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

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 Pitie-Salpetriere 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 Pitie-Salpetriere 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.

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 sPLA 2 Inhibitors / 480 Endothelial Lipase Inhibitors / 481 LpPLA 2 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