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Elucidating the Role of Hepatic Ppp1r3b in Glucose and Lipid Metabolism

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University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2017 Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism Minal B. Mehta University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Biology Commons, Cell Biology Commons, and the Molecular Biology Commons Recommended Citation Mehta, Minal B., "Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism" (2017). Publicly Accessible Penn Dissertations. 2469. https://repository.upenn.edu/edissertations/2469 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2469 For more information, please contact [email protected]. Elucidating The Role Of Hepatic Ppp1r3b In Glucose And Lipid Metabolism Abstract Genetic variants mapping to chromosome 8p23.1 have been associated with multiple metabolic traits in humans, including plasma constituents (glucose, lactate, insulin, HDL and non-HDL cholesterol), and hepatic steatosis with genome-wide significance. The closest gene of known function, PPP1R3B, (Protein Phosphatase 1 Regulatory Subunit 3B), encodes a protein (GL) that is known to regulate glycogen metabolism. We sought to test the hypothesis that hepatic PPP1R3B is the causal gene underlying the human genetic association with these metabolic attributes and to understand the mechanisms. We generated two separate mice with liver-specific deletion (Ppp1r3b∆hep) or liver-specific vo erexpression of Ppp1r3b. Hepatic deletion of Ppp1r3b significantly educedr glycogen levels and glycogen synthase activity in the liver, impairing fasting glucose homeostasis, and prompting early onset of non- carbohydrate metabolite utilization to sustain energy under long term fasting. Conversely, mice with overexpression of hepatic Ppp1r3b maintained augmented glycogen storage capacity, with larger glycogen pool creating a buffer towards delayed onset of hypoglycemia. Mice harboring deletion of hepatic Ppp1r3b exhibited glucose intolerance and insulin resistance, with increased hepatic triglyceride content, leading to hepatic steatosis, under chronic high sucrose feeding. In contrast, mice overexpressing hepatic Ppp1r3b remained glucose responsive, and insulin sensitive, and were protected from hepatic steatosis under chronic sucrose diet feeding. These studies implicate a major role of Ppp1r3b in glycogen and lipid homeostasis in the liver, and provide concrete evidence for its pleiotropic effect on metabolic state in a mammalian system, consistent with the human GWAS association. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Cell & Molecular Biology First Advisor DANIEL J. RADER Keywords GLUCOSE METABOLISM, GLYCOGEN, GLYCOGEN SYNTHASE, LIPID METABOLISM, PROTEIN PHOSPHORYLATION Subject Categories Biology | Cell Biology | Molecular Biology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2469 ELUCIDATING THE ROLE OF HEPATIC PPP1R3B IN GLUCOSE AND LIPID METABOLISM Minal B. Mehta A DISSERTATION in Cell and Molecular Biology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2017 Supervisor of Dissertation _________________________ Daniel J. Rader Professor, Department of Medicine Graduate Group Chairperson _________________________ Daniel S. Kessler Associate Professor, Department of Cell and Molecular Biology Dissertation Committee Doris A. Stoffers, M.D., Ph.D., Sylvan H. Eisman Professor of Medicine Charles A. Stanley, M.D., Professor, Department of Pediatrics Joseph A. Baur, Ph.D., Assistant Professor, Department of Physiology Rexford S. Ahima, M.D., Ph.D., Professor in Diabetes (Johns Hopkins SOM) ELUCIDATING THE ROLE OF HEPATIC PPP1R3B IN GLUCOSE AND LIPID METABOLISM COPYRIGHT 2017 Minal B. Mehta This work is licensed under the Creative Commons Attribution- NonCommercial-ShareAlike 3.0 License To view a copy of this license, visit https://creativecommons.org/licenses/by-nc-sa/3.0/us/ iii To my awesome mentors, family, colleagues, and friends who got me to this point! iv ACKNOWLEDGMENT I am grateful to many amazing individuals who have helped me be here today. First and foremost, to my parents, Bhadresh and Manju Mehta, who have always supported and encouraged me in everything I had always wished to achieve; to my older brother, Sandeep Mehta, who has been my biggest role model and guardian in life; to my loving sister-in-law, Jhalak Mehta, who has always been there for me, guiding me through in every step of my life; to my two wonderful bundles of joy, my nephew, Maneet Mehta, and my niece Kashvi Mehta, who have kept me going all these years. I am truly grateful to Dr. Daniel J. Rader for being an amazing advisor and a mentor. I can’t thank him enough for everything he has done for me and for each and every one of his students. His dedication, hard work and tireless efforts in helping his trainees learn and grow is beyond commendable. It really meant a lot to me—for his presence, for helping me learn and grow, and for his cheerful enthusiasm whenever I showed him my results, even when I thought they were not so great. I wouldn’t be standing here today without all his help and guidance. I am truly thankful for receiving the opportunity to be a part of his lab. It has been a true honor to have received his mentorship and guidance, and it has been a privilege and a wonderful academic journey. I also want to sincerely thank my thesis committee— Dr. Doris Stoffers,Dr. Joseph Baur, Dr. Charles Stanley, Dr. Rexford Ahima, Dr. Morris Birnbaum, and Dr. Kendra Bence, for being my advocate and providing their valuable time, guidance and advice over the years on my research. I am genuinely thankful to Dr. Nicolas J. Hand for helping me with entirely everything— from preparing for thesis committee meetings, to conference talks, manuscripts/dissertation writing, and even when I just needed to cry about stupid feelings, he would be there for me. I want to sincerely thank him for providing heartfelt life lessons, for being patient with me and for providing a safe and fun atmosphere to chat about anything and everything! I wouldn’t be here today without his help and advice. It has meant a lot, Dr. Hand- Thank you so much! I want to thank Dr. Billheimer and Dr. Millar for their cheerful conversations about science, especially about teaching me about lipids and their properties, for helping me learn so much from their collective wisdom, and for providing advice on research directions for my project, Dr. Millar for running all the DNL experiments for us. Thank you for your valuable time and effort. It meant a lot. I want to thank each and every one of the member in the Rader Lab, both past and present. I want to thank Linda Carmichael, Cathy, Dawn, Stephanie and Susannah, for helping me with so many administrative tasks, and for making the lab run so smoothly! Thank you for all that you do! Thank you to Debbie for willingly running all my millions of MIRA samples over the years with her cheerful smile. Thank you to Linda Morell, for awesome talks about life, health and recently, politics. I want to thank Amrith and Aisha—for being my two pillars of strength during grad school, I am not sure how I would have survived without them! Thank you for all their moral support over the years, for our awesome v coffee and lunch breaks, our shared love for books, our introvertedness, and talks about life—you ladies are amazing!! I also want to thank Mayda for our awesome conversations and fun memories when we went Salsa dancing together. Thank you for being a great friend, Mayda! Thank you to Kevin Trindade for running FPLCs for my plasma samples and for our fun conversations about travel destinations, for giving me all the advice on where to go and what to do! I want to thank our incredible and brilliant Postdocs, both past and present. (Xin, Swapnil, Donna, Deepti, Sylvia, Cecilia, Marie, Rob, Bill, Salam, Jun, Paolo, Evi, and many other awesome individuals). Thank you for so many things— for your countless advice, for answering my stupid questions, for helping me learn science and get better at it, and for helping me grow and learn over the years-- thank you for everything. I want to thank my most awesome peers—my vital support system over the years—the amazing Graduate Students (Wen, Hye In, Chris, Devin, Sumeet, Kevin Patel, Alanna, Andy, Katherine). Thank you for all the great times, celebrations, fun and memories together…. Last but not the least, I want to thank the Animal Team, Aisha Wilson, Eduoard Edwige, and Maosen Sen—their superb technical support, their helping hands, and cheerful disposition had made doing the animal work so much fun. Without them I would not be here today! Thank you to my one and only work spouse, Aisha , as we jokingly call each other— for being my pillar of strength throughout graduate school, and I can’t thank you enough for all the beautiful memories we have shared together. You are gem of a person! Hope to stay in touch with all of you in the future- Thank you for letting me be a part of your lives! Finally, I want to thank my friends (Senthil, Prakirti, Karthi, Minnal, Shweta, Farzana, Madhuri, Amita, Anandita, Hiral, Nida, Neha and many others...) whose everlasting moral support and words of encouragement have kept me going in graduate school. Thank you for all the wonderful memories together and making these past 6 years of my life full of fun and laughter! With Sincere Gratitude and Best Regards, Minal vi ABSTRACT ELUCIDATING THE ROLE OF HEPATIC PPP1R3B GENE IN GLUCOSE AND LIPID METABOLISM Minal B. Mehta Genetic variants mapping to chromosome 8p23.1 have been associated with multiple metabolic traits in humans, including plasma constituents (glucose, lactate, insulin, HDL and non-HDL cholesterol), and hepatic steatosis with genome-wide significance.
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