The Liver: Biology and Pathobiology, Fifth Edition

Cover Page......Page 1
Editors......Page 5
ISBN 978-0470723135......Page 6
Dedication......Page 7
Contents......Page 9
List of Contributors......Page 15
Preface......Page 25
Acknowledgements......Page 26
PART ONE INTRODUCTION......Page 27
PRINCIPLES OF LIVER ORGANIZATION......Page 29
EMBRYOLOGY OF THE LIVER......Page 30
ANATOMY OF THE LIVER......Page 31
LIVER HEMODYNAMICS......Page 32
HEMODYNAMIC MICROSEGMENTATION OF THE LIVER PARENCHYMA......Page 33
THE CELLS OF THE LIVER PARENCHYMA......Page 35
FUNCTIONAL AND STRUCTURAL HETEROGENEITY ALONG HEPATIC PLATES AND SINUSOIDS......Page 36
LIVER PARENCHYMAL REPAIR......Page 37
REFERENCES......Page 38
ACQUISITION OF HEPATIC COMPETENCE WITHIN THE ENDODERM......Page 43
FROM DEFINITIVE TO HEPATIC ENDODERM......Page 44
FROM HEPATIC ENDODERM TO LIVER BUD......Page 45
BEYOND THE LIVER BUD: CHOLANGIOCYTE DIFFERENTIATION......Page 46
EMBRYOLOGIC CONTROL OF LIVER REGENERATION......Page 47
FUTURE AND PERSPECTIVES......Page 48
REFERENCES......Page 49
PART TWO THE CELLS......Page 53
MICROTUBULES AND ACTIN FILAMENTS: HISTORICAL CONTEXT......Page 55
MICROTUBULE COMPOSITION AND POLYMERIZATION DYNAMICS......Page 56
F-ACTIN COMPOSITION AND POLYMERIZATION DYNAMICS......Page 57
MICROTUBULE-BASED MOTOR PROTEINS......Page 58
Kinesins......Page 59
Myosins......Page 60
Myosin 1......Page 61
Myosin 6......Page 62
KINESINS AND CYTOPLASMIC DYNEIN IN EPITHELIAL CELLS......Page 63
REFERENCES......Page 64
INTRODUCTION......Page 71
Myo2......Page 72
Myo7a and Myo9......Page 73
DYNC1......Page 74
KIF3A (Kinesin2)......Page 75
EXAMPLES OF MOTOR MOLECULE FUNCTION IN LIVER CELLS Endocytic traf.cking in the hepatocyte......Page 76
Molecular motors of the cholangiocyte primary cilium......Page 78
REFERENCES......Page 79
P-type ATPase family members and their functions......Page 83
P-type ATPase structure and mechanism......Page 85
ATP SYNTHASE......Page 86
Structure of the ATP synthase complex......Page 87
Rotary catalytic mechanism......Page 88
V-TYPE ATPASES V-type ATPase function......Page 89
V-type ATPase structure and mechanism......Page 91
Regulation of V-type ATPase activity......Page 92
REFERENCES......Page 93
INTRODUCTION......Page 99
HEPATOCYTE ORGANIZATION Structural aspects......Page 100
CELL SYSTEMS FOR STUDYING THE ITINERARIES OF PM PROTEINS Intact tissue......Page 101
WIF-B cells......Page 102
Signals......Page 103
Recognition mechanisms......Page 107
What about the Hepatocyte?......Page 108
ESTABLISHING EPITHELIAL CELL POLARITY Development of hepatic polarity......Page 109
The junction proteins have key roles in establishing polarity......Page 110
Signaling molecules, effectors, and modulators......Page 117
MDCK cells can adopt a hepatic-like phenotype......Page 118
Apical/basal polarity requires vesicle traf.cking......Page 119
REFERENCES......Page 120
VESICLE FORMATION IN THE ENDOCYTIC PATHWAY......Page 133
Coated pit ultrastructure and coat proteins......Page 134
Coated pit/vesicle formation and associated factors......Page 135
Regulators of clathrin-mediated endocytosis and vesicle uncoating......Page 136
UBIQUITINYLATION AS A RECEPTOR DEGRADATION SIGNAL......Page 137
CAVEOLAE IN THE HEPATOCYTE......Page 138
Biogenesis and endocytosis of caveolae......Page 139
HEPATOCYTE-SPECIFIC ENDOCYTIC MEMBRANE TRAFFIC Iron homeostasis by speci.c traf.cking of the transferrin receptors 1 and 2......Page 140
Hepatitis B (HBV)......Page 141
REFERENCES......Page 142
VESICLE FORMATION IN THE SECRETORY PATHWAY......Page 151
COPI-COATED VESICLES COPI-coated vesicles and protein traf.cking through the ER and Golgi apparatus......Page 152
COPII-COATED VESICLES COPII-coated vesicles and ER-to-Golgi protein traf.cking......Page 153
TGN-DERIVED VESICLES Protein sorting and traf.cking events at the TGN......Page 154
Clathrin-coated TGN-derived vesicles......Page 155
Scission of TGN-derived vesicles......Page 156
FUTURE DIRECTIONS......Page 157
REFERENCES......Page 158
STRUCTURE......Page 163
ENERGY PRODUCTION: ROS UNCOUPLING......Page 164
ORIGIN AND INHERITANCE OF MITOCHONDRIA......Page 165
Nucleus......Page 166
DISTRIBUTION......Page 167
Cancer......Page 169
REFERENCES......Page 170
THE STRUCTURE OF THE NUCLEAR PORE COMPLEX (NPC)......Page 173
Subclasses of nucleoporins: scaffold Nups, FG Nups, and mobile Nup......Page 174
NUCLEAR TRANSPORT CYCLE......Page 176
NUCLEAR ENVELOPE BREAKDOWN (NEBD)......Page 177
REFERENCES......Page 178
THE SEGREGATION OF SECRETORY AND MEMBRANE PROTEINS TO THE ER......Page 183
Proteins are targeted to the ER membrane early in their synthesis......Page 184
Translocons mediate protein translocation into the ER......Page 185
Chaperones assist in protein maturation......Page 187
Multiple chaperone systems operate in the ER lumen......Page 188
Numerous Coand posttranslational modi.cations accompany protein maturation......Page 189
Many proteins are assembled into multimeric complexes......Page 190
QUALITY CONTROL AND THE CULLING OF IMMATURE PROTEINS......Page 191
A retrotranslocation pathway for misfolded protein degradation in the cytosol......Page 192
The multi-faceted mammalian UPR......Page 193
CONCLUSION......Page 194
REFERENCES......Page 195
INTRODUCTION TO INTRACELLULAR PROTEOLYSIS......Page 199
THE UBIQUITIN-PROTEASOME SYSTEM......Page 200
The enzymatic machinery......Page 202
Proteins at the lysosomal membrane......Page 203
Lysosomal pathways for proteolysis......Page 204
PROTEIN DEGRADATION IN LIVER DISEASE AND AGING......Page 209
REFERENCES......Page 211
INTRODUCTION......Page 217
Alpha oxidation......Page 218
Bile acid synthesis......Page 219
PEROXISOME BIOGENESIS......Page 220
Targeting of peroxisomal membrane protein......Page 221
Matrix protein targeting......Page 222
PEROXISOME DEGRADATION: PEXOPHAGY......Page 223
REFERENCES......Page 224
STRUCTURE OF JUNCTIONS IN THE LIVER......Page 227
MOLECULAR COMPONENTS AND GENES OF GAP AND TIGHT JUNCTIONS Gap junctions......Page 229
Tight junctions......Page 230
FUNCTIONS OF GAP JUNCTIONS IN THE LIVER......Page 232
Growth control......Page 234
REGULATION OF COUPLING BETWEEN HEPATOCYTES......Page 236
FUNCTION AND REGULATION OF TIGHT JUNCTIONS......Page 238
EXPRESSION AND FUNCTION OF TIGHT JUNCTIONS IN HUMAN LIVERS......Page 242
REFERENCES......Page 243
SECTION A HEPATOCYTE......Page 247
Copper transport proteins......Page 249
The digestive system......Page 251
Copper toxicity......Page 253
HUMAN DISORDERS OF COPPER METABOLISM Wilson disease......Page 254
Copper de.ciency syndromes......Page 255
REFERENCES......Page 256
THE LIVER AS A MAJOR IRON REPOSITORY......Page 261
THE ROLE OF TfR2, A SECOND TRANSFERRIN RECEPTOR HIGHLY EXPRESSED IN HEPATOCYTES......Page 262
NON-TRANSFERRIN-BOUND IRON UPTAKE AND HEPATIC IRON OVERLOAD......Page 263
HEPATOCYTES SYNTHESIZE AND SECRETE THE REGULATORY PEPTIDE HORMONE HEPCIDIN......Page 265
TRANSCRIPTIONAL REGULATION OF HEPCIDIN EXPRESSION IS THE MAJOR DETERMINANT OF SYSTEMIC IRON HOMEOSTASIS......Page 266
HEPCIDIN REGULATES SYSTEMIC IRON HOMEOSTASIS MAINLY THROUGH ITS EFFECTS ON MACROPHAGES AND THE DUODENAL MUCOSA......Page 267
MUTATIONS IN GENES INVOLVED IN HEPATOCYTE SENSING OF SYSTEMIC IRON LEVELS CAUSE HEMOCHROMATOSIS......Page 268
CAUSES OF JUVENILE HEMOCHROMATOSIS......Page 269
ELEVATED HEPCIDIN EXPRESSION EXPLAINS THE ANEMIA OF CHRONIC DISEASE......Page 270
REFERENCES......Page 271
BILIRUBIN METABOLISM......Page 277
DISORDERS OF BILIRUBIN METABOLISM......Page 278
REFERENCES......Page 281
HEPATIC TRIGLYCERIDE BIOSYNTHESIS AND METABOLISM......Page 283
CYTOPLASMIC TRIGLYCERIDE LIPID DROPLETS......Page 284
REGULATION OF HEPATIC TRIGLYCERIDE BIOSYNTHESIS......Page 285
PATHOBIOLOGY OF HEPATIC TRIGLYCERIDE......Page 286
ADIPOSE FAT STORAGE AND HEPATIC INSULIN RESISTANCE......Page 287
REGULATING THE BALANCE BETWEEN HEPATIC LIPOGENESIS AND FATTY ACID OXIDATION......Page 289
METABOLIC FATE OF “OLD” AND “NEW” FAT......Page 290
LINKS BETWEEN UPR AND HEPATIC LIPOGENESIS......Page 291
REFERENCES......Page 292
BIOCHEMISTRY AND PHYSIOLOGY OF CHOLESTEROL AND LIPOPROTEIN METABOLISM......Page 297
Metabolism of apoB-containing lipoproteins......Page 298
HDL metabolism and reverse cholesterol transport......Page 303
Cholesterol balance......Page 306
Inhibitors of cholesterol absorption......Page 307
Omega-3 fatty acids......Page 308
REFERENCES......Page 309
SECTION B BILE SECRETION......Page 313
BILE ACID CHEMISTRY Bile acid biosynthesis......Page 315
Bile acid conjugation......Page 317
Bacterial modi.cation of bile acids......Page 318
ENTEROHEPATIC CYCLING OF BILE ACIDS Overview......Page 319
Intestinal conservation of bile acids......Page 320
Hepatic uptake of bile acids......Page 321
Plasma bile acids......Page 322
BILE ACID FUNCTIONS......Page 323
DISTURBANCES IN BILE ACID METABOLISM......Page 324
THERAPY WITH BILE ACID AGONISTS AND ANTAGONISTS Bile acid agonists: therapy with bile acids and bile acid congeners......Page 325
REFERENCES......Page 326
HEPATOCYTE UPTAKE OF BILE ACIDS Sodium-dependent bile acid uptake across the hepatocyte basolateral membrane......Page 331
Na+Taurocholate Cotransporting Polypeptide (Ntcp)......Page 332
Regulation of Ntcp transport activity by altering its subcellular distribution......Page 333
Regulation of Ntcp in cholestasis......Page 336
Microsomal epoxide hydrolase......Page 337
Function of Hepatocyte Oatps......Page 338
STUDIES OF Oatp1a1 AS A PROTOTYPICAL MEMBER OF THE Oatp FAMILY Membrane topology of oatp1a1......Page 339
Modulation of Oatp1a1 transport activity......Page 340
REFERENCES......Page 341
DIFFERENT RESPONSES OF CYP7A1 TO DIETARY CHOLESTEROL IN RABBITS AND RATS......Page 349
SHORT HETERODIMER PARTNER (SHP), LIVER RECEPTOR HOMOLOG-1 (LRH-1), AND HEPATOCYTE NUCLEAR FACTOR 4 (HNF4)......Page 351
THE ROLE OF NUCLEAR RECEPTORS IN THE REGULATION OF CYP7A1......Page 353
ENTEROHEPATIC CIRCULATION AND REGULATION OF BILE ACID ABSORPTION IN THE ILEUM......Page 355
MEASUREMENT OF THE BILE ACID POOL......Page 356
THE EFFECT OF BILE ACID MALABSORPTION......Page 357
NEW CHALLENGES......Page 358
REFERENCES......Page 359
TRANSPORT OF DRUGS, TOXINS, AND WASTE PRODUCTS INTO BILE......Page 365
BILIARY PHOSPHOLIPID EXCRETION......Page 367
BILIARY CHOLESTEROL EXCRETION......Page 368
MEMBRANE ASYMMETRY CREATES RESISTANCE AGAINST BILE SALTS......Page 369
REFERENCES......Page 371
INTRODUCTION......Page 375
TRAFFIC OF NEWLY SYNTHESIZED ABC TRANSPORTERS IN HEPATOCYTES......Page 376
INTRAHEPATIC ABC TRANSPORTER POOLS......Page 377
Constitutive canalicular cycling of ABC transporters......Page 378
Mechanisms involved in canalicular cycling of ABC transporter......Page 379
CONCLUSION......Page 381
REFERENCES......Page 382
CHOLANGIOCYTE CILIA IN LIVER HEALTH A brief overview of cholangiocyte primary cilia......Page 385
Cholangiocyte cilia and intracellular signaling......Page 386
CHOLANGIOCYTE CILIA IN LIVER DISEASES Cholangiopathies associated with primary cilia (Cholangiociliopathies)......Page 389
Pathogenesis of the cholangiociliopathies......Page 390
REFERENCES......Page 392
SECTION C SINUSOIDAL CELLS......Page 397
32 Ca2+ Signaling in the Liver......Page 399
Regulation of normal SEC phenotype......Page 400
FUNCTION Functional consequences of sinusoidal morphology......Page 401
SEC functions......Page 402
Drug-induced SEC injury......Page 403
Other forms of liver injury due to SEC damage......Page 406
Variable .rst step plus immunomagnetic separation......Page 407
REFERENCES......Page 408
HISTORICAL BACKGROUND......Page 415
MORPHOLOGY OF SINUSOIDAL VESSELS AND THEIR FENESTRATIONS AND SIEVE PLATES......Page 416
PHYSIOLOGICAL ROLES OF FENESTRATIONS......Page 419
REGULATION OF FENESTRATIONS......Page 420
Calcium–calmodulin and the actomyosin cytoskeleton......Page 421
PATHOPHYSIOLOGY OF FENESTRATIONS......Page 423
Sinusoidal obstruction syndrome......Page 424
REFERENCES......Page 425
INTRODUCTION......Page 433
WHAT ARE HSCs?......Page 434
WHAT IS THE FUNCTION OF HSCs?......Page 435
HSC TRANSDIFFERENTIATION (ACTIVATION)......Page 437
THE ADIPOGENIC PHENOTYPE......Page 439
THE ROLE OF LYMPHOCYTES IN HSC TRANSDIFFERENTIATION......Page 440
IS TRANSDIFFERENTIATION A REVERSIBLE PROCESS?......Page 442
FIBROGENESIS AND FIBROLYSIS......Page 443
REFERENCES......Page 444
CAUSES OF HEPATIC FIBROSIS......Page 459
CELLULAR BASIS......Page 461
CYTOKINES INVOLVED IN HEPATIC FIBROSIS......Page 464
SIGNALING PATHWAYS INVOLVED IN HEPATIC FIBROSIS......Page 466
PATHOPHYSIOLOGY-ORIENTED ANTIFIBROTIC THERAPIES......Page 469
REFERENCES......Page 471
ECM SYNTHESIS AND REMODELING DURING EMBRYONIC LIVER DEVELOPMENT......Page 479
ECM DURING LIVER INFLAMMATION......Page 481
NEWLY DESCRIBED COMPONENTS OF THE LIVER ECM......Page 484
MATRIX REMODELING......Page 486
MATURATION OF LIVER ECM, MATRIX STIFFNESS......Page 487
ECM REMODELING HAS A MAJOR IMPACT ON LIVER REGENERATION......Page 488
ECM OF HEPATOCELLULAR AND CHOLANGIOCELLULAR CARCINOMA (HCC AND CCC)......Page 489
REFERENCES......Page 490
PART THREE INTERRELATED CELL FUNCTIONS......Page 495
MECHANISM OF FAT-INDUCED SKELETAL MUSCLE INSULIN RESISTANCE......Page 497
How does lipid accumulate in muscle?......Page 498
PERIPHERAL INSULIN RESISTANCE CONTRIBUTES TO THE DEVELOPMENT OF HEPATIC STEATOSIS......Page 499
LPL over-expressing mouse......Page 501
PKCe links hepatic steatosis to hepatic insulin resistance......Page 502
From insulin resistance to fasting hyperglycemia......Page 503
INSULIN SENSITIZING AGENTS AND HEPATIC INSULIN RESISTANCE Metformin......Page 504
Weight loss......Page 505
REFERENCES......Page 506
MECHANISMS OF Ca2+ SIGNALING Hormone receptors and initiation of Ca2+ signals......Page 511
Inositol 1,4,5-Trisphosphate Receptor......Page 512
Mitochondria......Page 515
ORGANIZATION OF Ca2+ SIGNALS Detection of Ca2+ signals in hepatocytes......Page 517
Ca2+ signaling patterns in hepatocytes......Page 518
Subcellular Ca2+ signals and Ca2+ waves......Page 519
Spread of Ca2+ signals from cell to cell......Page 520
Nuclear Ca2+ signaling......Page 521
Glucose metabolism......Page 522
Exocytosis......Page 523
Regulation of cell volume......Page 524
Ductular secretion......Page 525
REFERENCES......Page 526
CHELATABLE IRON, OXIDATIVE STRESS, AND CELL DEATH......Page 537
IRON UPTAKE BY RECEPTOR-MEDIATED ENDOCYTOSIS AND RELEASE INTO THE CYTOSOL......Page 538
RELEASE OF CHELATABLE IRON FROM THE LYSOSOMAL/ENDOSOMAL COMPARTMENT......Page 539
TWO-HIT HYPOTHESIS OF IRON-CATALYZED HYDROXYL RADICAL FORMATION DURING OXIDATIVE STRESS......Page 541
CONCLUSION......Page 542
REFERENCES......Page 543
THE cAMP TRANSDUCTION PATHWAY......Page 547
COUPLING cAMP TO LIVER GENE TRANSCRIPTION......Page 548
THE CRE-BINDING PROTEIN (CREB) FAMILY......Page 549
Regulation by phosphorylation......Page 550
MECHANISMS OF TRANSCRIPTIONAL REPRESSION Dephosphorylation......Page 551
THE cAMP PATHWAY IN THE LIVER......Page 552
THE ROLE OF cAMP IN PROLIFERATION AND LIVER REGENERATION......Page 554
CONCLUSION......Page 555
REFERENCES......Page 557
AMPK STRUCTURE AND MECHANISM OF ACTIVATION......Page 561
UPSTREAM REGULATORS OF AMPK: LKB1 AND CAMKK......Page 563
DOWNSTREAM TARGETS I: REGULATION OF ACUTE METABOLIC RESPONSE– ENZYMES IN LIPOGENESIS......Page 564
DOWNSTREAM TARGETS II: REGULATION OF METABOLIC ADAPTATION: CONTROL OF TRANSCRIPTION......Page 565
DOWNSTREAM TARGETS III: REGULATION OF CELL GROWTH AND INSULIN SIGNALING VIA mTOR......Page 568
THERAPEUTICS AND FUTURE PERSPECTIVES......Page 570
REFERENCES......Page 571
HISTORICAL NOTES AND DEFINITIONS......Page 575
REGENERATIVE CAPACITY AND THE LIVER AND BODY WEIGHT EQUILIBRIUM......Page 576
DNA REPLICATION IN HEPATIC CELLS AND HEPATOCYTE PLOIDY......Page 577
Priming......Page 578
CYTOKINES AND THE INITIATION OF LIVER REGENERATION......Page 579
The toll-like receptor system......Page 580
The IL-6 system......Page 581
The suppressor of cytokine signaling (SOCS) system......Page 582
PROGRESSION PHASE: GROWTH FACTORS AND CELL CYCLE GENES......Page 583
Hepatocyte growth factor......Page 584
Other agents......Page 585
PERSPECTIVES......Page 586
REFERENCES......Page 587
INTRODUCTION......Page 593
THE NUCLEOLUS AND RIBOSOME BIOGENESIS......Page 594
Ribosomal protein translation and mTOR......Page 595
Regulation of the transcription of rRNA genes......Page 596
THE ROLE OF RIBOSOME BIOGENESIS IN CELL GROWTH AND PROLIFERATION IN THE LIVER......Page 597
REFERENCES......Page 599
HEPATOCYTE TRANSPLANTATION: RATIONALE AND EARLY STUDIES......Page 603
MOLECULAR REGULATION OF LIVER MASS......Page 604
ANIMAL MODELS TO AUGMENT LIVER REPOPULATION BY TRANSPLANTED HEPATOCYTES......Page 605
TRANSPLANTATION OF “OVAL CELLS”......Page 607
STEM CELLS IN THE ADULT LIVER AND THE HEPATIC STEM CELL NICHE......Page 608
HEPATIC STEM CELLS IN THE FETAL LIVER......Page 609
LIVER REPOPULATION BY FETAL LIVER STEM/PROGENITOR CELLS......Page 610
LIVER REPOPULATION BY EXTRAHEPATIC AND EMBRYONIC STEM CELLS......Page 611
OTHER ROLES FOR BM CELLS IN LIVER REGENERATION......Page 612
CLINICAL TRIALS OF HEPATOCYTE TRANSPLANTATION......Page 613
FUTURE HORIZONS......Page 614
REFERENCES......Page 615
PART FOUR RELATION TO OTHER ORGANS......Page 623
TypeAHEorHEassociated with acute liver failure......Page 625
Type C HE or HE associated with cirrhosis and portal hypertension/or portal–systemic shunts......Page 626
NEUROPATHOLOGY OF HEPATIC ENCEPHALOPATHY......Page 627
Ammonia......Page 628
Brain organic osmolytes and cell volume regulation......Page 629
Brain glucose and energy metabolism......Page 630
Oxidative/Nitrosative stress and mitochondrial dysfunction......Page 631
Neurotransmitter systems......Page 632
Cerebral blood .ow (CBF)......Page 633
Systemic factors in addition to ammonia......Page 635
THERAPEUTIC APPROACHES TO HE......Page 636
REFERENCES......Page 637
HEPATORENAL SYNDROME......Page 645
Hepatitis C......Page 648
Human immunode.ciency virus-1......Page 649
Decreased production of adiponectin......Page 650
Increased production of proin.ammatory, prothrombotic, and pro.brogenic adipocytokines......Page 652
Increased activity of the transcriptional factor hypoxia inducible factor-1a......Page 653
Role of SREBPs and ChREBP in NAFLD and kidney disease......Page 655
Potential role for SREBP in alcoholic fatty liver disease......Page 656
Potential role for SREBP in hepatitis C virus-associated hepatosteatosis......Page 657
Potential role of bile acid-regulated FXR and TGR5 in NAFLD and kidney disease......Page 658
REFERENCES......Page 659
The intrinsic pathway: contact activation......Page 665
The in vivo model......Page 666
LIVER DISEASE AND HEMOSTASIS......Page 667
The effects of liver disease on platelet activation......Page 668
Can von willebrand factor (VWF) compensate for platelet abnormalities in liver disease?......Page 669
Coagulation factors: overview of known congenital disorders......Page 670
The effect of liver infection and sepsis on coagulation......Page 671
Coagulation in liver disease......Page 672
Fibrinogen disruptions in those with liver disease......Page 673
Anticoagulation factors and the liver......Page 674
Vitamin K and coagulation......Page 675
Role of the liver in .brinolysis......Page 676
REFERENCES......Page 677
PART FIVE PATHOBIOLOGICAL ANALYSIS......Page 685
Infantile cholestatic syndromes with questionable heritable component......Page 687
Inherited forms of intrahepatic cholestasis......Page 688
Syndromic forms of inherited cholestasis (Table 42.3)......Page 692
REFERENCES......Page 697
Steps in bile formation......Page 707
GENERAL OVERVIEW – ACQUIRED DEFECTS IN BILE TRANSPORT PROTEINS......Page 708
Transporters on the basolateral membrane of the hepatocyte (Phase 0)......Page 713
Bile acid synthesis......Page 714
Bile acid conjugation (Phase II)......Page 715
Hepatic ef.ux mechanisms (Phase III)......Page 716
CONCLUSION......Page 719
REFERENCES......Page 720
RESISTANCE AND FLOW AS THE DETERMINANTS OF PORTAL PRESSURE......Page 729
ABNORMALITIES IN VASCULAR RESISTANCE TO PORTAL BLOOD FLOW Hepatic vascular resistance......Page 730
The hyperdynamic syndrome and the hepatic artery......Page 734
Increased vasodilatation in portal hypertension......Page 735
REFERENCES......Page 738
NAFLD AND OBESITY: AN EVOLUTIONARY PERSPECTIVE......Page 745
CELL AND MOLECULAR BIOLOGY OF NAFLD......Page 746
Molecular events leading to hepatic fat accumulation......Page 747
Molecular events that promote progression from steatosis to steatohepatitis......Page 753
Weight loss: diet, exercise, and bariatrics......Page 756
Targeting insulin signaling pathways......Page 757
Nuclear receptors and transcription factors as therapeutic targets......Page 758
REFERENCES......Page 759
INTRODUCTION......Page 769
PATHOGENESIS AND RISK FACTORS OF ALD Alcohol-related lipid alterations......Page 770
Insulin resistance......Page 771
Adipokines......Page 772
Acetaldehyde......Page 773
Cytokines, chemokines and growth factors......Page 774
Translocation of gram negative bacteria, endotoxin, and TNFa......Page 775
GENERATION OF ROS IN ALD Sources of ROS......Page 776
Species generated......Page 779
GSH......Page 781
RNS AND THEIR REACTIVITY WITH ROS Nitric oxide synthase 2 is required for ALD......Page 782
ALTERED PROTEASOME FUNCTION IN ALD......Page 783
THE UNFOLDED PROTEIN RESPONSE IN ALD......Page 784
FUTURE DIRECTIONS......Page 785
REFERENCES......Page 786
INFLAMMATION......Page 799
INTERACTION OF INFLAMMATION WITH DRUGS AND OTHER XENOBIOTIC AGENTS......Page 800
INFLAMMATORY STRESS-BASED ANIMAL MODELS OF IADRs......Page 802
MECHANISMS AND CONTRIBUTING FACTORS IN DRUG–INFLAMMATORY STRESS INTERACTION......Page 803
REFERENCES......Page 805
APOPTOTIC PATHWAYS......Page 809
Bcl-2 proteins......Page 812
Activation of intrinsic apoptotic pathway......Page 814
Death receptors......Page 815
APOPTOSIS IN SPECIFIC DISEASE STATES Cholestasis......Page 819
NASH......Page 820
IL-6......Page 821
REFERENCES......Page 822
49 Back to the Future: A Backward Glance at the Forward Progress of Hepatitis Virus Research......Page 829
REFERENCES......Page 831
INTRODUCTION......Page 833
Virion morphology......Page 834
Virus replication......Page 835
Classi.cation......Page 836
Genome structure......Page 837
Virus replication......Page 839
Infection and pathogenesis......Page 840
Virus evolution......Page 841
Genome structure......Page 842
Protein structure and functions......Page 843
Viral replication......Page 844
HCV and the response to interferon......Page 845
Virion Structure......Page 846
Viral replication......Page 847
Molecular pathogenesis......Page 848
Virion structure......Page 849
Viral replication......Page 850
REFERENCES......Page 851
INTRODUCTION......Page 861
HBV INFECTION Early innate and adaptive immune responses......Page 862
T cell responses in acute self-limited HBV infection......Page 863
T cell responses in chronically evolving acute HBV infection......Page 864
The humoral immune response......Page 865
Mechanisms of HBV persistence......Page 866
HCV INFECTION Innate immune responses......Page 867
Early kinetics of HCV-speci.c T cell responses: from virus exposure to the acute phase of infection......Page 868
B cell responses......Page 870
Mechanisms of failure of adaptive responses......Page 871
REFERENCES......Page 874
HBV INFECTION......Page 885
THE HBV LIFE CYCLE AND TARGETS OF ANTIVIRAL MEDICATIONS......Page 886
DNA polymerase......Page 887
Capsid protein......Page 888
Envelope proteins......Page 889
Covalently closed circular (ccc) DNA......Page 890
ANTIVIRAL THERAPY OF CHRONIC HEPATITIS B, FROM THE MOLECULAR PERSPECTIVE Available medications to manage chronic hepatitis B......Page 892
HBV VARIANTS AND THEIR CLINICAL SIGNIFICANCE Genotypes......Page 893
Mutations in core and precore genes......Page 894
Envelope gene mutations and the vaccine......Page 896
DETECTION OF HEPATOCELLULAR CARCINOMA (HCC)......Page 897
REFERENCES......Page 898
HCV PERSISTENCE......Page 903
DISRUPTION OF HOST DEFENSE SIGNALING PATHWAYS......Page 904
ADAPTIVE T CELL RESPONSES......Page 906
ADAPTIVE HUMORAL RESPONSES......Page 907
RATES OF AND FACTORS ASSOCIATED WITH VIRAL PERSISTENCE/VIRAL CLEARANCE......Page 908
PREVALENCE AND RATES OF PROGRESSION TO CIRRHOSIS......Page 909
OUTCOME OF ESTABLISHED CIRRHOSIS......Page 910
Host factors......Page 911
Viral factors......Page 912
HEPATITIS C AND HEPATOCELLULAR CARCINOMA......Page 913
REFERENCES......Page 914
HEPATITIS B VIRUS INFECTION General principles of treatment......Page 925
Molecular and pathophysiological basis for therapy......Page 926
Current agents......Page 927
HEPATITIS C VIRUS INFECTION General principles of treatment......Page 930
Molecular and pathophysiological basis for therapy......Page 931
Standard-of-care treatment of chronic hepatitis C with pegylated IFN-a and ribavirin......Page 932
Optimization of pegylated IFN-a– Ribavirin combination therapy......Page 933
New therapies for hepatitis C......Page 935
REFERENCES......Page 939
NATURAL HISTORY OF RECURRENT HCV......Page 947
PRE-TRANSPLANT ANTIVIRAL THERAPY......Page 948
TREATMENT OF ESTABLISHED DISEASE......Page 949
RISK OF ACUTE CELLULAR REJECTION......Page 950
UNANSWERED QUESTIONS AND THE FUTURE......Page 951
IDENTIFICATION OF PREDICTORS OF RECURRENCE OF HBV......Page 952
COMBINATION HBIG AND LAMIVUDINE......Page 953
REFERENCES......Page 954
PART SIX HORIZONS......Page 959
CELL-BASED THERAPIES FOR LIVER DISEASE AND FAILURE......Page 961
Cell transplantation and sourcing......Page 962
HEPATIC CULTURE MODELS......Page 963
Three-dimensional cultures......Page 964
Bioreactor cultures......Page 965
Microtechnology tools to optimize and miniaturize liver cultures......Page 966
Acellular scaffolds for cellular attachment......Page 967
Modi.cations in scaffold chemistry......Page 968
Controlling three-dimensional architecture and cellular organization......Page 969
Therapeutic assessment in animal models......Page 970
REFERENCES......Page 971
Effects of resveratrol on yeast replicative lifespan......Page 981
Sir2 in chronological aging in yeasts......Page 982
SIR2 ORTHOLOGS IN MAMMALS......Page 983
REFERENCES......Page 984
ADVANCEMENT IN PROTEOMICS TECHNOLOGIES......Page 987
REFERENCES......Page 988
INTRODUCTION......Page 991
Recombinant viruses......Page 993
NON-VIRAL VECTORS......Page 999
Triplex DNA......Page 1001
Ribozymes, Antisense, and DNA Ribonucleases, RNAi......Page 1002
Single nucleotide modi.cation......Page 1003
REFERENCES......Page 1008
INTRODUCTION......Page 1017
MICROARRAY-BASED TECHNOLOGIES......Page 1018
COMPARATIVE SYSTEMS GENOMICS: CROSS-SPECIES COMPARISON OF GENE EXPRESSION DATA......Page 1019
IDENTIFICATION OF THERAPEUTIC TARGETS BY INTEGRATIVE SYSTEMS GENOMICS......Page 1020
REFERENCES......Page 1021
HCC diagnosis......Page 1025
Microarray platforms......Page 1026
EMERGING CONCEPTS FROM MICROARRAY STUDIES Diagnostic signatures......Page 1027
Prognostic HCC signatures......Page 1030
CONCLUSION......Page 1032
REFERENCES......Page 1034
BASICS OF THE CELL CYCLE......Page 1041
CYCLINS, CDKS, AND ASSOCIATED REGULATORY PROTEINS......Page 1043
CELL CYCLE REGULATION IN THE LIVER......Page 1045
POTENTIAL RELEVANCE TO CLINICAL HEPATOLOGY......Page 1047
REFERENCES......Page 1048
BRIEF HISTORICAL PERSPECTIVE......Page 1055
miRNA GENETICS AND BIOLOGY Genomics......Page 1057
MODELS FOR TRANSLATIONAL REPRESSION BY miRNAs......Page 1058
PROETOMICS APPROACH TO TARGET IDENTIFICATION......Page 1059
miR-122, THE MAJOR LIVER miRNA......Page 1060
MINOR miRNAs IN THE LIVER......Page 1063
miRNA PROFILING OF THE FETAL LIVER AND HEPATOBLAST DIFFERENTIATION IN VITRO......Page 1066
PROFILING OF miRNAs IN HEPATOCARCINOGENESIS......Page 1067
miR-21......Page 1069
ROLE FOR miRNAs IN HEPATIC CYSTOGENESIS......Page 1070
REFERENCES......Page 1071
ADVANCES IN FLUORESCENT DYES AND PROTEINS......Page 1079
DIFFRACTION......Page 1081
Deconvolution......Page 1082
Confocal and Multiphoton Microscopy......Page 1083
4pi......Page 1084
NSOM......Page 1085
STED......Page 1086
High-speed Photomanipulation......Page 1088
REFERENCES......Page 1090
INTRODUCTION......Page 1093
USE OF ZEBRAFISH TO STUDY LIVER DEVELOPMENT Early liver development......Page 1094
Later liver and hepatobiliary development......Page 1095
USE OF LARVAL ZEBRAFISH TO GENERATE MODELS OF HUMAN LIVER DISEASE......Page 1096
USE OF ADULT ZEBRAFISH TO MODEL DISEASE......Page 1097
CONCLUSION......Page 1098
REFERENCES......Page 1099
INTRODUCTION......Page 1101
Role of transporters and phase I enzymes in hepatocytes (See also Chapters 21, 23, 24 and 43)......Page 1102
Lack of consensus on reliable clinical staging systems and gene signatures......Page 1105
The role of solute carriers (SLCs) in multidrug resistance (see also chapter 21)......Page 1106
ATP-binding cassette (ABC) transporters mediate multidrug resistance......Page 1107
Genetic variation in ABC transporters......Page 1108
CONCLUSION –DR JEKYLL OR MR HYDE?......Page 1109
REFERENCES......Page 1110
THE ENDOCANNABINOID SYSTEM......Page 1117
ENDOCANNABINOIDS AND THE HEMODYNAMIC CONSEQUENCES OF CIRRHOSIS......Page 1119
ENDOCANNABINOIDS AND LIVER FIBROSIS......Page 1121
ENDOCANNABINOIDS AND HEPATIC STEATOSIS Non-alcoholic fatty liver and related hormonal/metabolic changes......Page 1122
Alcoholic fatty liver......Page 1124
REFERENCES......Page 1126
TELOMERE SHORTENING LIMITS THE PROLIFERATIVE CAPACITY OF HUMAN CELLS......Page 1131
THE INFLUENCE OF TELOMERE SHORTENING ON ORGAN REGENERATION AND AGING: LESSONS FROM MOUSE MODELS......Page 1133
TELOMERE SHORTENING IN HUMAN AGING, LIVER DISEASE AND CIRRHOSIS......Page 1134
TELOMERES, TELOMERASE, AND CANCER: LESSONS FROM MOUSE MODELS......Page 1136
TELOMERE SHORTENING AND TELOMERASE ACTIVATION IN HUMAN HEPATOCARCINOGENESIS......Page 1137
Telomerase activation characterizes human hepatocarcinogenesis......Page 1138
TELOMERES AND TELOMERASE: THERAPEUTIC TARGETS AND CLINICAL BIOMARKER IN LIVER DISEASE AND HEPATOCARCINOGENESIS......Page 1139
REFERENCES......Page 1140
INTRODUCTION......Page 1147
MECHANISM OF HEPATIC FIBROSIS WITH SPECIAL REFERENCE TO THE ROLE OF HSC AND HSP47......Page 1148
Targeting HSC with VA–liposome......Page 1149
Fibrosis-resolving effect......Page 1150
EFFICACY......Page 1152
REFERENCES......Page 1153
INTRODUCTION......Page 1157
PLANT ARE’S......Page 1158
REDOX REGULATION OF KEAP1 AND NRF2......Page 1159
UBIQUITINATION AND THE RATE OF KEAP1 AND NRF2 TURNOVER......Page 1160
PLANT TGA FACTORS AND THEIR MEDIATOR PROTEINS......Page 1161
REFERENCES......Page 1162
A......Page 1165
B......Page 1170
C......Page 1172
D......Page 1179
E......Page 1180
F......Page 1182
G......Page 1184
H......Page 1186
I......Page 1193
J......Page 1195
L......Page 1196
M......Page 1198
N......Page 1202
O......Page 1203
P......Page 1204
R......Page 1208
S......Page 1210
T......Page 1212
U......Page 1215
V......Page 1216
Y......Page 1217
Colour Plates......Page 1219