Omics of human plasma lipoproteins : role in cardiometabolic diseases Emil Zakiev To cite this version: Emil Zakiev. Omics of human plasma lipoproteins : role in cardiometabolic diseases. Human health and pathology. Sorbonne Université, 2019. English. NNT : 2019SORUS436. tel-03001290 HAL Id: tel-03001290 https://tel.archives-ouvertes.fr/tel-03001290 Submitted on 12 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Sorbonne Université Ecole Doctorale Physiologie, Physiopathologie et Thérapeutique (ED394) INSERM-UMR-S 1166/Equipe 4 Omics of human plasma lipoproteins: Role in cardiometabolic diseases Par Emile ZAKIEV Thèse de Doctorat de Physiopathologie Dirigée par Dr. Anatol KONTUSH Présentée et soutenue publiquement le 28 Juin 2019 Devant un jury composé de : Directeur de Recherche INSERM Président du Dr. Philippe LESNIK Sorbonne Université Jury Directeur de Recherche CNRS Dr. Anne NEGRE-SALVAYRE Rapporteur Université Toulouse III Prof. Dominique BONNEFONT- PU-PH de l’Hôpital Pitié Salpêtrière Rapporteur ROUSSELOT Université Paris Descartes - Paris 5 Ingénieur d'études Dr. Mikael CROYAL Examinateur Université de Nantes MCU-PH de l’Hôpital Bichat - Claude Bernard Dr. Boris HANSEL Examinateur Université Paris Diderot – USPC Directeur de Recherche INSERM Directeur de Dr. Anatol KONTUSH Sorbonne Université thèse TABLE OF CONTENTS ACKNOWLEDGMENTS .......................................................................................................................... 1 LIST OF ABBREVIATIONS .................................................................................................................... 5 RESUME ..................................................................................................................................................... 8 ABSTRACT ............................................................................................................................................... 11 INTRODUCTION ..................................................................................................................................... 14 1. Introduction to lipoproteins ............................................................................................................. 14 1.1 LDL .............................................................................................................................................. 16 1.2 HDL .............................................................................................................................................. 16 1.3 Other lipoprotein classes ............................................................................................................ 17 2. Epidemiology of lipoproteins ........................................................................................................... 18 2.1 LDL .............................................................................................................................................. 18 2.2 HDL .............................................................................................................................................. 19 2.3 Other lipoprotein classes ............................................................................................................ 20 3. HDL .................................................................................................................................................... 20 3.1 Structure ...................................................................................................................................... 20 3.2 Composition ................................................................................................................................. 22 3.2.1 Classic techniques ................................................................................................................ 22 3.2.2 Omics approaches ................................................................................................................ 24 3.2.2.1 Proteome ........................................................................................................................ 25 3.2.2.2 Lipidome ........................................................................................................................ 27 3.2.2.3 Glycome ......................................................................................................................... 31 3.3 Heterogeneity ............................................................................................................................... 31 3.4 Metabolism .................................................................................................................................. 35 3.4.1 Biosynthesis .......................................................................................................................... 35 3.4.2 Remodelling .......................................................................................................................... 36 3.4.3 Catabolism ............................................................................................................................ 36 3.5 Biological activities and structure-function relationships ....................................................... 37 3.6 Dysfunctional HDL ..................................................................................................................... 41 3.6.1 Cardiometabolic diseases and atherosclerosis ................................................................... 41 3.6.2 Altered composition and impaired biological function ..................................................... 43 3.6.3 Altered metabolism .............................................................................................................. 45 3.7 Therapeutic targeting of abnormal HDL metabolism ............................................................. 45 3.7.1 CETP inhibition ............................................................................................................ 45 3.7.2 rHDL infusion ............................................................................................................... 46 I 3.7.3 LPL activation ............................................................................................................... 48 3.7.4 Nicotinic acid ................................................................................................................. 49 3.7.5. Other agents .................................................................................................................. 50 4. LDL .................................................................................................................................................... 51 4.1 Structure and composition ......................................................................................................... 51 4.1.1 Proteome ............................................................................................................................... 51 4.1.2 Lipidome ............................................................................................................................... 52 4.1.3 Glycome ................................................................................................................................ 52 4.2 Metabolism .................................................................................................................................. 52 4.2.1 Biosynthesis .......................................................................................................................... 52 4.2.2 Catabolism ............................................................................................................................ 54 4.3 Altered composition and metabolism in cardiometabolic diseases ......................................... 54 4.4 Therapeutic targeting of abnormal LDL metabolism ............................................................. 56 WORKING HYPOTHESIS AND OBJECTIVE ................................................................................... 59 METHODS ................................................................................................................................................ 61 1. Subjects .......................................................................................................................................... 61 2. Blood samples ................................................................................................................................ 62 3. Isolation of lipoproteins ................................................................................................................ 62 4. Chemical analysis of lipoproteins ................................................................................................ 64 5. Heterogeneity and mean size of HDL .......................................................................................... 64 6. Lipidomic analysis .......................................................................................................................