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Pparα: Master Regulator of Lipid Metabolism in Mouse and Human

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PPARα: Master regulator of lipid metabolism in mouse and human Identification of hepatic PPARα target genes by expression profiling Maryam Rakhshandehroo Thesis Committee Thesis supervisor Prof. dr. Michael R. Müller Professor of Nutrition, Metabolism and Genomics Division of Human Nutrition Wageningen University Thesis co-supervisor Dr. ir. Alexander H. Kersten Associate Professor Division of Human Nutrition Wageningen University Other members Prof. dr. ir. Jaap Keijer Wageningen University Prof. dr. Wouter H. Lamers University of Amsterdam Dr. Noam Zelcer University of Amsterdam Dr. Marc van Bilsen University of Maastricht This research was conducted under the auspices of the graduate school VLAG. PPARα: Master regulator of lipid metabolism in mouse and human Identification of hepatic PPARα target genes by expression profiling Maryam Rakhshandehroo Thesis Submitted in fulfillment of the requirements for the degree of doctor at Wageningen University by the authority of the Rector Magnificus Prof. dr. M.J. Kropff, in the presence of the Thesis Committee appointed by the Academic Board to be defended in public on Monday 4th October 2010 at 11 a.m. in the Aula Maryam Rakhshandehroo PPARα: Master regulator of lipid metabolism in mouse and human Identification of hepatic PPARα target genes by expression profiling Thesis Wageningen University, Wageningen, The Netherlands, 2010 With abstract – references – summaries in English and Dutch ISBN: 978-90-8585-771-6 Once your tree bears fruits of knowledge you will master the universe Naser Khosrow, Persian Poet, (1004 - 1088 AD) Abstract Abstract The peroxisome proliferator activated receptor alpha (PPARα) is a ligand activated tran- scription factor involved in the regulation of a variety of processes, ranging from inflam- mation and immunity to nutrient metabolism and energy homeostasis. PPARα serves as a molecular target for hypolipidemic fibrates drugs which bind the receptor with high affinity. Furthermore, PPARα binds and is activated by numerous fatty acids and fatty acid derived compounds. PPARα governs biological processes by altering the expression of large number of target genes. Although the role of PPARα as a gene regulator in liver has been well estab- lished, a comprehensive overview of its target genes has been missing so far. Additionally, it is not very clear whether PPARα has a similar role in mice and humans and to what extent target genes are shared between the two species. The aim of the research presented in this thesis was to identify PPARα-regulated genes in mouse and human liver and thereby further elucidate hepatic PPARα function. The applied nutrigenomics approaches are mainly expression microarrays combined with knockout mouse models and in vitro cell culture systems. By combining several independent nutrigenomics studies, we generated a comprehensive overview of PPARα-regulated genes in liver with the focus on lipid metabolism. We identi- fied a large number of PPARα target genes involved in different aspects of lipid metabolism. Furthermore, a major role of PPARα in lipogenesis was detected. Our data pointed to several novel putative PPARα target genes. Next, we compared PPARα-regulated genes in primary mouse and human hepatocytes treated with the PPARα agonist Wy14643 and generated an overview of overlapping and species specific PPARα target genes. A large number of genes were found to be regulated by PPARα activation in human primary hepatocytes, which iden- tified a major role for PPARα in human liver. Interestingly, we could characterize mannose binding lectin 2 (Mbl2) as a novel human specific PPARα target gene. Plasma Mbl2 levels were found to be changed in subjects receiving fenofibrate treatment or upon fasting. Regula- tion of Mbl2 by PPARα suggests that it may play a role in regulation of energy metabolism, although additional research is needed. We also compared the PPARα-induced transcriptome in HepG2 cells versus primary human hepatocytes to investigate the suitability of HepG2 cells in PPARα research. The results re- vealed that the HepG2 cell line poorly reflects the established PPARα target genes and func- tion, specifically with respect to lipid metabolism. Finally, we characterized the transcription factors Klf10 and Klf11 as novel PPARα target genes. Our preliminary findings using in 7 Abstract vitro transfection assays and in vivo tail vein injection of plasmid DNA suggested a potential metabolic role of Klf10 and Klf11 in liver. In conclusion, this thesis has extended our understanding of PPARα-regulated genes and function in liver, and has specifically highlightened a major role of PPARα in human hepa- tocytes. This research has also given birth to a possible biomarker of hepatic PPARα activity which is of great interest for future studies. Considering the need for proper biomarkers in the field of nutrigenomics and beyond, the properties of Mbl2 as a biomarker should be further investigated. The identification of other novel putative PPARα target genes offers ample op- portunities for continued research. 8 Contents Chapter 1 13 General introduction Chapter 2 25 Review- Peroxisome Proliferator Activated Receptor alpha target genes Chapter 3 73 Comprehensive analysis of PPARα-dependent regulation of hepatic lipid metabolism by expression profiling PPAR Res 26839 (2007) Chapter 4 103 Comparative analysis of gene regulation by the transcription factor PPARα between mouse and human PLoS One 4(8):e6796 (2009) Chapter 5 137 Mannose binding lectin is a circulating mediator of hepatic PPARα activity in Human Chapter 6 159 Comparative microarray analysis of PPARα induced gene expression in the human hepatoma cell line HepG2 and primary human hepatocytes Chapter 7 183 The Krüppel like factors KLF11 and KLF10 are putative novel PPARα target genes in liver with a potential metabolic role Chapter 8 209 General discussion Summary 225 Samenvatting (Summary in Dutch) 227 Acknowledgements 229 Curriculum vitae 233 List of publications 235 Overview of completed training activities 237 11 Chapter 1 General introduction Chapter 1 Nutrition Nutritional science has been through a major evolution in recent decades. Starting out as a scientific discipline focused on establishing nutrient requirements and the prevention of nutrient deficiencies, in modern times nutritional science has gradually placed increasing emphasis on the prevention of chronic diseases. Chronic diseases that are presently in the spotlight are obesity and the related metabolic syndrome, both of which have experienced a major surge in prevalence in the past decades. Metabolic syndrome is defined by a number of characteristics including visceral obesity, insulin resistance, hypertension and dyslipidemia and is associated longitudinally with increased risk for cardiovascular disease and diabetes [1-3]. As a consequence, obesity and the metabolic syndrome predispose individuals towards a reduced quality of life and increased healthcare associated costs. Although the first specific guidelines on the identification, evaluation and treatment of over- weight and obesity were released in 1998, since then the trend towards increased global obesity rates has continued unabated [4, 5]. In the meantime, the realization has grown that traditional nutritional science focused mainly on physiological and epidemiological aspects of nutrition may fall short of providing all the answers necessary for an effective strategy towards combating obesity and its complications. In response, interest has grown into un- derstanding the molecular mechanisms underlying the beneficial or adverse effects of food components, which became a basis for the introduction of the science of nutrigenomics. Nutrigenomics Nutritional genomics or nutrigenomics investigates the interaction between nutrients and genes at the molecular level by using genomics tools [6, 7]. As is the case for nutritional sci- ence in general, nutrigenomics research is mainly focused on disease prevention rather than to yield a specific cure. The main objective of nutrigenomics is to provide a solid mecha- nistic framework for evidence based nutrition aimed at reducing risk for chronic diseases such as cardiovascular disease, diabetes and cancer. Within this field of research, dietary nutrients and their metabolites are considered as signaling molecules that target cellular sens- ing systems, leading to changes in cellular and tissue function. The growing interest in un- derstanding how nutrition acts at the molecular level has been accompanied by impressive technological advancements, leading to the emergence of a novel field generally referred to as genomics, which include transcriptomics, proteomics and metabolomics. Large scale gene expression profiling or transcriptomics is extensively used to measure global changes in mRNA level (the transcriptome) of a cell or tissue in response to external stimuli such as 14 General Introduction nutrients or pharmacological reagents, or in response to certain types of diets and diseases. Application of these genomics tools in nutritional research gave rise to the birth of the field of nutrigenomics. One of the main goals of nutrigenomics is to try to distinguish healthy individuals from individuals that are in a pre-diseased or diseased state by utilizing large scale gene expres- sion profiling. In this way, by establishing biomarker profiles, nutritional interventions in the early diseased state may be guided towards restoring health, thereby preventing the need for intensive pharmacological therapy. Changes
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