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

• List of Contributors xPreface xxAcknowledgments xxiPart One: Introduction 11 Organizational Principles of the Liver 3Peter Nagy, Snorri S. Thorgeirsson, and Joe W. Grisham2 Embryonic Development of the Liver 14Kenneth S. Zaret, Roque Bort, and Stephen A. DuncanPart Two: The Cells 23Section A: Cell Biology of the Liver 253 Cytoskeletal Motors: Structure and Function in Hepatocytes 27Mukesh Kumar, Arnab Gupta, and Roop Mallik4 Hepatocyte Surface Polarity 36Anne Müsch and Irwin M. Arias5 Primary Cilia 50Carolyn M. Ott6 Endocytosis in Liver Function and Pathology 62Micah B. Schott, Barbara Schroeder, and Mark A. McNiven7 The Hepatocellular Secretory Pathway 75Catherine L. Jackson and Mark A. McNiven8 Mitochondrial Function, Dynamics, and Quality Control 86Marc Liesa, Ilan Benador, Nathanael Miller, and Orian S. Shirihai9 Nuclear Pore Complex 94Michelle A. Veronin and Joseph S. Glavy10 Protein Maturation and Processing at the Endoplasmic Reticulum 108Ramanujan S. Hegde11 Protein Degradation and the Lysosomal System 122Susmita Kaushik and Ana Maria Cuervo12 Peroxisome Assembly, Degradation, and Disease 137Rong Hua and Peter K. Kim13 Organelle–Organelle Contacts: Origins and Functions 151Uri Manor14 Gap and Tight Junctions in Liver: Structure, Function, and Pathology 160John W. Murray and David C. Spray15 Ribosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver 174Katherine I. Farley]Barnes and Susan J. Baserga16 miRNAs and Hepatocellular Carcinoma 183Yusuke Yamamoto, Isaku Kohama, and Takahiro Ochiya17 Hepatocyte Apoptosis: Mechanisms and Relevance in Liver Diseases 195Harmeet Malhi and Gregory J. GoresSection B: The Hepatocyte 20718 Copper Metabolism and the Liver 209Cynthia Abou Zeid, Ling Yi, and Stephen G. Kaler19 The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis 215Tracey A. Rouault, Victor R. Gordeuk, and Gregory J. Anderson20 Disorders of Bilirubin Metabolism 229Namita Roy Chowdhury, Yanfeng Li, and Jayanta Roy Chowdhury21 Hepatic Lipid Droplets in Liver Function and Disease 245Douglas G. Mashek, Wenqi Cui, Linshan Shang, and Charles P. Najt22 Lipoprotein Metabolism and Cholesterol Balance 255Mariana Acuña]Aravena and David E. CohenSection C: Transporters, Bile Acids, and Cholestasis 26923 Bile Acid Metabolism in Health and Disease: An Update 271Tiangang Li and John Y.L. Chiang24 TGR5 (GPBAR1) in the Liver 286Verena Keitel, Christoph G.W. Gertzen, Lina Spomer, Holger Gohlke, and Dieter Häussinger25 Bile Acids as Signaling Molecules 299Thierry Claudel and Michael Trauner26 Hepatic Adenosine Triphosphate]Binding Cassette Transport Proteins and Their Role in Physiology 313Peter L.M. Jansen27 Basolateral Plasma Membrane Organic Anion Transporters 327M. Sawkat Anwer and Allan W. Wolkoff28 Hepatic Nuclear Receptors 337Raymond E. Soccio29 Molecular Cholestasis 351Paul Gissen and Richard J. Thompson30 Pathophysiologic Basis for Alternative Therapies for Cholestasis 364Claudia D. Fuchs, Emina Halilbasic, and Michael Trauner31 Adaptive Regulation of Hepatocyte Transporters in Cholestasis 378James L. BoyerSection D: Non]Hepatocyte Cells 39132 Cholangiocyte Biology and Pathobiology 393Massimiliano Cadamuro, Romina Fiorotto, and Mario Strazzabosco33 Polycystic Liver Diseases: Genetics, Mechanisms, and Therapies 408Tatyana Masyuk, Anatoliy Masyuk, and Nicholas LaRusso34 The Liver Sinusoidal Endothelial Cell: Basic Biology and Pathobiology 422Karen K. Sørensen and Bård Smedsrød35 Fenestrations in the Liver Sinusoidal Endothelial Cell 435Victoria C. Cogger, Nicholas J. Hunt, and David G. Le Couteur36 Stellate Cells and Fibrosis 444Youngmin A. Lee and Scott L. FriedmanPart Three: Functions of The Liver 455Section A: Metabolic Functions 45737 Non]alcoholic Fatty Liver Disease and Insulin Resistance 459Max C. Petersen, Varman T. Samuel, Kitt Falk Petersen, and Gerald I. Shulman38 AMPK: Central Regulator of Glucose and Lipid Metabolism and Target of Type 2 Diabetes Therapeutics 472Daniel Garcia, Maria M. Mihaylova, and Reuben J. Shaw39 Insulin]Mediated PI3K and AKT Signaling 485Hyokjoon Kwon and Jeffrey E. Pessin40 Ca2+ Signaling in the Liver 496Mateus T. Guerra, M. Fatima Leite, and Michael H. Nathanson41 Clinical Genomics of NAFLD 509Frank LammertSection B: Liver Growth and Regeneration 52142 Stem Cell]Fueled Maturational Lineages in Hepatic and Pancreatic Organogenesis 523Wencheng 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 Reid43 Developmental Morphogens and Adult Liver Repair 539Mariana Verdelho Machado and Anna Mae Diehl44 Liver Repopulation by Cell Transplantation and the Role of Stem Cells in Liver Biology 550David A. Shafritz and Markus Grompe45 Liver Regeneration 566George K. Michalopoulos46 β]Catenin Signaling 585Satdarshan P.S. Monga47 Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer 603Evan R. Delgado, Elizabeth C. Stahl, Nairita Roy, Patrick D. Wilkinson, and Andrew W. DuncanPart Four: Pathobiology of Liver Disease 61548 Hepatic Encephalopathy 617Roger F. Butterworth49 The Kidney in Liver Disease 630Moshe Levi, Shogo Takahashi, Xiaoxin X. Wang, and Marilyn E. Levi50 α1]Antitrypsin Deficiency 645David A. Rudnick and David H. Perlmutter51 Pathophysiology of Portal Hypertension 659Yasuko Iwakiri and Roberto J. Groszmann52 Non]alcoholic Fatty Liver Disease: Mechanisms and Treatment 670Yaron Rotman and Devika Kapuria53 Alcoholic Liver Disease 682Bin Gao, Xiaogang Xiang, Lorenzo Leggio, and George F. Koob54 Drug]Induced Liver Injury 701Lily Dara and Neil Kaplowitz55 Oxidative Stress and Inflammation in the Liver 714John J. Lemasters and Hartmut Jaeschke56 The Role of Bile Acid]Mediated Inflammation in Cholestatic Liver Injury 728Shi]Ying Cai, Man Li, and James L. Boyer57 Toll]like Receptors in Liver Disease 737So Yeon Kim and Ekihiro SekiPart Five: Liver Cancer 74758 Experimental Models of Liver Cancer: Genomic Assessment of Experimental Models 749Sun Young Yim, Jae]Jun Shim, Bo Hwa Sohn, and Ju]Seog Lee59 Epidemiology of Hepatocellular Carcinoma 758Hashem B. El]Serag60 Mutations and Genomic Alterations in Liver Cancer 773Jessica Zucman]Rossi and Jean]Charles Nault61 Treatment of Liver Cancer 782Tim F. GretenPart Six: Hepatitis 79362 Molecular Biology of Hepatitis Viruses 795Christoph Seeger, William S. Mason, and Michael M.C. Lai63 Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis 821Carlo Ferrari, Valeria Barili, Stefania Varchetta, and Mario U. Mondelli64 Clinical Implications of the Molecular Biology of Hepatitis B Virus 851Timothy M. Block, Ju]Tao Guo, and W. Thomas London65 Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection 868Marc G. Ghany, Christopher M. Walker, and Patrizia Farci66 Tracking Hepatitis C Virus Interactions with the Hepatic Lipid Metabolism : A Hitchhiker’s Guide to Solve Remaining Translational Research Challenges in Hepatitis C 889Gabrielle Vieyres and Thomas Pietschmann67 Nucleoside Antiviral Agents for HCV: What’s Left to Do? 906Franck Amblard, Seema Mengshetti, Junxing Shi, Sijia Tao, Leda Bassit, and Raymond F. Schinazi68 Hepatitis E Virus: An Emerging Zoonotic Virus Causing Acute and Chronic Liver Disease 915Xiang]Jin Meng69 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 926Michael S. Kriss, James R. Burton, Jr., and Hugo R. Rosen70 Time for the Elimination of Hepatitis C Virus as a Global Health Threat 935John W. Ward, Alan R. Hinman, and Harvey J. AlterPart Seven: Horizons 95371 Genome Editing by Targeted Nucleases and the CRISPR/Cas Revolution 955Shawn M. Burgess72 Imaging Cellular Proteins and Structures: Smaller, Brighter, and Faster 965Aubrey V. Weigel and Erik Lee Snapp73 Liver]Directed Gene Therapy 979Patrik Asp, Chandan Guha, Namita Roy Chowdhury, and Jayanta Roy Chowdhury74 Telomeres and Telomerase in Liver Generation and Cirrhosis 992Sonja C. Schätzlein and K. Lenhard Rudolph75 Toxins and Biliary Atresia 1000Michael Pack and Rebecca G. Wells76 The Dual Role of ABC Transporters in Drug Metabolism and Resistance to Chemotherapy 1007Jean]Pierre Gillet, Marielle Boonen, Michel Jadot, and Michael M. Gottesman77 Stem Cell]Derived Liver Cells: From Model System to Therapy 1015Helmuth Gehart and Hans Clevers78 Extracellular Vesicles and Exosomes: Biology and Pathobiology 1022Gyongyi Szabo and Fatemeh Momen]Heravi79 Integrated Technologies for Liver Tissue Engineering 1028Tiffany N. Vo, Amanda X. Chen, Quinton B. Smith, Arnav Chhabra and Sangeeta N. Bhatia80 Pluripotent Stem Cells and Reprogramming: Promise for Therapy 1036James A. Heslop and Stephen A. Duncan81 Chromatin Regulation and Transcription Factor Cooperation in Liver Cells 1043Ido Goldstein82 Drug Interactions in the Liver 1050Guruprasad P. Aithal and Gerd A. Kullak]Ublick83 Metabolic Regulation of Hepatic Growth 1058Wolfram Goessling84 The Gut Microbiome and Liver Disease 1062Lexing Yu, Jasmohan S. Bajaj, and Robert F. Schwabe85 Lineage Tracing: Efficient Tools to Determine the Fate of Hepatic Cells in Health and Disease 1069Frédéric Lemaigre86 The Hepatocyte as a Household for Plasmodium Parasites 1075Vanessa Zuzarte]Luis and Maria M. MotaIndex 1081

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

• List of Contributors xPreface xxAcknowledgments xxiPart One: Introduction 11 Organizational Principles of the Liver 3Peter Nagy, Snorri S. Thorgeirsson, and Joe W. Grisham2 Embryonic Development of the Liver 14Kenneth S. Zaret, Roque Bort, and Stephen A. DuncanPart Two: The Cells 23Section A: Cell Biology of the Liver 253 Cytoskeletal Motors: Structure and Function in Hepatocytes 27Mukesh Kumar, Arnab Gupta, and Roop Mallik4 Hepatocyte Surface Polarity 36Anne Müsch and Irwin M. Arias5 Primary Cilia 50Carolyn M. Ott6 Endocytosis in Liver Function and Pathology 62Micah B. Schott, Barbara Schroeder, and Mark A. McNiven7 The Hepatocellular Secretory Pathway 75Catherine L. Jackson and Mark A. McNiven8 Mitochondrial Function, Dynamics, and Quality Control 86Marc Liesa, Ilan Benador, Nathanael Miller, and Orian S. Shirihai9 Nuclear Pore Complex 94Michelle A. Veronin and Joseph S. Glavy10 Protein Maturation and Processing at the Endoplasmic Reticulum 108Ramanujan S. Hegde11 Protein Degradation and the Lysosomal System 122Susmita Kaushik and Ana Maria Cuervo12 Peroxisome Assembly, Degradation, and Disease 137Rong Hua and Peter K. Kim13 Organelle–Organelle Contacts: Origins and Functions 151Uri Manor14 Gap and Tight Junctions in Liver: Structure, Function, and Pathology 160John W. Murray and David C. Spray15 Ribosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver 174Katherine I. Farley]Barnes and Susan J. Baserga16 miRNAs and Hepatocellular Carcinoma 183Yusuke Yamamoto, Isaku Kohama, and Takahiro Ochiya17 Hepatocyte Apoptosis: Mechanisms and Relevance in Liver Diseases 195Harmeet Malhi and Gregory J. GoresSection B: The Hepatocyte 20718 Copper Metabolism and the Liver 209Cynthia Abou Zeid, Ling Yi, and Stephen G. Kaler19 The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis 215Tracey A. Rouault, Victor R. Gordeuk, and Gregory J. Anderson20 Disorders of Bilirubin Metabolism 229Namita Roy Chowdhury, Yanfeng Li, and Jayanta Roy Chowdhury21 Hepatic Lipid Droplets in Liver Function and Disease 245Douglas G. Mashek, Wenqi Cui, Linshan Shang, and Charles P. Najt22 Lipoprotein Metabolism and Cholesterol Balance 255Mariana Acuña]Aravena and David E. CohenSection C: Transporters, Bile Acids, and Cholestasis 26923 Bile Acid Metabolism in Health and Disease: An Update 271Tiangang Li and John Y.L. Chiang24 TGR5 (GPBAR1) in the Liver 286Verena Keitel, Christoph G.W. Gertzen, Lina Spomer, Holger Gohlke, and Dieter Häussinger25 Bile Acids as Signaling Molecules 299Thierry Claudel and Michael Trauner26 Hepatic Adenosine Triphosphate]Binding Cassette Transport Proteins and Their Role in Physiology 313Peter L.M. Jansen27 Basolateral Plasma Membrane Organic Anion Transporters 327M. Sawkat Anwer and Allan W. Wolkoff28 Hepatic Nuclear Receptors 337Raymond E. Soccio29 Molecular Cholestasis 351Paul Gissen and Richard J. Thompson30 Pathophysiologic Basis for Alternative Therapies for Cholestasis 364Claudia D. Fuchs, Emina Halilbasic, and Michael Trauner31 Adaptive Regulation of Hepatocyte Transporters in Cholestasis 378James L. BoyerSection D: Non]Hepatocyte Cells 39132 Cholangiocyte Biology and Pathobiology 393Massimiliano Cadamuro, Romina Fiorotto, and Mario Strazzabosco33 Polycystic Liver Diseases: Genetics, Mechanisms, and Therapies 408Tatyana Masyuk, Anatoliy Masyuk, and Nicholas LaRusso34 The Liver Sinusoidal Endothelial Cell: Basic Biology and Pathobiology 422Karen K. Sørensen and Bård Smedsrød35 Fenestrations in the Liver Sinusoidal Endothelial Cell 435Victoria C. Cogger, Nicholas J. Hunt, and David G. Le Couteur36 Stellate Cells and Fibrosis 444Youngmin A. Lee and Scott L. FriedmanPart Three: Functions of The Liver 455Section A: Metabolic Functions 45737 Non]alcoholic Fatty Liver Disease and Insulin Resistance 459Max C. Petersen, Varman T. Samuel, Kitt Falk Petersen, and Gerald I. Shulman38 AMPK: Central Regulator of Glucose and Lipid Metabolism and Target of Type 2 Diabetes Therapeutics 472Daniel Garcia, Maria M. Mihaylova, and Reuben J. Shaw39 Insulin]Mediated PI3K and AKT Signaling 485Hyokjoon Kwon and Jeffrey E. Pessin40 Ca2+ Signaling in the Liver 496Mateus T. Guerra, M. Fatima Leite, and Michael H. Nathanson41 Clinical Genomics of NAFLD 509Frank LammertSection B: Liver Growth and Regeneration 52142 Stem Cell]Fueled Maturational Lineages in Hepatic and Pancreatic Organogenesis 523Wencheng 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 Reid43 Developmental Morphogens and Adult Liver Repair 539Mariana Verdelho Machado and Anna Mae Diehl44 Liver Repopulation by Cell Transplantation and the Role of Stem Cells in Liver Biology 550David A. Shafritz and Markus Grompe45 Liver Regeneration 566George K. Michalopoulos46 β]Catenin Signaling 585Satdarshan P.S. Monga47 Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer 603Evan R. Delgado, Elizabeth C. Stahl, Nairita Roy, Patrick D. Wilkinson, and Andrew W. DuncanPart Four: Pathobiology of Liver Disease 61548 Hepatic Encephalopathy 617Roger F. Butterworth49 The Kidney in Liver Disease 630Moshe Levi, Shogo Takahashi, Xiaoxin X. Wang, and Marilyn E. Levi50 α1]Antitrypsin Deficiency 645David A. Rudnick and David H. Perlmutter51 Pathophysiology of Portal Hypertension 659Yasuko Iwakiri and Roberto J. Groszmann52 Non]alcoholic Fatty Liver Disease: Mechanisms and Treatment 670Yaron Rotman and Devika Kapuria53 Alcoholic Liver Disease 682Bin Gao, Xiaogang Xiang, Lorenzo Leggio, and George F. Koob54 Drug]Induced Liver Injury 701Lily Dara and Neil Kaplowitz55 Oxidative Stress and Inflammation in the Liver 714John J. Lemasters and Hartmut Jaeschke56 The Role of Bile Acid]Mediated Inflammation in Cholestatic Liver Injury 728Shi]Ying Cai, Man Li, and James L. Boyer57 Toll]like Receptors in Liver Disease 737So Yeon Kim and Ekihiro SekiPart Five: Liver Cancer 74758 Experimental Models of Liver Cancer: Genomic Assessment of Experimental Models 749Sun Young Yim, Jae]Jun Shim, Bo Hwa Sohn, and Ju]Seog Lee59 Epidemiology of Hepatocellular Carcinoma 758Hashem B. El]Serag60 Mutations and Genomic Alterations in Liver Cancer 773Jessica Zucman]Rossi and Jean]Charles Nault61 Treatment of Liver Cancer 782Tim F. GretenPart Six: Hepatitis 79362 Molecular Biology of Hepatitis Viruses 795Christoph Seeger, William S. Mason, and Michael M.C. Lai63 Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis 821Carlo Ferrari, Valeria Barili, Stefania Varchetta, and Mario U. Mondelli64 Clinical Implications of the Molecular Biology of Hepatitis B Virus 851Timothy M. Block, Ju]Tao Guo, and W. Thomas London65 Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection 868Marc G. Ghany, Christopher M. Walker, and Patrizia Farci66 Tracking Hepatitis C Virus Interactions with the Hepatic Lipid Metabolism : A Hitchhiker’s Guide to Solve Remaining Translational Research Challenges in Hepatitis C 889Gabrielle Vieyres and Thomas Pietschmann67 Nucleoside Antiviral Agents for HCV: What’s Left to Do? 906Franck Amblard, Seema Mengshetti, Junxing Shi, Sijia Tao, Leda Bassit, and Raymond F. Schinazi68 Hepatitis E Virus: An Emerging Zoonotic Virus Causing Acute and Chronic Liver Disease 915Xiang]Jin Meng69 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 926Michael S. Kriss, James R. Burton, Jr., and Hugo R. Rosen70 Time for the Elimination of Hepatitis C Virus as a Global Health Threat 935John W. Ward, Alan R. Hinman, and Harvey J. AlterPart Seven: Horizons 95371 Genome Editing by Targeted Nucleases and the CRISPR/Cas Revolution 955Shawn M. Burgess72 Imaging Cellular Proteins and Structures: Smaller, Brighter, and Faster 965Aubrey V. Weigel and Erik Lee Snapp73 Liver]Directed Gene Therapy 979Patrik Asp, Chandan Guha, Namita Roy Chowdhury, and Jayanta Roy Chowdhury74 Telomeres and Telomerase in Liver Generation and Cirrhosis 992Sonja C. Schätzlein and K. Lenhard Rudolph75 Toxins and Biliary Atresia 1000Michael Pack and Rebecca G. Wells76 The Dual Role of ABC Transporters in Drug Metabolism and Resistance to Chemotherapy 1007Jean]Pierre Gillet, Marielle Boonen, Michel Jadot, and Michael M. Gottesman77 Stem Cell]Derived Liver Cells: From Model System to Therapy 1015Helmuth Gehart and Hans Clevers78 Extracellular Vesicles and Exosomes: Biology and Pathobiology 1022Gyongyi Szabo and Fatemeh Momen]Heravi79 Integrated Technologies for Liver Tissue Engineering 1028Tiffany N. Vo, Amanda X. Chen, Quinton B. Smith, Arnav Chhabra and Sangeeta N. Bhatia80 Pluripotent Stem Cells and Reprogramming: Promise for Therapy 1036James A. Heslop and Stephen A. Duncan81 Chromatin Regulation and Transcription Factor Cooperation in Liver Cells 1043Ido Goldstein82 Drug Interactions in the Liver 1050Guruprasad P. Aithal and Gerd A. Kullak]Ublick83 Metabolic Regulation of Hepatic Growth 1058Wolfram Goessling84 The Gut Microbiome and Liver Disease 1062Lexing Yu, Jasmohan S. Bajaj, and Robert F. Schwabe85 Lineage Tracing: Efficient Tools to Determine the Fate of Hepatic Cells in Health and Disease 1069Frédéric Lemaigre86 The Hepatocyte as a Household for Plasmodium Parasites 1075Vanessa Zuzarte]Luis and Maria M. MotaIndex 1081

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

• List of Contributors xPreface xxAcknowledgments xxiPart One: Introduction 11 Organizational Principles of the Liver 3Peter Nagy, Snorri S. Thorgeirsson, and Joe W. Grisham2 Embryonic Development of the Liver 14Kenneth S. Zaret, Roque Bort, and Stephen A. DuncanPart Two: The Cells 23Section A: Cell Biology of the Liver 253 Cytoskeletal Motors: Structure and Function in Hepatocytes 27Mukesh Kumar, Arnab Gupta, and Roop Mallik4 Hepatocyte Surface Polarity 36Anne Müsch and Irwin M. Arias5 Primary Cilia 50Carolyn M. Ott6 Endocytosis in Liver Function and Pathology 62Micah B. Schott, Barbara Schroeder, and Mark A. McNiven7 The Hepatocellular Secretory Pathway 75Catherine L. Jackson and Mark A. McNiven8 Mitochondrial Function, Dynamics, and Quality Control 86Marc Liesa, Ilan Benador, Nathanael Miller, and Orian S. Shirihai9 Nuclear Pore Complex 94Michelle A. Veronin and Joseph S. Glavy10 Protein Maturation and Processing at the Endoplasmic Reticulum 108Ramanujan S. Hegde11 Protein Degradation and the Lysosomal System 122Susmita Kaushik and Ana Maria Cuervo12 Peroxisome Assembly, Degradation, and Disease 137Rong Hua and Peter K. Kim13 Organelle–Organelle Contacts: Origins and Functions 151Uri Manor14 Gap and Tight Junctions in Liver: Structure, Function, and Pathology 160John W. Murray and David C. Spray15 Ribosome Biogenesis and its Role in Cell Growth and Proliferation in the Liver 174Katherine I. Farley]Barnes and Susan J. Baserga16 miRNAs and Hepatocellular Carcinoma 183Yusuke Yamamoto, Isaku Kohama, and Takahiro Ochiya17 Hepatocyte Apoptosis: Mechanisms and Relevance in Liver Diseases 195Harmeet Malhi and Gregory J. GoresSection B: The Hepatocyte 20718 Copper Metabolism and the Liver 209Cynthia Abou Zeid, Ling Yi, and Stephen G. Kaler19 The Central Role of the Liver in Iron Storage and Regulation of Systemic Iron Homeostasis 215Tracey A. Rouault, Victor R. Gordeuk, and Gregory J. Anderson20 Disorders of Bilirubin Metabolism 229Namita Roy Chowdhury, Yanfeng Li, and Jayanta Roy Chowdhury21 Hepatic Lipid Droplets in Liver Function and Disease 245Douglas G. Mashek, Wenqi Cui, Linshan Shang, and Charles P. Najt22 Lipoprotein Metabolism and Cholesterol Balance 255Mariana Acuña]Aravena and David E. CohenSection C: Transporters, Bile Acids, and Cholestasis 26923 Bile Acid Metabolism in Health and Disease: An Update 271Tiangang Li and John Y.L. Chiang24 TGR5 (GPBAR1) in the Liver 286Verena Keitel, Christoph G.W. Gertzen, Lina Spomer, Holger Gohlke, and Dieter Häussinger25 Bile Acids as Signaling Molecules 299Thierry Claudel and Michael Trauner26 Hepatic Adenosine Triphosphate]Binding Cassette Transport Proteins and Their Role in Physiology 313Peter L.M. Jansen27 Basolateral Plasma Membrane Organic Anion Transporters 327M. Sawkat Anwer and Allan W. Wolkoff28 Hepatic Nuclear Receptors 337Raymond E. Soccio29 Molecular Cholestasis 351Paul Gissen and Richard J. Thompson30 Pathophysiologic Basis for Alternative Therapies for Cholestasis 364Claudia D. Fuchs, Emina Halilbasic, and Michael Trauner31 Adaptive Regulation of Hepatocyte Transporters in Cholestasis 378James L. BoyerSection D: Non]Hepatocyte Cells 39132 Cholangiocyte Biology and Pathobiology 393Massimiliano Cadamuro, Romina Fiorotto, and Mario Strazzabosco33 Polycystic Liver Diseases: Genetics, Mechanisms, and Therapies 408Tatyana Masyuk, Anatoliy Masyuk, and Nicholas LaRusso34 The Liver Sinusoidal Endothelial Cell: Basic Biology and Pathobiology 422Karen K. Sørensen and Bård Smedsrød35 Fenestrations in the Liver Sinusoidal Endothelial Cell 435Victoria C. Cogger, Nicholas J. Hunt, and David G. Le Couteur36 Stellate Cells and Fibrosis 444Youngmin A. Lee and Scott L. FriedmanPart Three: Functions of The Liver 455Section A: Metabolic Functions 45737 Non]alcoholic Fatty Liver Disease and Insulin Resistance 459Max C. Petersen, Varman T. Samuel, Kitt Falk Petersen, and Gerald I. Shulman38 AMPK: Central Regulator of Glucose and Lipid Metabolism and Target of Type 2 Diabetes Therapeutics 472Daniel Garcia, Maria M. Mihaylova, and Reuben J. Shaw39 Insulin]Mediated PI3K and AKT Signaling 485Hyokjoon Kwon and Jeffrey E. Pessin40 Ca2+ Signaling in the Liver 496Mateus T. Guerra, M. Fatima Leite, and Michael H. Nathanson41 Clinical Genomics of NAFLD 509Frank LammertSection B: Liver Growth and Regeneration 52142 Stem Cell]Fueled Maturational Lineages in Hepatic and Pancreatic Organogenesis 523Wencheng 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 Reid43 Developmental Morphogens and Adult Liver Repair 539Mariana Verdelho Machado and Anna Mae Diehl44 Liver Repopulation by Cell Transplantation and the Role of Stem Cells in Liver Biology 550David A. Shafritz and Markus Grompe45 Liver Regeneration 566George K. Michalopoulos46 β]Catenin Signaling 585Satdarshan P.S. Monga47 Polyploidy in Liver Function, Mitochondrial Metabolism, and Cancer 603Evan R. Delgado, Elizabeth C. Stahl, Nairita Roy, Patrick D. Wilkinson, and Andrew W. DuncanPart Four: Pathobiology of Liver Disease 61548 Hepatic Encephalopathy 617Roger F. Butterworth49 The Kidney in Liver Disease 630Moshe Levi, Shogo Takahashi, Xiaoxin X. Wang, and Marilyn E. Levi50 α1]Antitrypsin Deficiency 645David A. Rudnick and David H. Perlmutter51 Pathophysiology of Portal Hypertension 659Yasuko Iwakiri and Roberto J. Groszmann52 Non]alcoholic Fatty Liver Disease: Mechanisms and Treatment 670Yaron Rotman and Devika Kapuria53 Alcoholic Liver Disease 682Bin Gao, Xiaogang Xiang, Lorenzo Leggio, and George F. Koob54 Drug]Induced Liver Injury 701Lily Dara and Neil Kaplowitz55 Oxidative Stress and Inflammation in the Liver 714John J. Lemasters and Hartmut Jaeschke56 The Role of Bile Acid]Mediated Inflammation in Cholestatic Liver Injury 728Shi]Ying Cai, Man Li, and James L. Boyer57 Toll]like Receptors in Liver Disease 737So Yeon Kim and Ekihiro SekiPart Five: Liver Cancer 74758 Experimental Models of Liver Cancer: Genomic Assessment of Experimental Models 749Sun Young Yim, Jae]Jun Shim, Bo Hwa Sohn, and Ju]Seog Lee59 Epidemiology of Hepatocellular Carcinoma 758Hashem B. El]Serag60 Mutations and Genomic Alterations in Liver Cancer 773Jessica Zucman]Rossi and Jean]Charles Nault61 Treatment of Liver Cancer 782Tim F. GretenPart Six: Hepatitis 79362 Molecular Biology of Hepatitis Viruses 795Christoph Seeger, William S. Mason, and Michael M.C. Lai63 Immune Mechanisms of Viral Clearance and Disease Pathogenesis During Viral Hepatitis 821Carlo Ferrari, Valeria Barili, Stefania Varchetta, and Mario U. Mondelli64 Clinical Implications of the Molecular Biology of Hepatitis B Virus 851Timothy M. Block, Ju]Tao Guo, and W. Thomas London65 Viral Escape Mechanisms in Hepatitis C and the Clinical Consequences of Persistent Infection 868Marc G. Ghany, Christopher M. Walker, and Patrizia Farci66 Tracking Hepatitis C Virus Interactions with the Hepatic Lipid Metabolism : A Hitchhiker’s Guide to Solve Remaining Translational Research Challenges in Hepatitis C 889Gabrielle Vieyres and Thomas Pietschmann67 Nucleoside Antiviral Agents for HCV: What’s Left to Do? 906Franck Amblard, Seema Mengshetti, Junxing Shi, Sijia Tao, Leda Bassit, and Raymond F. Schinazi68 Hepatitis E Virus: An Emerging Zoonotic Virus Causing Acute and Chronic Liver Disease 915Xiang]Jin Meng69 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 926Michael S. Kriss, James R. Burton, Jr., and Hugo R. Rosen70 Time for the Elimination of Hepatitis C Virus as a Global Health Threat 935John W. Ward, Alan R. Hinman, and Harvey J. AlterPart Seven: Horizons 95371 Genome Editing by Targeted Nucleases and the CRISPR/Cas Revolution 955Shawn M. Burgess72 Imaging Cellular Proteins and Structures: Smaller, Brighter, and Faster 965Aubrey V. Weigel and Erik Lee Snapp73 Liver]Directed Gene Therapy 979Patrik Asp, Chandan Guha, Namita Roy Chowdhury, and Jayanta Roy Chowdhury74 Telomeres and Telomerase in Liver Generation and Cirrhosis 992Sonja C. Schätzlein and K. Lenhard Rudolph75 Toxins and Biliary Atresia 1000Michael Pack and Rebecca G. Wells76 The Dual Role of ABC Transporters in Drug Metabolism and Resistance to Chemotherapy 1007Jean]Pierre Gillet, Marielle Boonen, Michel Jadot, and Michael M. Gottesman77 Stem Cell]Derived Liver Cells: From Model System to Therapy 1015Helmuth Gehart and Hans Clevers78 Extracellular Vesicles and Exosomes: Biology and Pathobiology 1022Gyongyi Szabo and Fatemeh Momen]Heravi79 Integrated Technologies for Liver Tissue Engineering 1028Tiffany N. Vo, Amanda X. Chen, Quinton B. Smith, Arnav Chhabra and Sangeeta N. Bhatia80 Pluripotent Stem Cells and Reprogramming: Promise for Therapy 1036James A. Heslop and Stephen A. Duncan81 Chromatin Regulation and Transcription Factor Cooperation in Liver Cells 1043Ido Goldstein82 Drug Interactions in the Liver 1050Guruprasad P. Aithal and Gerd A. Kullak]Ublick83 Metabolic Regulation of Hepatic Growth 1058Wolfram Goessling84 The Gut Microbiome and Liver Disease 1062Lexing Yu, Jasmohan S. Bajaj, and Robert F. Schwabe85 Lineage Tracing: Efficient Tools to Determine the Fate of Hepatic Cells in Health and Disease 1069Frédéric Lemaigre86 The Hepatocyte as a Household for Plasmodium Parasites 1075Vanessa Zuzarte]Luis and Maria M. MotaIndex 1081