High Density Lipoproteins: From Biological Understanding to Clinical Exploitation

Handbook of Experimental Pharmacology 224

Arnold von Eckardstein

Dimitris Kardassis Editors

High Density

Lipoproteins

From Biological Understanding to

Clinical Exploitation

Handbook of Experimental Pharmacology

Volume 224

Editor-in-Chief

W. Rosenthal, Jena

Editorial Board

J.E. Barrett, Philadelphia

V. Flockerzi, Homburg

M.A. Frohman, Stony Brook, NY

P. Geppetti, Florence

F.B. Hofmann, Mu¨nchen

M.C. Michel, Ingelheim

P. Moore, Singapore

C.P. Page, London

A.M. Thorburn, Aurora, CO

K. Wang, Beijing

More information about this series at

http://www.springer.com/series/164

Arnold von Eckardstein • Dimitris Kardassis

Editors

High Density Lipoproteins

From Biological Understanding

to Clinical Exploitation

Editors

Arnold von Eckardstein

University Hospital Zurich

Institute of Clinical Chemistry

Zurich

Switzerland

Dimitris Kardassis

University of Crete Medical School

Iraklion, Crete

Greece

ISSN 0171-2004 ISSN 1865-0325 (electronic)

ISBN 978-3-319-09664-3 ISBN 978-3-319-09665-0 (eBook)

DOI 10.1007/978-3-319-09665-0

Springer Cham Heidelberg New York Dordrecht London

Library of Congress Control Number: 2014958300

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Preface

In both epidemiological and clinical studies as well as the meta-analyses thereof,

low plasma levels of high-density lipoprotein (HDL) cholesterol (HDL-C)

identified individuals at increased risk of major coronary events. Observational

studies also found inverse associations between HDL-C and risks of ischemic

stroke, diabetes mellitus type 2, and various cancers. In addition, HDLs exert

many effects in vitro and in vivo which protect the organism from chemical or

biological harm and thereby may interfere with the pathogenesis of atherosclerosis,

diabetes, and cancer but also other inflammatory diseases. Moreover, in several

animal models transgenic overexpression or exogenous application of apolipopro￾tein Α-I (apoA-I), the most abundant protein of HDL, decreased or prevented the

development of atherosclerosis, glucose intolerance, or tissue damage induced by

ischemia or mechanical injury.

However, as yet drugs increasing HDL-C such as fibrates, niacin, or inhibitors of

cholesteryl ester transfer protein have failed to consistently and significantly reduce

the risk of major cardiovascular events, especially when combined with statins.

Moreover, mutations in several human genes as well as targeting of several murine

genes were found to modulate HDL-C levels without changing cardiovascular risk

and atherosclerotic plaque load, respectively, into the opposite direction as

expected from the inverse correlation of HDL-C levels and cardiovascular risk in

epidemiological studies. Because of these controversial data, the pathogenic role,

and, hence, the suitability of HDL as a therapeutic target, has been increasingly

questioned. Because of the frequent confounding of low HDL-C with hypertrigly￾ceridemia, it has been argued that low HDL-C is an innocent bystander of (post￾prandial) hypertriglyceridemia or another culprit related to insulin resistance or

inflammation.

These complex relationships are depicted in Fig. 1. It is important to note that

previous intervention and genetic studies targeted HDL-C, i.e., the cholesterol

measured by clinical laboratories in HDL. By contrast to the pro-atherogenic and,

hence, disease causing cholesterol in LDL (measured or estimated by clinical

laboratories as LDL cholesterol, LDL-C) which after internalization turns

macrophages of the arterial intima into pro-inflammatory foam cells, the cholesterol

in HDL (i.e., HDL-C) neither exerts nor reflects any of the potentially anti￾atherogenic activities of HDL. By contrast to LDL-C, HDL-C is only a nonfunc￾tional surrogate marker for estimating HDL particle number and size without

v

deciphering the heterogeneous composition and, hence, functionality of HDL. HDL

particles are heterogeneous and complex macromolecules carrying hundreds of

lipid species and dozens of proteins as well as microRNAs. This physiological

heterogeneity is further increased in pathological conditions due to additional

quantitative and qualitative molecular changes of HDL components which have

been associated with both loss of physiological function and gain of pathological

dysfunction. This structural and functional complexity of HDL has prevented clear

assignments of molecules to the many functions of HDL. Detailed knowledge of

structure–function relationships of HDL-associated molecules is a prerequisite to

test them for their relative importance in the pathogenesis of HDL-associated

diseases. The identification of the most relevant biological activities of HDL and

their mediating molecules within HDL, as well as their cellular interaction partners,

is pivotal for the successful development of anti-atherogenic and anti-diabetogenic

drugs as well as of diagnostic biomarkers for the identification, treatment stratifica￾tion, and monitoring of patients at increased risk for cardiovascular diseases or

diabetes mellitus but also other diseases which show associations with HDL.

This Handbook of Experimental Pharmacology on HDL emerged from the

European Cooperation in Science and Technology (COST) Action BM0904 entitled

“HDL—from biological understanding to clinical exploitation” (HDLnet: http://

cost-bm0904.gr/). This COST Action was run from 2010 to 2014 and involved

more than 200 senior and junior scientists from 16 European countries. HDLnet has

been a scientific network dedicated to the study of HDL in health and disease, to the

identification of targets for novel HDL-based therapies, and to the discovery of

biomarkers which can be used for diagnostics, prevention, and therapy of cardio￾vascular disease. HDLnet fostered the cooperation and interaction of European

HDL-researchers, the exchange of information and materials, the training and

macro￾vascular

diseases

micro—

vascular

diseases

neuro￾degenerative

diseases

cancer

reduced prognosis

in infection or

other acute

serious illnesses

cause?

(potentially treatable)

reverse causality?

(not treatable)

Innocent bystander?

(not treatable)

lipid efflux and transport

signalling effects

detoxification

anti-oxidation

insulin resistance

negative acute phase reaction

Catabolism

Poor health

immune

functions

cell

mig￾ration

vascular

biology

diabetes

mellitus

cholesterol

homeostasis

cell

Sur￾vival

cell

proli￾feration

oxi￾dation

cell

func￾tions

cell

differ￾entiation

hyperinsulinism

Inflammation, smoking

hypertriglyceridemia

something else?

Fig. 1 Possible pathophysiological relationships of low HDL cholesterol with its associated

diseases

vi Preface

promotion of early career scientists, the gain of technological know-how, and the

dissemination of old and new knowledge on HDL to the scientific and medical

community as well as the lay public. In this setting, the chapters of this handbook

have been written by cooperative and interactive efforts of many senior scientists of

the HDLnet consortium and colleagues from the United States. It is published as

open access through COST funding so that the knowledge on HDL can be spread

without limitation.

As the chairman and vice-chairman of HDLnet, the editors of this Handbook of

Experimental Pharmacology issue like to thank not only the authors of the

22 chapters of this handbook but all members of the COST Action for their engaged

participation and cooperation. We thank Ms. Zinovia Papatheodorou (senior

Administrative Officer of the grant holder FORTH, Heraklion) for excellent grant

administrative work in HDLnet, the Science Officers Dr. Magdalena Radwanska

and Dr Inga Dadeshidze, the Administrative Officers Ms Anja van der Snickt and

Ms Jeannette Nchung (all from COST Office, Brussels, Belgium), as well as the DC

Rapporteur, Prof. Marieta Costache (Bucharest, Romania), for their excellent

support and sustained interest in our Action. We gratefully acknowledge Andrea

Bardelli and Giulia Miotto from COST Publications Office for their help in

publishing this book as an open access Final Action Publication (FAP). Finally

we wish to thank Prof. Martin Michel for his interest and guidance as well as

Susanne Dathe and Wilma McHugh from Springer who supported us with patience

and enthusiasm in the production of this book.

Zurich Arnold von Eckardstein

Iraklion Dimitris Kardassis

Preface vii

.

Acknowledgement

This publication is supported by COST

COST is supported by the EU Framework Programme Horizon 2020

COST—European Cooperation in Science and Technology is an intergovernmen￾tal framework aimed at facilitating the collaboration and networking of scientists and

researchers at European level. It was established in 1971 by 19 member countries and

currently includes 35 member countries across Europe, and Israel as a cooperating

state.

COST funds pan-European, bottom-up networks of scientists and researchers

across all science and technology fields. These networks, called “COST Actions”,

promote international coordination of nationally funded research.

By fostering the networking of researchers at an international level, COST enables

break-through scientific developments leading to new concepts and products, thereby

contributing to strengthening Europe’s research and innovation capacities.

COST’s mission focuses in particular on:

• Building capacity by connecting high-quality scientific communities throughout

Europe and worldwide

• Providing networking opportunities for early career investigators

• Increasing the impact of research on policy makers, regulatory bodies, and

national decision makers as well as the private sector

Through its inclusiveness policy, COST supports the integration of research

communities in less research-intensive countries across Europe, leverages national

research investments, and addresses societal issues.

Over 45,000 European scientists benefit from their involvement in COST Actions

on a yearly basis. This allows the pooling of national research funding and helps

countries’ research communities achieve common goals.

ix

As a precursor of advanced multidisciplinary research, COST anticipates and

complements the activities of EU Framework Programmes, constituting a “bridge”

towards the scientific communities of emerging countries.

Traditionally, COST draws its budget for networking activities from successive

EU RTD Framework Programmes.

COST Mission: COST aims to enable breakthrough scientific developments leading

to new concepts and products. It thereby contributes to strengthening Europe’s

research and innovation capacities.

x Acknowledgement

Contents

Part I Physiology of HDL

Structure of HDL: Particle Subclasses and

Molecular Components ..................................... 3

Anatol Kontush, Mats Lindahl, Marie Lhomme, Laura Calabresi,

M. John Chapman, and W. Sean Davidson

HDL Biogenesis, Remodeling, and Catabolism . . . . . . . . . . . . . . . . . . . 53

Vassilis I. Zannis, Panagiotis Fotakis, Georgios Koukos, Dimitris Kardassis,

Christian Ehnholm, Matti Jauhiainen, and Angeliki Chroni

Regulation of HDL Genes: Transcriptional, Posttranscriptional,

and Posttranslational . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113

Dimitris Kardassis, Anca Gafencu, Vassilis I. Zannis,

and Alberto Davalos

Cholesterol Efflux and Reverse Cholesterol Transport . . . . . . . . . . . . . 181

Elda Favari, Angelika Chroni, Uwe J.F. Tietge, Ilaria Zanotti,

Joan Carles Escola`-Gil, and Franco Bernini

Functionality of HDL: Antioxidation and Detoxifying Effects . . . . . . . . 207

Helen Karlsson, Anatol Kontush, and Richard W. James

Signal Transduction by HDL: Agonists, Receptors, and

Signaling Cascades . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 229

Jerzy-Roch Nofer

Part II Pathology of HDL

Epidemiology: Disease Associations and Modulators of

HDL-Related Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 259

Markku J. Savolainen

Beyond the Genetics of HDL: Why Is HDL Cholesterol Inversely

Related to Cardiovascular Disease? . . . . . . . . . . . . . . . . . . . . . . . . . . . . 285

J.A. Kuivenhoven and A.K. Groen

xi

Mouse Models of Disturbed HDL Metabolism . . . . . . . . . . . . . . . . . . . . 301

Menno Hoekstra and Miranda Van Eck

Dysfunctional HDL: From Structure-Function-Relationships

to Biomarkers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337

Meliana Riwanto, Lucia Rohrer, Arnold von Eckardstein, and Ulf Landmesser

Part III Possible Indications and Target Mechanisms of HDL Therapy

HDL and Atherothrombotic Vascular Disease . . . . . . . . . . . . . . . . . . . . 369

Wijtske Annema, Arnold von Eckardstein, and Petri T. Kovanen

HDLs, Diabetes, and Metabolic Syndrome . . . . . . . . . . . . . . . . . . . . . . 405

Peter Vollenweider, Arnold von Eckardstein, and Christian Widmann

High-Density Lipoprotein: Structural and Functional Changes Under

Uremic Conditions and the Therapeutic Consequences . . . . . . . . . . . . . 423

Mirjam Schuchardt, Markus To¨lle, and Markus van der Giet

Impact of Systemic Inflammation and Autoimmune Diseases

on apoA-I and HDL Plasma Levels and Functions . . . . . . . . . . . . . . . . 455

Fabrizio Montecucco, Elda Favari, Giuseppe Danilo Norata,

Nicoletta Ronda, Jerzy-Roch Nofer, and Nicolas Vuilleumier

HDL in Infectious Diseases and Sepsis . . . . . . . . . . . . . . . . . . . . . . . . . . 483

Angela Pirillo, Alberico Luigi Catapano, and Giuseppe Danilo Norata

High-Density Lipoproteins in Stroke . . . . . . . . . . . . . . . . . . . . . . . . . . . 509

Olivier Meilhac

Therapeutic Potential of HDL in Cardioprotection and Tissue Repair . . . . 527

Sophie Van Linthout, Miguel Frias, Neha Singh, and Bart De Geest

Part IV Treatments for Dyslipidemias and Dysfunction of HDL

HDL and Lifestyle Interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 569

Joan Carles Escola`-Gil, Josep Julve, Bruce A. Griffin, Dilys Freeman,

and Francisco Blanco-Vaca

Effects of Established Hypolipidemic Drugs on HDL Concentration,

Subclass Distribution, and Function . . . . . . . . . . . . . . . . . . . . . . . . . . . 593

Monica Gomaraschi, Maria Pia Adorni, Maciej Banach, Franco Bernini,

Guido Franceschini, and Laura Calabresi

Emerging Small Molecule Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617

Sophie Colin, Giulia Chinetti-Gbaguidi, Jan A. Kuivenhoven,

and Bart Staels

xii Contents

ApoA-I Mimetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 631

R.M. Stoekenbroek, E.S. Stroes, and G.K. Hovingh

Antisense Oligonucleotides, microRNAs, and Antibodies . . . . . . . . . . . 649

Alberto Da´valos and Angeliki Chroni

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 691

Contents xiii

Part I

Physiology of HDL