<p>List of Contributors x</p> <p>Preface xx</p> <p>Acknowledgments xxi</p> <p><b>Part One: Introduction 1</b></p> <p>1 Organizational Principles of the Liver 3<br /><i>Peter Nagy, Snorri S. Thorgeirsson, and Joe W. Grisham</i></p> <p>2 Embryonic Development of the Liver 14<br /><i>Kenneth S. Zaret, Roque Bort, and Stephen A. Duncan</i></p> <p><b>Part Two: The Cells 23</b></p> <p><b>Section A: Cell Biology of the Liver 25</b></p> <p>3 Cytoskeletal Motors: Structure and Function in Hepatocytes 27<br /><i>Mukesh Kumar, Arnab Gupta, and Roop Mallik</i></p> <p>4 Hepatocyte Surface Polarity 36<br /><i>Anne Müsch and Irwin M. Arias</i></p> <p>5 Primary Cilia 50<br /><i>Carolyn M. Ott</i></p> <p>6 Endocytosis in Liver Function and Pathology 62<br /><i>Micah B. Schott, Barbara Schroeder, and Mark A. McNiven</i></p> <p>7 The Hepatocellular Secretory Pathway 75<br /><i>Catherine L. Jackson and Mark A. McNiven</i></p> <p>8 Mitochondrial Function, Dynamics, and Quality Control 86<br /><i>Marc Liesa, Ilan Benador, Nathanael Miller, and Orian S. Shirihai</i></p> <p>9 Nuclear Pore Complex 94<br /><i>Michelle A. Veronin and Joseph S. Glavy</i></p> <p>10 Protein Maturation and Processing at the Endoplasmic Reticulum 108<br /><i>Ramanujan S. Hegde</i></p> <p>11 Protein Degradation and the Lysosomal System 122<br /><i>Susmita Kaushik and Ana Maria Cuervo</i></p> <p>12 Peroxisome Assembly, Degradation, and Disease 137<br /><i>Rong Hua and Peter K. Kim</i></p> <p>13 Organelle–Organelle Contacts: Origins and Functions 151<br /><i>Uri Manor</i></p> <p>14 Gap and Tight Junctions in Liver: Structure, Function, and Pathology 160<br /><i>John W. Murray and David C. Spray</i></p> <p>15 Ribosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver 174<br /><i>Katherine I. Farley‐Barnes and Susan J. Baserga</i></p> <p>16 miRNAs and Hepatocellular Carcinoma 183<br /><i>Yusuke Yamamoto, Isaku Kohama, and Takahiro Ochiya</i></p> <p>17 Hepatocyte Apoptosis: Mechanisms and Relevance in Liver Diseases 195<br /><i>Harmeet Malhi and Gregory J. Gores</i></p> <p><b>Section B: The Hepatocyte 207</b></p> <p>18 Copper Metabolism and the Liver 209<br /><i>Cynthia Abou Zeid, Ling Yi, and Stephen G. Kaler</i></p> <p>19 The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis 215<br /><i>Tracey A. Rouault, Victor R. Gordeuk, and Gregory J. Anderson</i></p> <p>20 Disorders of Bilirubin Metabolism 229<br /><i>Namita Roy Chowdhury, Yanfeng Li, and Jayanta Roy Chowdhury</i></p> <p>21 Hepatic Lipid Droplets in Liver Function and Disease 245<br /><i>Douglas G. Mashek, Wenqi Cui, Linshan Shang, and Charles P. Najt</i></p> <p>22 Lipoprotein Metabolism and Cholesterol Balance 255<br /><i>Mariana Acuña‐Aravena and David E. Cohen</i></p> <p><b>Section C: Transporters, Bile Acids, and Cholestasis 269</b></p> <p>23 Bile Acid Metabolism in Health and Disease: An Update 271<br /><i>Tiangang Li and John Y.L. Chiang</i></p> <p>24 TGR5 (GPBAR1) in the Liver 286<br /><i>Verena Keitel, Christoph G.W. Gertzen, Lina Spomer, Holger Gohlke, and Dieter Häussinger</i></p> <p>25 Bile Acids as Signaling Molecules 299<br /><i>Thierry Claudel and Michael Trauner</i></p> <p>26 Hepatic Adenosine Triphosphate‐Binding Cassette Transport Proteins and Their Role in Physiology 313<br /><i>Peter L.M. Jansen</i></p> <p>27 Basolateral Plasma Membrane Organic Anion Transporters 327<br /><i>M. Sawkat Anwer and Allan W. Wolkoff</i></p> <p>28 Hepatic Nuclear Receptors 337<br /><i>Raymond E. Soccio</i></p> <p>29 Molecular Cholestasis 351<br /><i>Paul Gissen and Richard J. Thompson</i></p> <p>30 Pathophysiologic Basis for Alternative Therapies for Cholestasis 364<br /><i>Claudia D. Fuchs, Emina Halilbasic, and Michael Trauner</i></p> <p>31 Adaptive Regulation of Hepatocyte Transporters in Cholestasis 378<br /><i>James L. Boyer</i></p> <p><b>Section D: Non‐Hepatocyte Cells 391</b></p> <p>32 Cholangiocyte Biology and Pathobiology 393<br /><i>Massimiliano Cadamuro, Romina Fiorotto, and Mario Strazzabosco</i></p> <p>33 Polycystic Liver Diseases: Genetics, Mechanisms, and Therapies 408<br /><i>Tatyana Masyuk, Anatoliy Masyuk, and Nicholas LaRusso</i></p> <p>34 The Liver Sinusoidal Endothelial Cell: Basic Biology and Pathobiology 422<br /><i>Karen K. Sørensen and Bård Smedsrød</i></p> <p>35 Fenestrations in the Liver Sinusoidal Endothelial Cell 435<br /><i>Victoria C. Cogger, Nicholas J. Hunt, and David G. Le Couteur</i></p> <p>36 Stellate Cells and Fibrosis 444<br /><i>Youngmin A. Lee and Scott L. Friedman</i></p> <p><b>Part Three: Functions of The Liver 455</b></p> <p><b>Section A: Metabolic Functions 457</b></p> <p>37 Non‐alcoholic Fatty Liver Disease and Insulin Resistance 459<br /><i>Max C. Petersen, Varman T. Samuel, Kitt Falk Petersen, and Gerald I. Shulman</i></p> <p>38 AMPK: Central Regulator of Glucose and Lipid Metabolism and Target of Type 2 Diabetes Therapeutics 472<br /><i>Daniel Garcia, Maria M. Mihaylova, and Reuben J. Shaw</i></p> <p>39 Insulin‐Mediated PI3K and AKT Signaling 485<br /><i>Hyokjoon Kwon and Jeffrey E. Pessin</i></p> <p>40 Ca<sup>2+</sup> Signaling in the Liver 496<br /><i>Mateus T. Guerra, M. Fatima Leite, and Michael H. Nathanson</i></p> <p>41 Clinical Genomics of NAFLD 509<br /><i>Frank Lammert</i></p> <p><b>Section B: Liver Growth and Regeneration 521</b></p> <p>42 Stem Cell‐Fueled Maturational Lineages in Hepatic and Pancreatic Organogenesis 523<br /><i>Wencheng Zhang, Amanda Allen, Eliane Wauthier, Xianwen Yi, Homayoun Hani, Praveen</i> <i>Sethupathy, David Gerber, Vincenzo Cardinale, Guido Carpino, Juan Dominguez‐Bendala, Giacomo</i> <i>Lanzoni, Domenico Alvaro, Eugenio Gaudio, and Lola Reid</i></p> <p>43 Developmental Morphogens and Adult Liver Repair 539<br /><i>Mariana Verdelho Machado and Anna Mae Diehl</i></p> <p>44 Liver Repopulation by Cell Transplantation and the Role of Stem Cells in Liver Biology 550<br /><i>David A. Shafritz and Markus Grompe</i></p> <p>45 Liver Regeneration 566<br /><i>George K. Michalopoulos</i></p> <p>46 β‐Catenin Signaling 585<br /><i>Satdarshan P.S. Monga</i></p> <p>47 Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer 603<br /><i>Evan R. Delgado, Elizabeth C. Stahl, Nairita Roy, Patrick D. Wilkinson, and Andrew W. Duncan</i></p> <p><b>Part Four: Pathobiology of Liver Disease 615</b></p> <p>48 Hepatic Encephalopathy 617<br /><i>Roger F. Butterworth</i></p> <p>49 The Kidney in Liver Disease 630<br /><i>Moshe Levi, Shogo Takahashi, Xiaoxin X. Wang, and Marilyn E. Levi</i></p> <p>50 α1‐Antitrypsin Deficiency 645<br /><i>David A. Rudnick and David H. Perlmutter</i></p> <p>51 Pathophysiology of Portal Hypertension 659<br /><i>Yasuko Iwakiri and Roberto J. Groszmann</i></p> <p>52 Non‐alcoholic Fatty Liver Disease: Mechanisms and Treatment 670<br /><i>Yaron Rotman and Devika Kapuria</i></p> <p>53 Alcoholic Liver Disease 682<br /><i>Bin Gao, Xiaogang Xiang, Lorenzo Leggio, and George F. Koob</i></p> <p>54 Drug‐Induced Liver Injury 701<br /><i>Lily Dara and Neil Kaplowitz</i></p> <p>55 Oxidative Stress and Inflammation in the Liver 714<br /><i>John J. Lemasters and Hartmut Jaeschke</i></p> <p>56 The Role of Bile Acid‐Mediated Inflammation in Cholestatic Liver Injury 728<br /><i>Shi‐Ying Cai, Man Li, and James L. Boyer</i></p> <p>57 Toll‐like Receptors in Liver Disease 737<br /><i>So Yeon Kim and Ekihiro Seki</i></p> <p><b>Part Five: Liver Cancer 747</b></p> <p>58 Experimental Models of Liver Cancer: Genomic Assessment of Experimental Models 749<br /><i>Sun Young Yim, Jae‐Jun Shim, Bo Hwa Sohn, and Ju‐Seog Lee</i></p> <p>59 Epidemiology of Hepatocellular Carcinoma 758<br /><i>Hashem B. El‐Serag</i></p> <p>60 Mutations and Genomic Alterations in Liver Cancer 773<br /><i>Jessica Zucman‐Rossi and Jean‐Charles Nault</i></p> <p>61 Treatment of Liver Cancer 782<br /><i>Tim F. Greten</i></p> <p><b>Part Six: Hepatitis 793</b></p> <p>62 Molecular Biology of Hepatitis Viruses 795<br /><i>Christoph Seeger, William S. Mason, and Michael M.C. Lai</i></p> <p>63 Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis 821<br /><i>Carlo Ferrari, Valeria Barili, Stefania Varchetta, and Mario U. Mondelli</i></p> <p>64 Clinical Implications of the Molecular Biology of Hepatitis B Virus 851<br /><i>Timothy M. Block, Ju‐Tao Guo, and W. Thomas London</i></p> <p>65 Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection 868<br /><i>Marc G. Ghany, Christopher M. Walker, and Patrizia Farci</i></p> <p>66 Tracking Hepatitis C Virus Interactions with the Hepatic Lipid Metabolism : A Hitchhiker’s Guide to Solve Remaining Translational Research Challenges in Hepatitis C 889<br /><i>Gabrielle Vieyres and Thomas Pietschmann</i></p> <p>67 Nucleoside Antiviral Agents for HCV: What’s Left to Do? 906<br /><i>Franck Amblard, Seema Mengshetti, Junxing Shi, Sijia Tao, Leda Bassit, and Raymond F. Schinazi</i></p> <p>68 Hepatitis E Virus: An Emerging Zoonotic Virus Causing Acute and Chronic Liver Disease 915<br /><i>Xiang‐Jin Meng</i></p> <p>69 Biological Principles and Clinical Issues Underlying Liver Transplantation for Viral‐Induced End‐Stage Liver Disease in the Era of Highly Effective Direct‐Acting Antiviral Agents 926<br /><i>Michael S. Kriss, James R. Burton, Jr., and Hugo R. Rosen</i></p> <p>70 Time for the Elimination of Hepatitis C Virus as a Global Health Threat 935<br /><i>John W. Ward, Alan R. Hinman, and Harvey J. Alter</i></p> <p><b>Part Seven: Horizons 953</b></p> <p>71 Genome Editing by Targeted Nucleases and the CRISPR/Cas Revolution 955<br /><i>Shawn M. Burgess</i></p> <p>72 Imaging Cellular Proteins and Structures: Smaller, Brighter, and Faster 965<br /><i>Aubrey V. Weigel and Erik Lee Snapp</i></p> <p>73 Liver‐Directed Gene Therapy 979<br /><i>Patrik Asp, Chandan Guha, Namita Roy Chowdhury, and Jayanta Roy Chowdhury</i></p> <p>74 Telomeres and Telomerase in Liver Generation and Cirrhosis 992<br /><i>Sonja C. Schätzlein and K. Lenhard Rudolph</i></p> <p>75 Toxins and Biliary Atresia 1000<br /><i>Michael Pack and Rebecca G. Wells</i></p> <p>76 The Dual Role of ABC Transporters in Drug Metabolism and Resistance to Chemotherapy 1007<br /><i>Jean‐Pierre Gillet, Marielle Boonen, Michel Jadot, and Michael M. Gottesman</i></p> <p>77 Stem Cell‐Derived Liver Cells: From Model System to Therapy 1015<br /><i>Helmuth Gehart and Hans Clevers</i></p> <p>78 Extracellular Vesicles and Exosomes: Biology and Pathobiology 1022<br /><i>Gyongyi Szabo and Fatemeh Momen‐Heravi</i></p> <p>79 Integrated Technologies for Liver Tissue Engineering 1028<br /><i>Tiffany N. Vo, Amanda X. Chen, Quinton B. Smith, Arnav Chhabra and Sangeeta N. Bhatia</i></p> <p>80 Pluripotent Stem Cells and Reprogramming: Promise for Therapy 1036<br /><i>James A. Heslop and Stephen A. Duncan</i></p> <p>81 Chromatin Regulation and Transcription Factor Cooperation in Liver Cells 1043<br /><i>Ido Goldstein</i></p> <p>82 Drug Interactions in the Liver 1050<br /><i>Guruprasad P. Aithal and Gerd A. Kullak‐Ublick</i></p> <p>83 Metabolic Regulation of Hepatic Growth 1058<br /><i>Wolfram Goessling</i></p> <p>84 The Gut Microbiome and Liver Disease 1062<br /><i>Lexing Yu, Jasmohan S. Bajaj, and Robert F. Schwabe</i></p> <p>85 Lineage Tracing: Efficient Tools to Determine the Fate of Hepatic Cells in Health and Disease 1069<br /><i>Frédéric Lemaigre</i></p> <p>86 The Hepatocyte as a Household for Plasmodium Parasites 1075<br /><i>Vanessa Zuzarte‐Luis and Maria M. Mota</i></p> <p>Index 1081</p>