Bridging the gap between basic scientific advances and the understanding of liver disease — the extensively revised new edition of the premier text in the field. 

The latest edition of The Liver: Biology and Pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease pathology and treatment. Contributions from leading researchers examine the cell biology of the liver, the pathobiology of liver disease, the liver’s growth, regeneration, metabolic functions, and more.

Now in its sixth edition, this classic text has been exhaustively revised to reflect new discoveries in biology and their influence on diagnosing, managing, and preventing liver disease. Seventy new chapters — including substantial original sections on liver cancer and groundbreaking advances that will have significant impact on hepatology — provide comprehensive, fully up-to-date coverage of both the current state and future direction of hepatology. Topics include liver RNA structure and function, gene editing, single-cell and single-molecule genomic analyses, the molecular biology of hepatitis, drug interactions and engineered drug design, and liver disease mechanisms and therapies. Edited by globally-recognized experts in the field, this authoritative volume:

• Relates molecular physiology to understanding disease pathology and treatment
• Links the science and pathology of the liver to practical clinical applications
• Features 16 new “Horizons” chapters that explore new and emerging science and technology
• Includes plentiful full-color illustrations and figures

The Liver: Biology and Pathobiology, Sixth Edition is an indispensable resource for practicing and trainee hepatologists, gastroenterologists, hepatobiliary and liver transplant surgeons, and researchers and scientists in areas including hepatology, cell and molecular biology, virology, and drug metabolism.

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 Müsch 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 Acuña‐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 Häussinger

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. Sørensen and Bård Smedsrød

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 β‐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 α1‐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. Schätzlein 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 Tranx_scription 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
Frédéric Lemaigre

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

Index 1081

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