The Retinoids

Description

The Retinoids: Biology, Biochemistry, and Disease provides an overview and synthesis of the retinoid molecules, from basic biology to mechanisms of diseases and therapy. Divided into five sections, the book covers retinoic acid signaling from biochemical, genetic, developmental, and clinical perspectives.

The text is divided into five sections, the first of which examines vitamin A metabolic and enzymatic pathways. Focus then shifts to the role of retinoic acid signaling in development, and then to retinoids and physiological function. The book concludes with chapters on retinoids, disease and therapy.

Comprehensive in scope and written by leading researchers in the field, The Retinoids: Biology, Biochemistry, and Disease will be an essential reference for biologists, biochemists, geneticists and developmental biologists, as well as for clinicians and pharmacists engaged in clinical research involving retinoids.

Title Page 6
Copyright Page 7
Contents 8
Contributors 12
Preface 16
Part I Vitamin A Metabolic and Enzymatic Pathways 22
- Chapter 1 Vitamin A Metabolism, Storage and Tissue Delivery Mechanisms 24
  - I. Introduction 24
  - II. Vitamin A Metabolism Relevant to its Storage 25
  - III. Vitamin A Storage 31
  - IV. Vitamin A Transport in the Circulation 40
  - V. Integration within the Intact Organism of Vitamin A Metabolism, Storage and Transport 45
  - References 46
  - Acknowledgments 46

Title Page 6
Copyright Page 7
Contents 8
Contributors 12
Preface 16
Part I Vitamin A Metabolic and Enzymatic Pathways 22
- Chapter 1 Vitamin A Metabolism, Storage and Tissue Delivery Mechanisms 24
  - I. Introduction 24
  - II. Vitamin A Metabolism Relevant to its Storage 25
  - III. Vitamin A Storage 31
  - IV. Vitamin A Transport in the Circulation 40
  - V. Integration within the Intact Organism of Vitamin A Metabolism, Storage and Transport 45
  - References 46
  - Acknowledgments 46
- Chapter 2 Assimilation and Conversion of Dietary Vitamin A into Bioactive Retinoids 56
  - I. Introduction 56
  - II. Dietary Sources of Vitamin A and Provitamin A Carotenoids 57
  - III. Intestinal Absorption and Metabolism of Dietary Vitamin A and Provitamin A Carotenoids 58
  - IV. Formation of β-Apocarotenoids 64
  - V. Possible Biological Functions of Apocarotenoids 70
  - VI. Conclusions and Perspectives 71
  - Acknowledgments 72
  - References 72
- Chapter 3 Intracellular Storage and Metabolic Activation of Retinoids: Lipid Droplets 78
  - I. Introduction 78
  - II. Multilocular Lipid Droplets 78
  - III. The Mitochondrial-Associated Membrane 80
  - IV. Birth of Lipid Droplets 81
  - V. Lipid Droplets and Retinoid Homeostasis 83
  - VI. In the Absence of Lipid Droplets, LRAT and RDH1 Localize with the ER, Whereas CRBP1 and RDH10 Localize with Mitotracker 85
  - VII. During Acyl Ester Biosynthesis LRAT, CRBP1 and RDH10 Associate with LIPID Droplets 86
  - VIII. Lipid Droplet Association Activates RDH10 88
  - IX. Lipid Droplet Association Requires the N-termini of LRAT and RDH10 89
  - X. Summary 90
  - XI. Conclusions and Future Directions 91
  - References 91
- Chapter 4 Evolution of the Retinoic Acid Signaling Pathway 96
  - I. Introduction 96
  - II. An Overview of Chordate Retinoid Metabolism 97
  - III. Retinoic Acid Signaling in Chordates 99
  - IV. Evolution of Retinoic Acid Signaling 101
  - V. Conclusions 105
  - Acknowledgments 106
  - References 106
- Part II Biochemistry and Cellular Biology of Retinoic Acid Signaling 112
  - Chapter 5 Control of Gene Expression by Nuclear Retinoic Acid Receptors: Post-Translational and Epigenetic Regulatory Mechanisms 114
    - I. Introduction 114
    - II. The Basics of Rar Structure 115
    - III. Repressive Epigenetic Landscape of Rar Target Genes in the Absence of Retinoic Acid 116
    - IV. Reorganization of the Epigenetic Landscape after Retinoic Acid Addition 119
    - V. Noncoding RNAs in the Regulation of the Epigenetic Landscape 121
    - VI. Back to a Repressive Epigenetic Landscape when Transcription Turns “OFF” 122
    - VII. Phosphorylation: Another Post-Translational Modification Code Induced by Retinoic Acid 123
    - VIII. Two Models for the Activation of RAR Target Genes Via a Sea of Post-Translational Modifications and Epigenetic Changes 127
    - IX. Aberrant Epigenics in Cancer: Consequences on the Retinoic Acid Response 130
    - X. Conclusion and Future Prospects 131
    - References 131
  - Chapter 6 Retinoic Acid Receptor Coregulators in Epigenetic Regulation of Target Genes 138
    - I. Introduction 138
    - II. Coregulators OF RARs and RXRs 139
    - III. Coregulators in Epigenetic Regulation 143
    - IV. The Future 146
    - References 147
    - Acknowledgments 147
  - Chapter 7 Retinoid Receptors: Protein Structure, DNA Recognition and Structure–Function Relationships 152
    - I. Introduction 152
    - II. General Organization of Retinoid Receptors 153
    - III. Structure of Full-Length RAR–RXR–DNA Complexes 159
    - IV. Coregulator Binding 161
    - V. Structural Basis for Allosteric Control Mechanisms of Cofactor Binding 164
    - References 166
    - VI. Conclusions 166
  - Chapter 8 How the RAR–RXR Heterodimer Recognizes the Genome 172
    - I. Introduction 172
    - II. Hormone Response Elements 173
    - III. VDR and TR Occupy DR3 and DR4 Elements in Cultured Cells 174
    - IV. PPAR and LXR Prefer Nonconsensus Elements 176
    - V. Genomic Binding of the RAR–RXR Heterodimer 177
    - VI. Summary and Conclusions 181
    - Acknowledgments 182
    - References 182
  - Chapter 9 Retinoid Receptor-Selective Modulators: Chemistry, 3D Structures and Systems Biology 186
    - I. Introduction 186
    - II. RXR Versus RAR Selectivity as a Function of the Ligand-Binding Pocket Architectures 188
    - III. Systems Biology of Retinoid Action 201
    - IV. Conclusions 207
    - References 208
    - Acknowledgments 208
  - Chapter 10 Use of Retinoid Receptor Ligands to Identify Other Nuclear Receptor Ligands: Retinoid-Related Molecules are Ligands f 214
    - I. Introduction 214
    - II. Nuclear Receptor and Ligand Similarities 216
    - III. Apoptosis Induction by AHPN 217
    - IV. Structure–Activity Relationship Studies Leading to a Preclinical Candidate 218
    - V. Identification of Small Heterodimer Partner (SHP) as a Retinoid-Related Molecule (RRM) Target 232
    - VI. Small Heterodimer Partner Structure and Function 233
    - VII. Construction of a Small Heterodimer Partner Model to Facilitate Ligand Design 234
    - VIII. Retinoid-Related Molecule Mechanism of Action Studies 237
    - X. Retinoid-Related Molecule Mechanism of Action Studies by Other Groups 238
    - IX. Additional Targets of Retinoid-Related Molecules 238
    - XI. Investigations on the Mechanism of Action of Small Heterodimer Partner in the Absence of an Added Retinoid-Related Molecule 272
    - References 287
  - Chapter 11 The Dual Transcriptional Activity of Retinoic Acid 294
    - I. Retinoic Acid Receptors: PPARβ/δ Joins Rars 294
    - II. Retinoic Acid-Binding Proteins: CRABP2 and FABP5 Cooperate with RAR and PPARβ/δ 295
    - III. Biological Activities of Retinoic Acid Critically Rely on Precise Balance between its Dual Transcriptional Pathways 300
    - Acknowledgments 306
    - References 306
    - IV. Conclusions 306
  - Chapter 12 Retinoids, Epigenetic Changes During Stem Cell Differentiation, and Cell Lineage Choice 312
    - I. Introduction 312
    - II. Retinoic Acid Signaling is Associated with Transcriptional Activation and Epigenetic Changes in Stem Cells 313
    - III. Retinoids and Epigenetic Modifications 314
    - IV. Retinoic Acid and the Differentiation of Embryonic Stem Cells Along Various Lineages: Six Examples 318
    - V. Determinants of the Stability of the Differentiated Phenotype 321
    - VI. Summary and Future Directions 322
    - Acknowledgments 322
    - References 322
  - Part III Retinoic Acid Signaling in Development 328
    - Chapter 13 Retinoic Acid Signaling and Central Nervous System Development 330
      - I. Introduction 330
      - II. The Beginning of Retinoic Acid Signaling at Early Node Stages (Figure 13.1A, hn) 331
      - III. Retinoic Acid Signaling as the Neural Plate Forms and Undergoes Anteroposterior Patterning (Figure 13.1B, np) 333
      - IV. Hindbrain Specification (Figure 13.1C, hb) 336
      - V. The Hindbrain Gradient of Retinoic Acid (Figure 13.1C, hb) 337
      - VI. Spinal Cord Formation and Patterning at the Posterior End of the Embryo (Figure 13.1C, 13.1D, cs) 339
      - VII. Dorsoventral Patterning in the Spinal Cord and Motor Neuron Specification (Figure 13.1D, sc) 340
      - VIII. Return to the Front of the Embryo: Outgrowth of the Telencephalon (Figure 13.1E, fn) 343
      - IX. Olfactory Development (Figure 13.1E, olf) 344
      - X. The Eye (Figure 13.1E, 13.1F) 345
      - XI. Patterning Within the Telencephalon: The Lateral Ganglionic Eminence (Figure 13.1F, lge) 347
      - XII. The Later Hindbrain and Cortex (Figure 13.1F) 348
      - XIII. Conclusion 349
      - References 350
    - Chapter 14 The Role of Retinoic Acid in Limb Development 360
      - II. Enzymes and Receptors for Retinoic Acid Synthesis and Signaling 360
      - I. Introduction 360
      - III. Genetic Models for Investigation of Retinoic Acid Function During Limb Development 362
      - IV. Retinoic Acid is not Required for Limb Axial Patterning 363
      - V. Forelimb Induction Requires Retinoic Acid Signaling 365
      - VI. Retinoic Acid is Required for Interdigital Development 367
      - Acknowledgments 368
      - VII. Conclusions 368
      - References 369
    - Chapter 15 Retinoic Acid Signaling and Heart Development 374
      - I. Introduction 374
      - II. Early Functions in Formation and Patterning of the Second Heart Field 375
      - III. The Epicardium: A Source of Ra-Regulated Signals Controlling Myocardial Cell Proliferation and Differentiation 379
      - IV. Actions on Progenitor Cell Populations 382
      - V. Interactions with Other Signaling Pathways: Clues to Congenital Malformations 383
      - VI. Conclusions and Perspectives 385
      - Acknowledgments 385
      - References 386
    - Chapter 16 Retinoic Acid in the Developing Lung and Other Foregut Derivatives 392
      - I. Introduction 392
      - II. From Patterning of the Foregut to Lung Development 393
      - III. Retinoic Acid Signaling Controls a Gene Network Crucial for Early Lung Development 393
      - IV. Involvement of Retinoic Acid in Branching Morphogenesis and Lung Epithelial Differentiation 396
      - V. Other Functions of Retinoic Acid in Lung Development 397
      - VI. Retinoic Acid in Postnatal Lung Development and Lung Repair 398
      - VII. Distinct Roles for Retinoic Acid in Organogenesis of Other Foregut Derivatives 399
      - References 400
      - VIII. Conclusions 400
      - Acknowledgments 400
    - Chapter 17 Retinoic Acid and the Control of Meiotic Initiation 404
      - I. Introduction 404
      - II. Germ Cells and Meiosis 405
      - III. A Role for Retinoic Acid in Initiating Meiosis in the Fetal Ovary 406
      - IV. What is the Source of Retinoic Acid in the Ovary? 408
      - V. What About Meiosis in the Testis? 408
      - VI. Retinoic Acid Triggers Meiosis in a Range of Vertebrates 410
      - VII. Why do Only Germ Cells Respond to Retinoic acid by Upregulating Stra8? 411
      - VIII. Is there Sufficient Retinoic Acid in the Mouse Fetal Ovary to Trigger Stra8 Expression? 412
      - IX. Other Factors Involved in Induction of Meiosis in the Fetal Gonad 413
      - X. Conclusions 415
      - References 416
    - Part IV Retinoids and Physiological Functions 422
      - Chapter 18 Retinoids and the Visual Cycle: New Actors for an “Old” Function 424
        
        I. Introduction 424
        
        II. Carotenoid Cleaving Enzymes 426
        
        III. Absorption and Transport of Chromophore Precursors 428
        
        IV. The “Canonical” Visual Cycle 430
        
        V. An Alternative Visual Cycle for Cones 433
        
        VI. Conclusions 433
        
        References 434
      - Chapter 19 Retinoid Signaling in the Central Nervous System 442
        
        I. Introduction 442
        
        II. Retinoic Acid and Regulation of Neuronal Function 443
        
        III. Retinoic Acid and Regulation of Glial Function 445
        
        IV. Regionalization of Retinoic Acid Signaling in the Brain 446
        
        V. Role of Retinoic Acid in Central Nervous System Physiology and Disease 453
        
        References 458
        
        VI. Conclusion 458
      - Chapter 20 Retinoid Turnover and Catabolism: Influences of Diet and Inflammation 470
        
        I. Introduction 470
        
        II. Interactions and Interference between Vitamin A Transport and Inflammation 471
        
        III. Modulation by Diet and Inflammation of Genes that Regulate Retinoid Storage and Oxidation 477
        
        Acknowledgments 481
        
        References 481
        
        IV. Conclusion 481
      - Chapter 21 Retinoids and the Immune System 486
        
        I. Introduction 486
        
        II. Role of Retinoic Acid in Lymphocyte Migration (Homing) to the Gut 487
        
        III. Retinoic Acid Effects on T and B Cell Differentiation upon Activation 490
        
        IV. Differentiation of Retinoic Acid-Producing Dendritic Cells in Gut-Associated Tissues 493
        
        V. Roles of Retinoic Acid in Immune Protection, Inflammation, and Tolerance 496
        
        VI. Summary and Conclusions 498
        
        References 499
        
        Acknowledgments 499
      - Chapter 22 Retinoic Acid Receptor Signaling in Post-Natal Male Germ Cell Differentiation 506
        
        I. Introduction 506
        
        II. The Seminiferous Epithelium 507
        
        III. Vitamin a Signaling in the Seminiferous Epithelium 508
        
        IV. RARα AND RXRβ Play Crucial Functions in Sertoli Cells 510
        
        V. RARα and RARγ, but not RARβ, Are Crucial in Germ Cells 515
        
        VI. Conclusions 519
        
        References 520
      - Part V Retinoids, Disease and Therapy 526
        
        Chapter 23 Epidemiology and Prevention of Vitamin A Deficiency Disorders 528
        
        I. Introduction 528
        
        II. Extent of Vitamin a Deficiency 529
        
        III. Vitamin A Deficiency Disorders 531
        
        IV. Risk Factors for VA Deficiency 537
        
        V. Prevention 538
        
        VI. Conclusion 542
        
        References 542
        
        Chapter 24 Retinoid Pathway Gene Mutations and the Pathophysiology of Related Visual Diseases 550
        
        I. Introduction 550
        
        II. Retinal Diseases Associated with Impaired Visual Cycle 552
        
        III. Therapeutic Strategies for Disorders Caused by an Impaired Visual Cycle 558
        
        Acknowledgments 560
        
        References 560
        
        Chapter 25 Retinoic Acid in Acute Myeloid Leukemias 564
        
        I. Introduction 564
        
        III. The Standard Approach: RA and Chemotherapy 565
        
        II. Diagnosis of Apl 565
        
        IV. Arsenic Combined to RA 566
        
        VI. Pathogenesis of APL 567
        
        V. From Treatment to Biology: The X-RARA Fusions 567
        
        VII. Basis of Retinoic Acid Response 569
        
        VIII. A Role for Retinoic Acid in Other Acute Myeloid Leukemias? 571
        
        IX. Conclusions 571
        
        References 571
        
        Chapter 26 Advances in the Use of Retinoids in Cancer Therapy and Prevention 578
        
        I. Introduction 578
        
        II. History of Retinoids in Cancer 579
        
        III. Cancers in Which Retinoids Have Therapeutic Activity 580
        
        IV. Role of Retinoids as Cancer Preventive Agents 582
        
        V. Recent Advances and Mechanistic Insights on the Use of Retinoids to Treat and Prevent Cancer 585
        
        VI. Summary: Current and Future Place for Retinoids in Cancer Therapy and Prevention 587
        
        References 590
        
        Acknowledgments 590
        
        Index 596
        
        Supplemental Images 607
        
        EULA 635

Biology, Biochemistry, and Disease

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