Plasma Lipids and Their Role in Disease (Advances in Vascular Biology)

Plasma Lipids and Their Role in Disease

Advances in Vascular Biology A series of books bringing together important advances and reviewing all areas of vascular biology. Edited by Mathew A.Vadas, The Hanson Centre for Cancer Research, Adelaide, South Australia and John Harlan, Division of Hematology, University of Washington, Seattle, USA.

Volume One Vascular Control of Hemostasis edited by Victor W.M.van Hinsbergh Volume Two Immune Functions of the Vessel Wall edited by Göran K.Hansson and Peter Libby Volume Three The Selectins: Initiators of Leukocyte-Endothelial Adhesion edited by Dietmar Vestweber Volume Four The Role of Herpesviruses in Atherogenesis edited by David P.Hajjar and Stephen M.Schwartz Volume Five Plasma Lipids and Their Role in Disease edited by Philip J.Barter and Kerry-Anne Rye Volumes in Preparation Platelets, Thrombosis and the Vessel Wall edited by Michael C.Berndt Structure and Function of Endothelial Cell to Cell Junctions edited by Elisabetta Dejana This book is part of a series. The publisher will accept continuation orders which may be cancelled at any time and which provide for automatic billing and shipping of each title in the series upon publication. Please write for details.

Plasma Lipids and Their Role in Disease edited by

Philip J.Barter University Department of Medicine Royal Adelaide Hospital Adelaide Australia and Kerry-Anne Rye Lipid Research Laboratory Hanson Centre Adelaide Australia

harwood academic publishers Australia • Canada • China • France • Germany • India • Japan Luxembourg • Malaysia • The Netherlands • Russia • Singapore Switzerland

This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge's collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” Copyright © 1999 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint, part of The Gordon and Breach Publishing Group. All rights reserved. No part of this book may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying and recording, or by any information storage or retrieval system, without permission in writing from the publisher. Printed in Singapore. Amsteldijk 166 1st Floor 1079 LH Amsterdam The Netherlands British Library Cataloguing in Publication Data Plasma lipids and their role in disease.—(Advances in vascular biology; v. 5) 1. Blood lipids I. Barter, Philip J. II. Rye, Kerry-Anne 547.7′7 ISBN 0-203-30481-0 Master e-book ISBN

ISBN 0-203-35287-4 (Adobe eReader Format) ISBN 9057024667 (Print Edition)

CONTENTS

Series Preface Preface List of Contributors 1. Overview of Plasma Lipid Transport Kerry-Anne Rye , Moira A.Clay and Philip J.Barter 2. Abnormalities of Plasma Lipoprotein Transport Gilbert R.Thompson 3. Epidemiological Evidence Linking Plasma Lipoprotein Disorders to Atherosclerosis and Other Diseases Jacques Genest Jr. and Jeffrey Cohn 4. Atherogenicity of Low-density Lipoproteins: Mechanisms M.John Chapman 5. High Density Lipoproteins: The Anti-atherogenic Fraction Philip J.Barter , Moira A.Clay and Kerry-Anne Rye 6. Chylomicron Remnants and Atherosclerosis John C.L.Mamo and Spencer D.Proctor 7. High Density Lipoprotein Receptors Noel H.Fidge 8. Regulation of the Low Density Lipoprotein (B/E) Receptor Petri T.Kovanen and Wolfgang J.Schneider 9. The Role of the Microsomal Triglyceride Transfer Protein in the Assembly and Secretion of Plasma Lipoproteins John R.Wetterau and David A.Gordon 10. Role of Endothelial Lipases in Disease Ira J.Goldberg and Catherine H.Tuck 11. Relationship of the Cholesteryl Ester Transfer Protein (CETP) to Atherosclerosis Laurent Lagrost 12. Familial Lecithin: Cholesterol Acyltransferase Deficiency Syndromes P.Haydn Pritchard , Amir F.Ayyobi and John S.Hill 13. Apolipoprotein E and Human Disease Yadong Huang and Robert W.Mahley 14. Role of the Plasma Phospholipid Transfer Protein in Plasma Lipid Transport Matti Jauhiainen and Christian Ehnholm 15. Oxidation of Plasma Lipids and Lipoproteins J.M.Upston and Roland Stocker

viii x xii 1 19 51

83 105 138 177 211 240

261 279

301 334 373 392

16. Plasma Lipoprotein Disorders and Endothelial Function Mark R.Adams and David S.Celermajer Subject Index

429

461

SERIES PREFACE It is our privilege to live at a time when scientific discoveries are providing insights into human biology at an unprecedented rate. It is also a time when the sheer quantity of information tends to obscure underlying principles, and when hypotheses or insights that simplify and unify may be relegated to the shadow of hard data. The driving force for editing a series of books on Vascular Biology was to partially redress this balance. In inviting editors of excellence and experience, it is our aim to draw together important facts, in particular areas of vascular biology, and to allow the generation of hypotheses and principles that unite an area and define newer horizons. We also anticipate that, as is often the case in biology, the formulation and application of these principles will interrelate with other disciplines. Vascular biology is a frontier that has been recognised since at least the time of Cohnheim and Metchikoff, but has really come into prominence over the last 10–15 years, once the molecules that mediate the essential functions of the blood vessel started to be defined. The boundaries of this discipline are, however, not clear. There are intersections, for example, with hypertension and atherogenesis that bring in, respectively, neuroendocrine control of vessel tone and lipid biochemistry which exist as separate bodies of knowledge. Moreover, it would be surprising if some regional vascular biology (for example, pulmonary, renal etc.) were not to emerge as subgroups in the future. Our aims for the moment, however, are to concentrate on areas of vascular biology that have a wide impact. It is our hope to publish two books each year for the next 3–4 years. Indeed the first five books have been commissioned and address areas primarily in endothelial biology (hemostasis and thrombosis), immunology, leukocyte adhesion molecules, platelet adhesion molecules, adhesion molecules that mediate cell-cell contact. Subsequent volumes will cover the physiology and pathology of other vascular cells as well as developmental vascular biology. We thank the editors and contributors for their very hard work. Mathew VADAS John HARLAN

PREFACE Disease associated with abnormalities of plasma lipids has been recognised since the beginning of the 20th century when it was shown that diet-induced hypercholesterolaemia in rabbits resulted in the development of atherosclerosis. However, it has taken until the last two decades of the century to generate the scientific evidence that has finally persuaded the sceptics that disorders of plasma lipids are also causally related to atherosclerosis and coronary artery disease in humans. Results of human population studies have demonstrated once and for all that hyperlipidaemia is associated with an increased risk of developing atherosclerotic coronary artery disease. Subsequent large-scale intervention trials have established that this risk can be markedly reduced by reducing plasma lipid levels. The transport of lipids in plasma is complex and is subject to multiple abnormalities, most of which reflect an interaction between genes and a variety of lifestyle factors. Several of these abnormalities lead to severe clinical disease. This volume commences with an overview of plasma lipid transport, followed by a chapter describing various categories of plasma lipid disorders. The chapters that follow address the relationships of plasma lipid levels and of the different plasma lipoprotein fractions with atherosclerotic disease. There are two main cholesterol carrying lipoproteins in plasma: low density lipoproteins (LDL) and high density lipoproteins (HDL). A relationship between elevated levels of LDL and the development of atherosclerosis has been known for many years. As indicated in Chapter 4, there has been a growing understanding of the mechanism of this effect of LDL and of the factors that influence the atherogenicity of these lipoproteins. In contrast to LDL, plasma HDL do not cause atherosclerosis. Rather, there is now good evidence that they protect against development of the disease. The mechanism of the protection is not yet known with certainty but, as outlined in Chapter 5, may relate to several well documented functions of HDL. It is now known that LDL are not the only lipoproteins that cause atherosclerosis. As outlined in Chapter 6, there has been recognition over the past few years that the metabolic remnants of triglyceride-rich lipoproteins (very low density lipoproteins and chylomicrons) may also contribute substantially to the disease. Knowledge of the regulation of plasma lipoproteins has been greatly increased with the recognition and characterisation of cell surface receptors which bind plasma HDL and LDL. Receptors for HDL and LDL are described in Chapters 7 and 8. Chapters 9 to 14 are concerned with a number of key proteins that play fundamental roles in the metabolism and remodelling of plasma lipoproteins. While some of these factors have been known for many years, the past few years have provided fundamental new information about all of them. Well characterised genetic abnormalities of these proteins have been shown to impact on plasma lipid transport and, in some cases, to predispose to clinical disease states.

There has been much recent interest in the oxidation of plasma lipids and lipoproteins. It has been suggested by some that LDL become atherogenic only after being oxidatively modified. The growing body of information about plasma lipid and lipoprotein oxidation is presented in Chapter 15. The possible relationship between lipid oxidation and the development of atherosclerosis has led a number of researchers to postulate that antioxidants may protect against the development of coronary heart disease. While there is still no conclusive evidence from large-scale end-point studies, it has been shown that antioxidants do improve endothelial function. Thus, the volume concludes with a topical chapter on the effects of disorders of plasma lipids and lipoproteins on endothelial function. We believe that this volume provides up to date information for physicians and scientists who are interested in plasma lipid transport and how abnormalities of plasma lipids and lipoproteins relate to disease states such as atherosclerosis. We owe a major debt to our co-authors who have not only given freely of their time and knowledge to the generation of the volume but who have also managed somehow to meet the necessary deadlines. Philip BARTER Kerry-Anne RYE

LIST OF CONTRIBUTORS Adams, Mark R. Department of Cardiology Royal Prince Alfred Hospital Missenden Road Camperdown New South Wales 2050 Australia Ayyobi, Amir F. Healthy Heart Program St. Paul’s Hospital 1101 Burrara Street Vancouver, BC Canada V6Z 1Y6 Barter, Philip J. University Department of Medicine Royal Adelaide Hospital North Terrace Adelaide, South Australia 5000 Australia Celermajer, David S. Department of Cardiology Royal Prince Alfred Hospital Missenden Road Camperdown New South Wales 2050 Australia Chapman, M.John INSERM Unit 321, Hopital de la Pitie Pavillon Benjamin Delessert 83, Boulevard de L’Hopital 75651 Paris, Cedex 13 France Clay, Moira A. Lipid Research Laboratory

Hanson Centre Frome Road Adelaide, South Australia 5000 Australia Cohn, Jeffrey Cardiovascular Genetics Laboratory Clinical Research Institute of Montreal 110 Avenue des Pins Quest Montreal, Quebec Canada H2W 1R7 Ehnholm, Christian Department of Biochemistry National Public Health Institute Mannerheimintie 166 FIN-00300 Helsinki Finland Fidge, Noel H. Baker Medical Research Institute PO Box 348 Prahrah, Victoria 3181 Australia Genest, Jr., Jacques Cardiovascular Genetics Laboratory Clinical Research Institute of Montreal 110 Avenue des Pins Quest Montreal, Quebec Canada H2W 1R7 Goldberg, Ira J. Department of Medicine Columbia University College of Physicians and Surgeons 630 West 168th Street New York, NY 10032 USA Gordon, David A. Department of Metabolic Diseases Bristol-Myers Squibb P.O. Box 4000 Princeton, NJ 08543 USA

Hill, John S. Healthy Heart Program St. Paul’s Hospital 1101 Burrara Street Vancouver, BC Canada V6Z 1Y6 Huang, Yadong Gladstone Institute of Cardiovascular Disease University of California P.O. Box 419100 San Francisco, CA 94141–9100 USA Jauhiainen, Matti Department of Biochemistry National Public Health Institute Mannerheimintie 166 FIN-00300 Helsinki Finland Kovanen, Petri T. Wihuri Research Institute Kalliolinnantie 4 FIN-00140 Helsinki Finland Lagrost, Laurent Laboratoire de Biochimie des Lipoprotéines INSERM U498 Hôpital du Bocage BP 1542 21034 Dijon Cedex France Mahley, Robert W. Departments of Pathology and Medicine University of California PO Box 419100 San Francisco, CA 94141–9100 USA Mamo, John C.L. University Department of Medicine

Medical Research Foundation Building Rear of 50 Murray Street Perth, Western Australia 6000 Australia Pritchard, P.Haydn Healthy Heart Program St. Paul’s Hospital 1101 Burrara Street Vancouver, BC Canada, V6Z 1Y6 Proctor, Spencer D. University Department of Medicine Medical Research Foundation Building Rear of 50 Murray Street Perth, Western Australia 6000 Australia Rye, Kerry-Anne Lipid Research Laboratory Hanson Centre Frome Road Adelaide, South Australia 5000 Australia Schneider, Wolfgang J. Department of Molecular Genetics Vienna Biocenter University of Vienna Dr. Bohrgasse 9 1030 Vienna Austria Stocker, Roland Biochemistry Group The Heart Research Institute 145 Missenden Road Camperdown, New South Wales 2050 Australia Thompson, Gilbert R. MRC Lipoprotein Team Clinical Sciences Centre Imperial College School of Medicine

Hammersmith Hospital DuCane Road London W12 ONN UK Tuck, Catherine H. Department of Medicine Columbia University College of Physicians and Surgeons 630 West 168th Street New York, NY 10032 USA Upston, J.M. Biochemistry Group The Heart Research Institute 145 Missenden Road Camperdown, New South Wales 2050 Australia Wetterau, John R. Department of Metabolic Diseases Bristol-Myers Squibb P.O. Box 4000 Princeton, NJ 08543 USA

1 Overview of Plasma Lipid Transport Kerry-Anne Rye 1 , Moira A.Clay 1 and Philip J.Barter 2 1

Lipid Research Laboratory, Hanson Centre, Frome Road, Adelaide, South Australia 5000, Australia 2 University Department of Medicine, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia

Cholesterol and triglyceride are normal components of plasma. The fact that abnormalities of their transport in plasma underlie a substantial proportion of premature coronary heart disease has stimulated enormous interest in their metabolism and regulation. This overview chapter describes the transport of cholesterol and triglyceride in plasma lipoproteins and summarises the roles played by the different lipoprotein fractions in the process of atherosclerosis. KEYWORDS: Cholesterol, triglyceride, chylomicrons, VLDL, LDL, HDL.

INTRODUCTION Cholesterol, triglyceride and the plasma lipoproteins that transport them are normal, physiological components of plasma. The lipoproteins in plasma are responsible for redistributing cholesterol and triglyceride between tissues in processes that are fundamental to energy metabolism and cell membrane homeostasis. There are three functional pathways of cholesterol transport in plasma: a pathway that delivers dietary cholesterol from the intestine to the liver, a pathway that delivers cholesterol from the liver to extrahepatic tissues and a pathway in which extrahepatic cholesterol is transported back to the liver. The third pathway is often referred to as reverse cholesterol transport. There are two main pathways of triglyceride transport in plasma, each of which is concerned with the transport of energy between tissues. One involves triglyceride of dietary origin. The other involves triglyceride which has been newly synthesised in the liver. In each case the triglyceride is transported as a component of lipoproteins in the plasma to tissues throughout the body, where it is used either as an immediate source of energy or, in the case of adipose tissue, is stored for later use.

Plasma lipids and their role in disease

2

PLASMA LIPOPROTEINS Plasma lipoproteins are the vehicles by which cholesterol and triglyceride are transported in plasma. About 70% of plasma cholesterol exists as cholesteryl esters.

Table 1.1 Plasma lipoprotein classes

Lipoprotein Class Main Lipid Constituents

Main apolipoproteins

Hydrated Density (g/ml)

Diameter (nm)

Chylomicrons

Triglyceride

apoB-48