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Modulation Nukleärer Rezeptoren Durch Thyroidhormone Und Deren Metabolite

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Modulation Nukleärer Rezeptoren Durch Thyroidhormone Und Deren Metabolite Modulation nukleärer Rezeptoren durch Thyroidhormone und deren Metabolite Dissertation zur Erlangung des Doktorgrades der Naturwissenschaften vorgelegt beim Fachbereich Biochemie, Chemie und Pharmazie der Johann Wolfgang Goethe-Universität in Frankfurt am Main von Leonie Gellrich aus Wiesbaden Frankfurt (2019) (D 30) 1 vom Fachbereich Biochemie, Chemie und Pharmazie der Johann Wolfgang Goethe-Universität als Dissertation angenommen. Dekan: Prof. Dr. Clemens Glaubitz Gutachter: PD Dr. Merk Prof. Dr. Robert Fürst Datum der Disputation: 2 Inhaltsverzeichnis 1. Einleitung .................................................................................................................... 6 1.1 Nukleäre Rezeptoren .................................................................................................. 7 1.1.1 Einteilung und Aufbau der nukleären Rezeptoren ................................................... 7 1.1.2 Mechanismen der Funktion nukleärer Rezeptoren .................................................12 1.1.3 Pharmazeutische Relevanz nukleärer Rezeptoren .................................................18 1.2 THRs .........................................................................................................................21 1.2.1 Struktur und Aktivierung des Rezeptors .................................................................21 1.2.2 Isoformen und Splicevarianten der THRs ...............................................................22 1.2.3 Physiologische Funktion der THRs .........................................................................24 1.2.4 Ligandenbindung ....................................................................................................30 1.2.5 Endogene Liganden der THRs und deren pharmakologische Bedeutung ...............34 1.2.6 Synthetische Liganden der THRs und deren pharmakologische Bedeutung ..........37 1.3 PPARγ .......................................................................................................................41 1.3.1 Struktur und Aktivierung des Rezeptors .................................................................41 1.3.2 Isoformen und Splicevarianten von PPARγ ............................................................43 1.3.3 Physiologische Funktion von PPARγ ......................................................................45 1.3.4 Ligandenbindung ....................................................................................................50 1.3.5 Endogene Liganden von PPARγ und deren pharmakologische Bedeutung ............54 1.3.6 Synthetische Liganden von PPARγ und deren pharmakologische Bedeutung........56 1.4 RXR ...........................................................................................................................65 1.4.1 Struktur und Aktivierung des Rezeptors .................................................................65 1.4.2 Isoformen und Splicevarianten der RXRs ...............................................................67 1.4.3 Physiologische Funktion von RXR ..........................................................................68 1.4.4 Ligandenbindung ....................................................................................................74 1.4.5 Endogene Liganden der RXRs und deren pharmakologische Bedeutung ..............78 1.4.6 Natürliche Liganden der RXRs und deren pharmakologische Bedeutung ...............80 1.4.7 Synthetische Liganden der RXRs und deren pharmakologische Bedeutung ..........83 1.5 Thyroidhormone .........................................................................................................87 1.5.1 Endogene Thyroidhormon-Derivate ........................................................................87 3 1.5.2 Biosynthese und Transport von Thyroidhormonen .................................................89 1.5.3 Die Thyroidhormon-Spiegel-Regulation ..................................................................91 1.5.4 Metabolismus .........................................................................................................94 1.5.5 Genomische Wirkmechanismen ........................................................................... 102 1.5.6 Nicht-genomische Wirkmechanismen................................................................... 102 1.5.7 Physiologische Effekte mit unbekanntem Wirkmechanismus ............................... 105 2. Zielsetzung .............................................................................................................. 108 3. Ergebnisse und Diskussion ...................................................................................... 109 3.1. Thyroidhormon-PPARγ Bindung .............................................................................. 109 3.1.1 Gal4-Luciferase-Reportergen Assay ..................................................................... 109 3.1.2 ITC ....................................................................................................................... 115 3.1.3 Coaktivator-Rekrutierungs-Assay ......................................................................... 118 3.1.4 Kristallstrukturanalyse .......................................................................................... 126 3.2 Physiologische Effekte der Thyroidhormon-PPARγ-Bindung (in vitro) ...................... 130 3.2.1 Adipocyten-Differenzierung .................................................................................. 130 3.2.2 Knockdown Experimente ...................................................................................... 133 3.2.2.1 Auswertung auf mRNA-Ebene mittels qPCR ....................................................... 135 3.2.2.1 Auswertung auf Protein-Ebene mittels Western Blot-Analyse .............................. 139 3.3 Physiologische Bedeutung der Thyroidhormon-PPARγ-Bindung ............................. 142 3.3.1 Quantifizierung von Thyroidhormonen in HepG2 Zellen durch LC-MS/MS ........... 143 3.3.2 In vivo pharmakologische Charakterisierung ........................................................ 145 3.4 Diskussion ............................................................................................................... 149 3.4.1 Physiologische Bedeutung der Thyroidhormon-PPARγ-Interaktion ...................... 149 3.4.2 Pharmakologische Bedeutung der Thyroidhormon-PPARγ-Interaktion ................ 155 3.5 Zusammenfassung, Bewertung und Ausblick .......................................................... 158 4. Experimenteller Teil ................................................................................................. 164 4.1 Allgemein ..................................................................................................................... 164 4.2 Gal4-Luciferase-Reportergen Assay ........................................................................ 164 4.3 ITC ........................................................................................................................... 166 4.4 Coaktivator-Rekrutierungs-Assay............................................................................. 167 4 4.4.1 PPARγ Coaktivator-Rekrutierungs-Assay ............................................................. 167 4.4.2 RXRα Coaktivator-Rekrutierungs-Assay............................................................... 169 4.4.3 PPARγ/tRXRα Coaktivator-Rekrutierungs-Assay ................................................. 169 4.5 Kristallstrukturanalyse .............................................................................................. 169 4.6 Adipocyten-Differenzierung ...................................................................................... 170 4.7 Knockdown Experimente ......................................................................................... 172 4.7.1 Auswertung mittels qPCR ..................................................................................... 173 4.7.2 Auswertung mittels Western Blot Analyse ............................................................ 174 4.8 Quantifizierung von Thyroidhormonen in HepG2 Zellen durch LC-MS/MS ............... 175 4.9 In vivo pharmakologische Charakterisierung ............................................................ 179 4.10 Synthese und Charakterisierung von Br-T4 (92) und Br-TETRAC (93) .................... 180 4.10.1 Analytik von Br-TETRAC (93) und Br-T4 (92) ....................................................... 181 5. Anhang .................................................................................................................... 182 5.1 Abkürzungsverzeichnis ............................................................................................ 182 5.2. Datensätze .............................................................................................................. 190 5.2.1 Gal4-Luciferase-Reportergen Assay Daten .......................................................... 190 5.2.2 ITC-Daten der Thyroidhormon-PPARγ-Bindung ................................................... 196 5.2.3 ITC-Daten der Thyroidhormon-RXRα-Bindung ..................................................... 198 5.2.4 Kristallstrukturanalyse: Daten-Sammlung und refinement .................................... 200 5.2.5 Western Blot Daten .............................................................................................. 201 5.2.5.1 Knockdown-Effizienz (Protein-Ebene) .................................................................. 201 5.2.5.2 CD36-Expression (Protein-Ebene) ......................................................................
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