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High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics

ISBN: 978-0-470-40821-6
648 pages
January 2012
High-Density Lipoproteins: Structure, Metabolism, Function and Therapeutics (0470408219) cover image

A complete guide to the role of high-density lipoproteins (HDL) in new and emerging therapies

With high-density lipoproteins (HDL) playing an increasing role in cardiovascular disease prevention, there is a growing need for an in-depth look at HDL and its clinical value. This book summarizes the current state of knowledge in the field, providing for the first time a comprehensive, systematic, stylistically coherent, and up-to-date review of the composition, structure, heterogeneity, metabolism, epidemiology, genetics, and function of HDL.

Divided into three main parts, High-Density Lipoproteins first examines normal HDL particles, then describes defective HDL, and finally addresses the therapeutic normalization of subnormal levels and defective biological activities of this lipoprotein class. The book highlights the functional properties of HDL, which are relevant to the pathophysiology of atherosclerosis and thrombosis, and discusses the compositional and metabolic heterogeneity of HDL particles.

Readers will come away with a clear understanding of the role of HDL in biological processes, the potential value of functional HDL as a therapeutic target, and how current and emerging therapies are poised to influence the treatment of heart disease in the future.

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PREFACE xv

ACKNOWLEDGMENTS xxxi

ABBREVIATIONS xxxiii

SECTION 1 NORMAL FUNCTIONAL HIGH-DENSITY LIPOPROTEIN 1

1 COMPOSITION 3

1.1 Proteome / 9

Apolipoproteins / 9

Apolipoprotein A-I / 9

ApoA-II / 9

ApoA-IV / 9

ApoA-V / 10

ApoC-I, ApoC-II, ApoC-III, ApoC-IV / 12

ApoD / 12

ApoE / 13

ApoF / 14

ApoH / 14

ApoJ / 14

ApoL-I / 15

ApoM / 15

Other Apolipoproteins / 15

Enzymes / 16

LCAT / 16

PON1 and PON3 / 16

PAF-AH (LpPLA2) / 17

GSPx-3 / 18

Lipid Transfer Proteins / 18

PLTP / 18

CETP / 19

Acute-Phase Response Proteins / 19

Serum Amyloid A / 19

Other Proteins / 20

Complement Components / 21

Proteinase Inhibitors and Related Proteins / 23

Other Protein Components / 25

1.2 Lipidome / 27

Phospholipids / 27

Steroids / 28

Cholesteryl Esters / 28

Triglycerides / 28

Minor Lipids / 28

2 HETEROGENEITY 39

2.1 Heterogeneity in Physicochemical Properties / 42

Heterogeneity in Density / 42

Heterogeneity in Electrophoretic Mobility / 43

Heterogeneity in Size / 45

2.2 Heterogeneity in Chemical Composition / 47

Heterogeneity in Proteins / 47

Heterogeneity in Lipids / 49

2.3 Relationships Between HDL Subfractions Separated by Different Methods / 50

3 STRUCTURE 59

3.1 Lipid-Free ApoA-I / 59

3.2 Discoid HDL / 62

3.3 Spherical HDL / 66

4 METABOLISM 74

4.1 Formation and Intravascular Remodeling / 74

ABC Transporters / 77

ABCA1 / 77

ABCG1 / 85

Enzymes / 86

LCAT / 86

Lipases / 88

Lipid Transfer Proteins / 90

CETP / 90

PLTP / 92

Receptors / 93

SR-BI / 93

4.2 Catabolism / 96

5 EPIDEMIOLOGY 113

5.1 Epidemiology of HDL-C / 113

HDL-C and Cardiovascular Risk / 113

Relevance Across Multiple Populations and Disease States / 116

HDL-C and Other Cardiovascular Risk Factors / 120

Prevalence of Low HDL-C / 122

HDL-C and Cardiovascular Risk in Patients Receiving Statins / 123

HDL-C and Other Major Diseases / 125

5.2 Epidemiology of HDL-Associated Proteins and Enzymes / 126

ApoA-I / 126

Other Apolipoproteins / 129

SAA / 130

PON1 / 130

PAF-AH / 131

Other Enzymes / 133

Lipid Transfer Proteins / 133

5.3 Epidemiology of HDL Particle Subpopulations / 134

Separated by Density / 134

Separated by Electrophoretic Mobility / 135

Separated by Composition / 135

Separated by Size / 135

6 GENETICS 161

6.1 ABC Transporters and Other Receptors / 165

ABCA1 / 165

SR-BI / 167

LDL Receptor / 167

6.2 Apolipoproteins / 167

ApoA-I / 167

ApoA-V / 168

ApoC-III / 168

ApoE / 168

6.3 Enzymes / 169

LCAT / 169

PON1 / 169

LPL / 170

Hepatic Lipase / 171

Endothelial Lipase / 171

6.4 Lipid Transfer Proteins / 172

CETP / 172

6.5 Other Genes / 174

6.6 Gene Interactions / 176

7 BIOLOGIC ACTIVITIES 192

7.1 Cholesterol Efflux Capacity / 197

Mechanisms of Cellular Cholesterol Efflux / 199

ABCA1-Mediated Efflux / 199

ABCG1-Mediated Efflux / 203

SR-BI-Mediated Efflux / 204

Other Pathways / 205

Role of HDL Components / 206

Proteins / 206

Lipids / 208

Functional Heterogeneity of HDL / 210

7.2 Antioxidative Activity / 213

Mechanisms of Protection Against Oxidative Stress / 216

Role of HDL Components / 219

Apolipoproteins / 219

Enzymes / 220

Lipids / 223

Functional Heterogeneity of HDL / 224

7.3 Anti-Inflammatory Activity / 226

Mechanisms of Anti-Inflammatory Protection / 231

Role of HDL Components / 234

Proteome / 234

Lipidome / 235

Functional Heterogeneity of HDL / 236

7.4 Cytoprotective Activity / 236

Mechanisms of Cytoprotection / 238

Role of HDL Components / 241

Proteome / 241

Lipidome / 241

Functional Heterogeneity of HDL / 242

7.5 Anti-Infectious Activity / 243

Mechanisms of Protection from Infection / 245

Role of HDL Components / 246

Proteome / 246

Lipids / 248

Functional Heterogeneity of HDL / 248

7.6 Vasodilatory Activity / 249

Mechanisms of Vasodilatory Activity / 250

Role of HDL Components / 252

Proteins / 252

Lipids / 252

Functional Heterogeneity of HDL / 253

7.7 Antithrombotic Activity / 253

Mechanisms of Antithrombotic Effects / 256

Role of HDL Components / 257

Functional Heterogeneity of HDL / 258

7.8 Antidiabetic Activity / 259

SECTION 2 FUNCTIONALLY DEFECTIVE HDL 305

8 ALTERED COMPOSITION 307

8.1 Proteome / 307

8.2 Lipidome / 311

8.3 Enzymatic Activities / 313

9 ABNORMAL METABOLISM 329

9.1 Dyslipidemias / 329

9.2 Insulin-Resistant States / 337

9.3 Inflammatory States / 339

9.4 Infectious Diseases / 341

9.5 Cardiovascular Disease / 342

9.6 Post-Prandial State / 343

9.7 Smoking / 344

10 IMPAIRED BIOLOGIC ACTIVITIES 360

10.1 Cholesterol Efflux Capacity / 361

Dyslipidemia / 361

Role of HDL Components / 364

Insulin Resistance / 365

Role of HDL Components / 367

Inflammation / 369

Cardiovascular Disease / 372

Pathophysiologic Relevance / 373

10.2 Antioxidative Activity / 373

Dyslipidemia / 373

Role of HDL Components / 374

Insulin Resistance / 376

Role of HDL Components / 376

Inflammation / 379

Infection / 380

Cardiovascular Disease / 380

Pathophysiologic Relevance / 381

10.3 Anti-Inflammatory Activity / 382

Dyslipidemia / 382

Insulin Resistance / 385

Inflammation / 386

Cardiovascular Disease / 388

Pathophysiologic Relevance / 389

10.4 Cytoprotective Activity / 391

10.5 Vasodilatory Activity / 392

10.6 Anti-Infectious Activity / 394

10.7 Antithrombotic Activity / 395

SECTION 3 THERAPEUTIC NORMALIZATION OF SUBNORMAL LEVELS AND DEFECTIVE BIOLOGIC ACTIVITIES OF HDL 417

11 ENHANCEMENT OF HDL FORMATION AND NORMALIZATION OF INTRAVASCULAR HDL REMODELING 423

11.1 Apolipoproteins / 423

11.2 Reconstituted HDL / 428

Effects on HDL Levels and Metabolism / 428

Effects on HDL Functionality / 430

Role of HDL Components / 432

11.3 Apolipoprotein-Mimetic Peptides / 434

Effects on HDL Levels and Metabolism / 434

Effects on HDL Functionality / 434

11.4 Statins / 440

Effects on HDL Levels and Metabolism / 440

Effects on HDL Functionality / 444

Clinical Trials / 446

11.5 PPAR Alpha Agonists / 447

Effects on HDL Levels / 447

Mechanisms of Action / 448

Effects on HDL Functionality / 451

Clinical Trials / 452

11.6 Nicotinic Acid / 454

Mechanisms of Action / 455

Clinical Trials / 458

Effects on HDL Functionality / 460

Adverse Effects / 461

11.7 CETP Inhibitors / 463

Torcetrapib / 464

Dalcetrapib / 467

Anacetrapib / 467

Effects on RCT / 469

Clinical Trials / 471

Effects on HDL Functionality / 474

11.8 Other Agents / 477

LXR Agonists / 477

PPAR Gamma Agonists / 478

Lipase Inhibitors / 479

sPLA2 Inhibitors / 480

Endothelial Lipase Inhibitors / 481

LpPLA2 Inhibitors / 481

SR-BI Inhibitors / 482

Others / 483

12 COMBINATION THERAPIES 524

12.1 Niacin and Statins / 524

12.2 Fibrates and Statins / 527

12.3 Other Combinations / 528

13 OTHER PHARMACOLOGIC APPROACHES 533

13.1 Cannabinoid Type 1 Receptor Antagonists / 533

13.2 Estrogens / 536

13.3 Others / 538

14 LIFESTYLE MODIFICATIONS 542

14.1 Exercise / 542

14.2 Alcohol / 546

14.3 Nutritional Factors / 548

Dietary Fats / 548

Cholesterol / 548

Phospholipids / 549

Saturated Fatty Acids / 549

Monounsaturated Fatty Acids / 550

PUFAs / 550

Carbohydrates / 552

Proteins / 553

Minor Dietary Components / 554

Polyphenols / 554

Vitamins / 556

Other Minor Components / 556

CONCLUSIONS AND PERSPECTIVES 572

INDEX 577

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Anatol Kontush, BSc (Hons), PhD, is Research Director at the Dyslipidemia and Atherosclerosis Research Unit of the National Institute of Health and Medical Research (INSERM) at the Pitié-Salpêtrière Hospital, Paris, France. An award-winning scientist, Dr. Kontush has authored more than 100 original papers and book chapters.

M. John Chapman, BSc, PhD, DSc, FESC, is President of the European Atherosclerosis Society and Director of the Dyslipidemia and Atherosclerosis Research Unit of the National Institute of Health and Medical Research (INSERM) at the Pitié-Salpêtrière Hospital in Paris, France, affiliated with the medical faculty of the Pierre and Marie Curie University, Paris. He has authored more than 400 articles and book chapters.

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“In summary, the need for this book is immense: It is an encyclopedia where everyone working in or near the field can quickly find the fact or reference they need. It is a textbook one can give to a student on the first day in the lab. It is a novel that can be read when running out of controversies in your own field.”  (ChemMedChem, 1 April 2013)

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