ABSTRACT
Contents Preface V About the Editors xiii About the Authors
1. Collagen Gene Regulation in the Hepatic Stellate Cell Branko Stefanovic and Richard A. Rippe (USA)
3-26
Introduction 3 Molecular mechanisms controlling collagen synthesis 5 Mediators influencing collagen expression in HSCs 10 Posttranscriptional regulation of type I collagen expression 13
2. CYP2E1-Biochemical and Toxicological Aspects and Role in Alcohol-induced Liver Injury Arthur I. Cederbaum (USA)
27-44
Introduction 27 CYP2E1 29 CYP2E1 and alcohol-induced liver injury 35 Biochemical and toxicological properties of CYP2E1 in HEPG2 cells 35 Future perspectives 38
3. Alcohol and Methyl Transfen Implications for Alcohol-related Hepatocarcinogenesis Felix Stickel (Switzerland), Christoph Herold, Helmut K. Seitz and Detlef Schuppan (Germany)
45-58
Introduction 45 Alcohol-related hepatocarcinogenesis: A multi-step process 46 Mechanisms of alcohol toxicity 47 Lipotropes as a target of alcohol toxicity 47 SAMe for chemoprevention in hepatocarcinogenesis 54 Conclusion 54
4. Methionine Adenosyltransferase and S-adenosylmethionine in Liver Health and Disease Shelly C. Lu and Jose M. Mato (USA)
59-78
Introduction 59 Historical perspective 60 Hepatic methionine metabolism 61 MAT genes and enzyme isoforms 61 Abnormalities of MAT in liver disease 62 Mechanisms of altered MAT gene expression in liver cirrhosis and cancer 65 SAMe as control switch in maintaining normal liver function 66 Importance of MAT and SAMe in liver disease-lessons learned from the MAT1A null mice 68 Concluding remarks 72
5. Acetone Metabolism in the Liver: Two Approaches to the Same Phenomenon Med. Habil. Miklos Peter Kalapos (Hungary)
79-92
Introduction and history 79 Metabolic pathways for acetone and role of liver 80 Effects of acetone on biotransformation of xenobiotics 82 Summary of clinical implications 84 Possible pathophysiological role(s) of acetone biodegradation: two approaches to the same phenomenon 86 Conclusion, perspectives and unanswered questions 87
6. Oxidative Stress and Liver Fibrosis: From Liver Injury to Modulation of Cell Signalling and Response Elena Zamara, Erica Novo and Maurizio Parola (Italy)
93-114
Introduction 94 Oxidative stress, liver fibrosis, and chronic liver diseases: major concepts 96 Major consequences of oxidative stress generation in relation to liver fibrosis and its progression 101 Antioxidants: a possible tool to support conventional therapy for CLDs to reduce fibrosis progression? 107 Concluding remarks 108
7. Role of Nitric Oxide in Liver Disorders Pablo Muriel (Mexico)
115-132
Introduction 115 Nitric oxide and hepatic fibrosis 116 Nitric oxide and hyperdynamic circulation 117 Nitric oxide and paracetamol-induced liver injury 119 Nitric oxide, and liver inflammation and septic shock 120 Nitric oxide and hepatic ischemia-reperfusion injury 122 Role of nitric oxide in hepatocellular carcinoma 123 Nitric oxide effects on mitochondria and other organelles 124 Concluding remarks 125
8. Renin-Angiotensin System and Liver Fibrosis Hitoshi Yoshiji, Shigeki Kuriyama and Hiroshi Fukui (Japan)
133-140
Introduction 133 Angiotensin II and liver fibrosis 135 Angiotensin II and angiogenesis 135 Angiotensin II and TIMP-1 136 Conclusions
9. Cell and Molecular Mechanisms in the Development of Chronic Liver Inflammation Simon C. Afford and Patricia F. Lalor (UK)
143-158
Introduction 143 Triggering hepatic inflammation 145 Trafficking and retention of inflammatory cells in the liver and role of hepatic endothelium 146 Role of cholangiocytes and hepatocytes during Inflammation 149 Regulation of hepatic stellate cell function and survival 153 Potential targets for therapeutic intervention 154
10. Role of Activated Macrophages in Liver Disease Ion V. Deaciuc and Craig J. McClain (USA)
159-178
Introduction 159 Markers of macrophage activation 160 Mechanisms of monocyte and Kupffer cell activation 162 Liver injury by MC-and KC-secreted mediators 165 Conclusions and future directions 171
11. Basis for Immune Recognition of Cellular Targets in Primary Biliary Cirrhosis 179-196 Ruth Joplin (UK) Introduction 179 Cellular targets in PBC 180 Antigenic targets in PBC 184 Models of PBC 187 Infectious agent as basis of immune recognition of cellular targets in PBC? 190
12. Cross Talk of Hepatocytes and Nonparenchymal Liver Cells in Physiology and Pathology: Monoxides and Eicosanoids 197-216 Zbigniew Kmiec (Poland) Nitric oxide in normal and diseased liver 197 Role of heme oxygenase and carbon monoxide in liver function 202 Eicosanoids in liver physiology and pathobiology 204
13. Activity of Cytokines in Chronic HCV Infection and Influence of Antiviral Drugs 217-226 Tadeusz Wojciech Lapinski (Poland) Introduction 217 Role of IL-1 in HCV infection 217 Implication of IL-12 in HCV infection 219 Role of IL-18 in HCV infection 219 Synergy of cytokines in activation of apoptosis 219 Significance of Thl and Th2 lymphocytes in HCV infection 220 Role of IL-2 in HCV infection 220 Significance of IL-15 in hepatitis C infection 220 IFN-y activity in HCV infection 222 Role of IL-4 in HCV infection 222 Influence of HCV infection on IL-6 concentration 222 Activity of other cytokines in HCV infected patients 223
14. Role of Chemokines in Liver Pathophysiology 227-242 Fabio Marra (Italy) Introduction 228 Alcoholic liver disease 230 Ischemia-reperfusion injury 230 Transplant rejection 231 Viral hepatitis 232 Other causes of liver inflammation 233 Liver cancer 234 Angiogenesis 234 Liver regeneration 234 Chemokines and the biliary system 235 Liver fibrosis 235 Conclusions 237
15. Nonalcoholic Fatty Liver Diseases: Clinical and Pathophysiological Features 245-272 Frank A. Anania (USA) Introduction 245 Primary and secondary causes of hepatic steatosis-macrosteatosis 246 Epidemiology of NAFLD and NASH 248 Pathogenesis of nonalcoholic fatty liver disease and steatohepatitis: current concepts 251 Rodent models of NAFL and NASH-in vivo tools to study NAFLD 255
Status of the utility of animal models 257 How is the diagnosis of NAFLD made? 259 Medical therapy for human fatty liver disease 261 Weight reduction for NAFLD: a multidisciplinary approach 262 Novel therapies specifically for NAFLD 265 Surgical therapy for NAFLD 266
16. Genetic Basis of Hepatocellular Cancer 273-308 Sigal Tal-Kremer, Christopher P. Day and Helen L. Reeves Introduction 273 Mechanisms of gene deregulation in HCC 274 Genetic instability in hepatocellular cancer 278 Cell cycle regulation and its disruption in HCC 281 Inactivation of p53 286 Wnt/p-catenin pathway 289 Apoptosis 291 Roles of various aetiologies of chronic liver disease in initiation and progression of HCC 295 Future directions 301
17. Haemochromatosis: Recent Advances 309-330 A/M Davis and WM Rosenberg Introduction 309 Iron biology 309 Genetics of HH-HFE 311 HFE epidemiology 311 HFE molecule 311 Effect of HFE mutations 313 Other genetic causes of iron overload 313 Rare HFE mutations 315 Other genes causing HH 315 Prevalence of HH 316 Role of HFE in other liver disorders 320 Role of HFE in extrahepatic disorders 320 Advances in diagnosis 322 Management of HFE 322 Screening for HH 324 Concluding remarks 324
18. Pathophysiology of Cirrhotic Ascites: Recent Advances 331-350 George Therapondos and Florence Wong Introduction 331 Historical perspective 331 Currently accepted hypothesis: peripheral arterial vasodilatation 332 Evolving concepts 332 Pathogenesis of sodium retention at various stages of cirrhosis 343
19. Cryptogenic Hepatitis 351-366 Isabelle Chemin Introduction 351 Diagnostic settings 352 External agents 352 Common aetiologies to eliminate 352 Other forms of cryptogenic hepatitis 354 Identification of new hepatitis viruses 357 'Candidates' viruses in the field of cryptogenic hepatitis 357 Conclusion 361
20. HIVI and the Liver 367-378 Sandro Vento, M.D. and Francesca Cainelli, M.D. Introduction 367 Peculiar aspects of the liver in HIV1 infection 367 Hepatitis B Virus infection in HIV-infected patients 368 Hepatitis D and HIV1 infection 370 Hepatitis C Virus infection in HIV1-infected patients 371 Antiretroviral drugs and the liver 373 Conclusions 373
21. Cell Death by Necrosis: Mechanisms and Interception in the Liver 379-398 Shakir Ali Introduction 379 Liver necrosis; a cytolytic injury 380 Necrosis vs apoptosis, and autolysis 381 Mechanisms of liver necrosis 382 Deranged biochemical, cellular and molecular pathways in liver necrosis 389 Biochemical manifestations of liver necrosis 392 Liver necrosis: Interception 393
22. Fulminant Hepatic Failure: Etiology, Pathogenesis, and Treatment 399-420 Eran Elinav and Rafael Bruck Introduction 399 Definition 400 Pathophysiology 400 Etiology 400 Clinical manifestations 403 Evaluation 405 Treatment 406 Prognosis 408 Liver transplantation 409 Extracorporeal hepatic replacement systems 410 Conclusion 412
23. Advances in Biology and Therapy of Hepatitis B Virus Infection 423-438 Frank Tacke, Michael P. Manns and Christian Trautwein Introduction 423 Hepatitis B virus genome and Proteins 423 Hepatitis B virus life cycle 424 Hepatitis B virus mutants 427 Current vaccination and treatment strategies 430 Novel antiviral strategies and future directions 431 Conclusions 434
24. Hepatitis C Virus: Molecular Virology and Therapeutic Targets 439-458 Andrew Macdonald and Mark Harris Introduction 439 Genome of HCV 440 Functions of HCV polypeptides in viral replication 440 HCV replication cycle 442 Study of HCV replication-problems and solutions 443 Current therapies for HCV infection 446 Pathogenic mechanisms 447 Concluding remarks 453
25. Drug Targeting to Hepatic Stellate Cells: A New Strategy to Treat Liver Fibrosis 459-474 Leonie Beljaars, Dirk K.F. Meijer and Klaas Poelstra Introduction 459 Liver fibrosis and hepatic stellate cells 460 Antifibrotic drugs and hepatic stellate cells 460 Drug targeting: problems and possibilities 461 Drug targeting to hepatocytes, Kupffer cells, and endothelial cells in relation to liver fibrosis 464 Hepatic stellate cell-selective therapy: emerging prospects 465 Important considerations for drugs to be targeted 466 Drugs targeted to hepatic stellate cells 470 Perspectives 471
26. Developing Therapeutic Strategies for Hepatic Fibrosis 475-488 Ichiro Shimizu Introduction 475 Oxidative stress in liver injury 476 Immunity in liver injury 476 Oxidative stress and HSC activation 476 Antioxidant protective mechanisms 477 Hepatic steatosis 478 HSC activation and ECM 478 Growth factors 478 HSC contractility 479 Termination of HSC activation 479 Antifibrotic therapy 479 Conclusions 484
27. Liver Disease, Oxidative Stress and Ursodeoxycholic Acid 489-510 Predrag Ljubuncic and Arieh Bomzon Introduction 489 Mitochondria: the machines of cell survival 491 Apoptosis or programmed cell death 491 Apoptosis and oxidative stress 493 Liver disease and bile acids 496 Ursodeoxycholic acid (UDCA) 498 Conclusion 502
28. Plasma TGF-fJ as a Diagnostic and Prognostic Marker 511-518 M. Antoine, M. Mavituna, R. Weiskirchen, AM . Gressner and P. Kiefer Introduction 511 Methods to measure TGF-p concentrations in plasma 512 Changes in plasma levels of TGF and human disease 514 Concluding remarks 516
29. Hepatocytes as the Gold Standard for Predicting in vivo Hepatotoxicity of Xenobiotics Using Accelerated Cytotoxicity Mechanism Screening Techniques 519-530
Peter J. O'Brien, Arno Siraki, Shahrzad Tafazoli and Katie Chan Introduction 519 Application of in vitro hepatocyte cytotoxicity research to determine molecular mechanisms
of in vivo xenobiotic-induced liver toxicity 520 Literature review of hepatotoxic mechanisms of halobenzene derivatives 520 Comparison of hepatotoxicity and toxicity mechanisms of halobenzene derivatives in vivo 522 "Accelerated Cytotoxic Mechanism Screening" with hepatocytes 523 Comparison of hepatocyte cytotoxicity and molecular cytotoxic mechanisms of xenobiotics in vitro using an
ACMS/QSAR approach 523 Idiosyncratic hepatotoxicity promotion by inflammation, H20 2 and peroxidases 527 Conclusions 527
Index 531-540
