The Liver

IRWIN M. ARIAS, MD, National Institutes of Health, Bethesda, Maryland, USA.

HARVEY J. ALTER, MD, National Institutes of Health, Bethesda, Maryland, USA.

JAMES L. BOYER, MD, Yale University School of Medicine, New Haven, Connecticut, USA.

DAVID E. COHEN, MD, Weill Cornell Medical College, New York, USA.

DAVID A. SHAFRITZ, MD, Albert Einstein College of Medicine, New York, USA.

SNORRI S. THORGEIRSSON, MD, National Institutes of Health, Bethesda, Maryland, USA.

List of Contributors x


Preface xx


Acknowledgments xxi


Part One: Introduction 1


1 Organizational Principles of the Liver 3
Peter Nagy, Snorri S. Thorgeirsson, and Joe W. Grisham


2 Embryonic Development of the Liver 14
Kenneth S. Zaret, Roque Bort, and Stephen A. Duncan


Part Two: The Cells 23


Section A: Cell Biology of the Liver 25


3 Cytoskeletal Motors: Structure and Function in Hepatocytes 27
Mukesh Kumar, Arnab Gupta, and Roop Mallik


4 Hepatocyte Surface Polarity 36
Anne Musch and Irwin M. Arias


5 Primary Cilia 50
Carolyn M. Ott


6 Endocytosis in Liver Function and Pathology 62
Micah B. Schott, Barbara Schroeder, and Mark A. McNiven


7 The Hepatocellular Secretory Pathway 75
Catherine L. Jackson and Mark A. McNiven


8 Mitochondrial Function, Dynamics, and Quality Control 86
Marc Liesa, Ilan Benador, Nathanael Miller, and Orian S. Shirihai


9 Nuclear Pore Complex 94
Michelle A. Veronin and Joseph S. Glavy


10 Protein Maturation and Processing at the Endoplasmic Reticulum 108
Ramanujan S. Hegde


11 Protein Degradation and the Lysosomal System 122
Susmita Kaushik and Ana Maria Cuervo


12 Peroxisome Assembly, Degradation, and Disease 137
Rong Hua and Peter K. Kim


13 Organelle-Organelle Contacts: Origins and Functions 151
Uri Manor


14 Gap and Tight Junctions in Liver: Structure, Function, and Pathology 160
John W. Murray and David C. Spray


15 Ribosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver 174
Katherine I. Farley?Barnes and Susan J. Baserga


16 miRNAs and Hepatocellular Carcinoma 183
Yusuke Yamamoto, Isaku Kohama, and Takahiro Ochiya


17 Hepatocyte Apoptosis: Mechanisms and Relevance in Liver Diseases 195
Harmeet Malhi and Gregory J. Gores


Section B: The Hepatocyte 207


18 Copper Metabolism and the Liver 209
Cynthia Abou Zeid, Ling Yi, and Stephen G. Kaler


19 The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis 215
Tracey A. Rouault, Victor R. Gordeuk, and Gregory J. Anderson


20 Disorders of Bilirubin Metabolism 229
Namita Roy Chowdhury, Yanfeng Li, and Jayanta Roy Chowdhury


21 Hepatic Lipid Droplets in Liver Function and Disease 245
Douglas G. Mashek, Wenqi Cui, Linshan Shang, and Charles P. Najt


22 Lipoprotein Metabolism and Cholesterol Balance 255
Mariana Acuna?Aravena and David E. Cohen


Section C: Transporters, Bile Acids, and Cholestasis 269


23 Bile Acid Metabolism in Health and Disease: An Update 271
Tiangang Li and John Y.L. Chiang


24 TGR5 (GPBAR1) in the Liver 286
Verena Keitel, Christoph G.W. Gertzen, Lina Spomer, Holger Gohlke, and Dieter Haussinger


25 Bile Acids as Signaling Molecules 299
Thierry Claudel and Michael Trauner


26 Hepatic Adenosine Triphosphate?Binding Cassette Transport Proteins and Their Role in Physiology 313
Peter L.M. Jansen


27 Basolateral Plasma Membrane Organic Anion Transporters 327
M. Sawkat Anwer and Allan W. Wolkoff


28 Hepatic Nuclear Receptors 337
Raymond E. Soccio


29 Molecular Cholestasis 351
Paul Gissen and Richard J. Thompson


30 Pathophysiologic Basis for Alternative Therapies for Cholestasis 364
Claudia D. Fuchs, Emina Halilbasic, and Michael Trauner


31 Adaptive Regulation of Hepatocyte Transporters in Cholestasis 378
James L. Boyer


Section D: Non?Hepatocyte Cells 391


32 Cholangiocyte Biology and Pathobiology 393
Massimiliano Cadamuro, Romina Fiorotto, and Mario Strazzabosco


33 Polycystic Liver Diseases: Genetics, Mechanisms, and Therapies 408
Tatyana Masyuk, Anatoliy Masyuk, and Nicholas LaRusso


34 The Liver Sinusoidal Endothelial Cell: Basic Biology and Pathobiology 422
Karen K. Sorensen and Bard Smedsrod


35 Fenestrations in the Liver Sinusoidal Endothelial Cell 435
Victoria C. Cogger, Nicholas J. Hunt, and David G. Le Couteur


36 Stellate Cells and Fibrosis 444
Youngmin A. Lee and Scott L. Friedman


Part Three: Functions of The Liver 455


Section A: Metabolic Functions 457


37 Non?alcoholic Fatty Liver Disease and Insulin Resistance 459
Max C. Petersen, Varman T. Samuel, Kitt Falk Petersen, and Gerald I. Shulman


38 AMPK: Central Regulator of Glucose and Lipid Metabolism and Target of Type 2 Diabetes Therapeutics 472
Daniel Garcia, Maria M. Mihaylova, and Reuben J. Shaw


39 Insulin?Mediated PI3K and AKT Signaling 485
Hyokjoon Kwon and Jeffrey E. Pessin


40 Ca2+ Signaling in the Liver 496
Mateus T. Guerra, M. Fatima Leite, and Michael H. Nathanson


41 Clinical Genomics of NAFLD 509
Frank Lammert


Section B: Liver Growth and Regeneration 521


42 Stem Cell?Fueled Maturational Lineages in Hepatic and Pancreatic Organogenesis 523
Wencheng Zhang, Amanda Allen, Eliane Wauthier, Xianwen Yi, Homayoun Hani, Praveen Sethupathy, David Gerber, Vincenzo Cardinale, Guido Carpino, Juan Dominguez?Bendala, Giacomo Lanzoni, Domenico Alvaro, Eugenio Gaudio, and Lola Reid


43 Developmental Morphogens and Adult Liver Repair 539
Mariana Verdelho Machado and Anna Mae Diehl


44 Liver Repopulation by Cell Transplantation and the Role of Stem Cells in Liver Biology 550
David A. Shafritz and Markus Grompe


45 Liver Regeneration 566
George K. Michalopoulos


46 ?Catenin Signaling 585
Satdarshan P.S. Monga


47 Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer 603
Evan R. Delgado, Elizabeth C. Stahl, Nairita Roy, Patrick D. Wilkinson, and Andrew W. Duncan


Part Four: Pathobiology of Liver Disease 615


48 Hepatic Encephalopathy 617
Roger F. Butterworth


49 The Kidney in Liver Disease 630
Moshe Levi, Shogo Takahashi, Xiaoxin X. Wang, and Marilyn E. Levi


50 1?Antitrypsin Deficiency 645
David A. Rudnick and David H. Perlmutter


51 Pathophysiology of Portal Hypertension 659
Yasuko Iwakiri and Roberto J. Groszmann


52 Non?alcoholic Fatty Liver Disease: Mechanisms and Treatment 670
Yaron Rotman and Devika Kapuria


53 Alcoholic Liver Disease 682
Bin Gao, Xiaogang Xiang, Lorenzo Leggio, and George F. Koob


54 Drug?Induced Liver Injury 701
Lily Dara and Neil Kaplowitz


55 Oxidative Stress and Inflammation in the Liver 714
John J. Lemasters and Hartmut Jaeschke


56 The Role of Bile Acid?Mediated Inflammation in Cholestatic Liver Injury 728
Shi?Ying Cai, Man Li, and James L. Boyer


57 Toll?like Receptors in Liver Disease 737
So Yeon Kim and Ekihiro Seki


Part Five: Liver Cancer 747


58 Experimental Models of Liver Cancer: Genomic Assessment of Experimental Models 749
Sun Young Yim, Jae?Jun Shim, Bo Hwa Sohn, and Ju?Seog Lee


59 Epidemiology of Hepatocellular Carcinoma 758
Hashem B. El?Serag


60 Mutations and Genomic Alterations in Liver Cancer 773
Jessica Zucman?Rossi and Jean?Charles Nault


61 Treatment of Liver Cancer 782
Tim F. Greten


Part Six: Hepatitis 793


62 Molecular Biology of Hepatitis Viruses 795
Christoph Seeger, William S. Mason, and Michael M.C. Lai


63 Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis 821
Carlo Ferrari, Valeria Barili, Stefania Varchetta, and Mario U. Mondelli


64 Clinical Implications of the Molecular Biology of Hepatitis B Virus 851
Timothy M. Block, Ju?Tao Guo, and W. Thomas London


65 Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection 868
Marc G. Ghany, Christopher M. Walker, and Patrizia Farci


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
Gabrielle Vieyres and Thomas Pietschmann


67 Nucleoside Antiviral Agents for HCV: What's Left to Do? 906
Franck Amblard, Seema Mengshetti, Junxing Shi, Sijia Tao, Leda Bassit, and Raymond F. Schinazi


68 Hepatitis E Virus: An Emerging Zoonotic Virus Causing Acute and Chronic Liver Disease 915
Xiang?Jin Meng


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
Michael S. Kriss, James R. Burton, Jr., and Hugo R. Rosen


70 Time for the Elimination of Hepatitis C Virus as a Global Health Threat 935
John W. Ward, Alan R. Hinman, and Harvey J. Alter


Part Seven: Horizons 953


71 Genome Editing by Targeted Nucleases and the CRISPR/Cas Revolution 955
Shawn M. Burgess


72 Imaging Cellular Proteins and Structures: Smaller, Brighter, and Faster 965
Aubrey V. Weigel and Erik Lee Snapp


73 Liver?Directed Gene Therapy 979
Patrik Asp, Chandan Guha, Namita Roy Chowdhury, and Jayanta Roy Chowdhury


74 Telomeres and Telomerase in Liver Generation and Cirrhosis 992
Sonja C. Schatzlein and K. Lenhard Rudolph


75 Toxins and Biliary Atresia 1000
Michael Pack and Rebecca G. Wells


76 The Dual Role of ABC Transporters in Drug Metabolism and Resistance to Chemotherapy 1007
Jean?Pierre Gillet, Marielle Boonen, Michel Jadot, and Michael M. Gottesman


77 Stem Cell?Derived Liver Cells: From Model System to Therapy 1015
Helmuth Gehart and Hans Clevers


78 Extracellular Vesicles and Exosomes: Biology and Pathobiology 1022
Gyongyi Szabo and Fatemeh Momen?Heravi


79 Integrated Technologies for Liver Tissue Engineering 1028
Tiffany N. Vo, Amanda X. Chen, Quinton B. Smith, Arnav Chhabra and Sangeeta N. Bhatia


80 Pluripotent Stem Cells and Reprogramming: Promise for Therapy 1036
James A. Heslop and Stephen A. Duncan


81 Chromatin Regulation and Transcription Factor Cooperation in Liver Cells 1043
Ido Goldstein


82 Drug Interactions in the Liver 1050
Guruprasad P. Aithal and Gerd A. Kullak?Ublick


83 Metabolic Regulation of Hepatic Growth 1058
Wolfram Goessling


84 The Gut Microbiome and Liver Disease 1062
Lexing Yu, Jasmohan S. Bajaj, and Robert F. Schwabe


85 Lineage Tracing: Efficient Tools to Determine the Fate of Hepatic Cells in Health and Disease 1069
Frederic Lemaigre


86 The Hepatocyte as a Household for Plasmodium Parasites 1075
Vanessa Zuzarte?Luis and Maria M. Mota


Index 1081

ALLAN W. WOLKOFF, MD, Albert Einstein College of Medicine, New York, USA.