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THE HDL HANDBOOK: Biological Functionsand Clinical Implications

THE HDL HANDBOOK: Biological Functionsand Clinical Implications

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CONTENTS

LIST OF CONTRIBUTORS

PREFACE

1 - Molecular Mechanisms of Hyperalphalipoproteinemia

1. INTRODUCTION

2. REGULATION OF PLASMA HDL-CHOLESTEROL LEVELS AND MODIFICATION OF HDL

3. MULTIPLE FUNCTIONS OF HDL AND APO A-I

4. FUNCTIONAL HDL AND DYSFUNCTIONAL HDL

5. MOLECULAR MECHANISMS OF HALP

5.1 Primary HALP

5.1.1 Familial CETP Deficiency

5.1.2 Hepatic Lipase Deficiency

5.1.3 Familial HALP With Premature Corneal Opacity (Combined Deficiency of CETP and HL Activity)

5.1.4 Familial HALP With Genetic Abnormalities in the EL Gene (LIPG)

5.1.5 Familial HALP With Genetic Mutations in the SR-BI Gene

5.1.6 Familial HALP Caused by Increased Production of Apo A-I

5.1.7 Familial HALP With Reduced Uptake of HDL by Lymphocytes

5.1.8 Familial HALP With Apo C-III Gene Mutations

5.1.9 Variants at the GALNT2 Locus Associated With High HDL-C Levels

5.2 Secondary HALP

5.2.1 Primary Biliary Cirrhosis

5.2.2 Chronic Heavy Alcohol Drinking

5.2.3 HALP Caused by Plasma Inhibitors of CETP

5.2.4 Other Factors or Disease Statuses Accompanied by HALP

5.2.5 Drugs

6. CONCLUSION

LIST OF ABBREVIATIONS

ACKNOWLEDGMENTS

REFERENCES

2 - CETP Deficiency and Concerns in CETP Inhibitor Development

1. INTRODUCTION

2. NEW FINDINGS IN FUNCTION AND REGULATION OF CETP

3. CORONARY ARTERY DISEASE AND AGE-ASSOCIATED MACULAR DEGENERATION DISEASE RISK IN ASSOCIATION WITH CETP GENE (TABLE 2.1)

4. ROLE OF CETP ACTIVITY IN ADIPOCYTE, METABOLIC SYNDROME, AND DIET THERAPY FOR WEIGHT REDUCTION

5. HDL FUNCTION AND ANTIINFLAMMATORY EFFECTS IN CETP DEFICIENCY AND CETP INHIBITOR (FIG. 2.1)

6. SMALL AND DENSE LDL, LP(A), AND PROPROTEIN CONVERTASE SUBTILISIN/KEXIN 9 LEVELS IN CETP DEFICIENCY AND CETP INHIBITORS (FIG. ...

7. EFFECTS ON REVERSE CHOLESTEROL TRANSPORT OF CETP INHIBITORS

8. OFF-TARGET EFFECTS AND VASCULAR EFFECTS OF CETP INHIBITORS

9. NEW THERAPY INHIBITING CETP ACTIVITY BY OTHER THAN LOW MOLECULAR WEIGHT COMPOUNDS AND SELECTIVE TG TRANSFER INHIBITION

10. CONCLUSION

REFERENCES

3 - Degenerated HDL and Its Clinical Implications

1. INTRODUCTION

2. STRUCTURAL ALTERATIONS IN HDL COMPONENTS CAUSED BY OXIDATION

2.1 Oxidation of HDL

2.2 Oxidation-Induced Changes in Apoproteins

2.3 Changes in Lipids Caused by Oxidation

2.4 Changes in Other Components Caused by Oxidation

3. FUNCTIONAL ALTERATIONS IN HDL BY OXIDATION

3.1 Reverse Cholesterol Transport

3.2 Antioxidant Activity

3.3 Nitric Oxide Generation

3.4 Antiinflammatory Effects

3.5 Other Functions

4. CONCLUSION

REFERENCES

4 - HDL Apoprotein Mimetic Peptides as Antiinflammatory Molecules

1. INTRODUCTION

2. APOA-I AND THE HISTORY OF ITS DERIVED MIMETIC PEPTIDES

3. ANTIATHEROGENIC EFFECTS OF APOA-I MIMETIC PEPTIDES

4. THE FORM OF PEPTIDES EFFECTIVE FOR REDUCTION OF ATHEROSCLEROSIS

5. ANTIATHEROGENIC FUNCTIONS OF APOA-I MIMETIC PEPTIDES

5.1 Reduction of Oxidative Stress

5.2 The Role of Reverse Cholesterol Transport (Cholesterol Efflux) in Mediating the Efficacy of Mimetic Peptides

5.2.1 Monohelical Peptides

5.2.2 Tandem ApoA-I Peptides

5.3 Antiinflammatory Properties of ApoA-I-Derived Mimetic Peptides

6. HYBRID AND APOE MIMETICS

6.1 Single Domain Peptides

6.2 Dual Domain Peptides

7. ADDITIONAL APOPROTEIN-RELATED MIMETIC PEPTIDES

8. CONCLUSIONS

LIST OF ABBREVIATIONS

REFERENCES

5 - Reverse Cholesterol Transport in HDL Metabolism: Relevance to Atherosclerosis Progression and Cardiovascular Diseases

1. INTRODUCTION

2. RELATIONSHIP BETWEEN MACROPHAGE CHOLESTEROL EFFLUX AND CARDIOVASCULAR DISEASES

2.1 Cellular Cholesterol Efflux Pathways

2.1.1 Passive Diffusion

2.1.2 ABCA1 Pathway

2.1.3 ABCG1 Pathway

2.1.4 SR-BI/CLA-1 Pathway

2.2 Interactions Between Efflux Pathways

2.2.1 Interactions Between ABCA1 and ABCG1

2.2.2 Interactions Between SR-BI and ABCG1 and ABCA1

2.3 Relative Contribution of Each Efflux Pathway

2.4 Various Cellular Cholesterol Efflux Acceptors

2.5 Cholesterol Efflux and Atherosclerosis

3. RELATIONSHIP BETWEEN CETP-MEDIATED CE TRANSFER FROM HDL TO APOB-CONTAINING LIPOPROTEINS AND CARDIOVASCULAR DISEASES: CETP A P...

3.1 Proatherogenic Evidence From Animal studies

3.2 Antiatherogenic Evidence From Animal Studies

3.3 Is CETP Anti- or Proatherogenic in Humans?

3.3.1 Reduction in Plasma CETP Activity or Mass

3.3.2 Elevation in Plasma CETP Activity or Mass

3.4 Pharmacological CETP Inhibition

3.4.1 CETP Inhibitors

3.4.2 Impact of CETP Inhibition on Atherosclerosis

3.4.3 Impact of CETP Inhibition on HDL Function

4. CONCLUSION

REFERENCES

6 - Role of ATP-Binding Cassette Transporters A1 and G1 in Reverse Cholesterol Transport and Atherosclerosis

1. INTRODUCTION

2. THE ROLE OF REVERSE CHOLESTEROL TRANSPORT IN LIPID METABOLISM

3. MAJOR PATHWAYS FOR CELLULAR CHOLESTEROL EFFLUX

4. MECHANISMS FOR CHOLESTEROL EFFLUX AND GENERATION OF NASCENT HDL: ROLE OF ABCA1

5. MECHANISMS FOR MATURATION OF HDL PARTICLE AND MAINTENANCE OF CIRCULATING HDL LEVELS: ROLE OF ABCA1

6. THE ROLE OF ABCG1 IN CHOLESTEROL EFFLUX AND HDL METABOLISM

7. TRANSCRIPTIONAL REGULATION OF ABCA1/G1

8. POSTTRANSCRIPTIONAL/POSTTRANSLATIONAL REGULATION OF ABCA1/G1

9. THE ROLE OF ABCA1/G1 IN REVERSE CHOLESTEROL TRANSPORT AND ATHEROSCLEROSIS IN ANIMAL MODELS

10. THE ROLE OF ABCA1/G1 IN ATHEROSCLEROSIS IN HUMANS

11. THERAPEUTIC STRATEGIES AGAINST ATHEROSCLEROSIS INVOLVING RCT MODIFICATION

12. CONCLUSION

LIST OF ABBREVIATIONS

REFERENCES

7 - Sphingosine-1-Phosphate and HDL Metabolism

1. INTRODUCTION

2. BIOSYNTHESIS AND REGULATION OF S1P

3. EXPORT OF S1P

4. S1P AND ITS RECEPTORS

5. PLASMA S1P

6. S1P AND APOM

7. S1P AND METABOLIC DISEASES

7.1 S1P and CVD

7.2 Role for S1P in Diabetes and Obesity

7.3 S1P and Other Diseases

8. CONCLUSION

REFERENCES

8 - Role of SR-BI in HDL Metabolism

1. INTRODUCTION

2. ROLE OF SR-BI IN REVERSE CHOLESTEROL TRANSFER

3. SR-BI—A BIDIRECTIONAL CHOLESTEROL TRANSPORTER

4. ROLE OF SR-BI IN HDL UPTAKE AND TRANSCYTOSIS

5. SR-BI MEDIATES SELECTIVE CHOLESTERYL ESTER UPTAKE

6. CONCLUSIONS

ACKNOWLEDGMENTS

REFERENCES

9 - Paraoxonase 1 and Its Clinical Relevance

1. INTRODUCTION: THE HDL CHOLESTEROL GORDIAN KNOT: PARAOXONASE 1 TO THE RESCUE?

2. PON1 IS A KEY ANTIOXIDANT IN HDL

3. PON1 POLYMORPHISMS HAVE LITTLE IMPACT ON CVD, WHEREAS PON1 ACTIVITY IS A PREDICTOR

4. PON1 ACTIVITY IS LOWER IN DISEASES ASSOCIATED WITH CVD

5. PON1 INTERACTION WITH MYELOPEROXIDASE: A NEW LINK BETWEEN INFLAMMATION AND ATHEROSCLEROSIS?

6. BEYOND TOTAL PON1 ACTIVITY: PON1 IN HDL SUBCLASSES

7. CETP INHIBITORS PREVENT PON1 ACTIVATION DURING HDL MATURATION: A LIKELY EXPLANATION FOR THEIR FAILURE?

8. PON1 IN APOB-CONTAINING LIPOPROTEINS: A ROLE FOR PON1 IN SMALL-DENSE LDL?

9. CONCLUSION AND PERSPECTIVES: PON1 IN CLINICAL PRACTICE?

LIST OF ABBREVIATIONS

ACKNOWLEDGMENTS

REFERENCES

10 - MicroRNA Regulation of HDL Homeostasis

1. INTRODUCTION

2. MIRNAS

3. MIRNAS AND HDL METABOLISM

3.1 MiR-33

3.2 MiR-758

3.3 MiR-144

3.4 MiR-223

3.5 MiR-27b

3.6 MiR-302a

3.7 MiR-128-1 and MiR-148

3.8 Other MiRNAs

4. MIRNAS AS POTENTIAL THERAPEUTICS

4.1 Rescue MiRNA Expression

4.2 Inhibit MiRNA Expression

5. FUTURE CHALLENGES AND OPPORTUNITIES

6. CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

11 - The Application of Proteomic Techniques in the Study of HDL Particle Characterization and Biomarker Discovery

1. INTRODUCTION

2. PROTEOMIC APPROACHES TO THE STUDY OF HDL

3. GEL-BASED AND GEL-FREE PROTEOMICS

3.1 Quantitative Proteomics

3.1.1 Label-Free Quantification

3.1.2 Stable Isotopic Label Quantification

3.1.3 Targeted Quantification

4. HDL COMPOSITION AND ITS RELATION TO DISEASES

4.1 Proteomic Cargo

4.2 Functionality

4.3 Subpopulations

4.4 HDL Proteome in Disease

4.4.1 HDL Analysis in Cardiovascular Diseases

4.4.2 HDL Analysis in Renal Disease

4.4.3 HDL Analysis in Rheumatoid Arthritis

4.4.4 HDL Analysis in Endotoxemia

4.4.5 HDL Analysis in Psoriasis

4.5 Modification of HDL by Treatments or Diet

4.5.1 Hemodialysis

4.5.2 HDL and Testosterone Replacement

4.5.3 HDL, Omega-3 Fatty Acids, and Olive Oil

4.5.4 Modification of the HDL Proteome by Statin and Niacin Therapy

5. CONCLUSION

ACKNOWLEDGMENTS

REFERENCES

12 - Therapies Targeting HDLc Levels and HDL Function

1. INTRODUCTION

2. SMALL MOLECULE PHARMACEUTICALS

2.1 Niacin

2.2 PPAR-α Agonists

2.2.1 Fibrates

2.2.2 New PPAR-α Agonists

2.3 CETP Inhibitors

2.4 LXR Agonists

2.5 RVX-208

3. APOA-I SMALL MIMETIC PEPTIDES

4. HDL INFUSION THERAPIES

4.1 ApoA-I Milano (MDCO-216)

4.2 CSL111 and CSL112

4.3 CER-001

4.4 Delipidated HDL

5. FUTURE DIRECTIONS IN HDL-RAISING THERAPY

5.1 LCAT Modulators

5.2 Antisense Oligonucleotides

5.3 miRNA Inhibition

6. CONCLUSIONS

REFERENCES

INDEX

A

B

C

D

E

F

G

H

I

K

L

M

N

O

P

Q

R

S

T

U

V

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