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Transcriptional Control of Dietary Sugar Metabolism and Homeostasis by Mondo-Mlx Transcription Factors Recent Publications in This Series

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Transcriptional Control of Dietary Sugar Metabolism and Homeostasis by Mondo-Mlx Transcription Factors Recent Publications in This Series ESSI HAVULA Transcriptional Control of Dietary Sugar Metabolism and Homeostasis by Mondo-Mlx Transcription Factors Mondo-Mlx Transcription and Homeostasis by Control of Dietary Sugar Metabolism Transcriptional ESSI HAVULA Recent Publications in this Series 62/2016 Wojciech Cypryk Extracellular Vesicles in Innate Immunity - Proteomic Investigations 63/2016 Lauri Vaahtera Apoplastic ROS and Transcriptional Response in Plant Stress Signaling 64/2016 Hannele Poutiainen Mikä herättää terveydenhoitajan huolen? Huolen tunnistamisen ja toimimisen haasteet DISSERTATIONES SCHOLAE DOCTORALIS AD SANITATEM INVESTIGANDAM lastenneuvolassa ja kouluterveydenhuollossa UNIVERSITATIS HELSINKIENSIS 1/2017 65/2016 Jenni Viinamäki Analysis of Fatal Poisonings Due to Toxic Alcohols and Drugs — Focus on Metabolites 66/2016 Sari Riihijärvi Host- and Tumour-related Prognostic Factors in Diffuse Large B-cell Lymphoma 67/2016 Tatu Lajunen Liposomal Drug Delivery: Light Triggered Drug Release and Targeting to the Posterior Segment ESSI HAVULA of the Eye 68/2016 Kristian Taipale Immunologic Effects of Cancer Therapy with Oncolytic Adenoviruses Transcriptional Control of Dietary Sugar Metabolism 69/2016 Maarit Dimitrow Development and Validation of a Drug-related Problem Risk Assessment Tool for Use by and Homeostasis by Mondo-Mlx Transcription Factors Practical Nurses Working With Community-Dwelling Aged 70/2016 Vilma Aho Kuolema kuittaa univelat? Effects of Cumulative Sleep Loss on Immune Functions and Lipid Metabolism 71/2016 Aino Salminen Matrix Metalloproteinase 8: Genetic, Diagnostic, and Therapeutic Approaches 72/2016 Maili Jakobson Molecular Mechanisms Controlling Neuronal Bak Expression 73/2016 Lukasz Kuryk Strategies to Enhance Efficacy of Oncolytic Virotherapy 74/2016 Sini Heinonen Adipose Tissue Metabolism in Acquired Obesity 75/2016 Elina Karhu Natural Products as a Source for Rational Antichlamydial Lead-Discovery 76/2016 Zhilin Li Inflammatory Polarization of Immune Cells in Neurological and Neuropsychiatric Disorders 77/2016 Aino Salonsalmi Alcohol Drinking, Health-Related Functioning and Work Disability 78/2016 Heini Wennman Physical Activity, Sleep and Cardiovascular Diseases: Person-oriented and Longitudinal Perspectives 79/2016 Andres Lõhmus Helper Component-Proteinase and Coat Protein are Involved in the Molecular Processes of Potato Virus A Translation and Replication 80/2016 Li Ma INSTITUTE OF BIOTECHNOLOGY AND Brain Immune Gene Network in Inbred Mouse Models of Anxiety- and DEPARTMENT OF BIOSCIENCES Sociability-related Neuropsychiatric Disorders FACULTY OF BIOLOGICAL AND ENVIRONMENTAL SCIENCES 81/2016 Finny S. Varghese DOCTORAL PROGRAMME IN INTEGRATIVE LIFE SCIENCE Cracking the Code of Chikungunya Virus: Inhibitors as Tools to Explore UNIVERSITY OF HELSINKI Alphavirus Biology 1/2017 Helsinki 2017 ISSN 2342-3161 ISBN 978-951-51-2675-7 Transcriptional control of dietary sugar metabolism and homeostasis by Mondo-Mlx transcription factors Essi Havula Faculty of Biological and Environmental Sciences Department of Biosciences Division of Genetics and Institute of Biotechnology Research Program in Cell and Molecular Biology and Doctoral Programme in Integrative Life Science University of Helsinki ACADEMIC DISSERTATION To be presented for public examination with the permission of the Faculty of Biological and Environmental Sciences of the University of Helsinki in Auditorium 2041 in Biocenter 2, Viikinkaari 5, Helsinki, on January 5th, at 12 noon. Helsinki 2017 Supervisor Associate Professor Ville Hietakangas Department of Biosciences Division of Genetics Institute of Biotechnology University of Helsinki, Finland Thesis Advisory Committee Professor Howard Jacobs Institute of Biotechnology University of Helsinki, Finland and Ph.D. Thomas Sandmann Verily, USA Reviewed by Professor Anna-Liisa Levonen A.I. Virtanen Institute University of Eastern Finland and Docent Henna Tyynismaa Faculty of Medicine University of Helsinki, Finland Opponent Ph.D. Christen Mirth Monash University Melbourne, Australia Custodian Professor Juha Partanen Department of Biosciences Division of Genetics University of Helsinki, Finland ISBN 978-951-51-2675-7 (paperback) ISBN 978-951-51-2720-4 (PDF) ISSN 2342-3161 (print) ISSN 2342-317X (online) Press: Hansaprint, Vantaa 2016 Cover image: Salla Rytövuori “Just keep swimming” – Dory TABLE OF CONTENTS LIST OF ORIGINAL PUBLICATIONS ........................................................................................................ 6 ABBREVIATIONS ........................................................................................................................................... 7 SUMMARY ..................................................................................................................................................... 11 YHTEENVETO .............................................................................................................................................. 12 1. INTRODUCTION ...................................................................................................................................... 13 1.1. Nutrient sensing and metabolic homeostasis ............................................................................................. 13 1.1.1. Metabolic organs, tissues and digestion of macronutrients .......................................................... 13 1.1.2. Control of food intake ................................................................................................................... 15 1.1.3. Nutrient sensing pathways ............................................................................................................ 16 1.1.3.1. Amino acid sensing ......................................................................................................... 16 1.1.3.2. Lipid sensing ................................................................................................................... 19 1.1.3.3. Carbohydrate sensing ...................................................................................................... 19 1.2. Carbohydrate Response Element Binding Protein ChREBP, MondoA and Mlx ...................................... 20 1.2.1. ChREBP, MondoA and Mlx belong to the bHLH/LZ family of transcription factors ................. 20 1.2.2. Myc-Max-Mad-Mlx-Mondo transcription factor network ........................................................... 21 1.2.3. Mondo proteins are highly conserved .......................................................................................... 22 1.2.4. Glucose-6-phosphate regulates the activity of ChREBP/MondoA .............................................. 23 1.2.5. Regulation of ChREBP activity by posttranslational modifications and protein interactions ..... 24 1.2.6. Transcriptional regulation of ChREBP/MondoA-Mlx ................................................................. 25 1.3. ChREBP/MondoA as a key regulator of sugar-induced transcription ....................................................... 26 1.3.1. Regulation of glycolysis and lipogenesis by MondoA and ChREBP .......................................... 27 1.3.2. SREBP-1c controls expression of lipogenic genes in response to Insulin ................................... 27 1.3.3. Coordinated regulation of de novo lipogenesis by ChREBP and SREBP .................................... 29 1.3.4. ChREBP-Mlx controls the glucose induced expression of genes related to circadian rhythm .... 29 1.3.5. ChREBP and MondoA in human disease ..................................................................................... 30 1.4. Drosophila melanogaster as a model organism ......................................................................................... 31 1.4.1. Physiology and tissue organization of Drosophila melanogaster ................................................ 32 1.4.2. Nutrient sensing pathways in Drosophila .................................................................................... 34 1.4.3. Studies on nutrient-regulated transcription in Drosophila ........................................................... 35 2. AIMS OF THE STUDY ............................................................................................................................. 37 3. MATERIALS AND METHODS ............................................................................................................... 38 4. RESULTS .................................................................................................................................................... 40 4.1. Mondo-Mlx is essential for dietary sugar tolerance in Drosophila (I) ...................................................... 40 4.1.1. Loss of mlx leads to late pupal lethality in Drosophila ................................................................ 40 4.1.2. Mondo-Mlx deficient animals show intolerance to dietary sugars ............................................... 40 4.1.3. Loss of Mondo-Mlx leads to severe metabolic defects in vivo .................................................... 40 4.1.4. Mondo and mlx are expressed in the metabolic tissues of Drosophila ......................................... 41 4.2. Identification of putative Mondo-Mlx target genes by Agilent gene expression analysis (I) ................... 41 4.3. Sugar intolerance and hyperglycaemia are phenotypes that can be genetically uncoupled (I) ................. 42 4.4. Sugar-induced transcription in Drosophila melanogaster (II) ..................................................................
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