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Lean NAFLD: a Distinct Entity Shaped by Differential Metabolic Adaptation

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Lean NAFLD: A distinct entity shaped by differential metabolic adaptation Dr. Fei Wen Chen A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Medicine University of Sydney 2020 1 DECLARATION Unless otherwise acknowledged, the work described within this thesis was carried out personally by the author, at the Westmead Institute of Medical Research and University of Sydney, between March 2017 and December 2019. None of this work has been submitted previously for the purpose of obtaining any other degree. Fei Wen Chen i ACKNOWLEDGEMENTS Undertaking this PhD has been a truly life-changing experience that would not have been possible without the support from key people and organisations. Firstly, I would like to express my sincere gratitude to my supervisors for this project, Professor Jacob George and A/Prof Mohammed Eslam, without whom this project would not have been possible. Thank you very much for your guidance, patience, feedback and motivation and for always believing in the potential that this project has despite the many setbacks and doubts casted by many. I would also like to thank the Storr liver unit, all the scientists, nurses, patients, collaborators as well as the funding bodies, the Research Training Program scholarship and the Westmead Institute for Medical Research Top-up grant, for their time, intellectual and financial contribution towards this PhD. A very heartfelt thank you to my family and their support during my PhD journey. My parents, Thiam Wong Chen and Meh Nio Kwan, who are both scientists themselves, have been my constant rock of support during every ups and downs of this journey. My mum, especially, who has spent as much time travelling between Kuala Lumpur, China and Sydney, as I have preparing this thesis, juggling between work, caring for my father, my other siblings, her other grandchildren and me, in order to lend me a hand so I could finish this PhD on time. ii To my wonderful husband, Joko Boentarya, father of our beautiful daughter Josie Boentarya and our newborn son Jordan, who has put up with me through all these years of medical studies and training, and my PhD journey. Thank you for always being by my side through all this, keeping our family together and helping me cope with motherhood, being a student and a doctor at the same time. And to all my friends and colleagues, and all those I have not mentioned, thank you for sparing your time and ears, and being a part of this memorable journey, without your support this project would not have been possible. iii TABLE OF CONTENTS TABLE OF CONTENTS DECLARATION ...................................................................................................... i ACKNOWLEDGEMENTS .................................................................................... ii TABLE OF CONTENTS ....................................................................................... iv ABSTRACT ......................................................................................................... viii PUBLICATIONS .................................................................................................... ix AWARDS AND GRANTS ...................................................................................... x LIST OF TABLES ................................................................................................. xi LIST OF FIGURES ............................................................................................... xii ABBREVIATIONS ............................................................................................... xiv CHAPTER ONE ..................................................................................................... 1 1 INTRODUCTION ............................................................................................. 2 1.1 BURDEN OF LIVER DISEASE ............................................................................. 2 1.2 Epidemiology and definition of NAFLD ........................................................... 3 1.3 Factors affecting NAFLD development ............................................................ 4 1.3.1 Modifiable risk factors ......................................................................................... 4 Lifestyle factors................................................................................................................... 4 Role of diet and microbiome .............................................................................................. 5 Role of bile acids and its regulators .................................................................................... 7 1.3.2 Non-modifiable risk factors ............................................................................... 12 Genetic factors ................................................................................................................. 12 Epigenetic factors ............................................................................................................. 17 1.4 Factors affecting NAFLD progression ............................................................ 21 1.5 METABOLIC HEALTH ..................................................................................... 22 1.5.1 Definition .......................................................................................................... 22 1.5.2 Adiposopathy .................................................................................................... 24 1.5.3 Effect of metabolic health on NAFLD .................................................................. 27 1.6 Metabolic adaptation ................................................................................... 28 1.7 LEAN NAFLD ................................................................................................. 30 1.7.1 Definition and epidemiology .............................................................................. 30 1.7.2 Histological characteristics................................................................................. 32 1.7.3 Pathogenesis ..................................................................................................... 33 1.7.4 Prognosis ........................................................................................................... 33 1.8 HYPOTHESIS AND AIMS ................................................................................ 38 CHAPTER TWO .................................................................................................. 39 2 MATERIALS AND METHODS ..................................................................... 40 2.1 MATERIALS .......................................................................................................... 40 iv 2.1.1 Polymerase chain reaction (PCR) primers ........................................................... 40 2.1.2 Sources of Clinical Information and Human Biological Tissue ............................. 41 2.1.2.1 Clinical and laboratory assessments ................................................................... 41 2.1.2.2 NAFLD cohort ....................................................................................................... 42 2.1.2.3 Healthy controls ................................................................................................... 43 2.1.3 Sources of mice tissue ....................................................................................... 44 2.2 METHODS ............................................................................................................ 46 2.2.1 Histopathology .................................................................................................. 46 2.2.2 Phosphatidylethanol measurement ................................................................... 46 2.2.3 Methods for bile acid quantification .................................................................. 47 2.2.3.1 Bile acid extraction .............................................................................................. 47 2.2.3.2 Bile acid measurement ........................................................................................ 47 2.2.4 Method of FGF-19 measurement ....................................................................... 48 2.2.5 Method of C4 measurement .............................................................................. 49 2.2.6 Genotyping ........................................................................................................ 50 2.2.7 Method of RNA extraction from animal tissues .................................................. 50 2.2.8 Method of cDNA synthesis................................................................................. 51 2.2.9 Method of qPCR ................................................................................................ 52 2.2.10 Method of mice ileal fgf-15 measurement ....................................................... 52 2.2.11 Microbiota analysis ......................................................................................... 53 2.2.12 Inflammatory cytokines measurement ............................................................ 54 2.2.13 Statistical analysis ........................................................................................... 54 CHAPTER THREE .............................................................................................. 56 3 COMPARISON OF LEAN NAFLD WITH LEAN AND NON-LEAN HEALTHY CONTROLS .....................................................................................
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