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Dissertation YL.Pdf (4.445Mb) The Role of Sugar-sweetened Water in the Progression of Nonalcoholic Fatty Liver Disease by Yuwen Luo A dissertation submitted to the Graduate Faculty of Auburn University in partial fulfillment of the requirements for the Degree of Doctor of Philosophy Auburn, Alabama December 10, 2016 Keywords: Nonalcoholic fatty liver disease, adipose tissue, fructose, high-fat Western diet, RNA-seq, ORM Copyright 2016 by Yuwen Luo Approved by Michael W. Greene, Chair, Assistant Professor, Nutrition, Dietetics and Hospitality Management Kevin W. Huggins, Associate Professor, Nutrition, Dietetics and Hospitality Management Ramesh B. Jeganathan, Associate Professor, Nutrition, Dietetics and Hospitality Management Robert L. Judd, Associate Professor, Anatomy, Physiology and Pharmacology i Abstract Nonalcoholic fatty liver disease (NAFLD), which ranges from simple steatosis (fatty liver) to nonalcoholic steatohepatitis (NASH), has become the most common chronic liver disease in both children and adults, paralleling the increased prevalence of obesity and diabetes during the last decades. The rise in NASH prevalence is a major public health concern because there are currently no specific and effective treatments for NASH. In addition, the molecular mechanisms for the progression of steatosis to NASH remain largely undiscovered. To model the human condition, a high-fat Western diet that includes liquid sugar consumption has been used in mice. A high-fat Western diet (HFWD) with liquid sugar [fructose and sucrose (F/S)] induced acute hyperphagia above that observed in HFWD-fed mice, yet without changes in energy expenditure. Liquid sugar (F/S) exacerbated HFWD-induced glucose intolerance and insulin resistance and impaired the storage capacity of epididymal white adipose tissue (eWAT). Hepatic TG, plasma alanine aminotransferase, and normalized liver weight were significantly increased only in HFWD+F/S-fed mice. HFWD+F/S also resulted in increased hepatic fibrosis and elevated collagen 1a2, collagen 3a1, and TGFβ gene expression. Furthermore, HWFD+F/S- fed mice developed more profound eWAT inflammation characterized by adipocyte hypertrophy, macrophage infiltration, a dramatic increase in crown-like structures, and upregulated proinflammatory gene expression. An early hypoxia response in the eWAT led to reduced vascularization and increased fibrosis gene expression in the HFWD+F/S-fed mice. Our ii results indicate that the high fat Western diet plus liquid sugar consumption model of obesity is a good model for NAFLD research and likely other clinical conditions associated with adipose tissue dysfunction. The prevalence of obesity-related NAFLD and limitations of available therapeutic options highlight the need for identifying specific gene and pathway changes that drive progression of NAFLD using state-of-the-art sequencing analysis of human biospecimens or relevant animal models. RNA-seq analysis of a high fat Western diet model of NAFLD revealed differentially expressed genes (DEGs) associated with both HFWD (HFWD vs. Chow; 1065DEGs) and HFWD+F/S (HFWD+F/S vs Chow; 1689 DEGs). However, the addition of liquid sugar consumption resulted in 760 DEGs in the liver of HFWD+F/S-fed mice, which are mainly enriched in small GTPase mediated signal transduction, and lipid homeostasis biological processes. Further, pathway analysis showed pathways in immune response, fibrosis and cancer are major pathways enriched in the livers of HFWD+F/S-fed mice. Our study identified key genes, biological processes and pathway changes in the liver of HFWD+F/S mice and provided a molecular basis for understanding the mechanism through which the addition of liquid sugar promotes the progression of NAFLD. In addition, RNA-seq analysis also revealed hepatic expression of ORM3 gene was significantly elevated by 20-fold in HFWD+F/S-fed mice. Further validation of ORM3 hepatic expression in an independent dietary treatment experiment confirmed our RNA-seq findings, and found ORM1 and ORM2 hepatic expression was significantly elevated to a similar level as ORM3. Correlation analysis of ORM3 gene expression with NAFLD parameters examined in our recently published study indicated that ORM3 gene expression was significantly positively correlated with body weight, normalized liver weight, and alanine aminotransferase, a marker of iii liver dysfunction. Moreover, the gene expression of ORM was also induced in a cellular model of insulin resistance. Furthermore, ORM was observed to promote macrophage polarization toward an anti-inflammatory phenotype. Our observations suggest that ORM might have a protective role in NAFLD by regulate cellular insulin resistance and pro-inflammatory macrophages. iv Acknowledgments I would like to express my deepest gratitude to my advisor, Dr. Michael W. Greene, for his excellent mentorship throughout my course of study. I appreciate his encouragement, freedom to explore, and his insightful interpretations, which inspired me to ask meaningful research questions and motivated me to perform at my best. His patience and support has been an immense help in completing this dissertation. I would also like to thank Dr. Kevin Huggins, Dr. Ramesh Jeganathan, Dr. Robert Judd, and Dr. Richard Curtis Bird for serving on my dissertation committee, and guiding my research. I express my gratitude to Dr. Ann Marie O’Neill for her guidance and help in experiment preparation. I acknowledge and extend gratitude for the financial support received from the Auburn University start-up funds, USDA Hatch Grant and NDHM Graduate Research Award. I would like to express my deepest gratitude and gratefulness to my husband Mr. Yi Zhang for being a constant source of inspiration and motivation, for his enduring love and immense moral support at every step. I would also like to thank my parents Mr. Jingyuan Luo and Ms. Ruyu Gu for their unconditional love and support. I want to specially mention Dr. Jian Zhang, Mr. Michael Wayne, Ms. Lauren Woodie, and Mr. Bulbul Ahmed for their contribution. I thank my colleagues Mr. Vishal Kothari, Dr. Chen Zheng, Ms. Yueru Li, Ms. Yuxuan Zhang, Ms. Yijing Qi, and Dr. Shraddha Rege. It was a great pleasure studying and working together. I express my sincere gratitude to all faculty members in the Department of Nutrition, Dietetics and Hospitality v Managements, and the College of Veterinary Medicine at Auburn University for giving me this valuable opportunity and excellent atmosphere to conduct my research. Last but not least, I would like to specially mention my dog Brownie for his love and company during my PhD study. vi Reference Style This document is referenced using the citation style of the Journal of Hepatology vii Table of Contents Abstract ................................................................................................................................................... ii Acknowledgments ................................................................................................................................... v Reference Style ..................................................................................................................................... vii List of Tables ........................................................................................................................................ xii List of Figures ...................................................................................................................................... xiii Chapter 1: Introduction ............................................................................................................................ 1 Chapter 2: Review of Literature ............................................................................................................... 4 2.1 Nonalcoholic Fatty Liver Disease................................................................................................... 4 2.1.1 Introduction and definitions ..................................................................................................... 4 2.1.2 Prevalence and incidence ........................................................................................................ 5 2.1.3 Natural history ........................................................................................................................ 6 2.1.4 Pathogenesis of NAFLD.......................................................................................................... 7 2.1.5 Rodent model of NAFLD ...................................................................................................... 24 2.2 RNA-seq...................................................................................................................................... 36 2.2.1 Introduction .......................................................................................................................... 36 2.2.2 RNA-seq technology and benefits ......................................................................................... 37 2.2.3 Challenges for RNA-seq........................................................................................................ 39 viii 2.3 Acute Phase Proteins.................................................................................................................... 41 2.3.1 Overview .............................................................................................................................. 41 2.3.2 ORM....................................................................................................................................
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