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1. Nucleolar Reorganization After Cellular Stress is Orchestrated by SMN Shuttling Between Nuclear Compartments

Author

Shaqraa Musawi, Lise-Marie Donnio, Charlène Magnani, Olivier Binda, Jocelyn Côté, Patrick Lomonte, Pierre-Olivier Mari, Giuseppina Giglia-Mari, Institut NeuroMyoGène (INMG), 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), Jazan University [Jazan, Saudi Arabia], University of Ottawa [Ottawa], and Giglia-Mari, Ambra

Subjects
[SDV] Life Sciences [q-bio], [SDV]Life Sciences [q-bio]
Abstract

SMA is an autosomal recessive neuromuscular disease caused by mutations in the multifunctional protein SMN. Within the nucleus, SMN localizes to Cajal bodies (CBs), which have been shown to be associated with nucleoli, nuclear organelles dedicated to the first steps of ribosome biogenesis. The highly organized structure of the nucleolus can be dynamically altered by genotoxic agents. After a genotoxic stress, RNAP1, Fibrillarin (FBL) and nucleolar DNA are exported to the periphery of the nucleolus and once DNA repair is fully completed the organization of the nucleolus is restored. We found that SMN is required for the restoration of nucleolar structure after genotoxic stress. Unexpectedly, during DNA repair, SMN shuttles from the CBs to the nucleolus. This shuttling is important for the nucleolar homeostasis and relies on the presence of Coilin, FBL and the activity of PRMT1.

Published
2022

2. A stable XPG protein is required for proper ribosome biogenesis: Insights on the phenotype of combinate Xeroderma Pigmentosum/Cockayne Syndrome patients

Author

Ambra Giglia-Mari, Florent TAUPELET, Charlène Magnani, Pierre-Olivier MARI, Lise-Marie DONNIO, Institut NeuroMyoGène (INMG), 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), and Giglia-Mari, Ambra

Subjects
Xeroderma Pigmentosum, Multidisciplinary, DNA Repair, [SDV]Life Sciences [q-bio], Nuclear Proteins, Endonucleases, DNA, Ribosomal, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Phenotype, Rare Diseases, RNA, Ribosomal, RNA Precursors, Humans, Cockayne Syndrome, Ribosomes, Transcription Factors
Abstract

Nucleotide Excision Repair is one of the five DNA repair systems. More than 30 proteins are involved in this process, including the seven XP proteins. When mutated, the genes coding for these proteins are provoking the rare disease Xeroderma Pigmentosum, which causes cutaneous defects and a high prevalence of skin cancers in patients. The CSA and CSB proteins are also involved in Nucleotide Excision Repair, and their mutation leads to Cockayne Syndrome, another rare disease, causing dwarfism, neurodegeneration, and ultimately early death, but without high skin cancer incidence. Some mutations of ERCC5, the gene coding for XPG, may give rise to a combined Xeroderma Pigmentosum and Cockayne Syndrome. A defect in Nucleotide Excision Repair alone cannot explain all these phenotypes. XPG has been located in the nucleolus, where ribosome biogenesis happens. This energy-consuming process starts with the transcription of the ribosomal DNA in a long ribosomal RNA, the pre-rRNA 47S, by RNA Polymerase 1. 47S pre-rRNA undergoes several cleavages and modifications to form three mature products: the ribosomal RNAs 18S, 5.8S and 28S. In the cytoplasm, these three products will enter the ribosomes’ composition, the producers of protein in our cells. Our work aimed to observe ribosome biogenesis in presence of an unstable XPG protein. By working on Xeroderma Pigmentosum/Cockayne Syndrome cell lines, meaning in the absence of XPG, we uncovered that the binding of UBF, as well as the number of unresolved R-loops, is increased along the ribosomal DNA gene body and flanking regions. Furthermore, ribosomal RNA maturation is impaired, with increased use of alternative pathways of maturation as well as an increase of immature precursors. These defective processes may explain the neurodegeneration observed when the XPG protein is heavily truncated, as ribosomal homeostasis and R-loops resolution are critical for proper neuronal development.

Published
2022
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3. Human apolipoprotein C1 transgenesis reduces atherogenesis in hypercholesterolemic rabbits

Author

Erwana Harscoët, Naig Le Guern, Stéphanie Lemaire, Valérie Deckert, Bruno Da Silva, Geneviève Jolivet, Thomas Gautier, Lil Proukhnitzky, Marion Xolin, Amandine Bataille, Laurent Lagrost, Charlène Magnani, Virginie Aires, Louis-Marie Houdebine, David Masson, Guillaume Maquart, Danish Patoli, UFR des Sciences de Santé (Université de Bourgogne), Université de Bourgogne (UB), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Biologie de la Reproduction, Environnement, Epigénétique & Développement (BREED), École nationale vétérinaire - Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biologie du Développement [IBPS] (LBD), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), This work was supported by grants from the University of Bourgogne Franche-Comté, the Institut National de la Santé et de la Recherche Médicale (INSERM), the Fondation de France [Project Cardio 2013 R13057MM-RAF13002MMA to TG], ANR grant ATHEROLIP, the European Union program FEDER, and by a French Government grant managed by the French National Research Agency under the program ‘Investissements d’Avenir’ [reference ANR-11-LABX-0021 (Lipstic Labex)]., ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer(2011), ANR-06-PHYS-0002,ATHEROLIP,Identification et caractérisation des propriétés proathérogènes des protéines plasmatiques de transfert des lipides (CETP et PLTP).(2006), European Project: FEDER, Jolivet, Geneviève, Laboratoires d'excellence - Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du cancer - - Lipstic2011 - ANR-11-LABX-0021 - LABX - VALID, Physiopathologie des maladies humaines (Physio) - Identification et caractérisation des propriétés proathérogènes des protéines plasmatiques de transfert des lipides (CETP et PLTP). - - ATHEROLIP2006 - ANR-06-PHYS-0002 - PHYSIO - VALID, Fonds Européens de Développement Régional - FEDER - INCOMING, Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-École nationale vétérinaire d'Alfort (ENVA)-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Laboratoire de Biologie du Développement [Paris] (LBD), and ANR-11-LABX-0021,Lipstic,Lipoprotéines et santé : prévention et traitement des maladies inflammatoires non vasculaires et du(2011)

Subjects
0301 basic medicine, medicine.medical_specialty, Very low-density lipoprotein, Apolipoprotein B, HDL, Transgene, Apolipoprotein C1, Endogeny, Rabbit, 030204 cardiovascular system & hematology, Transgenic, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], CETP, medicine, Animals, Humans, 2. Zero hunger, Apolipoprotein C-I, biology, Triglyceride, Cholesterol, Cholesterol, HDL, Gene Transfer Techniques, Atherosclerosis, Cholesterol Ester Transfer Proteins, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, carbohydrates (lipids), Transgenesis, 030104 developmental biology, Endocrinology, chemistry, biology.protein, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], lipids (amino acids, peptides, and proteins), Rabbits, Cardiology and Cardiovascular Medicine
Abstract

International audience; Background and aims: Apolipoprotein (apo) C1 is a 6.6 kDa protein associated with HDL and VLDL. ApoC1 alters triglyceride clearance, and it also favors cholesterol accumulation in HDL, especially by inhibiting CETP in human plasma. Apart from studies in mice, which lack CETP, the impact of apoC1 on atherosclerosis in animal models expressing CETP, like in humans, is not known. This study aimed at determining the net effect of human apoC1 on atherosclerosis in rabbits, a species with naturally high CETP activity but with endogenous apoC1 without CETP inhibitory potential.Methods: Rabbits expressing a human apoC1 transgene (HuApoC1Tg) were generated and displayed significant amounts of human apoC1 in plasma.Results: After cholesterol feeding, atherosclerosis lesions were significantly less extensive (-22%, p < 0.05) and HDL displayed a reduced ability to serve as CETP substrates (-25%, p < 0.05) in HuApoC1Tg rabbits than in WT littermates. It was associated with rises in plasma HDL cholesterol level and PON-1 activity, and a decrease in the plasma level of the lipid oxidation markers 12(S)-HODE and 8(S)HETE. In chow-fed animals, the level of HDL-cholesterol was also significantly higher in HuApoC1Tg than in WT animals (0.83 ± 0.11 versus 0.73 ± 0.11 mmol/L, respectively, p < 0.05), and it was associated with significantly lower CETP activity (cholesteryl ester transfer rate, -10%, p < 0.05; specific CETP activity, -14%, p < 0.05).Conclusions: Constitutive expression of fully functional human apoC1 in transgenic rabbit attenuates atherosclerosis. It was found to relate, at least in part, to the inhibition of plasma CETP activity and to alterations in plasma HDL.

Published
2021
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4. Inhibition of mitophagy drives macrophage activation and anti-bacterial defense during sepsis

Author

Danish, Patoli, Franck, Mignotte, Valérie, Deckert, Alois, Dusuel, Adélie, Dumont, Aurélie, Rieu, Antoine, Jalil, Kevin, Van Dongen, Thibaut, Bourgeois, Thomas, Gautier, Charlène, Magnani, Naig, Le Guern, Stéphane, Mandard, Jean, Bastin, Fatima, Djouadi, Christine, Schaeffer, Nina, Guillaumot, Michel, Narce, Maxime, Nguyen, Julien, Guy, Auguste, Dargent, Jean-Pierre, Quenot, Mickaël, Rialland, David, Masson, Johan, Auwerx, Laurent, Lagrost, Charles, Thomas, Equipe LIPNESS (LNC - U1231) (LIPNESS), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Equipe CADIR (LNC - U1231), Procédés Alimentaires et Microbiologiques [Dijon] (PAM), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université de Paris (UP), Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires (DSA-IPHC), Institut Pluridisciplinaire Hubert Curien (IPHC), Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Service d'anesthésie - réanimation chirurgicale [CHU de Dijon], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service d'Hématologie Clinique (CHU de Dijon), Ecole Polytechnique Fédérale de Lausanne (EPFL), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université Bourgogne Franche-Comté [COMUE] (UBFC), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Université Paris Cité (UPCité), Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Institut National de Physique Nucléaire et de Physique des Particules du CNRS (IN2P3)-Centre National de la Recherche Scientifique (CNRS), and Mandard, Stéphane

Subjects
Lipopolysaccharides, Male, autophagy, inflammasome activation, mechanism, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Interferon-gamma, Mice, mitochondrial respiratory-chain, Sepsis, ubiquitin, innate, Animals, Humans, parkin, pink1, Inflammation, Innate immunity, Bacteria, hypoxia, pathway, Macrophages, Mitophagy, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Macrophage Activation, Mitochondria, RAW 264.7 Cells, Metabolism, Macrophages, Peritoneal, Female, Protein Kinases, Research Article
Abstract

International audience; Mitochondria have emerged as key actors of innate and adaptive immunity. Mitophagy has a pivotal role in cell homeostasis but its contribution to macrophage functions and host defense remains to be delineated. Here we showed that lipopolysaccharide (LPS) in combination with IFNγ, inhibits PINK1-dependent mitophagy in macrophages through a STAT1-dependent activation of the inflammatory caspases 1 and 11. In addition, we demonstrated that the inhibition of mitophagy triggers classical macrophage activation in a mitochondrial ROS-dependent manner. In a murine model of polymicrobial infection (cecal ligature and puncture, CLP), adoptive transfer of Pink1-deficient bone marrow or pharmacological inhibition of mitophagy promoted macrophage activation which favored bactericidal clearance and lead to a better survival. Reciprocally, mitochondrial uncouplers, that promote mitophagy, reverse LPS/IFNγ-mediated activation of macrophages and lead to immuno-paralysis with impaired bacterial clearance and lowered survival. In critically ill patients, we showed that mitophagy is inhibited in blood monocytes of patients with sepsis as compared to non-septic patients. Overall, this work demonstrates that the inhibition of mitophagy is a physiological mechanism that contributes to the activation of myeloid cells and improves the outcome of sepsis.

Published
2020
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5. Human apolipoprotein c1 transgenesis to inhibit cetp and to attenuate atherosclerosis in hypercholesterolemic rabbits

Author

Marion Xolin, B. Da Silva, Stéphanie Lemaire, Thomas Gautier, David Masson, Charlène Magnani, Guillaume Maquart, Louis-Marie Houdebine, Virginie Aires, Geneviève Jolivet, Danish Patoli, Amandine Bataille, Valérie Deckert, Laurent Lagrost, N. Le Guern, Erwana Harscoët, Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du Développement et Reproduction (BDR), and École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)

Subjects
Transgenesis, medicine.medical_specialty, Endocrinology, Human apolipoprotein, Internal medicine, [SDV]Life Sciences [q-bio], medicine, [INFO]Computer Science [cs], Biology, Cardiology and Cardiovascular Medicine, ComputingMilieux_MISCELLANEOUS, 3. Good health
Abstract

International audience

Published
2019
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6. LPCAT3 deficiency in hematopoietic cells alters cholesterol and phospholipid homeostasis and promotes atherosclerosis

Author

Jérôme Labbé, Victoria Bergas, Jean Paul Pais de Barros, Naig Le Guern, Thibaut Bourgeois, Charlène Magnani, Thomas Gautier, Minako Ishibashi, Laurent Lagrost, Ronan Quéré, Antoine Jalil, David Masson, Danish Patoli, Louise Ménégaut, Charles Thomas, Université Bourgogne Franche-Comté [COMUE] (UBFC), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire d'Excellence : Lipoprotéines et Santé : prévention et Traitement des maladies Inflammatoires et du Cancer (LabEx LipSTIC), Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-Université de Montpellier (UM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Plateforme Lipidomique [Dijon] (LAP), Lipides - Nutrition - Cancer (U866) (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-IFR100 - Structure fédérative de recherche Santé-STIC-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Laboratoire de biochimie médicale (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Université de Bourgogne (UB)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-Franche-Comté] (EFS [Bourgogne-Franche-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université de Montpellier (UM), Laboratoire de biochimie médicale (CHU Dijon), and Institut National de la Recherche Agronomique (INRA)-Université Montpellier 2 - Sciences et Techniques (UM2)-Université Paris-Sud - Paris 11 (UP11)-École pratique des hautes études (EPHE)-Institut Gustave Roussy (IGR)-Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy)-Université de Bourgogne (UB)-Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon)-Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc (CRLCC - CGFL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Fédération Francophone de la Cancérologie Digestive, FFCD-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Etablissement français du sang [Bourgogne-France-Comté] (EFS [Bourgogne-France-Comté])-Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon)-Université de Franche-Comté (UFC)-Université de Montpellier (UM)

Subjects
0301 basic medicine, Apolipoprotein E, medicine.medical_specialty, Plasmalogen, Macrophage, 03 medical and health sciences, chemistry.chemical_compound, Apolipoproteins E, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Internal medicine, Phospholipid homeostasis, medicine, Animals, Genetic Predisposition to Disease, Cholesterol efflux, Cells, Cultured, Phospholipids, ATP Binding Cassette Transporter, Subfamily G, Member 1, Liver X Receptors, Mice, Knockout, biology, Chemistry, Cholesterol, Macrophages, Hematopoietic Stem Cell Transplantation, 1-Acylglycerophosphocholine O-Acyltransferase, Hematopoietic Stem Cells, Atherosclerosis, Plaque, Atherosclerotic, 3. Good health, Mice, Inbred C57BL, Transplantation, Disease Models, Animal, Haematopoiesis, Phospholipid, Phenotype, 030104 developmental biology, Endocrinology, Receptors, LDL, Arachidonic acid, ABCA1, biology.protein, lipids (amino acids, peptides, and proteins), Cardiology and Cardiovascular Medicine, ATP Binding Cassette Transporter 1
Abstract

IF 4.239 (2016); International audience; Background and aimsLPCAT3 plays a major role in phospholipid metabolism in the liver and intestine. However, the impact of LPCAT3 on hematopoietic cell and macrophage functions has yet to be described. Our aim was to understand the functions of LPCAT3 in macrophages and to investigate whether LPCAT3 deficiency in hematopoietic cells may affect atherosclerosis development.MethodsMice with constitutive Lpcat3 deficiency (Lpcat3−/−) were generated. We used fetal hematopoietic liver cells to generate WT and Lpcat3−/− macrophages in vitro and to perform hematopoietic cell transplantation in recipient Ldlr−/− mice.ResultsLpcat3-deficient macrophages displayed major reductions in the arachidonate content of phosphatidylcholines, phosphatidylethanolamines and, unexpectedly, plasmalogens. These changes were associated with altered cholesterol homeostasis, including an increase in the ratio of free to esterified cholesterol and a reduction in cholesterol efflux in Lpcat3−/− macrophages. This correlated with the inhibition of some LXR-regulated pathways, related to altered cellular availability of the arachidonic acid. Indeed, LPCAT3 deficiency was associated with decreased Abca1, Abcg1 and ApoE mRNA levels in fetal liver cells derived macrophages. In vivo, these changes translated into a significant increase in atherosclerotic lesions in Ldlr−/− mice with hematopoietic LPCAT3 deficiency.ConclusionsThis study identifies LPCAT3 as a key factor in the control of phospholipid homeostasis and arachidonate availability in myeloid cells and underlines a new role for LPCAT3 in plasmalogen metabolism. Moreover, our work strengthens the link between phospholipid and sterol metabolism in hematopoietic cells, with significant consequences on nuclear receptor-regulated pathways and atherosclerosis development.

Published
2018
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7. The yeast multidrug transporter Qdr3 (Ybr043c): localization and role as a determinant of resistance to quinidine, barban, cisplatin, and bleomycin

Author

Miguel C. Teixeira, Isabel Sá-Correia, Sandra Tenreiro, Rita C. Vargas, and Charlène Magnani

Subjects
Quinidine, Saccharomyces cerevisiae Proteins, Time Factors, Saccharomyces cerevisiae, Biophysics, Antineoplastic Agents, Microbial Sensitivity Tests, Biochemistry, Bleomycin, Drug Resistance, Multiple, Fungal, medicine, Animals, Humans, Enzyme Inhibitors, Molecular Biology, Gene, Cisplatin, biology, Cell Membrane, Membrane Transport Proteins, Transporter, Cell Biology, biology.organism_classification, Yeast, Major facilitator superfamily, Multiple drug resistance, Carbamates, medicine.drug
Abstract

Saccharomyces cerevisiae ORF YBR043c, predicted to code for a transporter of the major facilitator superfamily required for multiple drug resistance, encodes a plasma membrane protein that confers resistance to quinidine and barban, as observed before for its close homologues QDR1 and QDR2. This ORF was, thus, named the QDR3 gene. The increased expression of QDR3, or QDR2, also leads to increased resistance to the anticancer agents cisplatin and bleomycin. However, no evidence for increased QDR3 expression in yeast cells exposed to all these inhibitory compounds was found. Transport assays support the concept that Qdr3 is involved, even if opportunistically, in the active export of quinidine out of yeast cell. A correlation was established between the efficiency of quinidine active export mediated by Qdr3p, Qdr2p or Qdr1p, and the efficacy of the expression of the encoding genes in alleviating the deleterious action of quinidine, as well as of the other compounds (QDR2 > QDR3 >>> QDR1).

Published
2005
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