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Proglucagon-Derived Peptides Copyright 2010 Jennifer Nicole Woodard BUTYRATE-INDUCED EXPRESSION OF PROGLUCAGON: IMPLICATIONS FOR ENTEROENDOCRINE SIGNALING AND INTESTINAL GROWTH BY JENNIFER NICOLE WOODARD DISSERTATION Submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Nutritional Sciences in the Graduate College of the University of Illinois at Urbana-Champaign, 2010 Urbana, Illinois Doctoral Committee: Professor Timothy Garrow, Chair Professor Kelly Tappenden, Director of Research Associate Professor Kelly Swanson Assistant Professor Michael Miller ABSTRACT While the gastrointestinal tract is primarily recognized for its digestive and absorptive capacity, it is also the largest endocrine organ in the body. There are a number of different types of endocrine cells in the gut which have the ability to mediate nutrient-gene interactions. Of interest for this research is the L cell of the distal ileum and colon which expresses the proglucagon gene. Proglucagon encodes a number of important hormones, namely glucagon- like peptide 1 (GLP-1), glucagon-like peptide 2 (GLP-2), glicentin, and oxyntomodulin and thus may impact intestinal development and dysfunction, type 2 diabetes, and obesity. Evidence suggests that fibers and short-chain fatty acids (SCFAs), particularly butyrate, are classes of nutrients capable of regulating the proglucagon gene. To examine this, we treated enteroendocrine L cells with butyrate and found increased proglucagon mRNA abundance. However, the mechanism by which butyrate affects proglucagon was less understood. Therefore, we isolated the human proglucagon gene promoter and treated with butyrate, revealing that butyrate regulates proglucagon transcription by activating the promoter. In addition, it has been suggested that butyrate may be interacting with receptors or transporters to stimulate its effects. To examine this, we silenced the SCFA receptor GPR43 and the bitter taste receptor T2R38 and revealed that butyrate no longer had the capacity to stimulate increased proglucagon abundance. Additionally, we also examined the abundance of SCFA transporters and noted increases in SLC5A8 in the ileum and MCT-1 in the colon following supplementation of fermentable fibers into the diet. Further interaction between butyrate and proglucagon was explored by infusing SCFAs and butyrate into the lumen of the ileum and colon. The greatest effects were noted in aspects of intestinal structure, with changes noted in crypt-villus ii architecture, DNA, RNA, and protein concentrations throughout the intestine. These improved structural parameters corresponded with increased proglucagon abundance, suggesting GLP-2 was likely mediating these adaptations to the nutrient. Thus, the provision of the SCFA butyrate may be particularly important and beneficial to patients suffering with intestinal dysfunction, type 2 diabetes, and obesity by upregulating proglucagon expression and ultimately stimulating greater hormone release. iii ACKNOWLEDGEMENTS I am very grateful to my advisor, Dr. Kelly Tappenden, for taking a chance on me so many years ago. When I first met Dr. Tappenden, I was an undergraduate, simply looking for a summer job. At the time, I thought it was just a way to earn a little money to get through a summer in Champaign, but working with her taught me so much and I found something that truly interested me, so much so that it inspired me to change my career path and enroll in graduate school to study nutrition. She opened my eyes as a scientist and I am indebted to her for that. I would also like to thank my committee, Dr. Tim Garrow, Dr. George Fahey, Dr. Kelly Swanson, and Dr. Mike Miller, for all of their insight and guidance throughout. They pushed me to think about and question my work in new ways, making me a better researcher in the process. To the Tappenden Lab members, past and present, a special thanks to all of you. You taught me so much as a researcher, from how to pipette and make solutions to designing and running a study of my own. You were there for the highs and lows of the lab, listening to me complain when I messed up an assay or was struggling with a class and sharing in the excitement when something worked and actually showed significance! More than that, you turned out to be more than just colleagues that I worked with; you were great friends who made my time here much more enjoyable. I know that I couldn’t have made it through all of this without you. To my family, thank you so much for all of your love and encouragement. I know that you haven’t always understood exactly what it is I have been doing or why I have been doing it, but you have always supported me nonetheless. Whether through all those many, many phone calls or trips home, you have always been there for me. To my mom, you taught me to dream big and gave me the confidence to accomplish anything I set my mind to. All of you have made me the person I am today and I couldn’t imagine my life without you. iv TABLE OF CONTENTS LIST OF FIGURES ................................................................................................................... viii LIST OF TABLES ....................................................................................................................... ix LIST OF ABBREVIATIONS .......................................................................................................x CHAPTER 1 LITERATURE REVIEW ......................................................................................1 INTRODUCTION ...................................................................................................................... 1 PROGLUCAGON ...................................................................................................................... 1 Proglucagon Gene Structure ................................................................................................... 2 Post-translational Processing .................................................................................................. 3 Peptide Secretion .................................................................................................................... 3 Proglucagon-Derived Peptides................................................................................................ 5 Glucagon-like peptide-1 ...................................................................................................... 5 Glucagon-like peptide 2 .................................................................................................... 11 Glicentin ............................................................................................................................ 19 Oxyntomodulin ................................................................................................................. 20 SHORT-CHAIN FATTY ACIDS ............................................................................................ 21 Production of Short-Chain Fatty Acids................................................................................. 22 Substrates for Short-Chain Fatty Acid Production ............................................................... 23 Absorption of Short-Chain Fatty Acids ................................................................................ 25 Metabolism of Short-Chain Fatty Acids ............................................................................... 26 Physiological Effects of Short-Chain Fatty Acids ................................................................ 27 Short-Chain Fatty Acids and Nutrient Absorption ........................................................... 27 Short-Chain Fatty Acids and Intestinal Injury .................................................................. 29 SUMMARY .............................................................................................................................. 32 AIMS AND SCOPE OF RESEARCH ..................................................................................... 32 CHAPTER 2 BUTYRATE INCREASES PROGLUCAGON mRNA ABUNDANCE THROUGH ACTIVATION OF THE PROGLUCAGON GENE PROMOTER IN NCI- H716 CELLS ................................................................................................................................38 ABSTRACT .............................................................................................................................. 38 INTRODUCTION .................................................................................................................... 39 MATERIALS AND METHODS .............................................................................................. 41 Culturing NCI-H716 Cells .................................................................................................... 41 Determination of Proglucagon mRNA Abundance with Real-Time PCR ........................... 41 Proglucagon Promoter Isolation and Construct Preparation ................................................. 43 v Transfection of NCI-H716 Cells ........................................................................................... 44 Luciferase Assays ................................................................................................................. 45 DNA Content ........................................................................................................................ 45 Statistical Analysis ................................................................................................................ 45 RESULTS ................................................................................................................................
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