Health economic analyses involve application of modeling scenarios integrating multiple parameters to ultimately yield values for quality-adjusted life-years and cost-effectiveness ratios. To date, these analyses have led to widely variable estimates of these benchmarks for PCSK9 inhibitors, causing confusion among stakeholders in the health care pathway. Clearly, a consensual approach to the conduct and reporting of health economic analyses involving all players, including noneconomists such as clinicians and patient advocates, is essential to bridge the gap between the clinical needs of patients and financial access to PCSK9 inhibition.

Published
2019
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3. Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: insights from metabolic biomarker profiling and network analysis

Author

Adiels, M., Chapman, M. J., Robillard, P., Krempf, Michel, Laville, Martine, Boren, J., University of Gothenburg (GU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), 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), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
0303 health sciences, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 030204 cardiovascular system & hematology, Cardiology and Cardiovascular Medicine, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract

International audience

Published
2018
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4. Early central blood pressure elevation in adult patients with 21-hydroxylase deficiency

Author

Randa Bittar, Jérôme Dulon, Nora Dahmoune, Marie Laure Tanguy, Philippe Touraine, Gaelle Lethielleux, Joe-Elie Salem, Bernard I. Levy, Antonio Gallo, David Rosenbaum, Monique Leban, Eric Bruckert, Xavier Girerd, Anne Bachelot, Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre des Pathologies gynécologiques Rares [CHU Pitié-Salpêtrière], Centre de référence des maladies endocriniennes rares de la croissance et du développement [CHU Pitié-Salpêtrière], Service d’endocrinologie et médecine de la reproduction [CHU Pitié-Salpêtrière], Institut E3M [CHU Pitié-Salpêtrière], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], Service de Biochimie Endocrinienne et Oncologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de biochimie et hormonologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Service d'endocrinologie-métabolisme [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Sorbonne Université (SU), Centre de référence des maladies endocriniennes rares de la croissance [CHU Pitié-Salpêtrière], Service d'endocrinologie et de la médecine reproductive [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), and Service de pharmacologie biologique [CHU Pitié-Salpâtrière]

Subjects
Adult, medicine.medical_specialty, Physiology, [SDV]Life Sciences [q-bio], Context (language use), Blood Pressure, 030204 cardiovascular system & hematology, Pulse Wave Analysis, Carotid Intima-Media Thickness, Microcirculation, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Humans, Congenital adrenal hyperplasia, 030212 general & internal medicine, Prospective Studies, Prospective cohort study, Child, Pulse wave velocity, biology, Adrenal Hyperplasia, Congenital, business.industry, 21-Hydroxylase, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, 3. Good health, Blood pressure, biology.protein, Cardiology, Female, Cardiology and Cardiovascular Medicine, business, Rare disease
Abstract

International audience; CONTEXT:Controversial data exist on cardiovascular damages in patients with congenital adrenal hyperplasia (CAH).OBJECTIVE:To assess blood pressure and early cardiovascular damages on a large cohort of adult CAH patients and control individuals.DESIGN:Case-control study.SETTING:Referral Center for Rare Disease, Pitié Salpêtrière Hospital, Paris, France.PATIENTS OR OTHER PARTICIPANTS:Fifty-eight women and 26 men with CAH diagnosed in childhood and 85 controls matched-paired for sex, age and smoking status were prospectively included.INTERVENTION:Measurement of large arteries and microcirculatory anatomical and functional indices as well as hormonal status and cardiovascular risk factors evaluation.MAIN OUTCOME MEASURE:The primary objective was to compare carotid intima-media thickness (cIMT) in CAH patients and controls. The secondary objectives were to compare blood pressure (BP), radial augmentation index (rAI), central BP, carotid-femoral pulse wave velocity (PWV), skin microcirculation indices and inflammation parameters in CAH patients and controls.RESULTS:Although PWV and cIMT were identical in patients and controls, higher rAI (64.6 ± 1.7 vs. 59.9 ± 1.6%, P = 0.02) and higher central SBP (101.8 ± 1.5 vs. 95.1 ± 1.5 mmHg, P

Published
2018
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5. Niacin action in the atherogenic mixed dyslipidemia of metabolic syndrome: Insights from metabolic biomarker profiling and network analysis

Author

Adiels, Martin, Chapman, M John, Robillard, Paul, Krempf, Michel, Laville, Martine, Borén, Jan, Niacin Study Group, ., Hôpital Guillaume et René Laennec - Centre Hospitalier Universitaire de Nantes, Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), University of Gothenburg (GU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie des Adaptations Nutritionnelles (PhAN), Université de Nantes (UN)-Institut National de la Recherche Agronomique (INRA), Mécanisme Moléculaire du Diabète (MMD), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), GlaxoSmithKline (Les Ulis, France), Randox Laboratories (Crumlin, N. Ireland), Sahlgrenska University Hospital ALF Research Grants, National Institute for Health and Medical Research, ARLA (Association for Research on Lipoproteins and Atherogenesis), Randox Laboratories, 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), Institut National de la Recherche Agronomique (INRA)-Université de Nantes (UN), and ProdInra, Migration

Subjects
Male, HDL, [SDV]Life Sciences [q-bio], cardiovascular-disease, adipose-tissue, Triglyceride, Niacin, insulin-resistance, LDL, hepg2 cells, high-risk, Apolipoprotein CIII, Mixed dyslipidemia, Humans, Pharmacology & Pharmacy, ER niacin, Blood Coagulation, nicotinic-acid, Dyslipidemias, Inflammation, Metabolic Syndrome, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, adiponectin, Interleukin-6, Macrophages, extended-release niacin, Middle Aged, Apolipoprotein, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, apolipoprotein-a-i, Phenotype, Liver, lipids (amino acids, peptides, and proteins), type-2 diabetes-mellitus, Insulin Resistance, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, CIII, Biomarkers
Abstract

International audience; BACKGROUND: Niacin as an adjunct to statin treatment to reduce cardiovascular risk is questioned. OBJECTIVE: To evaluate interrelationships between the effects of niacin on mixed dyslipidemia and a spectrum of metabolic and inflammatory biomarkers. METHODS: Obese, nondiabetic, hypertriglyceridemic males (n = 19) with low high-density lipoprotein cholesterol levels received extended-release nicotinic acid for 8 weeks. Multiple biomarkers were measured using enzyme-linked immunosorbent assay, enzymatic/absorptiometric, or multiplex biochip assays. Treatment effects were determined for each variable and a differential correlation network created on the basis of univariate correlations between baseline and response to niacin treatment for all pairs of variables. RESULTS: Extended-release niacin treatment favoured normalization of plasma lipid and apolipoprotein profile. Plasma markers of inflammation, hepatic function, cellular adhesion and proliferation, and macrophage phenotype were attenuated; however, insulin resistance increased. Differential network analysis revealed that changes in triglycerides and high-density lipoprotein cholesterol were closely linked; equally, niacin mediated reductions in total cholesterol, apolipoprotein B, low-density lipoprotein cholesterol and lipoprotein(a) clustered together, as did homeostatic model assessment of insulin resistance, insulin, and interleukin-6 levels. Two clusters of inflammatory markers were identified, involving (1) intercellular adhesion molecule 1 and high-sensitive C-reactive protein and (2) soluble tumor necrosis factor receptors; and novel clusters involving matrix metallopeptidase 9 and apolipoprotein E, and adiponectin and cystatin C, respectively, were equally revealed. At lower stringency, lipid and insulin resistance clusters were linked; a C-reactive protein-centered cluster linked reduction in apolipoprotein Cu to intercellular adhesion molecule 1, gamma-glutamyltransferase, soluble tumor necrosis factor receptors, and E-selectin. CONCLUSION: A niacin-mediated trend to normalize atherogenic mixed dyslipidemia was intimately linked to attenuation of biomarkers of inflammation, cell adhesion, hepatic dysfunction and cell proliferation, but to enhanced insulin resistance and plasma homocysteine elevation. (C) 2018 National Lipid Association. Published by Elsevier Inc.

Published
2017
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6. Early Coronary Calcifications are Related to Cholesterol Burden in Heterozygous Familial Hypercholesterolemia

Author

Valérie Carreau, Eric Bruckert, Alain Carrié, Philippe Giral, Randa Bittar, Sophie Béliard, Marianna Maranghi, Philippe Cluzel, Antonio Gallo, David Rosenbaum, Alban Redheuil, Marcello Arca, HAL-UPMC, Gestionnaire, Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Policlinico 'Umberto I', Universita' 'La Sapienza', Université Pierre et Marie Curie - Paris 6 (UPMC), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Service de radiologie cardiovasculaire et interventionnelle [CHU Pitié-Salpêtrière], and Laboratoire d'Imagerie Biomédicale [Paris] (LIB)

Subjects
Male, Multivariate analysis, Endocrinology, Diabetes and Metabolism, Familial hypercholesterolemia, Coronary Artery Disease, 030204 cardiovascular system & hematology, Cardiovascular disease prevention, Gastroenterology, Calcium Score, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Familial Hypercholesterolemia, education.field_of_study, Nutrition and Dietetics, Calcinosis, Middle Aged, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Cholesterol burden, Cholesterol, Coronary Artery Calcification, Female, medicine.symptom, Cardiology and Cardiovascular Medicine, Adult, medicine.medical_specialty, Heterozygote, Population, Asymptomatic, Hyperlipoproteinemia Type II, 03 medical and health sciences, Young Adult, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Internal Medicine, medicine, Humans, In patient, education, Coronary atherosclerosis, business.industry, nutritional and metabolic diseases, medicine.disease, Surgery, chemistry, Coronary artery calcification, business, Calcium score
Abstract

Background The identification of high-risk patients with Heterozygous Familial Hypercholesterolemia (HeFH) that may benefit from early treatment is challenging. Coronary Artery Calcification (CAC) score accounts for coronary atherosclerotic burden. It has proven its accuracy in cardiovascular risk (CVR) assessment in the general population but data in HeFH are lacking. Objective The aim of our study was to assess CAC prevalence and its relationship with lifelong cholesterol exposure, calculated by Total Cholesterol Burden (TCB) in patients with HeFH. Methods 112 HeFH patients (50% males, median age 45) regularly followed-up since diagnosis were prospectively recruited at Pitie-Salpetriere Hospital, Paris, France. CAC score was assessed using non contrast multi-detector computed tomography. TCB was calculated as total cholesterol (TC) x age at diagnosis plus annually assessed TC. Results The prevalence of CAC was 58%. Patients without CAC showed lower TCB than patients with CAC (298±110 vs 417.9±89 mmol-years/l, p

Published
2017
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7. Characterization of Hepatitis C Virus Particle Subpopulations Reveals Multiple Usage of the Scavenger Receptor BI for Entry Steps

Author

Marlène Dreux, Ophélia Granio, Thomas F. Baumert, Ralf Bartenschlager, Maryse Guerin, Christelle Granier, François-Loïc Cosset, François Penin, Mirjam B. Zeisel, Viet Loan Dao Thi, Dimitri Lavillette, Jimmy Mancip, Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Medicine II, University of Freiburg [Freiburg], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Department of Molecular Virology (DMV), Universität Heidelberg [Heidelberg], Plate-forme de R&D - Puces à Cellules Transfectées (PCT), Cancéropôle du Grand-Est (CGE)-Centre Européen de Biologie et de Génomique Structurale (CEBGS), Naiglin, Laurence, Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Bases moléculaires et structurales des systèmes infectieux (BMSSI), Universität Heidelberg [Heidelberg] = Heidelberg University, Virus, mmunité innée et trafic vésiculaire - Vesicular trafficking, innate response and viruses (VIV), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Référent HAL, CIRI, Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL)

Subjects
Apolipoprotein E, Very low-density lipoprotein, MESH: Virus Internalization, Hepacivirus, medicine.disease_cause, Biochemistry, MESH: Protein Structure, Tertiary, Mice, 0302 clinical medicine, Viral Envelope Proteins, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Animals, MESH: Hepacivirus, Receptor, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, chemistry.chemical_classification, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, virus diseases, Scavenger Receptors, Class B, MESH: Apolipoproteins E, 3. Good health, Cell biology, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, lipids (amino acids, peptides, and proteins), 030211 gastroenterology & hepatology, MESH: Cell Line, Tumor, MESH: Rats, Viral protein, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Biology, Microbiology, Apolipoproteins E, 03 medical and health sciences, Cell Line, Tumor, medicine, Animals, Humans, Scavenger receptor, MESH: Mice, Molecular Biology, 030304 developmental biology, MESH: Humans, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Cell Biology, Virus Internalization, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Scavenger Receptors, Class B, digestive system diseases, Protein Structure, Tertiary, Rats, chemistry, MESH: Viral Envelope Proteins, Glycoprotein, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lipoprotein
Abstract

International audience; Hepatitis C virus (HCV) particles assemble along the very low density lipoprotein pathway and are released from hepatocytes as entities varying in their degree of lipid and apolipoprotein (apo) association as well as buoyant densities. Little is known about the cell entry pathway of these different HCV particle subpopulations, which likely occurs by regulated spatiotemporal processes involving several cell surface molecules. One of these molecules is the scavenger receptor BI (SR-BI), a receptor for high density lipoprotein that can bind to the HCV glycoprotein E2. By studying the entry properties of infectious virus subpopulations differing in their buoyant densities, we show that these HCV particles utilize SR-BI in a manifold manner. First, SR-BI mediates primary attachment of HCV particles of intermediate density to cells. These initial interactions involve apolipoproteins, such as apolipoprotein E, present on the surface of HCV particles, but not the E2 glycoprotein, suggesting that lipoprotein components in the virion act as host-derived ligands for important entry factors such as SR-BI. Second, we found that in contrast to this initial attachment, SR-BI mediates entry of HCV particles independent of their buoyant density. This function of SR-BI does not depend on E2/SR-BI interaction but relies on the lipid transfer activity of SR-BI, probably by facilitating entry steps along with other HCV entry co-factors. Finally, our results underscore a third function of SR-BI governed by specific residues in hypervariable region 1 of E2 leading to enhanced cell entry and depending on SR-BI ability to bind to E2.

Published
2012
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8. Lipoprotein(a) as a cardiovascular risk factor: current status

Author

Jan Borén, Alberico L. Catapano, Zeljko Reiner, Gerald F. Watts, Edward A. Fisher, Børge G. Nordestgaard, Olivier S. Descamps, Felicita Andreotti, Philippe Lesnik, Jan Albert Kuivenhoven, Marja-Riitta Taskinen, Anne Tybjærg-Hansen, Lale Tokgozoglu, Kausik K. Ray, Luis Masana, Henry N. Ginsberg, M. John Chapman, Petri T. Kovanen, Pierre Amarenco, Department of Clinical Biochemistry, Copenhagen University Hospital-Herlev and Gentofte Hospital-University of Copenhagen = Københavns Universitet (KU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), St George's University of London, University of Gothenburg (GU), Catholic University Medical School, The University of Western Australia (UWA), Columbia University [New York], Hôpital Bichat - Claude Bernard, University of Milan, Hopital de Jolimont, State University of New York (SUNY), Wihuri Research Institute, University of Amsterdam [Amsterdam] (UvA), Universitat Rovira & Virgili, Universitat Rovira i Virgili, University Hospital Center Zagreb, Biomedicum, Hacettepe University = Hacettepe Üniversitesi, Rigshospitalet [Copenhagen], Copenhagen University Hospital, European Atherosclerosis Society Consensus Panel, Cardiovascular Centre (CVC), Lifestyle Medicine (LM), Vascular Ageing Programme (VAP), Center for Liver, Digestive and Metabolic Diseases (CLDM), Chapman, John, Copenhagen University Hospital-Herlev and Gentofte Hospital-University of Copenhagen = Københavns Universitet (UCPH), Università degli Studi di Milano = University of Milan (UNIMI), Wihuri Research Institute [Helsinki, Finland], ACS - Amsterdam Cardiovascular Sciences, Experimental Vascular Medicine, and Kardiyoloji

Subjects
Male, Hyperlipoproteinemias, Coronary Disease, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Transgenic, Mice, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Hyperlipidemia, Medicine, Immunoassay, 0303 health sciences, biology, Age Factors, Lipoprotein(a), Lipids, lipids, hyperlipidemia, prevention, myocardial infarction, stroke, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Stroke, Current Opinion, Cardiovascular Diseases, Cardiology, Female, Cardiology and Cardiovascular Medicine, Niacin, medicine.medical_specialty, Mice, Transgenic, 1102 Cardiovascular Medicine And Haematology, 03 medical and health sciences, Sex Factors, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Animals, Humans, cardiovascular diseases, Risk factor, 030304 developmental biology, business.industry, Cholesterol, Patient Selection, Prevention, medicine.disease, Myocardial infarction, Early Diagnosis, Endocrinology, Cardiovascular System & Hematology, chemistry, biology.protein, business, Fibrinolytic agent, Lipoprotein
Abstract

AIMS: The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.METHODS AND RESULTS: The robust and specific association between elevated Lp(a) levels and increased cardiovascular disease (CVD)/coronary heart disease (CHD) risk, together with recent genetic findings, indicates that elevated Lp(a), like elevated LDL-cholesterol, is causally related to premature CVD/CHD. The association is continuous without a threshold or dependence on LDL- or non-HDL-cholesterol levels. Mechanistically, elevated Lp(a) levels may either induce a prothrombotic/anti-fibrinolytic effect as apolipoprotein(a) resembles both plasminogen and plasmin but has no fibrinolytic activity, or may accelerate atherosclerosis because, like LDL, the Lp(a) particle is cholesterol-rich, or both. We advise that Lp(a) be measured once, using an isoform-insensitive assay, in subjects at intermediate or high CVD/CHD risk with premature CVD, familial hypercholesterolaemia, a family history of premature CVD and/or elevated Lp(a), recurrent CVD despite statin treatment, ≥3% 10-year risk of fatal CVD according to European guidelines, and/or ≥10% 10-year risk of fatal + non-fatal CHD according to US guidelines. As a secondary priority after LDL-cholesterol reduction, we recommend a desirable level for Lp(a) CONCLUSION: We recommend screening for elevated Lp(a) in those at intermediate or high CVD/CHD risk, a desirable level

Published
2010
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9. Antiatherogenic function of HDL particle subpopulations: focus on antioxidative activities

Author

Anatol Kontush, M. John Chapman, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chapman, John, and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Apolipoprotein B, Endocrinology, Diabetes and Metabolism, PAF-AH, 030204 cardiovascular system & hematology, medicine.disease_cause, MESH: Lipoproteins, HDL, Antioxidants, MESH: Atherosclerosis, lipid hydroperoxides, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, oxidative stress, MESH: Animals, 0303 health sciences, MESH: Oxidative Stress, Nutrition and Dietetics, biology, Lipidome, PON1, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, rigidity, Biochemistry, Low-density lipoprotein, oxidized phospholipids, lipids (amino acids, peptides, and proteins), Lipoproteins, HDL, Cardiology and Cardiovascular Medicine, medicine.medical_specialty, LCAT, apolipoprotein A-I, fluidity, Proinflammatory cytokine, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Genetics, medicine, Animals, Humans, Molecular Biology, 030304 developmental biology, MESH: Humans, MESH: Antioxidants, nutritional and metabolic diseases, Cell Biology, Atherosclerosis, Endocrinology, chemistry, oxidized LDL, biology.protein, Oxidative stress, Lipoprotein
Abstract

International audience; Oxidative stress, an emerging risk factor for premature atherosclerosis and cardiovascular disease, mediates the formation of proinflammatory, pro-atherogenic oxidized low-density lipoprotein (oxLDL) in the arterial intima. Circulating HDL particles, and particularly small, dense, protein-rich HDL3, may provide potent protection of LDL in vivo from oxidative damage by free radicals in the arterial intima, resulting in the inhibition of the generation of proinflammatory oxidized lipids, primarily lipid hydroperoxides (LOOH) but also short-chain oxidized phospholipids (oxPL). HDL-mediated inactivation of LOOH involves initial transfer of phospholipid hydroperoxides (PLOOH) from LDL to HDL3, which is governed by the rigidity of the surface monolayer of HDL, and subsequent reduction of PLOOH by redox-active Met residues of apolipoprotein A-I (apoA-I) with the formation of phospholipid hydroxides (PLOH) and methionine sulphoxides. HDL-associated enzymes may in turn contribute to the hydrolytic inactivation of short-chain oxPL. Mounting evidence suggests that the integrated antioxidative activity of HDL appear to be defective in atherogenic dyslipidaemias involving low HDL-cholesterol levels; anomalies in the proteome and lipidome of HDL particles in dyslipidaemic patients may underlie such functional deficiency. Pharmacological normalization of HDL metabolism concomitantly with correction of circulating levels, composition and biological activities of HDL particles, with enrichment in apoA-I and reduction in HDL surface rigidity, may constitute an efficacious therapeutic approach to attenuate atherosclerosis in dyslipidaemic patients at high cardiovascular risk.

Published
2010
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10. Relationship between alcohol intake, health and social status and cardiovascular risk factors in the urban Paris-Ile-De-France Cohort: is the cardioprotective action of alcohol a myth?

Author

Eric Bruckert, K. Bean, Boris Hansel, F. Thomas, M J Chapman, L. Guize, Anatol Kontush, B Pannier, Endocrinology, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Investigations Préventives et Cliniques (IPC), CPAM, Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Chapman, John

Subjects
Male, cardiovascular risk factors, Calorie, Health Status, Medicine (miscellaneous), 030204 cardiovascular system & hematology, Cohort Studies, 0302 clinical medicine, Risk Factors, MESH: Risk Factors, Epidemiology, Respiratory function, 030212 general & internal medicine, MESH: Cohort Studies, MESH: Health Status, 2. Zero hunger, MESH: Middle Aged, Nutrition and Dietetics, alcohol, MESH: Paris, MESH: Research Design, Confounding, Confounding Factors, Epidemiologic, Middle Aged, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Cardiovascular Diseases, Research Design, Cohort, Female, epidemiology, Cohort study, Paris, medicine.medical_specialty, MESH: Ethanol, Alcohol Drinking, MESH: Multivariate Analysis, MESH: Social Class, 03 medical and health sciences, Sex Factors, MESH: Sex Factors, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Environmental health, medicine, Humans, HDL-C, Exercise, MESH: Humans, Ethanol, business.industry, MESH: Confounding Factors (Epidemiology), MESH: Cardiovascular Diseases, medicine.disease, Obesity, MESH: Male, Endocrinology, Social Class, MESH: Exercise, Multivariate Analysis, business, MESH: Female, Body mass index, MESH: Alcohol Drinking
Abstract

International audience; BACKGROUND/OBJECTIVES: Observational studies document the inverse relationship between cardiovascular disease (CVD) and moderate alcohol intake. However, the causal role for alcohol in cardioprotection remains uncertain as such protection may be caused by confounders and misclassification. The aim of our study was to evaluate potential confounders, which may contribute to putative cardioprotection by alcohol. SUBJECTS/METHODS: We evaluated clinical and biological characteristics, including cardiovascular (CV) risk factors and health status, of 149,773 subjects undergoing examination at our Center for CVD Prevention (The Urban Paris-Ile-de-France Cohort). The subjects were divided into four groups according to alcohol consumption: never, low (30 g/day); former drinkers were analyzed as a separate group. RESULTS: After adjustment for age, moderate male drinkers were more likely to display clinical and biological characteristics associated with lower CV risk, including low body mass index, heart rate, pulse pressure, fasting triglycerides, fasting glucose, stress and depression scores together with superior subjective health status, respiratory function, social status and physical activity. Moderate female drinkers equally displayed low waist circumference, blood pressure and fasting triglycerides and low-density lipoprotein-cholesterol. Alcohol intake was strongly associated with plasma high-density lipoprotein-cholesterol in both sexes. Multivariate analysis confirmed that moderate and low drinkers displayed better health status than did never drinkers. Importantly, few factors were causally related to alcohol intake. CONCLUSIONS: Moderate alcohol drinkers display a more favorable clinical and biological profile, consistent with lower CV risk as compared with nondrinkers and heavy drinkers. Therefore, moderate alcohol consumption may represent a marker of higher social level, superior health status and lower CV risk.

Published
2010
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11. The year in cardiology 2015: prevention

Author

Stefan Blankenberg, Ulf Landmesser, M. John Chapman, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC), Clinic for Cardiology [Hamburg], German Center for Cardiovascular Research, Dpt of Cardiology [Berlin], Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), and HAL-UPMC, Gestionnaire

Subjects
lcsh:Diseases of the circulatory (Cardiovascular) system, Hydrocortisone, Epidemiology, medicine.medical_treatment, Disease, 030204 cardiovascular system & hematology, Global Health, Hydrochlorothiazide, 0302 clinical medicine, Vitamin E, 030212 general & internal medicine, Randomized Controlled Trials as Topic, biology, Anticholesteremic Agents, Therapies, Investigational, PCSK9 Inhibitors, Antibodies, Monoclonal, Lipoprotein(a), Plaque, Atherosclerotic, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Editorial, Cardiovascular Diseases, Cardiology, language, Disease Progression, Risk assessment, Cardiology and Cardiovascular Medicine, medicine.drug, medicine.medical_specialty, Hypercholesterolemia, Diabetic angiopathy, Culprit, Risk Assessment, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Adrenocorticotropic Hormone, Internal medicine, medicine, Empagliflozin, Coronary Diseases / therapy, Humans, Mortality, Dyslipidemias, Croatian, business.industry, PCSK9, Cholesterol, LDL, Omics, medicine.disease, language.human_language, Clinical trial, lcsh:RC666-701, biology.protein, Diuretic, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Morbidity, business, Biomarkers, Diabetic Angiopathies, Cardiovascular Diseases / prevention & control
Abstract

International audience; Improved prevention of cardiovascular disease (CVD) is of critical importance, as coronary heart disease (CHD) still represents the most common cause of death worldwide, engendering inestimable socioeconomic cost. The year 2015 has witnessed dramatic progress in CVD prevention on several fronts. Notably, this includes (i) event reduction in high-risk patients in general practice following introduction of a comprehensive strategy to attenuate modifiable risk factors, including lifestyle and dietary habits; (ii) the study of hybrid imaging to detect subclinical atherosclerosis, with potential improvement in risk prediction/management; (iii) the clinical demonstration, that culprit plaque rupture was observed in only 50–77% of patients with acute coronary syndromes; (iv) the emergence of ‘omics’ technologies to identify new causal biofactors; (v) the validation in clinical trials of the efficacy of monoclonal antibodies targeted to proprotein convertase subtilisin/kexin type 9 (PCSK9) in markedly reducing levels of low-density lipoprotein cholesterol (LDL-C) across a spectrum of patients at high risk of premature CVD, with preliminary findings strongly suggestive of reduction in cardiovascular events; (vi) significant reduction of cardiovascular and all-cause mortality in diabetic patients in the EMPA-REG OUTCOME trial with the anti-hyperglycaemic agent, empagliflozin, a selective sodium-glucose co-transporter-2 (SGLAT-2) inhibitor; (vii) new pharmacotherapeutic strategies for superior control of hypertension emanating from the PATHWAY-2 and PATHWAY-3 clinical trials involving spironoloactone add-on therapy in resistant hypertension, and amiloride plus hydrochlorothiazide in hypertensive patients requiring a diuretic, respectively; and finally (viii) a reduced mortality associated with a lower blood pressure target of 120 mmHg in patients at high cardiovascular risk in the SPRINT trial. Considered together, such progress augurs well for the future control of dyslipidaemia, hyperglycaemia, and hypertension, and with it, progressive reduction in atherosclerotic vascular disease and associated cardiovascular events in high-risk patients.

Published
2016
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12. Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

Author

Elise F. Villard, Lobna Miftah-Alkhair, Maryline Olivier, Sophie Gilibert, Alexandre Superville, Soazig Le Lay, Geesje M. Dallinga-Thie, M. John Chapman, Henri Hooton, Nicolas Venteclef, Lucie Poupel, Isabelle Dugail, Christine Poitou, Eric Frisdal, Marie Lhomme, Wanee Plengpanich, Maryse Guerin, Rohia Alili, Wilfried Le Goff, Anatol Kontush, Karine Clément, Philippe Lesnik, Thierry Huby, Joan Tordjman, Stress Oxydant et Pathologies Métaboliques (SOPAM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche des Cordeliers (CRC (UMR_S 872)), Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Sanofi-Aventis R&D, SANOFI Recherche, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche des Cordeliers (CRC), Université Paris Diderot - Paris 7 (UPD7)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-École pratique des hautes études (EPHE), and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases [IHU ICAN]

Subjects
Adult, Male, medicine.medical_specialty, Lipoproteins, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Adipose tissue, White adipose tissue, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Weight Gain, Polymorphism, Single Nucleotide, Mice, chemistry.chemical_compound, 3T3-L1 Cells, Adipocyte, Lipid droplet, Internal medicine, Adipocytes, Internal Medicine, medicine, Animals, Humans, RNA, Small Interfering, Triglycerides, ComputingMilieux_MISCELLANEOUS, ATP Binding Cassette Transporter, Subfamily G, Member 1, Adiposity, Lipoprotein lipase, biology, Triglyceride, [SDV.BA]Life Sciences [q-bio]/Animal biology, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, Obesity, Morbid, Endocrinology, Adipose Tissue, chemistry, ABCG1, biology.protein, ATP-Binding Cassette Transporters, Female, lipids (amino acids, peptides, and proteins), medicine.symptom, Weight gain, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPARγ expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity.

Published
2015
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13. Up-regulation of the ATP-binding cassette transporter A1 inhibits hepatitis C virus infection

Author

Claire Gondeau, Simone Bocchetta, François Helle, Philippe Roingeard, Florian Douam, Wanee Plengpanich, Agata Budkowska, Maryse Guerin, Stanislas Pol, Sylvie Lagaye, Dimitri Lavillette, Marie Michel, Stéphanie Lebreton, Wilfried Le Goff, Patrick Maillard, Maryline Bourgine, Mami Yamamoto, Hépacivirus et Immunité innée, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Dipartimento di Medicina Translazionale, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Department of Biochemistry, Nihon University School of Medicine, Nihon University-Nihon University, Cellules souches normales et cancéreuses, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire d'Ecologie Microbienne - UMR 5557 (LEM), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Ecole Nationale Vétérinaire de Lyon (ENVL)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Trafic membranaire et Pathogénèse, Institut Pasteur [Paris] (IP), Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Paris 5 (UPD5), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'hépatologie médicale [CHU Cochin], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Pathogenèse des Virus de l'Hépatite B (PVHB), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie humaine, École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH - U1259 Inserm - CHRU Tours ), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Ecole Nationale Vétérinaire de Lyon (ENVL), Institut Pasteur [Paris], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Centre National de la Recherche Scientifique (CNRS)-Université de Lille, Droit et Santé, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Università degli Studi del Piemonte Orientale-Amedeo Avogadro (ITALY), Centre National de la Recherche Scientifique (CNRS)-Ecole Nationale Vétérinaire de Lyon (ENVL)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS), CHU Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Cochin [AP-HP], Morphogénèse et antigénicité du VIH et du virus des Hépatites (MAVIVH), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours)-Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Universita ' del Piemonte Orientale, 'Amedeo Avogadro', Université Montpellier 1 ( UM1 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Ecologie microbienne ( EM ), Centre National de la Recherche Scientifique ( CNRS ) -Ecole Nationale Vétérinaire de Lyon ( ENVL ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique ( INRA ) -VetAgro Sup ( VAS ), Université Paris Descartes - Paris 5 ( UPD5 ), Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Cochin [AP-HP], Institut de biologie de Lille - IBL ( IBLI ), Réseau International des Instituts Pasteur ( RIIP ) -Réseau International des Instituts Pasteur ( RIIP ) -Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Santé et de la Recherche Médicale ( INSERM ), Pathogenèse des Virus de l'Hépatite B ( PVHB ), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale ( INSERM ), École normale supérieure - Lyon ( ENS Lyon ) -IFR128-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Morphogénèse et antigénicité du VIH et du virus des Hépatites ( MAVIVH ), Université de Tours-CHRU Tours-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Tours-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS)

Subjects
Benzylamines, [ SDV.TOX ] Life Sciences [q-bio]/Toxicology, lcsh:Medicine, Pathogenesis, Hepacivirus, [ SDV.BA ] Life Sciences [q-bio]/Animal biology, Pathology and Laboratory Medicine, Virus Replication, Benzoates, Cell Fusion, chemistry.chemical_compound, [ SDV.MP ] Life Sciences [q-bio]/Microbiology and Parasitology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Molecular Cell Biology, Medicine and Health Sciences, ABCA1 Gene, lcsh:Science, Lipid raft, [SDV.EE]Life Sciences [q-bio]/Ecology, environment, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Multidisciplinary, Cell fusion, [ SDV.MHEP.ME ] Life Sciences [q-bio]/Human health and pathology/Emerging diseases, biology, Antimicrobials, [SDV.BA]Life Sciences [q-bio]/Animal biology, Cell Cycle, Antivirals, Hepatitis C, Up-Regulation, 3. Good health, Cell biology, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Cholesterol, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Liver, Biochemistry, Medical Microbiology, [SDV.TOX]Life Sciences [q-bio]/Toxicology, Host-Pathogen Interactions, RNA, Viral, Receptors, Virus, lipids (amino acids, peptides, and proteins), Research Article, ATP Binding Cassette Transporter 1, Virus Attachment, Gastroenterology and Hepatology, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Microbiology, [ SDV.EE ] Life Sciences [q-bio]/Ecology, environment, Membrane Microdomains, Viral entry, Microbial Control, Virology, Cell Line, Tumor, Humans, Secretion, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Liver X receptor, [ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology, Microbial Pathogens, [ SDV.BID ] Life Sciences [q-bio]/Biodiversity, lcsh:R, Virion, Biology and Life Sciences, Cell Biology, Virus Internalization, Lipid Metabolism, HEK293 Cells, chemistry, ABCA1, Hepatocytes, biology.protein, lcsh:Q
Abstract

International audience; Hepatitis C virus (HCV) establishes infection using host lipid metabolism pathways that are thus considered potential targets for indirect anti-HCV strategies. HCV enters the cell via clathrin-dependent endocytosis, interacting with several receptors, and virus-cell fusion, which depends on acidic pH and the integrity of cholesterol-rich domains of the hepatocyte membrane. The ATP-binding Cassette Transporter A1 (ABCA1) mediates cholesterol efflux from hepatocytes to extracellular Apolipoprotein A1 and moves cholesterol within cell membranes. Furthermore, it generates high-density lipoprotein (HDL) particles. HDL protects against arteriosclerosis and cardiovascular disease. We show that the up-regulation of ABCA1 gene expression and its cholesterol efflux function in Huh7.5 hepatoma cells, using the liver X receptor (LXR) agonist GW3965, impairs HCV infection and decreases levels of virus produced. ABCA1-stimulation inhibited HCV cell entry, acting on virus-host cell fusion, but had no impact on virus attachment, replication, or assembly/secretion. It did not affect infectivity or properties of virus particles produced. Silencing of the ABCA1 gene and reduction of the specific cholesterol efflux function counteracted the inhibitory effect of the GW3965 on HCV infection, providing evidence for a key role of ABCA1 in this process. Impaired virus-cell entry correlated with the reorganisation of cholesterol-rich membrane microdomains (lipid rafts). The inhibitory effect could be reversed by an exogenous cholesterol supply, indicating that restriction of HCV infection was induced by changes of cholesterol content/distribution in membrane regions essential for virus-cell fusion. Stimulation of ABCA1 expression by GW3965 inhibited HCV infection of both human primary hepatocytes and isolated human liver slices. This study reveals that pharmacological stimulation of the ABCA1-dependent cholesterol efflux pathway disrupts membrane cholesterol homeostasis, leading to the inhibition of virus-cell fusion and thus HCV cell entry. Therefore besides other beneficial roles, ABCA1 might represent a potential target for HCV therapy.

Published
2014
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14. Small, dense high-density lipoprotein-3 particles are enriched in negatively charged phospholipids: relevance to cellular cholesterol efflux, antioxidative, antithrombotic, anti-inflammatory, and antiapoptotic functionalities

Author

Marie Lhomme, Laurent Camont, Michel Lagarde, Anne Nègre-Salvayre, Wilfried Le Goff, Fabiana Rached, M. John Chapman, Anatol Kontush, Catherine Calzada, Robert Salvayre, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP], Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Heart Institute-InCor, Faculdade de Medicina da Universidade de São Paulo-Medical School Hospital, Service de Biochimie, CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), 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), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), 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), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Simon, Marie Francoise, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Biochimie [CHU Toulouse], Institut Fédératif de Biologie (IFB), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Pôle Biologie [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
Male, MESH: Inflammation, MESH: Oxidation-Reduction, MESH: Lipoproteins, LDL, MESH: Lipoproteins, HDL3, Apoptosis, 030204 cardiovascular system & hematology, MESH: Atherosclerosis, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, Tandem Mass Spectrometry, MESH: Endothelial Cells, Phospholipids, MESH: Blood Platelets, MESH: Aged, 0303 health sciences, MESH: Middle Aged, MESH: Oxidative Stress, Lipoproteins, HDL3, Phosphatidylserine, Phosphatidic acid, Middle Aged, Lipoproteins, LDL, Lysophosphatidylcholine, Cholesterol, Biochemistry, lipids (amino acids, peptides, and proteins), Inflammation Mediators, Cardiology and Cardiovascular Medicine, Sphingomyelin, Oxidation-Reduction, Adult, Blood Platelets, Ceramide, MESH: Cell Line, Tumor, MESH: Inflammation Mediators, Phospholipid, Biology, Ceramides, MESH: Sphingolipids, 03 medical and health sciences, Cell Line, Tumor, Humans, MESH: Particle Size, MESH: Thrombosis, Particle Size, 030304 developmental biology, Aged, Phosphatidylethanolamine, Inflammation, MESH: Phospholipids, Sphingolipids, MESH: Humans, Macrophages, MESH: Apoptosis, Endothelial Cells, MESH: Macrophages, MESH: Tandem Mass Spectrometry, Thrombosis, MESH: Adult, Atherosclerosis, Sphingolipid, MESH: Ceramides, MESH: Male, Oxidative Stress, chemistry, MESH: Chromatography, Liquid, Chromatography, Liquid
Abstract

Objective— High-density lipoprotein (HDL) displays multiple atheroprotective activities and is highly heterogeneous in structure, composition, and function; the molecular determinants of atheroprotective functions of HDL are incompletely understood. Because phospholipids represent a major bioactive lipid component of HDL, we characterized the phosphosphingolipidome of major normolipidemic HDL subpopulations and related it to HDL functionality. Approach and Results— Using an original liquid chromatography–mass spectrometry/mass spectrometry methodology for phospholipid and sphingolipid profiling, 162 individual molecular lipid species were quantified across the 9 lipid subclasses, in the order of decreasing abundance, phosphatidylcholine>sphingomyelin>lysophosphatidylcholine>phosphatidylethanolamine>phosphatidylinositol>ceramide>phosphatidylserine>phosphatidylglycerol>phosphatidic acid. When data were expressed relative to total lipid, the contents of lysophosphatidylcholine and of negatively charged phosphatidylserine and phosphatidic acid increased progressively with increase in hydrated density of HDL, whereas the proportions of sphingomyelin and ceramide decreased. Key biological activities of HDL subpopulations, notably cholesterol efflux capacity from human THP-1 macrophages, antioxidative activity toward low-density lipoprotein oxidation, antithrombotic activity in human platelets, cell-free anti-inflammatory activity, and antiapoptotic activity in endothelial cells, were predominantly associated with small, dense, protein-rich HDL3. The biological activities of HDL particles were strongly intercorrelated, exhibiting significant correlations with multiple components of the HDL phosphosphingolipidome. Specifically, the content of phosphatidylserine revealed positive correlations with all metrics of HDL functionality, reflecting enrichment of phosphatidylserine in small, dense HDL3. Conclusions— Our structure–function analysis thereby reveals that the HDL lipidome may strongly affect atheroprotective functionality.

Published
2013
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15. Consistent high concentration of the viral microRNA BART17 in plasma samples from nasopharyngeal carcinoma patients - evidence of non-exosomal transport

Author

Ana Barat, Arij Ben Chaaben, François-Régis Ferrand, Aurore Gelin, Charles-Henry Gattolliat, Claire Gourzones, Fethi Guemira, Corinne Amiel, Joël Guigay, Anne-Sophie Jimenez-Pailhes, Philippe Lang, Jihène Klibi, Maryse Guerin, Véronique Schneider, Benjamin Verillaud, Philippe Busson, Interactions moléculaires et cancer ( IMC (UMR 8126) ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Centre National de la Recherche Scientifique ( CNRS ), École du Val de Grâce ( EVDG ), Service de Santé des Armées, Service de virologie, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Tenon [APHP], Service ORL, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Clinical Biology Department, Institut Salah Azaiz, Département de cancérologie cervico-faciale [Gustave Roussy] ( CCF ), Institut Gustave Roussy ( IGR ), Service de Radiothérapie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], This study was supported by grants from the Gustave Roussy Foundation (Head and Neck tumors - 2011), the Institut National du Cancer (INCa-DHOS translational grant) and the Ligue Nationale contre le Cancer (comité du Val de Marne). CG was supported by the Association pour la Recherche sur le Cancer., BMC, Ed., Interactions moléculaires et cancer (IMC (UMR 8126)), Signalisation, noyaux et innovations en cancérologie (UMR8126), Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Institut Gustave Roussy (IGR)-Centre National de la Recherche Scientifique (CNRS), École du Val de Grâce (EVDG), CHU Tenon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de cancérologie cervico-faciale [Gustave Roussy] (CCF), Institut Gustave Roussy (IGR), Service d'Oncologie Radiothérapie [CHU Pitié Salpétrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
Male, Herpesvirus 4, Human, medicine.disease_cause, Exosomes, Plasma, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, 0303 health sciences, microRNA, Middle Aged, 3. Good health, [ SDV.MHEP.MI ] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Real-time polymerase chain reaction, Infectious Diseases, 030220 oncology & carcinogenesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA, Viral, Female, Adult, Lipoproteins, Nasopharyngeal neoplasm, miR-BART, Biology, Real-Time Polymerase Chain Reaction, Exosome, 03 medical and health sciences, Virology, Head and Neck carcinomas, medicine, Carcinoma, Nasopharyngeal carcinoma, Humans, Epstein-Barr virus, 030304 developmental biology, Aged, Research, Biological Transport, Nasopharyngeal Neoplasms, Biomarker, medicine.disease, Epstein–Barr virus, Head and neck squamous-cell carcinoma, Microvesicles, MicroRNAs, DNA, Viral, Biomarkers, DNA load
Abstract

Background Because latent Epstein Barr (EBV)-infection is a specific characteristic of malignant nasopharyngeal carcinoma (NPC), various molecules of viral origin are obvious candidate biomarkers in this disease. In a previous study, we could show in a few clinical samples that it was possible to detect a category of EBV microRNAs called miR-BARTs in the plasma of at least a fraction of NPC patients. The first aim of the present study was to investigate the status of circulating miR-BART17-5p (one of the miR-BARTs hereafter called miR-BART17) and EBV DNA in a larger series of NPC plasma samples. The second aim was to determine whether or not circulating miR-BART17 was carried by plasma exosomes. Patients and methods Plasma samples were collected from 26 NPC patients and 10 control donors, including 9 patients with non-NPC Head and Neck squamous cell carcinoma and one healthy EBV carrier. Concentrations of miR-BART17 and two cellular microRNAs (hsa-miR-16 and -146a) were assessed by real-time quantitative PCR with spike-in normalization and absolute quantification. In addition, for 2 patients, exosome distributions of miR-BART17 and miR-16 were investigated following plasma lipoprotein fractionation by isopycnic density gradient ultrcentrifugation. Results The miR-BART17 was significantly more abundant in plasma samples from NPC patients compared to non-NPC donors. Above a threshold of 506 copies/mL, detection of miR-BART17 was highly specific for NPC patients (ROC curve analysis: AUC=0.87 with true positive rate = 0.77, false positive rate = 0.10). In this relatively small series, the concentration of plasma miR-BART17 and the plasma EBV DNA load were not correlated. When plasma samples were fractionated, miR-BART17 co-purified with a protein-rich fraction but not with exosomes. Conclusions Detection of high concentrations of plasma miR-BART17 is consistent in NPC patients. This parameter is, at least in part, independent of the viral DNA load. Circulating miR-BART17 does not co-purify with exosomes.

Published
2013
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16. The postbinding activity of scavenger receptor class B type I mediates initiation of hepatitis C virus infection and viral dissemination

Author

Marine Turek, Thomas F. Baumert, John F. Thompson, Viet Loan Dao Thi, Dorothea Bankwitz, Mirjam B. Zeisel, François-Loïc Cosset, Fei Xiao, Isabel Fofana, Johan Neyts, Marlène Dreux, Philippe Bachellier, Maryse Guerin, Fritz Grunert, Leen Delang, Thomas Pietschmann, Muhammad N. Zahid, Baumert, Thomas F., Molecular Analysis of Hepatitis C Virus Neutralization and Entry For the Development of Novel Antiviral Immunopreventive Strategies - HEPCENT - - EC:FP7:ERC2009-04-01 - 2014-03-31 - 233130 - VALID, Interaction virus-hôte et maladies du foie, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Virologie humaine, École normale supérieure - Lyon (ENS Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pôle des Pathologies Digestives Hépatiques et Transplantation [Hôpital Hautepierre-Strasbourg], Hôpital de Hautepierre [Strasbourg], Aldevron GmbH, Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Division of Experimental Virology, Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), European Union (ERC-2008-AdG-233130-HEPCENT, INTERREG-IV-Rhin Supérieur-FEDER-Hepato-Regio-Net 2009), Laboratoire d'Excellence HEPSYS (Investissement d'Avenir, ANR-10-LAB-28), ANR-05-CEXC-008, ANRS (2008/354, 2009/183, 2011/132), Pro Inno II (KA0690901UL8), Région Alsace, Inserm, University of Strasbourg, and Aldevron Freiburg. The group in Leuven was funded by a grant from the Fund for Scientific Research (FWO) (G.0728.09N) and KULeuven GOA 10/014. M. N. Z. was supported by HEC fellowship., European Project: 233130,EC:FP7:ERC,ERC-2008-AdG,HEPCENT(2009), École normale supérieure de Lyon (ENS de Lyon)-IFR128-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Nouvel Hôpital Civil de Strasbourg, and INSERM, U748, Strasbourg, France.

Subjects
CD36 Antigens, [SDV]Life Sciences [q-bio], Hepacivirus, Antigens, CD36, virus entry, medicine.disease_cause, MESH: Lipoproteins, HDL, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, MESH: Animals, MESH: Hepacivirus, Receptor, ComputingMilieux_MISCELLANEOUS, chemistry.chemical_classification, 0303 health sciences, biology, Hepatitis C virus, Antibodies, Monoclonal, scavenger receptor BI, Hepatitis C, antiviral, 3. Good health, 030211 gastroenterology & hepatology, Antibody, MESH: Cholesterol, HDL, Lipoproteins, HDL, MESH: Rats, medicine.drug_class, Monoclonal antibody, viral dissemination, Cell Line, 03 medical and health sciences, Viral entry, medicine, Animals, Humans, Scavenger receptor, MESH: Receptors, Lipoprotein, MESH: Mice, 030304 developmental biology, Receptors, Lipoprotein, MESH: Hepatitis C, MESH: Humans, Hepatology, MESH: Antigens, CD36, Cholesterol, HDL, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Virology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Rats, MESH: Cell Line, chemistry, Cell culture, biology.protein, Glycoprotein
Abstract

International audience; UNLABELLED: Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function. CONCLUSION: Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI.

Published
2013
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17. Unacylated Ghrelin is associated with the isolated low HDL-cholesterol obese phenotype independently of insulin resistance and CRP level

Author

Bruno Berthet, Rachel Grangeot, Juan Patricio Nogueira, Alain Nicolay, Sophie Béliard, Audrey Bégu-Le Corroller, Jean Gaudart, Noémie Dubois, René Valéro, Catherine Mattei, Marie Maraninchi, B. Vialettes, A.M. Lorec, Henri Portugal, Nutriments Lipidiques et Prévention des Maladies Métaboliques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de biochimie, Assistance Publique - Hôpitaux de Marseille (APHM)-Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Service de chirurgie digestive, Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Service d'endocrinologie, diabète et maladies métaboliques, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire d'Enseignement et de Recherche sur le Traitement de l'Information Médicale (LERTIM), Université de la Méditerranée - Aix-Marseille 2, and BMC, Ed.

Subjects
[SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Endocrinology, Diabetes and Metabolism, medicine.medical_treatment, Adiponectin, Apolipoprotein, Cardiovascular risk, Ghrelin, HDL-cholesterol, Inflammation, Insulin resistance, Lipids, Obesity, Medicine (miscellaneous), Blood lipids, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, High-density lipoprotein, lcsh:RC620-627, Nutrition and Dietetics, Leptin, lcsh:Nutritional diseases. Deficiency diseases, Alimentation et Nutrition, lipids (amino acids, peptides, and proteins), lcsh:Nutrition. Foods and food supply, medicine.medical_specialty, 030209 endocrinology & metabolism, lcsh:TX341-641, 03 medical and health sciences, Internal medicine, medicine, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Food and Nutrition, Physiologie, business.industry, Research, Insulin, nutritional and metabolic diseases, medicine.disease, [SDV.AEN] Life Sciences [q-bio]/Food and Nutrition, Endocrinology, chemistry, physiology, Resistin, business, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

Background Low plasma high-density lipoprotein-cholesterol (HDL-c) level is commonly present in obesity and represents an independent cardiovascular risk factor. However, obese patients are a very heterogeneous population and the factors and mechanisms that contribute to low HDL-c remain unclear. The aim of this study was to investigate the association between plasma HDL-c levels and plasma hormonal profiles (insulin, adiponectin, resistin, leptin and ghrelin) in subsets of class II and III obese patients. Methods Fasting plasma levels of glucose, total cholesterol, LDL-c, HDL-c, triglycerides, free fatty acids, apoproteins A-I, B-100, B-48, C-II, C-III, insulin, hs-CRP, adipocytokines (adiponectin, resistin, leptin), unacylated ghrelin, body composition (DXA) and resting energy expenditure were measured in three subsets of obese patients: 17 metabolically abnormal obese (MAO) with metabolic syndrome and the typical metabolic dyslipidaemia, 21 metabolically healthy obese (MHO) without metabolic syndrome and with a normal lipid profile, and 21 isolated low HDL-c obese patients (LHO) without metabolic syndrome, compared to 21 healthy lean control subjects. Results Insulin resistance (HOMA-IR) increased gradually from MHO to LHO and from LHO to MAO patients (p < 0.05 between MHO and MAO and between LHO and MAO). In multiple regression analysis, serum unacylated ghrelin levels were only positively and independently associated with HDL-c levels in the LHO group (p = 0.032). Conclusions These results suggest that, in class II and III obese patients with an isolated low HDL-c phenotype, unacylated ghrelin is positively associated with HDL-c level independently of insulin resistance and CRP levels, and may contribute to the highly prevalent low HDL-c level seen in obesity.

Published
2012
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18. Implication des phagocytes mononucléés dans les pathologies inflammatoires chroniques : exploration d'un modèle murin d'athérosclérose et du xanthogranulome chez l'homme

Author

Pirault, John, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris VI, Philippe GIRAL, Philippe LESNIK, and Bupmc, Theses

Subjects
Inflammation, Athérosclérose, [SDV.MHEP.PHY] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Apoptose, Macrophages, Cellules dendritiques, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Xanthome
Abstract

Chronic inflammatory diseases are the leading cause of death worldwide with a significant proportion of heart disease and other lipid-inflammatory disorders such as atherosclerosis. Thus, understanding the mechanisms involved in the initiation but also the resolution of these diseases is a major issue in public health. Our work on the involvement of mononuclear phagocytes in murine models of atherosclerosis show that modulating the half-life of cell subtypes of the immune system can limit the development of the pathology. These results are associated with an overall decrease of the inflammation in animals and an improvement of lipid metabolism.Thus, modulating the actors of inflammation within the immune system may be a new therapeutic target complementary to the cholesterol-lowering drugs today.To this end, we realized the most important characterization of a human pathology: the xanthogranuloma. Patients show an association between dysregulation of lipid metabolism and inflammation of the skin supported by the macrophages and dendritic cells. Treatment with intravenous immunoglobulin infusions in a patient shows an overall reduction of inflammation, normalization of blood cell actors which results in improved clinical symptoms of the disease., Les pathologies inflammatoires chroniques représentent la première cause de mortalité dans le monde avec une part importante des cardiopathies et autres maladies lipido-inflammatoires telles que l'athérosclérose. Ainsi, comprendre l'ensemble des mécanismes impliqués dans l'initiation mais aussi la résolution de ces maladies représente un enjeu majeur en santé publique. Nos travaux sur l'implication des phagocytes mononucléés dans des modèles murins d'athérosclérose montrent qu'en modulant la demi-vie de certaines cellules du système immunitaire on est capable de limiter le développement de la pathologie. Ces résultats sont associés à une diminution globale de l'inflammation dans les animaux et une amélioration du métabolisme lipidique. Ainsi, moduler les acteurs de l'inflammation au sein du système immunitaire peut s'avérer une nouvelle cible thérapeutique complémentaires aux médicaments hypocholestérolémiants actuels. Dans cette optique, nous avons réalisé la plus importante caractérisation d'une pathologie humaine : le xanthogranulome. Les patients atteints montrent une association entre une dérégulation du métabolisme des lipides et l'inflammation cutanée soutenue par les macrophages et les cellules dendritiques. Le traitement par injection intraveineuse d'immunoglobulines d'une des patientes montre une réduction globale de l'inflammation, une normalisation des acteurs cellulaires sanguins qui se traduit cliniquement par une amélioration des symptômes de la pathologie.

Published
2012

19. Etude du rôle des sous-populations monocytaires dans l'obésité et l'insulinorésistance

Author

Béliard-Lasserre, Sophie, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris VI, and Philippe Lesnik

Subjects
insulinorésistance, CX3CR1, inflammation, [SDV.MHEP.PHY]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], tissu adipeux, Obésité, monocytes
Abstract

Obesity is associated with low grade inflammation. Blood monocytes, key players in innate immunity, are expanded during obesity. In mice, monocytes are divided in two main subsets, the Gr1high and the Gr1low monocytes. These two subsets have different functions, but their role in the physiopathology of obesity is still unknown. Here we show that High Fat Diet (HFD) induces a monocytosis in mice that is mainly due to Gr1low monocytes expansion. Moreover, HFD induces a strong up-regulation of CD11c specifically on this cell subset. Using different mice models which differ in Gr1low monocytes number, we found a strinking correlation between the proportion of Gr1low monocytes and the body weight or with the insulin resistance statue. Indeed, CX3CR1 deficient mice, which have a reduced proportion of Gr1low monocytes upon HFD, were more insulin resistant and have a lower body weight than control mice. Conversely, mice expressing the anti-apoptotic gene hBcl2 under the CD11c promoter control, which have an increased Gr1low monocytes population, have higher insulin sensitivity upon HFD. Furthermore, in CD11chBcl2/CX3CR1 KI mice, a partial rescue of Gr1low monocytes was associated with a total rescue of body weight. Our data also strongly suggest that, in CX3CR1 KI mice, an increased adipose tissue inflammation due to a defect of M2 macrophages functions is responsible for the metabolic alterations. Our data strongly suggest that Gr1low monocytes i) play a new key protective role against obesity induced insulin-resistance and ii) promotes body weight gain in mice fed a HFD. Indeed, this monocyte subset likely promotes M2 macrophage functions in adipose tissue, decreasing its inflammation and thus favoring its development and insulin sensitivity.; L'obésité est associée à une inflammation de bas grade et à une augmentation du nombre de monocytes circulants. Ces cellules sont des acteurs majeurs de l'immunité innée. Chez la souris, ils se subdivisent en deux sous-populations : les monocytes Gr1high et les Gr1low. Des études récentes suggèrent que ces 2 sous-populations exercent des fonctions distinctes mais leur rôle respectif dans la physiopathologie de l'obésité est à ce jour inconnu. Nos travaux chez la souris démontrent qu'un régime riche en graisse induit une monocytose principalement due à l'expansion de monocytes Gr1low et une forte augmentation de l'intégrine CD11c spécifiquement sur les Gr1low. A l'aide de différents modèles murins dans lesquels la population de monocytes Gr1low est soit diminuée (souris déficientes pour CX3CR1), soit augmentée (souris CD11c-hBcl2), nous avons mis en évidence une corrélation entre les monocytes Gr1low et le poids et l'insulinorésistance. En effet, les souris déficientes pour CX3CR1 ont une augmentation de l'insulinorésistance malgré une moindre prise de poids mais alors que les souris CD11c-hBcl2 sont plus insulinosensibles que les contrôles. De plus, chez les souris CD11c-hBcl2/CX3CR1 KI, une restauration partielle des monocytes Gr1low est associée à une restauration complète du poids. Nos données suggèrent fortement que les monocytes Gr1low i) jouent un nouveau rôle clé de protection contre l'insulinorésistance ii) favorisent le gain de poids chez la souris sous régime obesogène. Ces monocytes favorisent vraisemblablement la fonction des macrophages M2 dans le tissu adipeux, diminuant son inflammation et favorisant ainsi son développement et la sensibilité à l'insuline.

Published
2011

20. Ghréline et adiponectine sont associées aux taux de HDL-cholestérol dans l’obésité indépendamment de la résistance à l’insuline et de l’inflammation

Author

Nogueira, J. P., Marie Maraninchi, Beliard, S., Lorec, A. M., Begu-Le Corroller, A., Dubois, N., Grangeot, R., Mattei, C., Nicolay, A., Portugal, H., Vialettes, B., Valero, R., Nutriments Lipidiques et Prévention des Maladies Métaboliques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine de la Timone, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Sainte Marguerite, and Service de Nutrition, Endocrinologie et Maladies Métaboliques

Subjects
obésité, inflammation, ghréline, hdl cholestérol, [SDV]Life Sciences [q-bio], adiponectine, résistance à l’insuline
Published
2011

21. Lipoprotein Lipase Inhibits Hepatitis C Virus (HCV) Infection by Blocking Virus Cell Entry

Author

Eve-Isabelle Pécheur, Agata Budkowska, Patrick Maillard, Philip Meuleman, Thierry Huby, Wilfried Le Goff, Farzin Roohvand, Geert Leroux-Roels, Marine Walic, Hépacivirus et immunité innée, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Cellule Pasteur, Université Paris Diderot - Paris 7 (UPD7)-PRES Sorbonne Paris Cité, Universiteit Gent = Ghent University (UGENT), Institut Pasteur d'Iran, Réseau International des Instituts Pasteur (RIIP), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Bases moléculaires et structurales des systèmes infectieux (BMSSI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), This work was supported by a grant from Agence nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS), and from the Ghent University (CRA n° 01G00507), the Belgian state (IUAP: P6/36-HEPRO) and the The Research Foundation - Flanders (31500910. MW was granted a fellowship from ANRS and Pasteur-Weizmann, FR a fellowship from ANRS., and Le Goff, Wilfried

Subjects
RNA viruses, Viral Diseases, Very low-density lipoprotein, UPA-SCID MOUSE, Hepacivirus, Mice, SCID, MESH: Base Sequence, Biochemistry, Membrane Fusion, Polymerase Chain Reaction, Mice, chemistry.chemical_compound, Viral classification, MESH: Microscopy, Immunoelectron, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Lipid droplet, MESH: Animals, MESH: Hepacivirus, MESH: Mice, SCID, Microscopy, Immunoelectron, IN-VIVO, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Lipoprotein lipase, Multidisciplinary, MESH: Lipoproteins, Infectious Diseases, Low-density lipoprotein, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Microscopy, Electron, Transmission, Medicine, lipids (amino acids, peptides, and proteins), Research Article, MESH: Lipoprotein Lipase, MESH: DNA Primers, MESH: Cell Line, Tumor, APOLIPOPROTEIN-B, Lipoproteins, Immunoelectron microscopy, Science, LOW-DENSITY-LIPOPROTEIN, MEMBRANE-FUSION, Biology, Microbiology, BUOYANT DENSITY, Microscopy, Electron, Transmission, HUMAN LIVER, Virology, Cell Line, Tumor, Animals, Humans, Secretion, MESH: Mice, DNA Primers, MESH: Humans, Base Sequence, Biology and Life Sciences, Proteins, MESH: Polymerase Chain Reaction, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Molecular biology, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, digestive system diseases, Lipoprotein Lipase, HUMAN HEPATOCYTES, chemistry, RICH LIPOPROTEINS, VIRION-ASSOCIATED CHOLESTEROL, Lipoprotein, Chylomicron
Abstract

International audience; A distinctive feature of HCV is that its life cycle depends on lipoprotein metabolism. Viral morphogenesis and secretion follow the very low-density lipoprotein (VLDL) biogenesis pathway and, consequently, infectious HCV in the serum is associated with triglyceride-rich lipoproteins (TRL). Lipoprotein lipase (LPL) hydrolyzes TRL within chylomicrons and VLDL but, independently of its catalytic activity, it has a bridging activity, mediating the hepatic uptake of chylomicrons and VLDL remnants. We previously showed that exogenously added LPL increases HCV binding to hepatoma cells by acting as a bridge between virus-associated lipoproteins and cell surface heparan sulfate, while simultaneously decreasing infection levels. We show here that LPL efficiently inhibits cell infection with two HCV strains produced in hepatoma cells or in primary human hepatocytes transplanted into uPA-SCID mice with fully functional human ApoB-lipoprotein profiles. Viruses produced in vitro or in vivo were separated on iodixanol gradients into low and higher density populations, and the infection of Huh 7.5 cells by both virus populations was inhibited by LPL. The effect of LPL depended on its enzymatic activity. However, the lipase inhibitor tetrahydrolipstatin restored only a minor part of HCV infectivity, suggesting an important role of the LPL bridging function in the inhibition of infection. We followed HCV cell entry by immunoelectron microscopy with anti-envelope and anti-core antibodies. These analyses demonstrated the internalization of virus particles into hepatoma cells and their presence in intracellular vesicles and associated with lipid droplets. In the presence of LPL, HCV was retained at the cell surface. We conclude that LPL efficiently inhibits HCV infection by acting on TRL associated with HCV particles through mechanisms involving its lipolytic function, but mostly its bridging function. These mechanisms lead to immobilization of the virus at the cell surface. HCV-associated lipoproteins may therefore be a promising target for the development of new therapeutic approaches.

Published
2011
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22. Ghreline and adiponectin are linked to HDL-cholesterol levels in obesity independently of insulin resistance and inflammation

Author

Nogueira, Juan Patricio, Maraninchi, Marie, Béliard, S., Lorec, A. M., Begu-Le Corroller, A., Dubois, N., Grangeot, R., Mattei, C., Nicolay, A., Portugal, H., Vialettes, B., Valéro, R., Nutriments Lipidiques et Prévention des Maladies Métaboliques, Université de la Méditerranée - Aix-Marseille 2-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Faculté de Médecine de la Timone, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), and Service de Nutrition, Endocrinologie et Maladies Métaboliques

Subjects
obésité, inflammation, ghréline, hdl cholestérol, [SDV]Life Sciences [q-bio], adiponectine, résistance à l’insuline, ComputingMilieux_MISCELLANEOUS
Abstract

National audience

Published
2011

23. Lipidomics as a tool for the study of lipoprotein metabolism

Author

Anatol Kontush, M. John Chapman, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), These studies were supported by the National Institute for Health and Medical Research (INSERM), University of Pierre and Marie Curie (UPMC), CODDIM Ile-de-France, the Fondation de France and the Fondation pour la Recherche Médicale (Paris, France). AK acknowledges the award of a Contrat d'Interface from Assistance Publique--Hôpitaux de Paris/INSERM (France)., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Chapman, John

Subjects
Very low-density lipoprotein, HDL, Lipoproteins, Blood lipids, 030204 cardiovascular system & hematology, Biology, Lipidome, LDL, 03 medical and health sciences, chemistry.chemical_compound, Plasma, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Risk Factors, MESH: Risk Factors, Lipidomics, medicine, Humans, Metabolomics, MESH: Metabolomics, 030304 developmental biology, Dyslipidemias, 0303 health sciences, MESH: Humans, Fatty liver, MESH: Dyslipidemias, MESH: Cardiovascular Diseases, Lipid metabolism, medicine.disease, MESH: Lipoproteins, Lipids, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Biochemistry, chemistry, MESH: Morbidity, Cardiovascular Diseases, Low-density lipoprotein, lipids (amino acids, peptides, and proteins), Morbidity, Cardiology and Cardiovascular Medicine, VLDL, Lipoprotein
Abstract

International audience; Although technologies for lipidomic and proteomic investigations have developed very recently, lipidomic and proteomic studies of plasma lipoproteins have already provided several impressive examples of detailed characterization of distinct metabolic pathways potentially involved in lipoprotein metabolism in both health and disease states (obesity, insulin resistance, fatty liver disease) as well as under lifestyle and dietary modification (fish consumption, carbohydrates, probiotics) and lipid-modifying treatments (statins, low-density lipoprotein apheresis). Available lipidomic methodologies have facilitated detailed characterization of lipid classes and molecular species present in plasma as well as in lipoprotein fractions. Together with emerging proteomic techniques, lipidomics of plasma lipoproteins will soon provide molecular details of lipoprotein composition, which will ultimately be translated into integrated knowledge of the structure, metabolism, and function of lipoproteins in health and disease.

Published
2010
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24. Cholesteryl ester transfer protein: at the heart of the action of lipid-modulating therapy with statins, fibrates, niacin, and cholesteryl ester transfer protein inhibitors

Author

Wilfried Le Goff, Maryse Guerin, M. John Chapman, Anatol Kontush, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Drs T. Haigh and C.V. Felton (Prime Healthcare) conducted the literature search and provided excellent editorial assistance supported by an educational grant from F. Hoffmann La-Roche Ltd, Basel, Switzerland. Funding to pay the Open Access charge was provided by an educational grant from F. Hoffmann La-Roche Ltd. M.J.C. and A.K. gratefully acknowledge the award of a Contrat d'Interface of the Assistance Publique-Hopitaux de Paris/INSERM. The studies of the authors were supported by INSERM., and Chapman, John

Subjects
Review, 030204 cardiovascular system & hematology, chemistry.chemical_compound, 0302 clinical medicine, MESH: Cholesterol, Anacetrapib, MESH: Hypolipidemic Agents, Hypolipidemic Agents, 0303 health sciences, biology, Cholesteryl ester transfer protein inhibitor, Reverse cholesterol transport, Fibric Acids, Cholesteryl ester transfer protein, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, 3. Good health, Cholesterol, Cardiovascular Diseases, MESH: Cholesterol Ester Transfer Proteins, lipids (amino acids, peptides, and proteins), MESH: Cardiovascular Agents, MESH: Cholesterol, HDL, Cardiology and Cardiovascular Medicine, Niacin, MESH: Fibric Acids, medicine.medical_specialty, HDL, Dalcetrapib, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Cholesterylester transfer protein, medicine, Humans, MESH: Hydroxymethylglutaryl-CoA Reductase Inhibitors, Triglycerides, 030304 developmental biology, MESH: Humans, business.industry, Cholesterol, HDL, nutritional and metabolic diseases, MESH: Cardiovascular Diseases, Cardiovascular Agents, Atherosclerosis, Cholesterol Ester Transfer Proteins, MESH: Niacin, Endocrinology, chemistry, Cardiovascular agent, biology.protein, Hydroxymethylglutaryl-CoA Reductase Inhibitors, business, Lipoprotein
Abstract

International audience; Subnormal plasma levels of high-density lipoprotein cholesterol (HDL-C) constitute a major cardiovascular risk factor; raising low HDL-C levels may therefore reduce the residual cardiovascular risk that frequently presents in dyslipidaemic subjects despite statin therapy. Cholesteryl ester transfer protein (CETP), a key modulator not only of the intravascular metabolism of HDL and apolipoprotein (apo) A-I but also of triglyceride (TG)-rich particles and low-density lipoprotein (LDL), mediates the transfer of cholesteryl esters from HDL to pro-atherogenic apoB-lipoproteins, with heterotransfer of TG mainly from very low-density lipoprotein to HDL. Cholesteryl ester transfer protein activity is elevated in the dyslipidaemias of metabolic disease involving insulin resistance and moderate to marked hypertriglyceridaemia, and is intimately associated with premature atherosclerosis and high cardiovascular risk. Cholesteryl ester transfer protein inhibition therefore presents a preferential target for elevation of HDL-C and reduction in atherosclerosis. This review appraises recent evidence for a central role of CETP in the action of current lipid-modulating agents with HDL-raising potential, i.e. statins, fibrates, and niacin, and compares their mechanisms of action with those of pharmacological agents under development which directly inhibit CETP. New CETP inhibitors, such as dalcetrapib and anacetrapib, are targeted to normalize HDL/apoA-I levels and anti-atherogenic activities of HDL particles. Further studies of these CETP inhibitors, in particular in long-term, large-scale outcome trials, will provide essential information on their safety and efficacy in reducing residual cardiovascular risk.

Published
2010
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25. Role of scavenger receptor class B type I in hepatitis C virus entry: kinetics and molecular determinants

Author

Thierry Huby, Maria Teresa Catanese, Martine Moreau, Giacomo Paonessa, Alfredo Nicosia, Alessandra Vitelli, Charles M. Rice, Jonathan K. Ball, Riccardo Cortese, Helenia Ansuini, Rita Graziani, Catanese, Mt, Ansuini, H, Graziani, R, Huby, T, Moreau, M, Ball, Jk, Paonessa, G, Rice, Cm, Cortese, R, Vitelli, A, Nicosia, Alfredo, Laboratory of Virology and Infectious Disease, Rockefeller University [New York]-Center for the Study of Hepatitis C, Istituto di Ricerche di Biologia Molecolare P. Angeletti, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d’Endocrinologie, Métabolisme et Prévention des Risques Cardio-Vasculaires [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institute of Infection, Immunity, and Inflammation, University of Nottingham, UK (UON), CEINGE, Okairos, This work was supported by funding from the European Union (grants QLK2-CT-2001-01120 and MRTN-CT-2006-035599) and PHS grant R01 AI072613. M.T.C. was supported by a Women & Science fellowship., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Chapman, John, Service d'Endocrinologie, Métabolisme et Prévention des Maladies Cardio-vasculaires [CHU Pitié-Salpêtrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
MESH: Virus Internalization, Hepacivirus, medicine.disease_cause, MESH: Lipoproteins, HDL, MESH: Antibodies, Monoclonal, Mice, 0302 clinical medicine, MESH: Animals, MESH: Hepacivirus, Cells, Cultured, 0303 health sciences, biology, MESH: Kinetics, Antibodies, Monoclonal, Scavenger Receptors, Class B, Ligand (biochemistry), Hepatitis C, 3. Good health, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Virus-Cell Interactions, Receptors, Virus, 030211 gastroenterology & hepatology, Lipoproteins, HDL, MESH: Cells, Cultured, Hepatitis C virus, Immunology, Microbiology, Virus, 03 medical and health sciences, Viral envelope, Species Specificity, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Viral entry, Virology, medicine, Animals, Humans, MESH: Species Specificity, Scavenger receptor, MESH: Mice, 030304 developmental biology, MESH: Hepatitis C, MESH: Humans, Virus Internalization, biology.organism_classification, MESH: Receptors, Virus, MESH: Scavenger Receptors, Class B, NS2-3 protease, Kinetics, Hepadnaviridae, Insect Science
Abstract

Scavenger receptor class B type I (SR-BI) is an essential receptor for hepatitis C virus (HCV) and a cell surface high-density-lipoprotein (HDL) receptor. The mechanism of SR-BI-mediated HCV entry, however, is not clearly understood, and the specific protein determinants required for the recognition of the virus envelope are not known. HCV infection is strictly linked to lipoprotein metabolism, and HCV virions may initially interact with SR-BI through associated lipoproteins before subsequent direct interactions of the viral glycoproteins with SR-BI occur. The kinetics of inhibition of cell culture-derived HCV (HCVcc) infection with an anti-SR-BI monoclonal antibody imply that the recognition of SR-BI by HCV is an early event of the infection process. Swapping and single-substitution mutants between mouse and human SR-BI sequences showed reduced binding to the recombinant soluble E2 (sE2) envelope glycoprotein, thus suggesting that the SR-BI interaction with the HCV envelope is likely to involve species-specific protein elements. Most importantly, SR-BI mutants defective for sE2 binding, although retaining wild-type activity for receptor oligomerization and binding to the physiological ligand HDL, were impaired in their ability to fully restore HCVcc infectivity when transduced into an SR-BI-knocked-down Huh-7.5 cell line. These findings suggest a specific and direct role for the identified residues in binding HCV and mediating virus entry. Moreover, the observation that different regions of SR-BI are involved in HCV and HDL binding supports the hypothesis that new therapeutic strategies aimed at interfering with virus/SR-BI recognition are feasible.

Published
2010
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26. Postprandial lipemia enhances the capacity of large HDL2 particles to mediate free cholesterol efflux via SR-BI and ABCG1 pathways in type IIB hyperlipidemia

Author

M. John Chapman, Wilfried Le Goff, Maryse Guerin, Emilie Duchene, Zélie Julia, Natacha Bellanger, Natalie Fournier, Chapman, John, Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Nutrition Lipidique et Régulation Fonctionnelle du Coeur et des Vaisseaux (NLRFC), Institut National de la Recherche Agronomique (INRA)-Université Paris-Sud - Paris 11 (UP11), Service de biochimie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Européen Georges Pompidou [APHP] (HEGP), and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)-Hôpitaux Universitaires Paris Ouest - Hôpitaux Universitaires Île de France Ouest (HUPO)

Subjects
CD36 Antigens, Male, MESH: Hyperlipidemias, MESH: Lipoproteins, HDL2, Cardiologie et système cardiovasculaire, 030204 cardiovascular system & hematology, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, High-density lipoprotein, MESH: Cholesterol, Hyperlipidemia, ATP Binding Cassette Transporter, Subfamily G, Member 1, ATP binding cassette transporter G1, 0303 health sciences, MESH: Middle Aged, MESH: Kinetics, Reverse cholesterol transport, Middle Aged, Postprandial Period, Lipoproteins, HDL2, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Postprandial, Cholesterol, Liver, high density lipoprotein, Cholesteryl ester, MESH: ATP-Binding Cassette Transporters, MESH: Postprandial Period, Female, lipids (amino acids, peptides, and proteins), Cholesterol Esters, Adult, MESH: Triglycerides, medicine.medical_specialty, MESH: Biological Transport, Hyperlipidemias, QD415-436, type I, scavenger receptor class B, 03 medical and health sciences, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, medicine, Humans, MESH: Particle Size, Scavenger receptor, Particle Size, Triglycerides, 030304 developmental biology, cellular cholesterol efflux, MESH: Humans, MESH: Antigens, CD36, Biological Transport, MESH: Adult, Cell Biology, medicine.disease, MESH: Male, Cardiology and cardiovascular system, Kinetics, chemistry, scavenger receptor class B, type I, MESH: Cholesterol Esters, ATP-Binding Cassette Transporters, Antigens, CD36, Lipoproteins, HDL2, Patient-Oriented and Epidemiological Research, MESH: Female, Lipoprotein, MESH: Liver
Abstract

Lipid and cholesterol metabolism in the post- prandial phase is associated with both quantitative and qual- itative remodeling of HDL particle subspecies that may infl uence their anti-atherogenic functions in the reverse cholesterol transport pathway. We evaluated the capacity of whole plasma or isolated HDL particles to mediate cellular free cholesterol (FC) effl ux, cholesteryl ester transfer pro- tein (CETP)-mediated cholesteryl ester (CE) transfer, and selective hepatic CE uptake during the postprandial phase in subjects displaying type IIB hyperlipidemia (n = 16). Post- prandial, large HDL2 displayed an enhanced capacity to me- diate FC effl ux via both scavenger receptor class B type I (SR-BI)-dependent (+12%; P < 0.02) and ATP binding cas- sette transporter G1 (ABCG1)-dependent (+31%; P < 0.008) pathways in in vitro cell systems. In addition, the capacity of whole postprandial plasma (4 h and 8 h postprandially) to mediate cellular FC effl ux via the ABCA1-dependent path- way was signifi cantly increased (+19%; P < 0.0003). Concom- itantly, postprandial lipemia was associated with elevated endogenous CE transfer rates from HDL2 to apoB lipopro- teins and with attenuated capacity ( 17%; P < 0.02) of total HDL to deliver CE to hepatic cells. Postprandial lipemia enhanced SR-BI and ABCG1-dependent effl ux to large HDL2 particles. However, postprandial lipemia is equally associated with deleterious features by enhancing forma- tion of CE-enriched, triglyceride-rich lipoprotein particles through the action of CETP and by reducing the direct re- turn of HDL-CE to the liver. — Julia, Z., E. Duchene, N. Fournier, N. Bellanger, M. J. Chapman, W. Le Goff, and M. Guerin. Postprandial lipemia enhances the capacity of large HDL2 particles to mediate free cholesterol effl ux via SR-BI and ABCG1 pathways in type IIB hyperlipidemia. J. Lipid Res. 2010. 51: 3350-3358 .

Published
2010
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27. A machine-learning approach to the prediction of oxidative stress in chronic inflammatory disease

Author

Michel Brack, M.J. Chapman, Anatol Kontush, Dominique Bonnefont-Rousselot, Gérard Dreyfus, A. Magon de la Villehuchet, Yacine Oussar, Laboratoire Signaux, Modèles et Apprentissage Statistique (SIGMA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Clinical Center for Oxidative Stress, SIGMA Laboratory, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Biochimie Métabolique [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN)

Subjects
Male, model selection, Physiology, Clinical Biochemistry, Endogeny, 030204 cardiovascular system & hematology, Biology, medicine.disease_cause, Chronic inflammatory disease, Biochemistry, Models, Biological, Antioxidants, Oxidative damage, 03 medical and health sciences, 0302 clinical medicine, [INFO.INFO-LG]Computer Science [cs]/Machine Learning [cs.LG], Artificial Intelligence, medicine, Biological fluids, Biochemical reactions, Humans, 030304 developmental biology, Inflammation, 0303 health sciences, training, Biochemistry (medical), Neurodegenerative Diseases, Cell Biology, neural networks, 3. Good health, Oxidative Stress, machine learning, Cardiovascular Diseases, Immunology, Chronic Disease, Female, [CHIM.OTHE]Chemical Sciences/Other, biological markers, Oxidative stress, Biomarkers, variable selection
Abstract

International audience; Oxidative stress is implicated in the development of a wide range of chronic human diseases, ranging from cardiovascular to neurodegenerative and inflammatory disorders. As oxidative stress results from a complex cascade of biochemical reactions, its quantitative prediction remains incomplete. Here, we describe a machine-learning approach to the prediction of levels of oxidative stress in human subjects. From a database of biochemical analyses of oxidative stress biomarkers in blood, plasma and urine, non-linear models have been designed, with a statistical methodology that includes variable selection, model training and model selection. Our data demonstrate that, despite a large inter- and intra-individual variability, levels of biomarkers of oxidative damage in biological fluids can be predicted quantitatively from measured concentrations of a limited number of exogenous and endogenous antioxidants.

Published
2009
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28. Local apoptosis mediates clearance of macrophages from resolving inflammation in mice

Author

Gwendalyn J. Randolph, Philippe Lesnik, Stoyan Ivanov, Emmanuel L. Gautier, Gautier, Emmanuel, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Dyslipidémies, inflammation et athérosclérose dans les maladies métaboliques, Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)

Subjects
Male, MESH: Inflammation, Adoptive cell transfer, [SDV]Life Sciences [q-bio], Gene Expression, Apoptosis, MESH: Lymph Nodes, Biochemistry, Mice, Phagocytes, Granulocytes, and Myelopoiesis, Immunophenotyping, Cell Movement, MESH: Animals, MESH: Cell Movement, Macrophage inflammatory protein, Hematology, Adoptive Transfer, [SDV] Life Sciences [q-bio], Acute Disease, MESH: Acute Disease, Female, Lymph, medicine.symptom, MESH: Macrophages, Peritoneal, MESH: Gene Expression, MESH: Peritonitis, MESH: Immunophenotyping, Immunology, Peritonitis, Inflammation, Biology, MESH: Mice, Inbred C57BL, medicine, Animals, MESH: Mice, MESH: Apoptosis, Cell Biology, medicine.disease, MESH: Male, Mice, Inbred C57BL, MESH: Adoptive Transfer, Macrophages, Peritoneal, Lymph Nodes, CC chemokine receptors, MESH: Female
Abstract

International audience; Chronic inflammatory diseases such as atherosclerosis are characterized by an accumulation of macrophages. To design therapies that would reduce macrophage burden during disease, understanding the cellular and molecular mechanisms that regulate macrophage removal from sites of resolving inflammation is critical. Although past studies have considered the local death of macrophages or the possibility that they emigrate out of inflammatory foci, methods to quantify death or emigration have never been employed. Here, we applied quantitative competition approaches and other methods to study resolution of thioglycollate-induced peritonitis, the model in which earlier work indicated that emigration to lymph nodes accounted for macrophage removal. We show that migration to lymph nodes occurred in a CC chemokine receptor 7–independent manner but, overall, had a quantitatively minor role in the removal of macrophages. Blocking migration did not significantly delay resolution. However, when macrophages resistant to death were competed against control macrophages, contraction of the macrophage pool was delayed in the apoptosis-resistant cells. These data refute the concept that macrophages are dominantly cleared through emigration and indicate that local death controls macrophage removal. This finding alters the emphasis on which cellular processes merit targeting in chronic diseases associated with accumulation of macrophages.

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