Signaling Pathways in Liver Diseases (eBook)

Signaling Pathways in Liver Diseases 1
The Cell Types and the Matrix 13
Hepatocytes 14
Introduction 14
Hepatocyte Development 14
Hepatocyte Structure and Renewal 16
Plasmamembrane 17
The Basolateral or Sinusoidal Domain 17
The Canalicular or Apical Domain 17
The Lateral Domain 18
Tight Junctions, Gap Junctions, and Desmosomes 18
Organelles 18
Endoplasmic Reticulum 18
Golgi Complex 19
Mitochondria 19
Lysosomes 20
Peroxysomes 20
Nucleus/Polyploidy 20
Physiology 21
Lipid/Lipoprotein, Cholesterol, and Bile Metabolism 21
Glucose Metabolism 22
Amino Acid and Ammonia Metabolism 25
Protein Synthesis 25
Acute Phase Response 25
Iron Metabolism 26
Hepatocyte as an Endocrine Cell 26
Transport-Systems 27
Na+ Dependent Bile Salt Uptake 27
Na+ Independent Hepatic Uptake of Amphipatic Substrates: The Organic Anion Transporting Polypeptide Family (OATP) 27
Na+ Independent Hepatic Uptake of Hydrophilic Organic Cations and Anions: The Organic Ion Transporter Family (OAT/OCT) 28
Basolateral Efflux Pumps 29
Bile Salt Excretion 29
Excretion of Nonbile Salt Organic Anions 29
Phospholipid Excretion 29
Copper Excretion 30
Summary 30
References 32
Signaling Pathways in Biliary Epithelial Cells 36
Introduction 36
Membrane Receptors 36
Cyclic Adenosine 3’, 5’-Monophosphate (cAMP) 38
Cytosolic Ca2+ 39
Protein Kinase C 42
MAPK Signaling 42
PI3-Kinase Signaling 43
Pathological Conditions 44
Summary 45
References 45
Stellate Cells 51
Polypeptide Growth Factor Receptors 54
TGF-b Receptor Superfamily 57
Seven Transmembrane Domain Receptors 59
TNF Receptor Superfamily 61
Nuclear Receptor Family 63
Other Cytokine Receptors 64
Adipokine Receptors 65
Cooperation Between Growth Factor Receptor and Integrin Signaling 66
HSC and Toll-like Receptors (TLRs) 67
Cannabinoids Receptors 68
Hedgehog Signal Pathway (See Also Chapter on this Pathway) 68
Senescence of Activated Stellate Cells 69
Summary 69
References 70
Signaling Pathways in Liver Diseases Kupffer Cells 79
Introduction 79
Molecular Mechanisms of Kupffer Cell Activation 79
Kupffer Cell: Neutrophil Interaction in Host Defense, Immune Tolerance, and Liver Regeneration 81
Host Defense 81
Immune Tolerance 81
Liver Regeneration 82
Role of Kupffer Cells in Liver Injury 83
Acetaminophen 83
Ischemia-Reperfusion Injury 83
Alcoholic Liver Disease 84
Kupffer Cells and Portal Pressure 84
Summary 85
References 85
Hepatic Sinusoidal Endothelial Cells 89
Development and Structure 89
Cellular Functions 89
Fenestration/Filtration 89
Expression of Adhesion Molecules 90
Signaling 91
Metabolism 92
Role in Blood Clearance 92
Antigen Presentation 92
Pathobiology 93
Alcoholic Liver Disease 93
Nonalcoholic Fatty Liver Disease 93
Portal Hypertension/Cirrhosis 93
Angiogenesis/Hepatic Malignancies 95
Drug Toxicity 95
Cellular Rejection 96
Ischemia-Reperfusion Injury 96
Aging Process 97
Summary 97
References 98
Extracellular Matrix 102
Introduction 102
Components of the ECM in Liver 102
The Collagen Scaffold 103
Proteoglycans 104
Laminin 104
Fibronectin 104
Matricellular Proteins 106
Changes in ECM from Normal to Fibrotic Liver 106
Pathways of Cell–Matrix Interaction 107
The Integrin Family 107
ADAM Molecules 108
Discoidin Domain Receptors 108
Growth Factors in ECM 108
ECM and the Stem Cell Niche 108
Metalloproteinases and Their Inhibitors 109
Conclusions 110
Summary 110
References 111
Platelets: A New Cell Type in Liver Physiology 114
List of Abbreviations 114
What Are Platelets? 114
Ischemia/Reperfusion Injury 115
Cold Ischemia 116
Warm Ischemia 117
Liver Regeneration 117
Role of Platelets 117
Role of Platelet-Derived Serotonin 119
Platelets in Chronic Liver Disease 120
Alterations in Platelets in Patients with Liver Disease 120
Platelet Involvement in Liver Diseases 120
Platelets and Viral Hepatitis 120
Platelets and Liver Fibrosis/Cirrhosis 121
Platelets in Nonalcoholic Steatohepatitis 121
Platelets in Chronic Cholestasis 121
Conclusion 122
SummaryBeside their well-known role in primary haemostasis, there is increasing evidence that platelets are also involved in m 122
References 123
Immune Cell Communication and Signaling Systems in Liver Disease 126
Introduction 126
TLR Signaling (See Chap. 9) 128
Innate Immunity Within the Liver 128
Dendritic Cells (DCs) 129
Natural Killer (NK) Cell, Natural Killer T (NKT)-Cells, and T-gd Cells 132
Adaptive Immunity Within the Liver 135
T-Cells 135
B-Cells 137
Regulation of the Immune Response 137
Immune Cell Function in Liver Disease 138
Liver Transplantation 138
Autoimmune Liver Disease 139
Alcoholic Liver Disease 141
Viral Hepatitis 142
Hepatic Immune Cell Regeneration 145
Summary 146
References 147
The Pathways 156
Toll-Like Receptors 157
Introduction 157
Toll-Like Receptors and Their Ligands 157
TLR Adapters and Signaling 159
Negative Regulation of TLR Signaling 160
TLR Expression in the Liver 161
Kupffer Cells 161
Dendritic Cells 161
Hepatocytes 161
Endothelial Cells 161
Biliary Epithelial Cells 161
Stellate Cells 161
Clinical Implications of TLR Activation in Liver Disease 162
Viral Hepatitis 162
Alcoholic Hepatitis 162
Nonalcoholic Fatty Liver Disease 163
Liver Fibrosis 163
Other Liver Conditions 163
Future Perspectives 164
Summary 164
References 165
TNF/TNF Receptors 168
Introduction 168
TNF and TNF Receptors: Molecules and Structure 168
TNF Signaling Pathways 169
Intracellular Death Signaling Complex 169
Mitochondrial Amplification of the Death Signal 170
NF-kB 171
c-Jun N-Terminal Kinase 173
Function of TNF Signaling in Hepatic Pathophysiology 174
Liver Regeneration 174
Toxin-Induced Liver Injury 175
Nonalcoholic Steatohepatitis 177
Viral Hepatitis 178
Conclusion 178
SummaryTNF is produced and secreted primarily by activated macrophages, i.e., in the liver by Kupffer cells.TNF is produce 179
References 180
Fas/FasL 185
Introduction 185
Fas (Cd95/Apo-1) and Fas Ligand(Fasl/CD95L 4) 187
Fas (CD95/APO-1) 187
Fas Ligand (Fasl/CD95l) 187
Fas/Fasl Signaling 187
Fas/FasL in Liver Diseases 188
Pathologic Conditions Associated with Reduced Fas-Mediated Apoptosis 189
Hepatocellular Carcinoma 189
Pathologic Conditions Associated with Excessive Fas-Mediated Apoptosis 189
Viral Hepatitis 189
Alcoholic Hepatitis 190
Cholestatic Liver Disease 190
Wilson’s Disease 191
Nonalcoholic Steatohepatitis (NASH) 191
Summary 191
References 192
Interferon Signaling 195
Interferons 195
Induction of Type I Interferons 195
Interferon Signaling Throughthe Jak–Stat Pathway 196
The Receptor–Kinase Complex 196
Signal Transducers and Activators of Transcription (STATs) 196
Negative Regulators of Interferon Signaling 198
Suppressor of Cytokine Signaling (SOCS) 198
USP18 198
Protein Inhibitor of Activated STAT1 (PIAS1) and PIAS3 198
TcPTP 198
Refractoriness of Interferon Signaling 199
Effects of Type I Interferons 199
Interferon Regulated Genes 199
Antiviral Effects 199
Antiproliferative Effects 200
Interferon Signaling in Viral Hepatitis 200
Interference of Hepatitis C Virus with Interferon Signaling 200
Hepatitis C Virus Induced Activation of the Interferon System 201
Interferon Signaling in ChronicHepatitis B 202
Interferon Signaling in Chronic Hepatitis D 202
References 203
NF-kB 207
Introduction 207
The NF-kB Transcription Factor Family 207
Regulation of NF-kB Activation 208
NF-kB in the Regulation of Hepatocyte Cell Death 210
NF-kB Protects Hepatocytes from TNF-Induced Apoptosis 210
Mediators of the Antiapoptotic NF-kB Function: Interactions with Stress-Related Signaling Pathways 212
NF-kB Promotes InflammatoryNecrosis of Hepatocytes upon Ischemia/Reperfusion 213
The Role of the NF-kB Pathway in Liver Disease 213
NF-kB in Liver Cancer 213
NF-kB in Liver Fibrosis 214
NF-kB in Viral Hepatitis and Fatty Liver Disease 215
NF-kB as a Therapeutic Target 215
Summary 216
References 217
JNKs in liver diseases 221
Introduction 221
Functions and Targets of JNKs in Cell Biology 221
JNK Isoforms 221
JNK Activation and Inactivation 221
Regulation of JNK Activity by Other Kinase Pathways 222
JNK Substrates and Target Genes 222
Regulation of Cell Death and Survival by JNKs 223
Regulation of Proliferation by JNKs 224
Regulation of Inflammation by JNKs 224
JNKs in Liver Disease 224
TNF-Mediated Liver Injury 224
Acetaminophen-Induced Liver Injury 226
Ischemia-Reperfusion Injury 227
Liver Fibrosis 228
Liver Regeneration 228
Hepatocellular Carcinoma 228
Fatty Liver and Steatohepatitis 229
Conclusion and Outlook 230
References 231
Insulin Pathway 234
Introduction 234
Insulin Receptor 235
IRS Proteins 235
Overview 235
Members of the IRS Protein Family 235
The IRS-1 and Hepatocellular Carcinoma 236
IRS and Hepatocyte Proliferation 237
Insulin Signaling Pathways Through IRS Proteins 238
Inhibition of Insulin Signaling 240
Insulin and Growth Hormone 241
Transcriptional Regulation by Insulin 241
Perspectives 242
Selected Reading 243
References 243
Role of PKB/Akt in Liver Diseases 247
Introduction 247
Description of the PKB Family 247
Activation and Regulation of PKB/Akt 248
Activating Stimuli and Upstream Kinases 248
Positive Regulation of PKB via Interaction with Other Proteins 250
Negative Regulation of PKBby Phosphatases 250
Further PKB/Akt Interactors 251
PKB Substrates and Their Functions 252
Regulation of Cell Size and Survival 252
Regulation of Apoptosis 252
Cell Cycle Control 253
Metabolism 253
Role of PKB in Glucose Metabolism 253
Regulation of Lipid Metabolism 254
FoxOs at the Crossroads of Metabolism and Survival: The Role of PGC-1a 254
Role of PKB in Liver Regeneration 254
Involvement of the PI3K/PTEN/PKB Pathway in Liver Diseases 255
Insulin Resistance, Nonalcoholic Fatty Liver Disease, and Hepatosteatosis 255
Involvement of Phosphatasesin Insulin Sensitivity 256
The PI3K/PTEN/PKB Pathwayin the Development of HCC 256
Viruses, PKB, and Liver Diseases 257
Conclusions 258
References 259
Targeting mTOR Signaling Pathways in Liver Disease 264
Introduction 264
mTOR Signaling Pathways 264
mTOR Complexes 264
Activation of mTOR Complexes 265
Physiological Effects of mTORC1 Activation 267
Positive Anabolic Effects of mTORC1 Signaling 267
Negative Feedback Effect of mTORC1 Signaling 267
mTORC1 Regulation in Liver Disease 268
Liver Regeneration 268
Metabolic Disorders of the Liver 269
Upregulation of mTOR Signaling in Human HCC 269
Pharmacological Inhibition of mTOR in HCC 270
Preclinical Studies in Animal Models of HCC as Tools to Decipher Molecular Mechanisms and Clinical Relevance 270
mTOR Inhibitors in Clinical Trials for HCC 271
Conclusion 271
SummaryThe Ser/Thr protein kinase mTOR is a critical regulator of cell growth, proliferation, apoptosis, and metabolism.The d 272
References 273
AMP-Activated Protein Kinase in Liver 277
The AMP-Activated Protein Kinase (AMPK) 277
AMPK Activation in Liver 278
Metabolic Effects of AMPK in Liver 278
Glucose Metabolism 279
Lipid Metabolism 279
Mitochondrial Effects of AMPK 280
Protein Synthesis 280
Non-Metabolic Effects of AMPK 280
AMPK in Liver Diseases 281
Type 2 Diabetes 281
Liver Steatosis 281
Other Implications: Hepatocellular Carcinoma and Inflammation 282
Conclusions 282
SummaryThe AMPK is involved in energy homeostasis both at the cellular and whole-body level. When cellular energy is out of ba 283
References 283
ER Stress Signaling in Hepatic Injury 288
Introduction 289
General Signaling Pathways Associated with ER Stress 289
Unfolded Protein Response 289
IRE1a-XBP1 Enhances Folding Capacity and Reduces Protein Load 289
ATF6 Modulates UPR Transcription 290
PERK-eIF2a Attenuates mRNA Translation 290
ER Stress Response 291
ER Stress Response Triggers Cell Death Pathways and Inflammation 291
ER Stress Response Leads to Lipid Accumulation 292
ER Stress in the Liver 292
Alcohol-Induced ER and/or Mitochondrial Stress and Liver Injury 293
Evidence of Alcohol-Induced ER Stress Response 293
Contribution of Alcohol-Induced Hyperhomocysteinemia to ER Stress 294
Contribution of Mitochondrial Stress to ALD 295
ER Stress in Nonalcoholic Fatty Liver Disease and Insulin Resistance 296
ER Stress and Liver Steatosis 296
ER Stress and Insulin Resistance 296
Proof of Concept from Therapeutic Interventions 297
ER Stress in Viral Infection 297
ER Stress in Other Liver Diseases 298
Genetic Disorders 298
Drug-Induced Liver Disease 299
Ischemia-Reperfusion Injury 299
Cholestasis and Bile Acid-Induced ER Stress 299
Scurvy and Damages by H2O2 and Heavy Metals 300
Conclusions 300
Summary 300
References 301
PPARa, A Key Regulator of Hepatic Energy Homeostasis in Health and Disease 306
Introduction 306
Peroxisome Proliferator Activated Receptors (PPARs) 306
The Role of PPARa in Lipid Metabolism 307
PPARa and Lipoprotein Metabolism 307
PPARa and Cellular Lipid Uptake and Transport 307
PPARa and Fatty Acid b-Oxidation 307
The Role of PPARa in Glucose Metabolism 308
The Role of PPARa in Amino Acid Metabolism 308
The Role of PPARa During Fasting 308
PPARa and the Hepatic Circadian Clock 309
The Role of PPARs in Disease 310
PPARs and the Metabolic Syndrome 310
PPARs and Hepatic Inflammation 310
PPARa and Hepatocarcinogenesis (HCC) 311
PPARs and Liver Fibrosis 311
PPARs and Nonalcoholic Fatty Liver Disease 312
Conclusion 312
Summary 313
References 313
Bile Acids and Their Receptors 317
Introduction 317
Role of Bile Acid Activated Nuclear Receptors for Bile Acid Metabolism, Bile Secretion and Cholestasis 317
Background 317
Regulation of Bile Acid Synthesis by NRs 318
Regulation of Phase I and II Bile Acid Metabolism 319
Regulation of Hepatobiliary Transport by NRs 320
Basolateral Hepatocellular Bile Acid Uptake 320
Canalicular Bile Acid Excretion 321
Alternative Basolateral Bile Acid Export 322
Therapeutic Principles Targeting Nuclear Receptors in Cholestasis 322
Role of Bile Acid Activated Nuclear Receptors for Lipid and Glucose Metabolism 323
HDL Metabolism 323
Triglyceride and Fat Metabolism 323
Glucose Metabolism 324
Non Alcoholic Fatty Liver Disease 325
G-Protein-Coupled-Receptor for Bile Acid 325
SummaryBAs activate nuclear receptor FXR and G-coupled membrane receptor TGR5.BAs repress their own synthesis by a negative f 326
References 326
Signaling Pathways in Liver Diseases: PXR and CAR 333
Nuclear Hormone Receptor Family 333
PXR Biology 334
CAR Biology 335
Gene Regulation by PXR and CAR 336
Response Elements in Target Genes 336
Spectrum of PXR and CAR Target Genes 336
Xenobiotic Metabolism 337
Endobiotic Homeostasis and Disease 338
Bile Acids 338
Bilirubin 338
Steroids and Thyroid Hormone 339
Hepatic Energy Homeostasis 339
Lipid Metabolism 339
Glucose Metabolism 339
Prospects for Use of PXR and CAR as Therapeutic Targets 340
SummaryPXR and CAR are closely related nuclear hormone receptors that heterodimerize with RXRa.They are receptors for xenob 340
References 341
p53 344
Introduction 344
The Transcription Factor p53 344
Protein Structure of p53 345
Regulation of p53 Protein Levels 347
Subcellular Localization of p53 349
Stress Response: Arrest of Cell Cycle and DNA Repair 349
Stress Response: Apoptosis 350
Selectivity in p53 Downstream Response 351
Liver-Specific Challenges to p53 Functions 352
Summary 352
References 353
The MYC Network and Cancer 357
Introduction 357
MYC Transcriptome Network 357
Biological Output of MYC In vivo 360
Conclusions 360
SummaryMyc is an oncogenic transcription factor which functions in a heterodimeric complex with MAXMYC could regulate as 361
References 362
The WNT/b-Catenin Pathway 364
Background 364
The WNT/b-Catenin Signal Transduction Pathway 365
The Canonical WNT Pathway or the WNT/b-Catenin Signaling 365
The Alternative WNT Signaling Pathways 367
The WNT/Ca2+ Pathway 367
The Planar Cell Polarity Pathway 368
b-Catenin-E-Cadherin Interactions 369
Miscelleneous Interactions/Crosstalks 370
WNT/b-Catenin Signaling in Liver: Physiological Relevance 371
Role in Liver Development 371
Role in Liver Growth, Metabolism, and Homeostasis 373
Liver Regeneration 373
Stem Cells in Adult Liver or Oval Cells 374
WNT/b-Catenin Signaling in Liver 374
Benign Liver Neoplasms 374
Hepatoblastomas 375
Hepatocellular Cancer 375
Bile Duct Tumors 377
Miscelleneous Pathologies 377
Therapeutic Implications 377
References 379
Sonic Hedgehog Pathway 389
Introduction 389
The Hedgehog Pathway 389
Hedgehog-Producing and Hedgehog-Responsive Cell Types in Adult Liver Repair 390
Hedgehog Pathway in Non-Malignant Liver Diseases 391
Biliary Fibrosis 391
Nonalcoholic/Alcoholic Fatty Liver Disease 392
Vascular Remodeling During Cirrhosis 393
Hedgehog Pathway in Hepatocarcinogenesis 393
Cholangiocarcinoma 393
Hepatoblastoma 394
Hepatocarcinoma 394
Conclusions 394
SummaryHh ligands (Sonic, Shh Indian, Ihh Desert, Dhh) are soluble, lipid-modified morphogens that may be secreted in two di395
References 396
Hypoxia-Inducible Factor-1 Signaling System 398
Introduction 398
Identification of HIF-1 398
Structure of HIF-1 398
HIF Target Genes 400
Regulation of HIF-1 400
Hydroxlation 400
Acetylation 403
Phosphorylation 403
S-Nitrosylation 404
SUMOylation 404
HIF Expression in the Liver 404
Importance of Hypoxia in Liver Pathologies 405
Ischemia-Reperfusion Injuryand Ischemic Preconditioning 405
Liver Cirrhosis 406
Liver Cell Carcinomas 406
Liver Regeneration 407
Other Signaling PathwaysInfluenced by Hypoxia 407
SummaryThe importance of O2 tension in liver pathologies has long been appreciated. In addition to the diverse signaling p 407
References 408
VEGF Signaling 415
Introduction 415
VEGF 415
Biological Functions of VEGF 415
VEGF Gene and Splice Variants 416
VEGF Protein Family 416
VEGF Gene Expression 417
Hypoxia 417
Cytokines and Growth Factors 418
VEGF Receptors 418
VEGFR-1 418
VEGFR-2 419
VEGFR-3 419
Neuropilin-1 and -2 419
VEGF Receptor Signaling 419
VEGF Signaling in SpecificLiver Conditions 420
Liver Organogenesis 420
Liver Regeneration 420
Liver Fibrosis and Cirrhosis 420
Portal Hypertension 421
Viral Hepatitis 421
Hepatocellular Carcinoma 422
Ascites Formation 423
Liver Transplantation 424
SummaryAlternative splicing of the human VEGF pre-mRNA produces six VEGF isoforms, which differ in their sequestration in the 424
References 425
Apoptosis and Mitochondria 432
Introduction 432
Death Receptor Mediated Apoptosis 433
Tnfr1 Internalization and Endosomal Trafficking 434
Mitochondrial Membrane Permeabilization and Release of Proapoptotic Proteins 435
Cytochrome c Mobilization 435
Omm Permeabilization: Mpt Vs The Bcl-2 Network 436
Mitochondrial Ros and Gsh 437
Cholesterol and Sphingolipids in Cell Death 438
Cholesterol and Hepatocyte Apoptosis 438
Sphingolipids and Cell Death 439
Apoptosis and Liver Diseases 439
Steatohepatitis 439
Ischemia/Reperfusion Liver Injury 440
Hepatocarcinogenesis 441
Closing and Future Remarks 441
References 443
Calcium Signaling 447
Introduction 447
Hepatocyte Ca2+ Oscillations 447
Intracellular Ca2+ Waves 448
Intercellular Ca2+ Waves in Hepatocytes 449
Physiological Significance of Ca2+ Oscillations and Waves in Hepatocytes 450
Calcium in the Hepatocyte Nucleus 450
Calcium and Hepatocyte Proliferation: Liver Regeneration and Carcinogenesis 451
Calcium and Cell Death in the Liver 451
Calcium and Ischemia-reperfusion Injury 452
Calcium and Viral Hepatitis 452
SummaryIntracellular calcium orchestrates a very large array of biological processes, thanks to modulation of signals in ter 453
References 454
HBV Signaling 457
The Hepatitis B Virus 457
HBV Life Cycle and the Role of Cellular Proteins 458
HBV Life Cycle 458
Cellular Proteins and HBV Replication 458
Chaperones and RT–pgRNA Interaction 459
Nucleocapsid Maturation 459
cccDNA Formation 459
cccDNA Transcription 459
HBX, Transcription and Cell Signaling 460
HBx and the Virus 460
HBx and Cellular Transcription 461
HBx and Signal Transduction 462
HBV and Liver Pathophysiology 462
HBV and Apoptosis 462
HBV and Lipid Metabolism 464
HBV and HCC 464
Viral Epidemiology 464
Genomic and Transcriptomic Analysisof HBV-Related HCCs 465
Mechanisms of HBV Oncogenesis 465
Genomic Instability 467
Insertional Mutatagenesis 467
Senescence and Telomerase Reactivation 467
Long-term Expression of Viral Proteins 467
Summary 468
References 469
Hepatitis C Virus and Insulin Signaling 474
Introduction 474
Clinical Evidence Supporting an Association Between HCV and T2D 474
HCV Interference with the Insulin Signaling: Potential Mechanisms 476
Clinical Consequences of IR/T2D in Chronic Hepatitis C 478
Perspectives for Clinical Management 478
Conclusions 479
Summary 479
References 480
MicroRNAs 483
History of MicroRNA 483
Types of miRNA and Its Biogenesis 483
General Mechanisms of Action 484
How is miRNA Function Identified and Assessed 484
Identification of miRNA Function 484
Luciferase Reporter Assay 484
Translation 485
Role of P Bodies in mRNA Degradation 486
Specific Examples in Liver Disease 486
Role of miRNA miR-122 486
Nonalcoholic Fatty Liver Disease 486
Hepatitis C Virus Infection 486
Liver Cancers 486
Conclusion 487
Summary 487
Reference 487
Hepatic Clocks 490
Introduction 490
A Circadian Oscillator in Every Single Cell 490
The Molecular Oscillator Model 491
Communicative and Autistic Clocks 491
Signaling to Peripheral Oscillators 492
Synchronization of Liver Clocks 493
Signaling Through Feeding–Fasting Cycles and Redox Sensing 493
Glucocorticoid Signaling 495
The Genome-Wide Identification of Putative Immediate Early Genes 495
FGF21 and PPAR Signaling 495
Signaling Through Components of the Cytoskeleton 496
Signaling Through Ubiquitin Ligases 496
Body Temperature Rhythms as Zeitgebers 497
Summary 497
References 498
Answers 502
Index 503