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19 results on '"MESH: Receptors, LDL"'

1. Identification and stable expression of vitellogenin receptor through vitellogenesis in the European eel

Author

Marina Morini, Sylvie Dufour, Gersende Maugars, S. Baloche, Juan F. Asturiano, Anne-Gaëlle Lafont, Luz Pérez, Centre de Ressources Biologiques APHP-SU (PASS-CRB-APHP-SU), Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (PASS), and Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Vitellogenins, Teleost, [SDV]Life Sciences [q-bio], MESH: Vitellogenesis, PRODUCCION ANIMAL, MESH: Sexual Maturation, Oogenesis, Vitellogenins, 0302 clinical medicine, Transcription (biology), MESH: Pituitary Gland, MESH: Animals, Sexual Maturation, Receptor, MESH: Receptors, Cell Surface, 0303 health sciences, teleost, biology, Anguilla anguilla, oogenesis, Reproduction, Vitellogenesis, MESH: Gene Expression Regulation, Cell biology, Animal culture, medicine.anatomical_structure, Liver, Pituitary Gland, Female, MESH: Ovary, endocrine system, MESH: Egg Proteins, food.ingredient, animal structures, Receptors, Cell Surface, SF1-1100, MESH: Oocytes, reproduction, 03 medical and health sciences, Vitellogenin, food, Yolk, medicine, Animals, MESH: Anguilla, lipoprotein receptor 8, 030304 developmental biology, Lipoprotein receptor 8, Egg Proteins, Ovary, Oocyte, Anguilla, Gene Expression Regulation, Receptors, LDL, MESH: Receptors, LDL, LDL receptor, biology.protein, Oocytes, Animal Science and Zoology, MESH: Female, 030217 neurology & neurosurgery, MESH: Liver
Abstract

[EN] In teleosts, vitellogenin (Vtg) is a phospholipoglycoprotein synthesized by the liver, released into the blood circulation and incorporated into the oocytes via endocytosis mediated by the Vtg receptor (VTGR) to form the yolk granules. The VTGR is crucial for oocyte growth in egg-laying animals but is also present in non-oviparous vertebrates, such as human. The VTGR belongs to the low-density lipoprotein receptor superfamily (LDLR) and is also named very-low-density lipoprotein receptor (VLDLR). In this study, we identified and phylogenetically positioned the VTGR of a basal teleost, the European eel, Anguilla anguilla. We developed quantitative real-time PCR (qRT-PCR) and investigated the tissue distribution of vtgr transcripts. We compared by qRT-PCR the ovarian expression levels of vtgr in juvenile yellow eels and pre-pubertal silver eels. We also analyzed the regulation of ovarian vtgr expression throughout vitellogenesis in experimentally matured eels. The Vtg plasma level was measured by homologous ELISA experimental maturation. Our in silico search and phylogenetical analysis revealed a single vtgr in the European eel, orthologous to other vertebrate vtgr. The qRT-PCR studies revealed that vtgr is mainly expressed in the ovary and also detected in various other tissues such as brain, pituitary, gill, fat, heart, and testis, suggesting some extra-ovarian functions of VTGR. We showed that vtgr is expressed in ovaries of juvenile yellow eels with no higher expression in pre-pubertal silver eels nor in experimentally matured eels. This suggests that vtgr transcription already occurs during early pre-vitellogenesis of immature eels and is not further activated in vitellogenic oocytes. European eel Vtg plasma level increased throughout experimental maturation in agreement with previous studies. Taken together, these results suggest that vtgr transcript levels may not be a limiting step for the uptake of Vtg by the oocyte in the European eel., M.M., A.G.L. and S.D. were granted with Short Term Scientific Missions by the COST Office (COST Action FA1205: AQUAGAMETE). S.D. was also awarded with a grant from the UPV's School of Doctorate (Accion para la Internacionalizacion de los Programas de Doctorado) in 2017. We thank E. Feunteun and colleagues, MNHN, Dinard, for the ovarian samples from eels of the Fremur, France.

Published
2020

2. Decreasing dietary linoleic acid promotes long chain omega-3 fatty acid incorporation into rat retina and modifies gene expression

Author

Stéphane Grégoire, Lionel Bretillon, Catherine Creuzot-Garcher, Niyazi Acar, Bertrand Bardet, Emilie Simon, Alain M. Bron, Centre des Sciences du Goût et de l'Alimentation [Dijon] (CSGA), Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique (CNRS), Service d'Ophtalmologie (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre des Sciences du Goût et de l'Alimentation [Dijon] ( CSGA ), Institut National de la Recherche Agronomique ( INRA ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre National de la Recherche Scientifique (CNRS)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Recherche Agronomique (INRA)-Université de Bourgogne (UB), INRA (Human Nutrition Department, France), Laboratoires Horus Pharma (Saint Laurent du Var, France) 29000305, and Regional Council of Burgundy (France) 29000362

Subjects
CD36 Antigens, Male, MESH : RNA, Messenger, MESH: 5-Lipoxygenase-Activating Proteins, MESH : Receptors, LDL, MESH: Electroretinography, 0302 clinical medicine, MESH: Fatty Acids, Omega-3, MESH: Animals, MESH : Retinal Ganglion Cells, chemistry.chemical_classification, 0303 health sciences, MESH : Gene Expression Regulation, MESH : Electroretinography, MESH: Retina, MESH: Chromatography, Gas, MESH: Dietary Fats, Unsaturated, docosahexaenoic acid, polyunsaturated fatty acid, Sensory Systems, 3. Good health, nutrition, MESH: Photic Stimulation, Adipose Tissue, MESH: Adipose Tissue, medicine.medical_specialty, Chromatography, Gas, macular degeneration, Linoleic acid, MESH : Arachidonate 12-Lipoxygenase, Arachidonate 12-Lipoxygenase, MESH : Adipose Tissue, MESH: Arachidonate 12-Lipoxygenase, pufa, 03 medical and health sciences, MESH : Dietary Fats, Unsaturated, lipid, Electroretinography, Rats, Long-Evans, RNA, Messenger, MESH: Linoleic Acid, MESH: Antigens, CD36, MESH : Retina, Fatty acid, MESH: Retinal Ganglion Cells, eye diseases, Ophthalmology, Endocrinology, chemistry, MESH: Receptors, LDL, 030221 ophthalmology & optometry, ATP-Binding Cassette Transporters, n 3, MESH: Female, Photic Stimulation, MESH: Liver, Retinal Ganglion Cells, retina, MESH : 5-Lipoxygenase-Activating Proteins, genetic structures, [ SDV.AEN ] Life Sciences [q-bio]/Food and Nutrition, retinal pigment epithelium, electroretinogram, MESH : Photic Stimulation, Adipose tissue, angiogenesis, chemistry.chemical_compound, MESH : Female, MESH : Rats, Long-Evans, 2. Zero hunger, medicine.diagnostic_test, MESH : Rats, MESH: Real-Time Polymerase Chain Reaction, MESH: Gene Expression Regulation, MESH : Antigens, CD36, medicine.anatomical_structure, Liver, ALOX12, Biochemistry, MESH: ATP-Binding Cassette Transporters, Female, ATP Binding Cassette Transporter 1, Polyunsaturated fatty acid, MESH : Fatty Acids, Omega-3, MESH: Rats, brain, MESH : Male, 5-Lipoxygenase-Activating Proteins, MESH : Real-Time Polymerase Chain Reaction, rhesus monkey, Biology, Real-Time Polymerase Chain Reaction, MESH : Chromatography, Gas, Linoleic Acid, Cellular and Molecular Neuroscience, Dietary Fats, Unsaturated, MESH : Linoleic Acid, MESH: Rats, Long-Evans, Internal medicine, Fatty Acids, Omega-3, medicine, Animals, MESH : ATP-Binding Cassette Transporters, Omega 3 fatty acid, MESH: RNA, Messenger, 030304 developmental biology, deficient diet, Retinal pigment epithelium, MESH : Liver, MESH: Male, Rats, Gene Expression Regulation, Receptors, LDL, gene expression, MESH : Animals, sense organs, [SDV.AEN]Life Sciences [q-bio]/Food and Nutrition
Abstract

International audience; Age-related macular degeneration (AMD) may be partially prevented by dietary habits privileging the consumption of ω3 long chain polyunsaturated fatty acids (ω3s) while lowering linoleic acid (LA) intake. The present study aimed to document whether following these epidemiological guidelines would enrich the neurosensory retina and RPE with ω3s and modulate gene expression in the neurosensory retina. Rat progenitors and pups were fed with diets containing low or high LA, and low or high ω3s. After scotopic single flash and 8-Hz-Flicker electroretinography, rat pups were euthanized at adulthood. The fatty acid profile of the neurosensory retina, RPE, liver, adipose tissue and plasma was analyzed using gas chromatography. Gene expression was analyzed with real-time PCR in the neurosensory retina. Diets rich in ω3s efficiently improved the incorporation of ω3s into the organs and tissues. This raising effect was magnified by lowering LA intake. Compared to a diet with high LA and low ω3s, low LA diets significantly upregulated LDL-receptor gene expression. Similar but not significant upregulation of CD36, ABCA1, ALOX5 and ALOX12 gene expression was observed in rats fed with low LA. No effect was observed on retinal function. Increasing the intake in ω3s and lowering LA improved the enrichment with ω3s of the tissues, including the neurosensory retina and RPE, and upregulated genes involved in lipid trafficking in the neurosensory retina. Those results consistently reinforced the beneficial role of ω3s in the prevention of AMD, especially when the diet contained low levels of LA, as suggested from epidemiological data.

Published
2011

3. Combined Deletion of Macrophage ABCA1 and ABCG1 Leads to Massive Lipid Accumulation in Tissue Macrophages and Distinct Atherosclerosis at Relatively Low Plasma Cholesterol Levels

Author

Menno Hoekstra, Illiana Meurs, Giovanna Chimini, Theo J.C. Van Berkel, Vivian de Waard, Miranda Van Eck, Ruud Out, Yanan Wang, Kim L. L. Habets, Johan Kuiper, Reeni B. Hildebrand, Division of Biopharmaceutics, Universiteit Leiden [Leiden], Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universiteit Leiden, and Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)

Subjects
MESH: Spleen, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, MESH: Atherosclerosis, Leukocyte Count, Mice, chemistry.chemical_compound, MESH: Cholesterol, 0302 clinical medicine, MESH: Animals, MESH: Bone Marrow Transplantation, ATP Binding Cassette Transporter, Subfamily G, Member 1, Bone Marrow Transplantation, Foam cell, Mice, Knockout, 0303 health sciences, biology, MESH: Hypercholesterolemia, MESH: Lipoproteins, Cholesterol, medicine.anatomical_structure, MESH: ATP-Binding Cassette Transporters, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), medicine.symptom, Cardiology and Cardiovascular Medicine, ATP Binding Cassette Transporter 1, medicine.medical_specialty, MESH: Foam Cells, Lipoproteins, Hypercholesterolemia, MESH: Diet, Atherogenic, Lesion, 03 medical and health sciences, Peritoneal cavity, Internal medicine, medicine, Animals, MESH: Mice, 030304 developmental biology, Atherosclerosis, Transplantation, Disease Models, Animal, Endocrinology, Receptors, LDL, chemistry, MESH: Receptors, LDL, MESH: Leukocyte Count, ABCA1, LDL receptor, biology.protein, Diet, Atherogenic, ATP-Binding Cassette Transporters, Bone marrow, MESH: Disease Models, Animal, Spleen, Foam Cells
Abstract

Objective— The purpose of this study was to evaluate the effect of the combined deletion of ABCA1 and ABCG1 expression in macrophages on foam cell formation and atherosclerosis. Methods and Results— LDL receptor knockout (KO) mice were transplanted with bone marrow from ABCA1/ABCG1 double KO (dKO) mice. Plasma cholesterol levels after 6 weeks of Western-type diet (WTD) feeding were significantly lower in dKO transplanted mice than ABCA1 KO, ABCG1 KO, and control transplanted animals. Extreme foam cell formation was present in macrophages of various tissues and the peritoneal cavity of dKO transplanted animals. Furthermore, severe hypoplasia of the thymus and a significant decrease in CD4-positive T cells in blood was observed. Despite relatively low plasma cholesterol levels dKO transplanted animals developed lesion sizes of 156±19×10 3 μm 2 after only 6 weeks of WTD feeding. Lesions, however, were smaller than single ABCA1 KO transplanted animals (226±30×10 3 μm 2 ; P 3 μm 2 ) and WT transplanted mice (112±15×10 3 μm 2 ). Conclusions— Macrophage ABCA1 and ABCG1 play a crucial role in the prevention of macrophage foam cell formation, whereas combined deletion only modestly influences atherosclerosis which is associated with an attenuated increase in WTD-induced plasma cholesterol and decreased proinflammatory CD4-positive T cell counts.

Published
2008

4. Transforming Growth Factor Activity Is a Key Determinant for the Effect of Estradiol on Fatty Streak Deposit in Hypercholesterolemic Mice

Author

Barbara Garmy-Susini, Cédric Filipe, Bertrand Calippe, Alexia Schambourg, François Tercé, Pierre Gourdy, Victorine Douin-Echinard, Jean-François Arnal, Francis Bayard, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de diabétologie, Pôle Cardio-Vasculaire et Métabolique, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS), Simon, Marie Francoise, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées- Institut Fédératif de Recherche Bio-médicale Institution (IFR150)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service Diabétologie [CHU Toulouse], Pôle Cardiovasculaire et Métabolique [CHU Toulouse], and Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)

Subjects
MESH: Interleukin-12, MESH: Signal Transduction, MESH: Interleukin-10, medicine.medical_treatment, MESH: Mice, Knockout, MESH: Drug Implants, MESH: Antibodies, Monoclonal, MESH: Atherosclerosis, Mice, MESH: Transforming Growth Factor beta1, 0302 clinical medicine, MESH: Animals, MESH: Bone Marrow Transplantation, Aorta, Bone Marrow Transplantation, Drug Implants, Mice, Knockout, 0303 health sciences, Estradiol, Antibodies, Monoclonal, MESH: Hypercholesterolemia, Interleukin, MESH: Aorta, MESH: Apolipoproteins E, Interleukin-12, Interleukin-10, Cytokine, 030220 oncology & carcinogenesis, Disease Progression, Female, MESH: Disease Progression, MESH: Estradiol, medicine.symptom, Cardiology and Cardiovascular Medicine, MESH: Whole-Body Irradiation, Whole-Body Irradiation, Signal Transduction, medicine.medical_specialty, MESH: Interferon-gamma, medicine.drug_class, Ratón, Ovariectomy, Hypercholesterolemia, MESH: Ovariectomy, Inflammation, Biology, Proinflammatory cytokine, Transforming Growth Factor beta1, Interferon-gamma, 03 medical and health sciences, Apolipoproteins E, MESH: Mice, Inbred C57BL, Internal medicine, medicine, Animals, MESH: Smad3 Protein, Smad3 Protein, MESH: Mice, 030304 developmental biology, Fatty streak, Atherosclerosis, Mice, Inbred C57BL, Disease Models, Animal, Endocrinology, Receptors, LDL, MESH: Receptors, LDL, Estrogen, MESH: Disease Models, Animal, MESH: Female, Transforming growth factor
Abstract

Objective— Whereas estradiol prevents fatty streak deposit in immunocompetent apoE −/− or LDLr −/− mice, it is totally ineffective in immunodeficient mice, underlining the key role of immunoinflammation in this effect. In the present work, the role of several major pro- and antiinflammatory cytokines involved in the atheromatous process was evaluated in the effect of estradiol on fatty streak constitution. Methods and Results— The preventive effect of estradiol was fully maintained in LDLr −/− mice grafted with bone marrow from either IFN-γ or interleukin (IL)-12–deficient mice, showing that this beneficial effect was not mediated through a specific decrease in the production of these 2 proinflammatory cytokines. Furthermore, IL-10 −/− apoE −/− mice remained protected by estradiol, excluding a significant contribution of this antiinflammatory cytokine. In contrast, the protective effect of estradiol was (1) associated with enhanced aortic expression of TGF-β1 in apoE −/− mice during early steps of atherogenesis; (2) abolished and even reversed in apoE −/− mice administered with a neutralizing anti–TGF-β antibody; (3) abolished in LDLr −/− mice grafted with bone marrow from Smad3-deficient mice. Conclusions— The status of the TGF-β pathway crucially determines the antiatherogenic effect of estradiol in hypercholesterolemic mice, whereas neither IFN-γ, IL-12, nor IL-10 are specifically involved in this protection.

Published
2007

5. Promoting macrophage survival delays progression of pre-existing atherosclerotic lesions through macrophage-derived apoE

Author

John Pirault, Laura Bouchareychas, Philippe Giral, Philippe Lesnik, Virginie Deswaerte, Thierry Huby, Tiphaine Le Roy, Wendy Jessup, Wilfried Le Goff, Emmanuel L. Gautier, Flora Saint-Charles, 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), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-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), The University of Sydney, and Gautier, Emmanuel

Subjects
Apolipoprotein E, Male, Physiology, Macrophage, [SDV]Life Sciences [q-bio], Apoptosis, MESH: Atherosclerosis, chemistry.chemical_compound, Mice, MESH: Cholesterol, Antigens, Ly, MESH: Animals, education.field_of_study, MESH: Antigens, Ly, MESH: Apolipoproteins E, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Cholesterol, Proto-Oncogene Proteins c-bcl-2, MESH: Cell Survival, Disease Progression, lipids (amino acids, peptides, and proteins), MESH: Disease Progression, Cardiology and Cardiovascular Medicine, Cell Survival, Population, Context (language use), Biology, Apolipoproteins E, Physiology (medical), medicine, Animals, education, MESH: Mice, Macrophages, MESH: Apoptosis, MESH: Macrophages, Atherosclerosis, MESH: Male, chemistry, Receptors, LDL, MESH: Proto-Oncogene Proteins c-bcl-2, MESH: Receptors, LDL, LDL receptor, Immunology, Cancer research, Bone marrow
Abstract

International audience; Aims: Macrophage apoptosis is a prominent feature of atherosclerosis, yet whether cell death-protected macrophages would favour the resolution of already established atherosclerotic lesions, and thus hold therapeutic potential, remains unknown.Methods and results: We irradiated then transplanted into Apoe(-/-) or LDLr(-/-) recipient mice harbouring established atherosclerotic lesions, bone marrow cells from mice displaying enhanced macrophage survival through overexpression of the antiapoptotic gene hBcl-2 (Mø-hBcl2 Apoe(-/-) or Mø-hBcl2 Apoe(+/+) LDLr(-/-)). Both recipient mice exhibited decreased lesional apoptotic cell content and reduced necrotic areas when repopulated with Mø-hBcl2 mouse-derived bone marrow cells. In contrast, only LDLr(-/-) recipients showed a reduction in plasma cholesterol levels and in atherosclerotic lesions. The absence of significant reduction of plasma cholesterol levels in the context of apoE deficiency highlighted macrophage-derived apoE as key in both the regulation of plasma and tissue cholesterol levels and the progression of pre-existing lesion. Accordingly, hBcl2 expression in macrophages was associated with larger pools of Kupffer cells and Ly-6C(low) monocytes, both high producers of apoE. Additionally, increased Kupffer cells population was associated with improved clearance of apoptotic cells and modified lipoproteins.Conclusion: Collectively, these data show that promoting macrophage survival provides a supplemental source of apoE, which hinders pre-existing plaque progression.

Published
2015

6. SKI-1/S1P inhibitor PF-429242 impairs the onset of HCV infection

Author

Camille Sureau, Patrick Labonté, Matthieu Blanchet, Nabil G. Seidah, Carl Guévin, Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), Institut National de la Transfusion Sanguine [Paris] (INTS), Institut de Recherches Cliniques de Montréal (IRCM), Université de Montréal (UdeM), P.L. is supported by a Canadian Institutes of Health Research (CIHR) Grant #MOP 93792 and received a salary support from LeFonds de recherche du Québec (FRSQ). M.B. was supported by a postdoctoral Fellowship from ‘‘La fondation UniversitaireArmand-Frappier’’. N.G.S. is supported by a CIHR Grant #MOP 93792 and by a Canada Research Chair #216684. C.S. is a CNRSinvestigator and is supported by a grant from the ‘‘Agence nationale de recherches sur le sida et les hépatites virales’’. We wouldlike to thank Ahmed M. Fahmy and Quoc-Tuan Le for technical assistance and Christine Kleinert for carefully reading the manu-script. We are grateful to Dr. Alan D. Attie and Dr. Lawrence L. Rudel for providing the pCI-LDLR and the pL1-EGFP plasmids,respectively, and to Dr. Charles M. Rice for providing the Huh7.5 cell line. Finally, we want to thank Dr. François-Loïc Cosset for providing us with the pseudotyped particles constructs, Institut National de la Recherche Scientifique [Québec] (INRS) - Réseau International des Instituts Pasteur - Institut Armand Frappier, and Université de Montréal - UdeM (CANADA)

Subjects
Pyrrolidines, Cirrhosis, [SDV]Life Sciences [q-bio], Regulator, Hepacivirus, Virus Replication, MESH: Genotype, MESH: Gene Expression Regulation, Viral, MESH: Hepacivirus, MESH: Serine Endopeptidases, PF-429242, Serine Endopeptidases, Viral entry, Hepatitis C, [SDV] Life Sciences [q-bio], Hepatocellular carcinoma, HCV, MESH: Proprotein Convertases, MESH: Virion, lipids (amino acids, peptides, and proteins), Proprotein Convertases, MESH: Membrane Proteins, Proprotein Convertase 9, Gene Expression Regulation, Viral, MESH: Antiviral Agents, MESH: Cell Line, Tumor, Genotype, Biology, Antiviral Agents, SREBP, Virus, Cell Line, Tumor, Virology, medicine, Humans, Secretion, Pharmacology, MESH: Hepatitis C, MESH: Humans, MESH: Pyrrolidines, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hepatology and Gastroenterology, MESH: Virus Replication, Subtilisin, Virion, Membrane Proteins, Membrane Transport Proteins, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, medicine.disease, Sterol regulatory element-binding protein, LDLR, Receptors, LDL, MESH: Receptors, LDL, LDL receptor, Immunology, SKI-1/S1P, MESH: Subtilisin
Abstract

International audience; Worldwide, approximately 170 million individuals are afflicted with chronic hepatitis C virus (HCV) infection. To prevent the development of inherent diseases such as cirrhosis and hepatocellular carcinoma, tremendous efforts have been made, leading to the development of promising new treatments. However, their efficiency is still dependent on the viral genotype. Additionally, these treatments that target the virus directly can trigger the emergence of resistant variants. In a previous study, we have demonstrated that a long-term (72h) inhibition of SKI-1/S1P, a master lipogenic pathway regulator through activation of SREBP, resulted in impaired HCV genome replication and infectious virion secretion. In the present study, we sought to investigate the antiviral effect of the SKI-1/S1P small molecule inhibitor PF-429242 at the early steps of the HCV lifecycle. Our results indicate a very potent antiviral effect of the inhibitor early in the viral lifecycle and that the overall action of the compound relies on two different contributions. The first one is SREBP/SKI-1/S1P dependent and involves LDLR and NPC1L1 proteins, while the second one is SREBP independent. Overall, our study confirms that SKI-1/S1P is a relevant target to impair HCV infection and that PF-429242 could be a promising candidate in the field of HCV infection treatment.

Published
2015

7. Maintenance of Macrophage Redox Status by ChREBP Limits Inflammation and Apoptosis and Protects against Advanced Atherosclerotic Lesion Formation

Author

Sarrazy, Vincent, Sore, Sophie, Viaud, Manon, Rignol, Guylène, Westerterp, Marit, Ceppo, Franck, Tanti, Jean-François, Guinamard, Rodolphe r., Gautier, Emmanuel L., Yvan-Charvet, Laurent, Gautier, Emmanuel, Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Columbia University [New York], 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), 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)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Center for Liver, Digestive and Metabolic Diseases (CLDM), Translational Immunology Groningen (TRIGR), and HAL UPMC, Gestionnaire

Subjects
MESH: Signal Transduction, MESH: Inflammation, MESH: Oxidation-Reduction, MESH: Lipoproteins, LDL, Glycolysis/genetics, MESH: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, [SDV]Life Sciences [q-bio], Apoptosis, MESH: Mice, Knockout, MESH: Atherosclerosis, Mice, Macrophages/drug effects, Glucose/metabolism, MESH: Animals, lcsh:QH301-705.5, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Macrophage Activation/drug effects, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, MESH: Bone Marrow Cells, Nuclear Proteins, MESH: Macrophage Activation, Plaque, Atherosclerotic/genetics, MESH: Toll-Like Receptor 4, MESH: Transcription Factors, MESH: Gene Expression Regulation, Plaque, Atherosclerotic, Lipoproteins, LDL, [SDV] Life Sciences [q-bio], MESH: Glucose, MESH: Glycolysis, Female, Glycolysis, Oxidation-Reduction, Signal Transduction, Primary Cell Culture, Transcription Factors/genetics, Bone Marrow Cells, Lipoproteins, LDL/pharmacology, Receptors, LDL/deficiency, MESH: Primary Cell Culture, Animals, Humans, MESH: Plaque, Atherosclerotic, MESH: Mice, Inflammation, MESH: Humans, Macrophages, MESH: Apoptosis, Apoptosis/drug effects, MESH: Macrophages, Macrophage Activation, Atherosclerosis, Toll-Like Receptor 4, Nuclear Proteins/genetics, Glucose, Atherosclerosis/genetics, lcsh:Biology (General), Receptors, LDL, Gene Expression Regulation, Bone Marrow Cells/drug effects, MESH: Receptors, LDL, MESH: Female, MESH: Nuclear Proteins, Toll-Like Receptor 4/genetics, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Transcription Factors
Abstract

International audience; Enhanced glucose utilization can be visualized in atherosclerotic lesions and may reflect a high glycolytic rate in lesional macrophages, but its causative role in plaque progression remains unclear. We observe that the activity of the carbohydrate-responsive element binding protein ChREBP is rapidly downregulated upon TLR4 activation in macrophages. ChREBP inactivation refocuses cellular metabolism to a high redox state favoring enhanced inflammatory responses after TLR4 activation and increased cell death after TLR4 activation or oxidized LDL loading. Targeted deletion of ChREBP in bone marrow cells resulted in accelerated atherosclerosis progression in Ldlr(-/-) mice with increased monocytosis, lesional macrophage accumulation, and plaque necrosis. Thus, ChREBP-dependent macrophage metabolic reprogramming hinders plaque progression and establishes a causative role for leukocyte glucose metabolism in atherosclerosis.

Published
2015

8. ABCA1 mediates high-affinity uptake of 25-hydroxycholesterol by membrane vesicles and rapid efflux of oxysterol by intact cells

Author

Shui-Pang Tam, Monika Vasa, Giovanna Chimini, Leo Mok, Roger G. Deeley, Centre d'Immunologie de Marseille - Luminy (CIML), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), and Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Embryo, Nonmammalian, Insecta, Physiology, ATP-binding cassette transporter, MESH: Hydroxycholesterols, Mice, chemistry.chemical_compound, MESH: Insects, Adenosine Triphosphate, MESH: Adenosine Triphosphate, polycyclic compounds, MESH: Animals, Phospholipids, Feedback, Physiological, Reverse cholesterol transport, Serum Albumin, Bovine, Cell biology, Biochemistry, MESH: ATP-Binding Cassette Transporters, [SDV.IMM]Life Sciences [q-bio]/Immunology, lipids (amino acids, peptides, and proteins), Efflux, Hydrophobic and Hydrophilic Interactions, ATP Binding Cassette Transporter 1, MESH: Mutation, Oxysterol, Phospholipid, Biology, Transfection, Cell Line, MESH: Transport Vesicles, Animals, Humans, Transport Vesicles, MESH: Mice, MESH: Phospholipids, MESH: Hydrophobicity, MESH: Humans, MESH: Transfection, MESH: Feedback, Biochemical, MESH: Embryo, Transporter, Cell Biology, Fibroblasts, Embryo, Mammalian, Hydroxycholesterols, MESH: Cell Line, MESH: Hydroxymethylglutaryl CoA Reductases, Receptors, LDL, chemistry, MESH: Receptors, LDL, MESH: Fibroblasts, ABCA1, Mutation, biology.protein, ATP-Binding Cassette Transporters, Hydroxymethylglutaryl CoA Reductases, MESH: Serum Albumin, Bovine
Abstract

ATP Binding Cassette (ABC) transporter, ABCA1, plays a pivotal role in reverse cholesterol transport by mediating the cellular efflux of phospholipid and cholesterol. Studies using intact cells strongly suggest that ABCA1 acts as a phospholipid floppase, but there has been no direct demonstration that the protein is a primary active sterol transporter. Using membrane vesicles from insect Sf21 cells, we found that ABCA1 mediated ATP-dependent uptake of [3H]25-hydroxycholesterol with an apparent Kmof 0.7 μM. Consistent with this high apparent affinity, expression of ABCA1 in human embryonic kidney cells both increased rapid efflux of 25-hydroxcholesterol and prevented oxysterol-mediated repression of low-density lipoprotein (LDL) receptor and 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase mRNAs. Comparison of wild-type and ABCA1−/−murine fibroblasts indicates that 25-hydroxycholesterol is effluxed ∼5-fold more rapidly by wild-type cells. In addition, the rate of efflux from the wild-type but not the ABCA1−/−fibroblasts is increased a further twofold by inducers of ABCA1 expression. Thus under the experimental conditions employed, endogenous ABCA1 is a major contributor to 25-hydroxycholesterol efflux from wild-type fibroblasts. Evidence from in vitro studies indicates that oxysterols are potent inducers of genes involved in cellular cholesterol efflux and metabolism, including the ABCA1 gene, and repressors of genes involved in cholesterol synthesis or uptake. Our observations raise the possibility that efflux of oxysterols by ABCA1 could contribute to a homeostatic mechanism, which both attenuates oxysterol-induced expression of its cognate gene and alleviates repression of genes encoding proteins, such as HMG-CoA reductase and LDL receptor.

Published
2006

9. LDL Receptor-Related Protein 5 (LRP5) Affects Bone Accrual and Eye Development

Author

Raoul C.M. Hennekam, Tim Cundy, E. Steichen-Gersdorf, Shauna Heeger, J. A. Batch, Andrea Superti-Furga, Francis H. Glorieux, Leena Peltonen, R. B. Slee, E. Lemyre, A. Kohlschuetter, Bjorn R. Olsen, W. Swoboda, A. Jans, M. J. van den Boogaard, Bernhard Zabel, Konrad Oexle, Graeme C.M. Black, M. Zacharin, B. Floege, Han G. Brunner, Rajkumar Ramesar, Wafaa M. Suwairi, Sergio Roman-Roman, Jose Marcelino, C. Borrone, Anthony M. Reginato, J. Allgrove, Beth A. Sullivan, A. De Paepe, Matthew L. Warman, H. Somer, Beat Steinmann, M. Arslan-Kirchner, Georges Rawadi, W. Van Hul, K. Keppler-Noreuil, W. N. Adkins, G. Sabatakos, Bruno Dallapiccola, Chong Ae Kim, Naomi Fukai, Dorit Lev, Tatsuo Hirose, Miikka Vikkula, Marcela Votruba, Teresa Garcia, M. Lambert, M. L. Halfhide, R. G. Boles, Roland Baron, G. F. Carle, H. W. Wang, L. M. Boon, M. Romanengo, Harald Jüppner, T. Letteboer, Barbara Hall, Peter Beighton, Yaoqin Gong, Didier Lacombe, Suneel S. Apte, Génétique et signalisation moléculaire (GSM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre Hospitalier Universitaire de Nice (CHU Nice)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Génétique et pathologies moléculaires (GPM), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Génétique, physiopathologie et ingénierie du tissu osseux (GéPITOS), Université Nice Sophia Antipolis (... - 2019) (UNS), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), and Other departments

Subjects
Male, Osteoporosis, Dishevelled Proteins, Bone Morphogenetic Protein 2, Wnt2 Protein, Mesoderm, MESH: Recombinant Proteins, Mice, MESH: Animals, Outbred Strains, 0302 clinical medicine, Transforming Growth Factor beta, MESH: Child, MESH: Animals, MESH: Proteins, Eye Abnormalities, Child, 0303 health sciences, MESH: Mesoderm, Wnt signaling pathway, MESH: Wnt Proteins, MESH: COS Cells, Child, Preschool, COS Cells, medicine.medical_specialty, Recombinant Fusion Proteins, MESH: Eye, MESH: Zebrafish Proteins, Transfection, Bone morphogenetic protein, Wnt-5a Protein, General Biochemistry, Genetics and Molecular Biology, Wnt3 Protein, 03 medical and health sciences, Organ Culture Techniques, Species Specificity, MESH: Wnt2 Protein, Animals, Outbred Strains, MESH: Recombinant Fusion Proteins, Humans, MESH: Species Specificity, LDL-Receptor Related Proteins, MESH: Genes, Recessive, MESH: Adaptor Proteins, Signal Transducing, Osteoblasts, MESH: Humans, Skull, MESH: Child, Preschool, Proteins, MESH: Adult, medicine.disease, MESH: Cercopithecus aethiops, Mice, Inbred C57BL, Wnt Proteins, Endocrinology, MESH: Receptors, LDL, Culture Media, Conditioned, Stromal Cells, Opheldering van erfelijke ziekten en hun moleculaire diagnostiek, MESH: Female, MESH: Signal Transduction, Bone density, MESH: Bone Morphogenetic Proteins, Eye, Bone Density, Wnt4 Protein, Chlorocebus aethiops, MESH: Syndrome, MESH: Bone Density, MESH: Heterozygote, MESH: Culture Media, Conditioned, LRP5, Syndrome, MESH: Eye Abnormalities, Recombinant Proteins, Low Density Lipoprotein Receptor-Related Protein-5, Bone Morphogenetic Proteins, Female, MESH: Skull, Signal Transduction, MESH: Osteoporosis, Adult, Peak bone mass, Heterozygote, DNA, Complementary, Elucidation of hereditary disorders and their molecular diagnosis, Genes, Recessive, 030209 endocrinology & metabolism, Biology, Bone morphogenetic protein 2, MESH: Phosphoproteins, MESH: LDL-Receptor Related Proteins, MESH: Mice, Inbred C57BL, Proto-Oncogene Proteins, Internal medicine, medicine, Animals, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Mice, MESH: Transforming Growth Factor beta, Adaptor Proteins, Signal Transducing, 030304 developmental biology, MESH: Osteoblasts, Biochemistry, Genetics and Molecular Biology(all), Chromosomes, Human, Pair 11, MESH: Transfection, MESH: DNA, Complementary, Zebrafish Proteins, Phosphoproteins, MESH: Male, MESH: Organ Culture Techniques, MESH: Proto-Oncogene Proteins, Receptors, LDL, LDL receptor, MESH: Chromosomes, Human, Pair 11, MESH: Stromal Cells
Abstract

Item does not contain fulltext In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass. Gong, Y

Published
2001
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10. Chemical optimization of new ligands of the low-density lipoprotein receptor as potential vectors for central nervous system targeting

Author

Jean Martinez, Michel Khrestchatisky, Vincent Lisowski, Marion David, Franck Debarbieux, Patrick Vlieghe, Karima Abouzid, Aude Faucon, Nadine Payrot, Geneviève Rougon, Guillaume Jacquot, Nicolas Floquet, Jean-Daniel Malcor, Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN (NICN), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Centre de génétique et de physiologie moléculaire et cellulaire (CGPhiMC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Institut Cochin (UMR_S567 / UMR 8104), 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 des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de la Méditerranée - Aix-Marseille 2, 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 National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des interactions cellulaires et neurophysiopathologie - NICN ( NICN ), Centre National de la Recherche Scientifique ( CNRS ) -Université de la Méditerranée - Aix-Marseille 2, Centre de génétique et de physiologie moléculaire et cellulaire ( CGPhiMC ), Centre National de la Recherche Scientifique ( CNRS ) -Université Claude Bernard Lyon 1 ( UCBL ), Institut Cochin ( UMR_S567 / UMR 8104 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] ( IBMM ), Ecole Nationale Supérieure de Chimie de Montpellier ( ENSCM ) -Université de Montpellier ( UM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut de Biologie du Développement de Marseille ( IBDM ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Institut National de la Recherche Agronomique ( INRA ) -Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Models, Molecular, Magnetic Resonance Spectroscopy, Phage display, MESH: Transcytosis, MESH : Receptors, LDL, Peptide, Ligands, 01 natural sciences, MESH : Blood-Brain Barrier, MESH: Blood-Brain Barrier, MESH: Spinal Cord, Mice, MESH: Structure-Activity Relationship, MESH : Peptides, Cyclic, MESH : Structure-Activity Relationship, Drug Discovery, MESH: Ligands, MESH : Fluorescent Dyes, MESH: Animals, Receptor, chemistry.chemical_classification, MESH : Ligands, 0303 health sciences, MESH : Transcytosis, Chemistry, MESH: Fluorescent Dyes, Cell biology, Spinal Cord, Transcytosis, Biochemistry, Blood-Brain Barrier, Drug delivery, MESH: Oligopeptides, Molecular Medicine, Oligopeptides, MESH: Models, Molecular, MESH : Oligopeptides, MESH : Models, Molecular, MESH : Mice, Inbred C57BL, Biopanning, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 010402 general chemistry, Peptides, Cyclic, Structure-Activity Relationship, 03 medical and health sciences, MESH: Mice, Inbred C57BL, MESH : Mice, Animals, Humans, MESH: Mice, MESH: Peptides, Cyclic, Fluorescent Dyes, 030304 developmental biology, MESH: Humans, [ SDV.BC ] Life Sciences [q-bio]/Cellular Biology, MESH: Magnetic Resonance Spectroscopy, MESH : Humans, MESH : Spinal Cord, 0104 chemical sciences, Mice, Inbred C57BL, Receptors, LDL, Docking (molecular), MESH: Receptors, LDL, LDL receptor, MESH : Magnetic Resonance Spectroscopy, MESH : Animals
Abstract

International audience; Drug delivery to the central nervous system is hindered by the presence of physiological barriers such as the blood-brain barrier. To accomplish the task of nutrient transport, the brain endothelium is endowed with various transport systems, including receptor-mediated transcytosis (RMT). This system can be used to shuttle therapeutics into the central nervous system (CNS) in a noninvasive manner. Therefore, the low-density lipoprotein receptor (LDLR) is a relevant target for delivering drugs. From an initial phage display biopanning, a series of peptide ligands for the LDLR was optimized leading to size reduction and improved receptor binding affinity with the identification of peptide 22 and its analogues. Further real-time biphoton microscopy experiments on living mice demonstrated the ability of peptide 22 to efficiently and quickly cross CNS physiological barriers. This validation of peptide 22 led us to explore its binding on the extracellular LDLR domain from an NMR-oriented structural study and docking experiments.

Published
2012

11. Endothelial estrogen receptor-alpha plays a crucial role in the atheroprotective action of 17beta-estradiol in low-density lipoprotein receptor-deficient mice

Author

Laurent Delpy, Coralie Fontaine, Jean-Charles Guéry, Audrey Billon-Galés, Bertrand Calippe, Victorine Douin-Echinard, Pierre Gourdy, Hortense Berges, Jean-François Arnal, Françoise Lenfant, Henrik Laurell, Institut de médecine moléculaire de Rangueil (I2MR), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiologie Moléculaire de la Réponse Immune et des Lymphoproliférations (PMRIL), Université de Limoges (UNILIM)-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Centre National de la Recherche Scientifique (CNRS), IFR 31 Louis Bugnard (IFR 31), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Toulouse [Toulouse]-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Integrases, Estrogen receptor, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, MESH: Atherosclerosis, Mice, 0302 clinical medicine, polycyclic compounds, MESH: Animals, Receptor, MESH: Bone Marrow Transplantation, MESH: Estrogen Receptor alpha, Bone Marrow Transplantation, Mice, Knockout, 0303 health sciences, Estradiol, Receptor, TIE-2, medicine.anatomical_structure, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Receptor Protein-Tyrosine Kinases, MESH: Endothelium, Vascular, MESH: Estradiol, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, Endothelium, medicine.drug_class, MESH: Mice, Transgenic, Transgene, Ovariectomy, MESH: Ovariectomy, Mice, Transgenic, Biology, 03 medical and health sciences, Physiology (medical), Internal medicine, medicine, Animals, MESH: Mice, 030304 developmental biology, Integrases, Estrogen Receptor alpha, Receptor Protein-Tyrosine Kinases, Atherosclerosis, Disease Models, Animal, Endocrinology, Receptors, LDL, Estrogen, MESH: Receptors, LDL, LDL receptor, Endothelium, Vascular, MESH: Disease Models, Animal, MESH: Female, Lipoprotein, Hormone
Abstract

Background— The prevention of early atheroma by estrogens has been clearly demonstrated in all animal models and appears to be mediated through a direct action on the arterial wall rather than through an effect on the lipoprotein profile. The goal of the present study was to evaluate which cellular target is crucial in this beneficial action of estradiol. Methods and Results— We first confirmed the key role of estrogen receptor-α (ERα) in the atheroprotective effect of estradiol, because this action was completely abolished in mice deficient in both the low-density lipoprotein receptor (LDLr) and ERα. Second, using chimeric mice with an ERα deficiency in the hematopoietic lineage, we showed the persistence of the protective action of estradiol, which suggests the involvement of extrahematopoietic ERα. Third, we showed that loxP-flanked ERα mice (ERα flox/flox ) bred with Tie2-Cre + mice on an LDLr −/− background had complete inactivation of ERα in most hematopoietic and all endothelial cells. Remarkably, in this mouse model, the atheroprotective effect of estradiol was completely abolished. Fourth, the atheroprotective effect of estradiol remained abolished in Tie2-Cre + ERα flox/flox LDLr −/− mice transplanted with either Tie2-Cre + ERα flox/flox or ERα −/− bone marrow, whereas it was present in analogous chimeric Tie2-Cre − ERα flox/flox LDLr −/− receivers expressing endothelial ERα. Conclusions— We demonstrate directly and for the first time that endothelial ERα represents a key target of the atheroprotective effect of estradiol, whereas hematopoietic ERα is dispensable. Selective estrogen receptor modulators that mimic the endothelial action of estradiol should now be considered in atheroprotection.

Published
2009

12. LRP4 : le co-récepteur de l'agrine enfin identifié ?

Author

Cartaud, Jean, Cartaud, Annie, Institut Jacques Monod (IJM (UMR_7592)), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), and Kropfinger, Antonia

Subjects
MESH: Signal Transduction, MESH: Receptors, Cholinergic, MESH: Receptors, LDL, MESH: Animals, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.BC]Life Sciences [q-bio]/Cellular Biology, MESH: Agrin, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, ComputingMilieux_MISCELLANEOUS
Abstract

International audience

Published
2009

13. Canonical Wnt signaling is antagonized by noncanonical Wnt5a in hepatocellular carcinoma cells

Author

Esra Erdal, Kamil Can Akcali, Serif Senturk, Mustafa Yilmaz, Neşe Atabey, Mehmet Ozturk, Nuri Ozturk, Emine Celik, Khemais Benhaj, Nilgun Tasdemir, Asli Toylu, Haluk Yuzugullu, BMC, Ed., Department of Medical Biology and Genetics, School of Medicine-Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Institut d'oncologie/développement Albert Bonniot de Grenoble (INSERM U823), Université Joseph Fourier - Grenoble 1 (UJF)-CHU Grenoble-EFS-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Biotechnologie de Sfax (CBS), This work was supported by a grant from TUBITAK. Additional support was provided by Terry Fox Fund of the Turkish Association for Research and Fight against Cancer, Turkish Academy of Sciences (Turkey), and Institut National de Cancer (France)., and Centre de Biotechnologie

Subjects
MESH: Neoplasm Proteins, MESH: Signal Transduction, Cancer Research, Frizzled, Unclassified drug, Cellular differentiation, TCF/LEF family, Ligands, 0302 clinical medicine, Genes, Reporter, MESH: Liver Neoplasms, MESH: Ligands, MESH: Carcinoma, Hepatocellular, 0303 health sciences, Liver Neoplasms, Wnt signaling pathway, LRP6, LRP5, Cell Differentiation, MESH: Gene Expression Regulation, Neoplastic, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Immunohistochemistry, 3. Good health, Neoplasm Proteins, Gene Expression Regulation, Neoplastic, MESH: Wnt Proteins, Autocrine Communication, Oncology, 030220 oncology & carcinogenesis, MESH: Frizzled Receptors, Molecular Medicine, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Signal transduction, TCF Transcription Factors, Signal Transduction, MESH: Cell Differentiation, MESH: Cell Nucleus, Carcinoma, Hepatocellular, MESH: Mutation, MESH: Cell Line, Tumor, Beta catenin, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, Low density lipoprotein receptor related protein 6, lcsh:RC254-282, Wnt-5a Protein, Low density lipoprotein receptor related protein 5, 03 medical and health sciences, Transcription factor 7, [SDV.CAN] Life Sciences [q-bio]/Cancer, Transcription factor 4, Cell Line, Tumor, Proto-Oncogene Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Biomarkers, Tumor, Humans, 030304 developmental biology, Cell Nucleus, MESH: Humans, Research, MESH: Genes, Reporter, MESH: Immunohistochemistry, HCCS, Wnt protein, digestive system diseases, Frizzled Receptors, Frizzled protein, Wnt Proteins, MESH: Proto-Oncogene Proteins, Receptors, LDL, MESH: Receptors, LDL, Mutation, MESH: Tumor Markers, Biological, Lymphoid enhancer factor 1, Cancer research, MESH: Autocrine Communication, MESH: TCF Transcription Factors
Abstract

Background β-catenin mutations that constitutively activate the canonical Wnt signaling have been observed in a subset of hepatocellular carcinomas (HCCs). These mutations are associated with chromosomal stability, low histological grade, low tumor invasion and better patient survival. We hypothesized that canonical Wnt signaling is selectively activated in well-differentiated, but repressed in poorly differentiated HCCs. To this aim, we characterized differentiation status of HCC cell lines and compared their expression status of Wnt pathway genes, and explored their activity of canonical Wnt signaling. Results We classified human HCC cell lines into "well-differentiated" and "poorly differentiated" subtypes, based on the expression of hepatocyte lineage, epithelial and mesenchymal markers. Poorly differentiated cell lines lost epithelial and hepatocyte lineage markers, and overexpressed mesenchymal markers. Also, they were highly motile and invasive. We compared the expression of 45 Wnt pathway genes between two subtypes. TCF1 and TCF4 factors, and LRP5 and LRP6 co-receptors were ubiquitously expressed. Likewise, six Frizzled receptors, and canonical Wnt3 ligand were expressed in both subtypes. In contrast, canonical ligand Wnt8b and noncanonical ligands Wnt4, Wnt5a, Wnt5b and Wnt7b were expressed selectively in well- and poorly differentiated cell lines, respectively. Canonical Wnt signaling activity, as tested by a TCF reporter assay was detected in 80% of well-differentiated, contrary to 14% of poorly differentiated cell lines. TCF activity generated by ectopic mutant β-catenin was weak in poorly differentiated SNU449 cell line, suggesting a repressive mechanism. We tested Wnt5a as a candidate antagonist. It strongly inhibited canonical Wnt signaling that is activated by mutant β-catenin in HCC cell lines. Conclusion Differential expression of Wnt ligands in HCC cells is associated with selective activation of canonical Wnt signaling in well-differentiated, and its repression in poorly differentiated cell lines. One potential mechanism of repression involved Wnt5a, acting as an antagonist of canonical Wnt signaling. Our observations support the hypothesis that Wnt pathway is selectively activated or repressed depending on differentiation status of HCC cells. We propose that canonical and noncanonical Wnt pathways have complementary roles in HCC, where the canonical signaling contributes to tumor initiation, and noncanonical signaling to tumor progression.

Published
2009

14. Genetic and pharmacological targeting of phosphoinositide 3-kinase-gamma reduces atherosclerosis and favors plaque stability by modulating inflammatory processes

Author

Bertrand Perret, Emilio Hirsch, Matthias Schwarz, Matthias P. Wymann, Stéphanie Gayral, Alexia Schambourg, Pierre Gourdy, Monique Breton-Douillon, Jean-François Arnal, Jean-Pierre Salles, Christian Rommel, Muriel Laffargue, Thomas Rückle, Anne Fougerat, Departement /u563 : Lipoproteines et Mediateurs Lipidiques, Centre de Physiopathologie Toulouse Purpan (CPTP), 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)-Centre National de la Recherche Scientifique (CNRS)-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)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Institut de médecine moléculaire de Rangueil (I2MR), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-IFR150-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Diabétologie - Maladies Métaboliques - Nutrition, CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Merck Serono Geneva Research Center, Geneva (MSGRCG), Laboratoire, University of Turin, Department of Genetics, Biology and Biochemistry, University of Turin, Hôpital des Enfants Unité d'Endocrinologie, Laboratoire de Biochimie [Purpan], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut Fédératif de Biologie (IFB) - Hôpital Purpan, Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], Institut of Biochemistry and Genetics, ihstitut, University of Basel, Department of Biomedicine, and University of Basel (Unibas)

Subjects
MESH: Inflammation, Apolipoprotein B, MESH: Thiazolidinediones, 030204 cardiovascular system & hematology, MESH: Mice, Knockout, MESH: Atherosclerosis, Mice, 0302 clinical medicine, Medicine, Macrophage, Class Ib Phosphatidylinositol 3-Kinase, MESH: Animals, Phosphoinositide-3 Kinase Inhibitors, Prostaglandin-E Synthases, phosphoinositide 3-kinase-gamma, atherosclerosis, inflammation, leukocytes, fibrous cap, Mice, Knockout, 0303 health sciences, biology, Kinase, Fibrous cap, MESH: Apolipoproteins E, 3. Good health, Intramolecular Oxidoreductases, Isoenzymes, medicine.anatomical_structure, MESH: Isoenzymes, medicine.symptom, Cardiology and Cardiovascular Medicine, Inflammation, 03 medical and health sciences, Apolipoproteins E, MESH: Quinoxalines, MESH: Mice, Inbred C57BL, Physiology (medical), Quinoxalines, Animals, Humans, MESH: Mice, 030304 developmental biology, MESH: Humans, Phosphoinositide 3-kinase, business.industry, Fatty streak, MESH: 1-Phosphatidylinositol 3-Kinase, Atherosclerosis, MESH: Intramolecular Oxidoreductases, Mice, Inbred C57BL, Disease Models, Animal, Receptors, LDL, MESH: Receptors, LDL, Immunology, Cancer research, biology.protein, Thiazolidinediones, MESH: Disease Models, Animal, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Lipoprotein
Abstract

Background— The role of inflammation at all stages of the atherosclerotic process has become an active area of investigation, and there is a notable quest for novel and innovative drugs for the treatment of atherosclerosis. The lipid kinase phosphoinositide 3-kinase-γ (PI3Kγ) is thought to be a key player in various inflammatory, autoimmune, and allergic processes. These properties and the expression of PI3Kγ in the cardiovascular system suggest that PI3Kγ plays a role in atherosclerosis. Methods and Results— Here, we demonstrate that a specific PI3Kγ inhibitor (AS605240) is effective in murine models of established atherosclerosis. Intraperitoneal administration of AS605240 (10 mg/kg daily) significantly decreased early atherosclerotic lesions in apolipoprotein E–deficient mice and attenuated advanced atherosclerosis in low-density lipoprotein receptor–deficient mice. Furthermore, PI3Kγ levels were elevated in both human and murine atherosclerotic lesions. Comparison of low-density lipoprotein receptor–deficient mice transplanted with wild-type or PI3Kγ-deficient bone marrow demonstrated that functional PI3Kγ in the hematopoietic lineage is required for atherosclerotic progression. Alleviation of atherosclerosis by targeting of PI3Kγ activity was accompanied by decreased macrophage and T-cell infiltration, as well as increased plaque stabilization. Conclusions— These data identify PI3Kγ as a new target in atherosclerosis with the potential to modulate multiple stages of atherosclerotic lesion formation, such as fatty streak constitution, cellular composition, and final fibrous cap establishment.

Published
2008

15. Effects of benzyl alcohol on transferrin and low density lipoprotein receptor mediated endocytosis in leukemic guinea pig B lymphocytes

Author

Jean Philippot, M. Vignes, Jacques Sainte-Marie, Michel Vidal, Alain Bienvenüe, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM), Plasticité cérébrale (PC), Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie de l'audition-plasticité synaptique, 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), and Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Lipoproteins, LDL, L2C cell, Biochemistry, chemistry.chemical_compound, 0302 clinical medicine, Structural Biology, Membrane fluidity, MESH: Animals, Inhibition, chemistry.chemical_classification, B-Lymphocytes, MESH: Iron, 0303 health sciences, Transferrin, Endocytosis, Lipoproteins, LDL, MESH: Benzyl Alcohols, Benzyl alcohol, 030220 oncology & carcinogenesis, MESH: Endocytosis, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Transferrin, MESH: Benzyl Compounds, Iron, Guinea Pigs, MESH: Leukemia, Experimental, Biophysics, Transferrin receptor, Biology, Receptor endocytosis, MESH: Guinea Pigs, Guinea pig, 03 medical and health sciences, MESH: B-Lymphocytes, Benzyl Compounds, Receptors, Transferrin, Genetics, Animals, Humans, MESH: Receptors, Transferrin, Molecular Biology, Benzyl Alcohols, 030304 developmental biology, Leukemia, Experimental, MESH: Humans, Cell Biology, Molecular biology, Receptors, LDL, chemistry, MESH: Receptors, LDL, LDL receptor, MESH: Benzyl Alcohol, Lipoprotein
Abstract

International audience; We demonstrated that benzyl alcohol, a neutral local anesthetic drug, inhibits the uptake and degradation of lowdensity lipoprotein and endocytosis of transferrin receptors of guinea pig leukemic B lymphocytes (L2C). This inhibition is very rapid, concentration dependant and reversible by simple washing. Membrane fluidity of the living cells is also modified.

Published
1990

16. The low-density lipoprotein receptor plays a role in the infection of primary human hepatocytes by hepatitis C virus

Author

Dror Harats, Paola Ghersa, Valérie Castet, Moshe Smolarsky, Dominique Larrey, Ronald Barbaras, Joliette Coste, Patrick Maurel, Fabio Malavasi, Antonio Sa-Cunha, Jean-Michel Fabre, Joseph Roitelman, Sonia Molina, Lydiane Pichard-Garcia, Ada Funaro, Rachel Avner, Pierre Graber, Chantal Fournier-Wirth, Physiopathologie hépatique, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM), EFS, Etablissement Français du Sang, Institute of Lipid and Atherosclerosis Research, Sheba Medical Center, Centre de Physiopathologie Toulouse Purpan (CPTP), 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)-Centre National de la Recherche Scientifique (CNRS), Serono SPRI, Serono InterPharm, Università degli studi di Torino (UNITO), Service d'Hépatogastroentérologie, CHU Saint-Eloi, Service de Chirurgie Digestive II, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-CHU Saint-Eloi, Service de Chirurgie Digestive, Hôpital Haut-Lévêque [CHU Bordeaux], CHU Bordeaux [Bordeaux]-CHU Bordeaux [Bordeaux], Maurel, Patrick, Università degli studi di Torino = University of Turin (UNITO), Hôpital Saint Eloi (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Saint Eloi (CHRU Montpellier), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)

Subjects
Male, MESH: Lipoproteins, LDL, Hepacivirus, medicine.disease_cause, MESH: Lipoproteins, HDL, MESH: Bicyclo Compounds, Heterocyclic, MESH: Hepatocytes, Virus entry, chemistry.chemical_compound, MESH: Hydroxycholesterols, 0302 clinical medicine, MESH: Hepacivirus, Cells, Cultured, MESH: Aged, MESH: Antigens, CD18, 0303 health sciences, MESH: Middle Aged, Anticholesteremic Agents, Virus receptor, Genome replication, Middle Aged, Scavenger Receptors, Class B, Viral Load, Hepatitis C, MESH: Gene Expression Regulation, 3. Good health, Lipoproteins, LDL, Low-density lipoprotein, MESH: RNA, Viral, RNA, Viral, MESH: Virion, Female, 030211 gastroenterology & hepatology, lipids (amino acids, peptides, and proteins), Lipoproteins, HDL, MESH: Viral Load, Viral load, MESH: Cells, Cultured, Adult, Adolescent, Hepatitis C virus, Biology, MESH: Anticholesteremic Agents, Antibodies, 03 medical and health sciences, Viral entry, medicine, Humans, Scavenger receptor, Aged, 030304 developmental biology, MESH: Adolescent, MESH: Hepatitis C, MESH: Humans, Hepatology, MESH: Antibodies, Virion, Tricarboxylic Acids, MESH: Adult, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Bridged Bicyclo Compounds, Heterocyclic, Virology, Hydroxycholesterols, [SDV.MHEP.HEG] Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, MESH: Male, MESH: Scavenger Receptors, Class B, Gene Expression Regulation, Receptors, LDL, chemistry, MESH: Receptors, LDL, MESH: Tricarboxylic Acids, CD18 Antigens, LDL receptor, Hepatocytes, MESH: Female, Lipoprotein
Abstract

International audience; BACKGROUND/AIMS: The direct implication of low-density lipoprotein receptor (LDLR) in hepatitis C virus (HCV) infection of human hepatocyte has not been demonstrated. Normal primary human hepatocytes infected by serum HCV were used to document this point. METHODS: Expression and activity of LDLR were assessed by RT-PCR and LDL entry, in the absence or presence of squalestatin or 25-hydroxycholesterol that up- or down-regulates LDLR expression, respectively. Infection was performed in the absence or presence of LDL, HDL, recombinant soluble LDLR peptides encompassing full-length (r-shLDLR4-292) or truncated (r-shLDLR4-166) LDL-binding domain, monoclonal antibodies against r-shLDLR4-292, squalestatin or 25-hydroxycholesterol. Intracellular amounts of replicative and genomic HCV RNA strands used as end point of infection were assessed by RT-PCR. RESULTS: r-shLDLR4-292, antibodies against r-shLDLR4-292 and LDL inhibited viral RNA accumulation, irrespective of genotype, viral load or liver donor. Inhibition was greatest when r-shLDLR4-292 was present at the time of inoculation and gradually decreased as the delay between inoculation and r-shLDLR4-292 treatment increased. In hepatocytes pre-treated with squalestatin or 25-hydroxycholesterol before infection, viral RNA accumulation increased or decreased in parallel with LDLR mRNA expression and LDL entry. CONCLUSIONS: LDLR is involved at an early stage in infection of normal human hepatocytes by serum-derived HCV virions.

Published
2007

17. Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse

Author

Martin J. Evans, Michael Kuehn, Muriel T. Davisson, Sylvie Tutois, Susan A. Cook, Dominique Simon-Chazottes, Jean-Louis Guénet, Franck Bourgade, Génétique Fonctionnelle de la Souris, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Biomove, Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Centre National de la Recherche Scientifique (CNRS), Frederick National Laboratory for Cancer Research (FNLCR), Cardiff University, The Jackson Laboratory [Bar Harbor] (JAX), Research on mdig/mdig mutants at TJL was supported by NIH Grant P40 RR01183., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Sequence Analysis, DNA, Mouse, [SDV]Life Sciences [q-bio], Mutant, DNA Mutational Analysis, MESH: Base Sequence, medicine.disease_cause, Animals, Genetically Modified, Mice, MESH: Reverse Transcriptase Polymerase Chain Reaction, Forelimb, MESH: Animals, MESH: DNA Mutational Analysis, MESH: Radiography, Limb development, Genetics, 0303 health sciences, Mutation, Reverse Transcriptase Polymerase Chain Reaction, 030302 biochemistry & molecular biology, Phenotype, LDL receptors, Female, MESH: Mutation, Positional cloning, Molecular Sequence Data, Mutagenesis (molecular biology technique), Biology, MESH: Animals, Genetically Modified, 03 medical and health sciences, Open Reading Frames, MESH: LDL-Receptor Related Proteins, medicine, Animals, Gene, MESH: Mice, LDL-Receptor Related Proteins, 030304 developmental biology, MESH: Molecular Sequence Data, Base Sequence, Sequence Analysis, DNA, MESH: Open Reading Frames, MESH: Male, MESH: Forelimb, Radiography, Mutagenesis, Insertional, Receptors, LDL, MESH: Mutagenesis, Insertional, MESH: Receptors, LDL, MESH: Syndactyly, LDL receptor, Syndactyly, MESH: Female
Abstract

International audience; Positional cloning of two recessive mutations of the mouse that cause polysyndactyly (dan and mdig-Chr 2) confirmed that the gene encoding MEGF7/LRP4, a member of the low-density lipoprotein receptor family, plays an essential role in the process of digit differentiation. Pathologies observed in the mutant mice provide insight into understanding the function(s) of LRP4 as a negative regulator of the Wnt-beta-catenin signaling pathway and may help identify the genetic basis for common human disorders with similar phenotypes.

Published
2006

18. Cellular glycosaminoglycans and low density lipoprotein receptor are involved in hepatitis C virus adsorption

Author

Raphaële Germi, Josette Guimet, Daniel Garin, Jean-Pierre Zarski, Emmanuel Drouet, Rob W.H. Ruigrok, Hugues Lortat-Jacob, Jean-Marc Crance, Laboratoire de virologie moléculaire et structurale (LVMS), Université Joseph Fourier - Grenoble 1 (UJF)-Centre National de la Recherche Scientifique (CNRS), Centre international d'études supérieures en sciences agronomiques (Montpellier SupAgro), Laboratoire de virologie du Centre de Recherches du Service de Santé des Armées (CRSSA), Ministère de la Défense, Institut de biologie structurale (IBS - UMR 5075 ), Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Unit of Virus Host Cell Interactions (UVHCI), Centre National de la Recherche Scientifique (CNRS)-Université Joseph Fourier - Grenoble 1 (UJF), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Heparin, viruses, Hepacivirus, medicine.disease_cause, 0302 clinical medicine, Chlorocebus aethiops, MESH: Animals, MESH: Hepacivirus, Receptor, MESH: Antigens, CD, Glycosaminoglycans, 0303 health sciences, biology, virus diseases, MESH: Glycosaminoglycans, 3. Good health, Infectious Diseases, Receptors, Virus, 030211 gastroenterology & hepatology, MESH: Membrane Proteins, Antibody, Hepatitis C virus, MESH: Vero Cells, Virus, Cell Line, Tetraspanin 28, 03 medical and health sciences, MESH: Antigens, CD81, Antigens, CD, Virology, medicine, Animals, Humans, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Vero Cells, 030304 developmental biology, MESH: Humans, Binding Sites, Heparin, Cell Membrane, Membrane Proteins, MESH: Receptors, Virus, MESH: Cercopithecus aethiops, digestive system diseases, MESH: Cell Line, NS2-3 protease, MESH: Binding Sites, Receptors, LDL, MESH: Receptors, LDL, LDL receptor, biology.protein, Vero cell, Adsorption, MESH: Adsorption, CD81, MESH: Cell Membrane
Abstract

International audience; The initial binding of Hepatitis C virus (HCV) to the cell membrane is a critical determinant of pathogenesis. Two putative HCV receptors have been identified, CD81 and low-density lipoprotein receptor (LDLr). CD81 interacts in vitro with the HCV E2 envelope glycoprotein, and LDLr interacts with HCV present in human plasma. In order to characterize these potential receptors for HCV, virus from plasma, able to replicate in cell culture, was inoculated on Vero cells or human hepatocarcinoma cells. HCV adsorption was assessed by quantitating cell-associated viral RNA by a real-time RT-PCR method. Anti-LDLr antibody, low and very low density lipoproteins inhibited significantly HCV adsorption, confirming the role of LDLr as HCV receptor. Only one out of the two anti-CD81 antibodies used in this study led to a partial inhibition of HCV binding. This study also highlights a role for glycosaminoglycans (GAGs) in HCV adsorption: treatment of virus with heparin led to 70% inhibition of attachment, as did desulfation of cellular GAGs. Treatment of Vero cells with heparin-lyase significantly inhibited virus attachment but by only 30%. These results demonstrate the complexity of the HCV binding step in which LDLr interacts strongly with HCV, whereas the interaction of HCV with GAGs and particularly with CD81 seem to be more moderate.

Published
2002

19. Software and database for the analysis of mutations in the human LDL receptor gene

Author

Jean-Pierre Rabès, Mathilde Varret, Gwenaëlle Collod-Béroud, Catherine Boileau, Christophe Béroud, Claudine Junien, Génétique, chromosome et cancer, Université Paris Descartes - Paris 5 (UPD5) - Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ) - Assistance publique - Hôpitaux de Paris (AP-HP) - Hôpital Ambroise Paré, This work was supported by grants from GREG (Groupe de Recherche et d’Etude du Génome), Fondation de France, AFM (Association Française contre les Myopathies), Université René Descartes Paris V, Ministère de l’Education Nationale, de l’Enseignement Supérieur, de la Recherche et de l’Insertion Professionnelle (ACC-SV2), and Faculté de Médecine Necker. M.V. is supported by a grant from Ministère de l’Education Nationale, de l’Enseignement Supérieur, de la Recherche et de l’Insertion Professionnelle, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biochimie, d'hormonologie et de génétique moléculaire [CHU Amrboise Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], and COLLOD-BEROUD, Gwenaëlle

Subjects
MESH: Mutation, Databases, Factual, Genotype, MESH: Chromosomes, Human, Pair 19, Familial hypercholesterolemia, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, MESH: Base Sequence, medicine.disease_cause, Bioinformatics, MESH: Phenotype, Hyperlipoproteinemia Type II, MESH: Genotype, MESH: Software, Genotype-phenotype distinction, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Chromosome 19, Genetics, medicine, Humans, cardiovascular diseases, Gene, [INFO.INFO-BI] Computer Science [cs]/Bioinformatics [q-bio.QM], Mutation, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Base Sequence, food and beverages, nutritional and metabolic diseases, medicine.disease, Phenotype, MESH: Databases, Factual, MESH: Genes, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MESH: Hyperlipoproteinemia Type II, Genes, Receptors, LDL, MESH: Receptors, LDL, LDL receptor, lipids (amino acids, peptides, and proteins), [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Chromosomes, Human, Pair 19, Software, Research Article
Abstract

The low-density lipoprotein receptor (LDLr) plays a pivotal role in cholesterol homeostasis. Mutations in the LDLr gene (LDLR), which is located on chromosome 19, cause familial hypercholesterolemia (FH), an autosomal dominant disorder characterized by severe hypercholesterolemia associated with premature coronary atherosclerosis. To date almost 300 mutations have been identified in the LDLR gene. To facilitate the mutational analysis of the LDLR gene, and promote the analysis of the relationship between genotype and phenotype, a software package along with a computerized database (currently listing 210 entries) have been created.

Published
1997

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