Discover millions of ebooks, audiobooks, and so much more with a free trial

Only $11.99/month after trial. Cancel anytime.

The HDL Handbook: Biological Functions and Clinical Implications
The HDL Handbook: Biological Functions and Clinical Implications
The HDL Handbook: Biological Functions and Clinical Implications
Ebook519 pages6 hours

The HDL Handbook: Biological Functions and Clinical Implications

Rating: 0 out of 5 stars

()

Read preview

About this ebook

The HDL Handbook: Biological Functions to Clinical Implications brings laboratory research in HDL from bench to bedside in this needed resource for researchers and clinicians studying cholesterol, lipids, epidemiology, biochemistry, molecular medicine, and pathophysiology of cardiovascular diseases. In addition, researchers and clinicians working with an aging population, corporate researchers, post-doctorates; medical students and graduate students will find this publication useful because the scope of coverage includes basic science, genetics, epidemiology, and treatment of HDL cholesterol as well as potential targets to modify HDL cholesterol.

  • Comprehensive coverage of basic science, genetics, epidemiology and treatment
  • Reputable content on latest advances in HDL cholesterol research
  • Inclusive, worldwide content with country specific information
  • In depth discussion of potential targets to modify HDL
LanguageEnglish
Release dateSep 6, 2010
ISBN9780123821720
The HDL Handbook: Biological Functions and Clinical Implications

Related to The HDL Handbook

Related ebooks

Medical For You

View More

Related articles

Related categories

Reviews for The HDL Handbook

Rating: 0 out of 5 stars
0 ratings

0 ratings0 reviews

What did you think?

Tap to rate

Review must be at least 10 words

    Book preview

    The HDL Handbook - Tsugikazu Komoda

    Table of Contents

    Cover Image

    Front Matter

    Copyright

    Preface

    Contributors

    Chapter 1. Role of Phospholipid Transfer Protein in HDL Remodeling and Atherosclerosis

    Chapter 2. The Role of Cholesteryl Ester Transfer Protein (CETP) in HDL Metabolism

    Chapter 3. Plasma Cholesteryl Ester Transfer Protein (CETP) in Relation to Human Pathophysiology

    Chapter 4. HDL and Reverse Cholesterol Transport

    Chapter 5. Serum Paraoxonase (PON1) and its Interactions with HDL

    Chapter 6. Paraoxonase-1 and its Interactions with HDL

    Chapter 7. Apolipoprotein A-I Mutations

    Chapter 8. The Scavenger Receptor Class B Type I

    Chapter 9. HDL Mimetic Peptides

    Chapter 10. Sterol Efflux by ABCA1 and ABCG1

    Chapter 11. Functional Change in the HDL Particle by Oxidative Modification and its Contribution to Atherogenesis

    Chapter 12. Preβ1-HDL, a Native Lipid-poor HDL, and its Potential as a New Marker for HDL Metabolism

    Chapter 13. Determination of Circulating Native and Denaturated HDL Concentrations and its Clinical Implications

    Index

    Front Matter

    The HDL Handbook

    Biological Functions and Clinical Implications

    Tsugikazu Komoda

    AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO

    Academic Press is an imprint of Elsevier

    Copyright © 2010 Elsevier Inc.. All rights reserved.

    Copyright

    Academic Press is an imprint of Elsevier

    32 Jamestown Road, London NW1 7BY, UK

    30 Corporate Drive, Suite 400, Burlington, MA 01803, USA

    525 B Street, Suite 1800, San Diego, CA 92101-4495, USA

    First edition 2010

    Copyright © 2010 Elsevier Inc. All rights reserved

    No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means electronic, mechanical, photocopying, recording or otherwise without the prior written permission of the publisher. Permissions may be sought directly from Elsevier's Science & Technology Rights Department in Oxford, UK: phone (+ 44) (0) 1865 843830; fax (+44) (0) 1865 853333; email: permissions@elsevier.com. Alternatively, visit the Science and Technology Books website at www.elsevierdirect.com/rights for further information

    Notice

    No responsibility is assumed by the publisher for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made

    British Library Cataloguing-in-Publication Data

    A catalogue record for this book is available from the British Library

    Library of Congress Cataloging-in-Publication Data

    A catalog record for this book is available from the Library of Congress

    ISBN: 978-0-12-382171-3

    For information on all Academic Press publications visit our website at elsevierdirect.com

    Typeset by TNQ Books and Journals Pvt Ltd.

    www.tnq.co.in

    Printed and bound in China

    10 11 12 13 14 15 10 9 8 7 6 5 4 3 2 1

    Preface

    When I started to write this book The HDL Handbook: Biological Functions and Clinical Applications, Professor Takashi Miida of Juntendo University in Tokyo strongly supported my plan. Of course, he is also an excellent contributor to this book. In addition, Professor David Alpers, Professor Emeritus of Washington University, School of Medicine, well revised the present HDL book. Therefore, I want to thank him for his revision of this book. Unfortunately, since planning to publish this HDL book, two and half years have passed. Some contributors immediately accepted my planning, however, half of the contributors have not been able to complete the publication of The HDL Handbook: Biological Functions and Clinical Applications.

    However, the contents of this HDL book include up-to-date progress on HDL research. The contents of this book are a crystallization of the work from all the contributors, because, despite being busy, all the contributors carefully revised their chapters under the suitable comments from eight reviewers. Therefore, if you read this book, you will be fascinated by the renewal of development of HDL researches and the present book is a very useful tool not only for basic researchers in institutes or pharmaceutical companies but also practical physicians. In addition, this book will be evaluated as an HDL Bible for medical and co-medical graduate students by their counselors.

    Furthermore, since this book is small, it is portable. However, the contents of this HDL book contain the latest news of HDL molecules.

    Finally, I believe that this book should be read to give an excellent impression of the HDL fields.

    Tsugikazu Komoda, MD

    Contributors

    Aishah Al-Jarallah

    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    G.M. Anantharamaiah

    Departments of Medicine, and Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA

    Rachelle Brunet

    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Giovanna Catalano

    INSERM UMRS939, Hôpital de la Pitié, Paris, France; UPMC Université Pierre et Marie Curie, Hôpital de la Pitié, Paris, France

    Eric Chabrière

    Institut de Recherche Biomédicale des Armées-Antenne CRSSA, Département de Toxicologie, Groupe Bioépurateurs Catalytiques et Réactivateurs, La Tronche, France

    Architecture et Fonction des Macromolécules Biologiques, Groupe Biocristallographie, Biotechnologie et Enzymologie Structurale, Université de la Méditerranée, Marseille, France

    Geeta Datta

    Department of Medicine, and Biochemistry, University of Alabama at Birmingham, Birmingham, AL, USA

    Maryse Guerin

    INSERM UMRS939, Hôpital de la Pitié, Paris, France; UPMC Université Pierre et Marie Curie, Hôpital de la Pitié, Paris, France

    Akira Hara

    Laboratory of Biochemistry, Gifu Pharmaceutical University, Japan

    Hiroaki Hattori

    Advanced Technology and Development Division, BML Inc., 1361-1 Matoba, Kawagoe, Saitama, Japan

    Neil J. Hime

    Centre for Vascular Research, Sydney Medical School (Pathology) and Bosch Institute, The University of Sydney, Medical Foundation Building, Camperdown, NSW, Australia

    Satoshi Hirayama

    Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

    Akihiro Inazu

    Department of Laboratory Sciences, School of Health Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Ishikawa, Japan

    Zorana Jelic-Ivanovic

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Tsugikazu Komoda

    Nihon Medical Science Institute, II-4 Minami-Tohrimachi, Kawagoe, Saitama, Japan

    Jelena Kotur-Stevuljevic

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Patrick Masson

    Institut de Recherche Biomédicale des Armées-Antenne CRSSA, Département de Toxicologie, Groupe Bioépurateurs Catalytiques et Réactivateurs, La Tronche, France

    Akira Matsunaga

    Department of Laboratory Medicine, Fukuoka University School of Medicine, Fukuoka, Japan

    Toshiyuki Matsunaga

    Laboratory of Biochemistry, Gifu Pharmaceutical University, Japan

    Takashi Miida

    Department of Laboratory Medicine, Juntendo University School of Medicine, Tokyo, Japan

    Takanari Nakano

    Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan

    Brentwood Biomedical Research Institute, Department of Medicine, School of Medicine, University of California Los Angeles, Los Angeles, CA, USA

    Daniel Rochu

    Institut de Recherche Biomédicale des Armées-Antenne CRSSA, Département de Toxicologie, Groupe Bioépurateurs Catalytiques et Réactivateurs, La Tronche, France; Bundeswehr Institute of Pharmacology and Toxicology, Munich, Germany

    Keijiro Saku

    Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan

    Makoto Seo

    Department of Biochemistry, Faculty of Medicine, Saitama Medical University, Saitama, Japan

    Slavica Spasic

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Vesna Spasojevic-Kalimanovska

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Aleksandra Stefanovic

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Naoki Terasaka

    Biological Research Laboratories, Daiichi Sankyo Co., Ltd, Tokyo, Japan

    Bernardo Trigatti

    Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada

    Yoshinari Uehara

    Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan

    Jelena Vekic

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    C. Roger White

    Department of Medicine, and Biochemistry, University of Alabama at Birmingham, Birmingham, AL, USA

    Aleksandra Zeljkovic

    Institute of Medical Biochemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia

    Bo Zhang

    Department of Cardiology, Fukuoka University School of Medicine, Fukuoka, Japan

    Chapter 1. Role of Phospholipid Transfer Protein in HDL Remodeling and Atherosclerosis

    Hiroaki Hattori

    Advanced Technology and Development Division, BML Inc., Kawagoe, Saitama, Japan

    Introduction

    Phospholipid transfer protein (PLTP) plays an important role in the regulation of high density lipoprotein (HDL) metabolism. The regulatory role of PLTP is achieved via its two main functions, phospholipid transfer activity (Tall et al., 1983 and Rao et al., 1997) and the ability to modulate HDL size and composition in a process called HDL remodeling (Rye and Barter, 1986Tu et al., 1993 and Jauhiainen et al., 1993). The regulation of HDL metabolism is achieved by the concerted action of a number of plasma and cellular factors. These include the cellular receptors, scavenger receptor class B type 1 (SR-B1) and ATP-binding cassette transporter A1 (ABC-A1), as well as plasma proteins such as cholesteryl ester transfer protein (CETP), lecithin-cholesterol acyltransferase (LCAT), and the endothelial-bound enzymes, lipoprotein lipase (LPL) and triglyceride (TG) hydrolase hepatic lipase (HL). As indicated by the inverse relationship between HDL cholesterol and incidence of coronary heart disease in many epidemiological studies (Gordon and Rifkind, 1989), the plasma HDL level has a major impact on the progression of atherosclerosis. Although the exact mechanism behind the athero-protective role of HDL is still not fully understood, the reverse cholesterol transport (RCT) hypothesis has been widely accepted (Curtiss et al., 2006). Reverse cholesterol transport is the process by which cholesterol is transported from peripheral cells to the liver for elimination (Eisenberg, 1984). Preβ-HDL particles, a subpopulation of HDL, act as efficient acceptors in the efflux process of cholesterol at the plasma membrane of peripheral cells (Eisenberg, 1984). PLTP is able to generate preβ-HDL particles through HDL remodeling, and has a major role also in maintaining plasma HDL levels owing to its ability to transport surface remnants produced by lipolysis of triglyceride-rich lipoproteins (Figure 1.1). Thus, PLTP can be envisioned to play an important role in the prevention of atherosclerosis (Castro and Fielding, 1988von Eckardstein et al., 1996van Haperen et al., 2000 and Tall and Lalanne, 2003). In spite of these effects on HDL, studies in genetically modified mouse models have suggested that systemic PLTP deficiency is athero-protective in vivo, and that PLTP overexpression is pro-atherogenic. Recent studies have focused on this apparent inconsistency, and have examined the effects of local PLTP on atherogenesis, using transplanted macrophages.

    Molecular biology and structure of phospholipid transfer protein

    The PLTP gene is located on chromosome 20 (20q12-q13.1), and has a length of 13.3 kilobases, including 15 introns. PLTP cDNA is 1750bp in length, and encodes a 17 amino acid hydrophobic signal peptide and a 476 amino acid mature protein (Day et al., 1994). Most tissues show expression of PLTP mRNA, but liver and adipose tissue are probably the major contributors to plasma PLTP (Dusserre et al., 2000). Although the predicted molecular weight mass of the mature protein is 55kDa, plasma PLTP appears as an 80-kDa protein by sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) under reducing and non-reducing conditions (Oka et al., 2000a). The discrepancy between the calculated molecular weight mass and the mass estimated by SDS-PAGE may be explained by the fact that PLTP has six potential N-glycosylation sites and numerous O-glycosylation sites (Day et al., 1994). As the protein additionally contains four cysteine residues, it also has the potential to form two intra-chain disulfide bonds. In contrast to apolipoproteins that are primarily hydrophilic, PLTP has a high content of hydrophobic residues scattered throughout, with over 40% of the amino acids being hydrophobic. Three other hydrophobic proteins of the lipid transfer/lipopolysaccharide binding protein family, namely lipopolysaccharide-binding protein (LBP), neutrophil bactericidal permeability-increasing protein (BPI), and CETP share structural homology with PLTP. However, these proteins also exhibit significant structural differences (Albers et al., 1996). For example, the carboxyl terminal portion of CETP is the most hydrophobic of these four proteins, and its main function is to bind and transfer neutral lipids (Tall et al., 1983 and Albers et al., 1984). Although the carboxyl terminal portion of PLTP is somewhat hydrophobic, it does not have the functional capacity to transfer neutral lipids (Tollefson et al., 1988). Unlike PLTP, BPI has a very basic amino-terminal domain, which is responsible for its cytotoxic activity, whereas the hydrophobic carboxyl-terminal domain is believed to anchor the protein in the granule membrane (Gray et al., 1989). LBP and BPI share 44% amino acid sequence identity to bind lipopolysaccharide (Schumann et al., 1990). Furthermore, both proteins have similar amino-terminal amino acids (Tobias et al., 1988). Secondary structure predictions suggest that PLTP has two potential transmembrane regions spanning from residues 169 through 181, and residues 288 through 304 (Albers et al., 1996). Two potential disulfide bonds exist between cysteine residues 5 and 129, and between cysteine residues 168 and 318. The cysteine residues 146 and 185 form a disulfide bridge that is essential for the correct folding and secretion of PLTP (Huuskonen et al., 1998Huuskonen et al., 1999 and Qu et al., 1999).

    We have shown that two forms of PLTP exist in human plasma, one with high activity (HA-PLTP) and another with low activity (LA-PLTP) (Oka et al., 2000b and Kärkkäinen et al., 2002). The LA-PLTP is associated with apoA-I, and the HA-PLTP co-purifies with apoE (Murdoch et al., 2002). LA-PLTP is located between LDL and HDL on size-exclusion chromatography, having an apparent molecular mass of 520kDa and a Stokes diameter of 12–17nm (Oka et al., 2000a and Murdoch et al., 2002). In contrast, HA-PLTP is associated with an average molecular mass of 160kDa and a Stokes diameter between 7.6 and 12.0nm. HA-PLTP but not LA-PLTP is able to remodel HDL, resulting in the formation of two types of particles, preβ-HDL and large fused HDL (Vikstedt et al., 2007a). The mechanism by which these two HDL subpopulations are generated is not known.

    PLTP-mediated lipid transfer

    PLTP is a rather non-specific lipid transfer protein. Several studies have shown that it is able to transfer all common phospholipid types (Massey et al., 1984Huuskonen et al., 1996 and Rao et al., 1997). Diacylglyceride, a significant lipid constituent of HDL particles, is also transferred efficiently (Rao et al., 1997). The PLTP-mediated transfer of phosphatidylcholine molecules varies with their fatty acyl chain length, decreasing with increasing length, a phenomenon similar to that observed for spontaneous transfer (Huuskonen et al., 1996).

    PLTP functions by forming a ternary complex between donor and acceptor lipoprotein particles, and may facilitate phospholipid transfer by lowering the energy barrier for lipid monomer dissociation and/or association (Huuskonen et al., 2001). Among lipoproteins, HDL particles are the most efficient as phospholipid donors and/or acceptors in PLTP-mediated phospholipid transfer (Rao et al., 1997). Thus, PLTP appears to display specificity towards HDL in the transfer reaction. As HDLs are by far the most numerous lipoprotein particles in plasma, collisions are more likely to occur between PLTP and them than between PLTP and other lipoproteins (Huuskonen et al., 2001). Two lipid-binding pockets in PLTP protein, at the entrance to and inside the pockets, participate in the phospholipid transfer process (Huuskonen et al., 1999).

    It has recently been demonstrated that the amphipathic α-helix in PLTP at amino acid residues 144–163, at the tip of the N-terminal barrel, is critical for removing the lipid domain formed by ABC-A1, interacting with phospholipids, and promoting cellular cholesterol and phospholipid transfer (Oram et al., 2008). This suggests that PLTP may shuttle lipids between cells and HDL particles. PLTP also binds and transfers several other amphipathic molecules, including α-tocopherol, diacylglycerides, cerebrosides and lipopolysaccharides (Lagrost et al., 1998 and Desrumaux et al., 1999).

    PLTP-mediated HDL remodeling

    In humans, both CETP and PLTP catalyze the conversion of HDL in vitro into larger and smaller particles, including preβ-HDL (Albers et al., 1995Pulcini et al., 1995Rye et al., 1995Rye et al., 1997 and Curtiss et al., 2000). The physiological significance of this process is that it increases the production of preβ-HDL and thereby enhances the capacity of HDL to accept cellular cholesterol (von Eckardstein et al., 1996). HDL remodeling is also catalyzed by pig and mouse PLTP proteins (Pussinen et al., 1995 and Marques-Vidal et al., 1997). PLTP has also been shown to mediate the conversion of HDL2 particles with a concomitant release of lipid-poor apoA-I (Marques-Vidal et al., 1997), and to transform reconstituted discoidal HDL particles into vesicular structures (Nishida et al., 1997). By using HDL particles containing phospholipids in the surface lipid layer or cholesteryl esters in the core, it has been demonstrated that PLTP rapidly transfers the surface phospholipids and reaches equilibrium prior to mixing of the cholesteryl ester core (Lusa et al., 1996). It is thought that the initial reaction in PLTP-mediated HDL remodeling is phospholipid transfer, followed by the release of lipid-poor apoA-I, and subsequent fusion of the unstable particles (Lusa et al., 1996).

    CETP also catalyzes HDL remodeling (Pulcini et al., 1995 and Rye et al., 1997). Although particle fusion is again involved (Pulcini et al., 1995), there are several differences between the PLTP-mediated and CETP-mediated processes. No release of lipid-poor apoA-I was observed in HDL remodeling by CETP (Albers et al., 1995). Furthermore, PLTP promoted preferentially the formation of large HDL particles, whereas CETP favored the production of small HDL (Pulcini et al., 1995 and Lagrost et al., 1998).

    The process of HDL remodeling by PLTP is controlled by at least three different factors: the HDL apolipoprotein/protein composition; the core lipid composition of HDL; and the phospholipid transfer activity of PLTP (Pussinen et al., 1997Pussinen et al., 2001Rye et al., 1998 and Huuskonen et al., 2000a). In pig HDL, which natively contains apoA-I but not apoA-II, both the formation of large particles and the release of apoA-I were inhibited by increasing the content of apoA-II (Pussinen et al., 1997). Addition of purified serum amyloid A (SAA), an acute-phase upregulated protein, into HDL3 particles facilitated their ability to undergo HDL remodeling, despite the lower content of apoA-I in SAA-HDL (Pussinen et al., 2001). HDL particles enriched in core triglycerides exhibited enhanced PLTP-mediated HDL remodeling (Rye et al., 1998). Phospholipid transfer is a prerequisite for efficient PLTP-mediated HDL remodeling (Huuskonen et al., 2000a).

    PLTP can also remodel triglyceride-rich lipoproteins (TGRLPs) (Rye et al., 1998). Particularly during the postprandial phase, lipolysis of TGRLPs is intricately linked to subsequent remodeling by PLTP, which results in the integration of lipolytic surface remnants into HDL (Huuskonen et al., 2001), profoundly altering HDL speciation (Jauhiainen et al., 1993). The ensuing imbalance between lipolysis and remodeling may contribute to the toxicity of lipolyzed TGRLPs, leading to damage to vascular endothelial cells and/or macrophage apoptosis (Wehinger et al., 2007). Moreover, PLTP remodeled spherical apoE-containing HDL into large and small particles without dissociation of apoE, suggesting that apoE enhances the capacity of PLTP to remodel HDL, but reduces the ability of HDL to participate in PLTP-mediated phospholipid transfers (Settasatian et al., 2008).

    Genetically modified animals

    Plasma from mice overexpressing human PLTP was more effective in preventing acetylated LDL-induced accretion of cholesteryl ester in macrophages (von Eckardstein et al., 1996). Nevertheless, systemic PLTP deficiency in mice is associated with a decrease in atherosclerosis susceptibility, despite a decrease in plasma HDL levels, and overexpression of PLTP is accompanied by an increase in susceptibility to the disease (von Eckardstein et al., 1996Jiang et al., 2001Jiang et al., 2002van Haperen et al., 2002 and Yang et al., 2003). Overexpression of human PLTP in transgenic mice (hPLTPtg) also increases preβ-HDL generation, but decreases plasma HDL cholesterol (Jiang et al., 1996 and von Eckardstein et al., 1996). Although preβ-HDL is a minor HDL subpopulation, it is believed to be a very efficient acceptor of cellular cholesterol (Oram and Yokoyama, 1996). Therefore an elevated production of preβ-HDL might enhance RCT (Huuskonen et al., 2001). These results suggest that PLTP may act as a pro-atherogenic, rather than an anti-atherogenic factor in vivo.

    Overexpression of hPLTP in LDL receptor-deficient (LDLr−/−) mice resulted in a dose-dependent decrease in HDL cholesterol, and a stimulation of VLDL secretion (van Haperen et al., 2002). LDLr−/− and hPLTPtg/LDLr−/− mice fed an atherogenic diet showed similar levels of hypercholesterolemia, but the hPLTPtg/LDLr−/− mice had lower plasma HDL levels and more atherosclerosis (van Haperen et al., 2002). In LDLr+/− mice expressing both hCETP and hPLTP, PLTP expression was accompanied by a dose-dependent decrease in HDL cholesterol and an increase in atherosclerosis, which was positively related to the level of hPLTP expression (Lie et al., 2004). These findings were confirmed and extended in apoE-deficient (apoE−/−) mice transfected with mouse PLTP using an adenovirus vector (Yang et al., 2003). On a chow diet, transient expression of PLTP caused a 30% reduction of HDL cholesterol and phospholipids, as well as a 20% reduction of plasma α-tocopherol content, resulting in increased susceptibility of apoB-containing lipoproteins to peroxidation in vitro (Yang et al., 2003). However, while complete deficiency of PLTP decreased both plasma HDL, apoB-secretion and atherosclerosis (Jiang et al., 2001), no such metabolic effects were produced by an approximately 50% decrease in PLTP activity in PLTP+/− mice (Tall and Lalanne, 2003). Pronounced overexpression of PLTP increased atherosclerosis (van Haperen et al., 2002 and Yang et al., 2003). However, moderate expression by two-fold in transgenics (van Haperen et al., 2002), and overexpression using low-dose adeno-associated virus, did not do so (Yang et al., 2003). Transgenic mice overexpressing a mutant PLTP, lacking phospholipid transfer activity, showed no increase in atherosclerosis lesion size (Samyn et al., 2008). Mice expressing inducible PLTP showed a strongly atherogenic lipoprotein profile, an increase of pre-existing atherosclerotic lesion size, and a decrease in lesion stability (Moreland et al., 2008).

    The role of PLTP deficiency in atherosclerosis has been studied in several mouse models: human apoB transgenic, apoE−/− and LDLr−/− mice (Jiang et al., 2001). PLTP−/− mice of different genetic backgrounds showed a reduction of atherosclerosis, which was related to the reduction of apoB lipoproteins. Mechanistically, depletion of apoB lipoproteins of vitamin E by PLTP was proposed to account for the reduction of atherosclerosis in PLTP-deficient mice (Jiang et al., 2002). While vitamin E reduces atherosclerosis in mice, vitamin E supplementation in humans has had no demonstrable effect on atherosclerosis (Navab et al., 2004), suggesting a more prominent role of vitamin E in murine than in human atherosclerosis. In PLTP-deficient mice, decreased LDL, HDL and apoE-rich lipoproteins, as well as increased biliary cholesterol secretion and hepatic ABCG5/ABCG8 gene expression and decreased intestinal cholesterol absorption, were observed (Shelly et al., 2008). Furthermore, PLTP-deficient mice showed reduced expression of the pro-inflammatory genes, intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1), and lower levels of interleukin-6 (IL-6), supporting the concept that PLTP may play a pro-atherogenic role. Taken together, the available data suggest that only very pronounced systemic variations of PLTP influence atherosclerosis in mice. Such variations have not been described in humans (Jänis et al., 2004).

    Local PLTP effects have attracted attention in relation to the function of macrophages in atherosclerogenesis (Valenta et al., 2006Valenta et al., 2008Liu et al., 2007 and Vikstedt et al., 2007b). Bone marrow transplantation from PLTP−/− mice into several background mice has been performed by three groups, yielding contradictory results (Table 1.1). In male LDLr−/− mice, Valenta et al. (2006) demonstrated an increase in atherosclerosis after transplantation of PLTP−/− bone marrow, suggesting an athero-protective potential of macrophage PLTP in the presence of normal apoA-I levels, but not in the presence of increased apoA-I levels. Moreover, double mutant LDLr−/− PLTP−/− mice transplanted with PLTP−/− bone marrow showed decreased plasma total cholesterol, increased HDL cholesterol, and smaller atherosclerotic lesions (Valenta et al., 2008). In contrast, Vikstedt et al. (2007b) demonstrated a decrease in both plasma PLTP activity and atherosclerosis after transplantation of PLTP−/− bone marrow in female LDLr−/− mice, implying an atherogenic potential of macrophage PLTP. ApoE−/− mice showed a pronounced increase in atherosclerosis after transplantation of PLTP−/− bone marrow, associated with a lower secretion of apoE by macrophages, and consequently much higher plasma cholesterol levels (Liu et al., 2007). In male LDLr−/− mice, macrophage-derived PLTP was athero-protective, suggesting that the influence of PLTP on atherogenesis is highly dependent upon its site of expression (Vikstedt et al., 2007b). Moreover, mechanisms affecting atherosclerosis, such as transport of vitamin E by lipoproteins, may profoundly differ between species. In C57Bl/6 mice transplanted with PLTP−/− bone marrow, increased cholesterol content of the PLTP−/− macrophages was observed, which was normalized by α-tocopherol supplementation, suggesting that macrophage-derived PLTP is anti-atherogenic owing to its ability to reduce cholesterol accumulation in macrophages through changes in the α-tocopherol content and antioxidative status of the cells (Valenta et al., 2008). More recently, van Haperen et al. (2008) demonstrated an atherogenic effect of PLTP in macrophages in LDLr−/− mice transplanted with bone marrow from mice overexpressing human PLTP.

    An important issue is how increased PLTP expression stimulates atherosclerosis. Elevation of PLTP activity results in HDL hypercatabolism and enhanced hepatic VLDL secretion. In addition to PLTP-mediated phospholipid transfer, the effects on the transfer of cholesterol and α-tocopherol may be important in this context (Ogier et al., 2007). Moreover, O'Brien et al. (2003) suggested that PLTP may have anti-atherogenic potential by acting as a bridging protein between lipoproteins and biglycan, one of the major extracellular proteoglycans found in human atherosclerotic lesions.

    PLTP and atherosclerosis in humans

    PLTP activity is increased in subjects with several risk factors for atherosclerosis. It increases with age (Tahvanainen et al., 1999), body mass index (Dullaart et al., 1994aRiemens et al., 1998Huuskonen et al., 2000bKaser et al., 2004 and Jänis et al., 2004), cigarette smoking (Dullaart et al., 1994b and Cheung et al., 2006), and type 1 and type 2 diabetes mellitus (Colholm et al., 2001Jonkers et al., 2003 and Attia et al., 2007). Studying coronary artery disease (CAD) patients with stable angina, unstable angina and acute myocardial infarction in a cross-sectional study, Schlitt et al. (2003) found that increased plasma PLTP activity is a risk factor for CAD. In a prospective study of CAD patients, however, PLTP activity was not predictive of future events (Rao et al., 1997). In a prospective Japanese study, plasma PLTP concentration was negatively associated with CAD (Yatsuya et al., 2004). Finally, a small cross-sectional study, comparing normolipidemic CAD patients with controls matched for plasma lipoproteins, found a non-significant trend for increased PLTP activity in the cases (Ruhling et al., 199). Schgoer et al. (2008) demonstrated that low PLTP activity was significantly decreased in peripheral artery disease (PAD) patients with no history of smoking or diabetes mellitus, and that the magnitude of the decrease increased with increasing PAD stage. PLTP activity was also a determinant of carotid intima media thickness in type 2 diabetes independent of plasma lipids, insulin resistance and C-reactive protein (de Vries et al., 2006).

    In human atherosclerotic lesions, PLTP was immunohistochemically co-localized in plaques with macrophages and smooth muscle foam cells (Desrumaux et al., 2003Laffitte et al., 2003 and O'Brien et al., 2003). In the atherosclerotic segments, PLTP had accumulated in the extracellular matrix, co-localizing with apoA-I, apoE and biglycan, suggesting that PLTP might promote HDL retention on extracellular matrix proteoglycans and reverse cholesterol transport (O'Brien et al., 2003). It has recently been demonstrated that PLTP-mediated remodeling of apoE-containing HDL generates large as well as small particles, which are potential acceptors of cellular phospholipids and cholesterol (Settasatian et al., 2008). This remodeling may be important for enhancing plasma cholesterol transport, especially under circumstances in which the activity of CETP is inhibited and the levels of apoE-containing HDL in plasma are increased. The PLTP-mediated remodeling of apoE-containing HDL may offset the deleterious effects of increased PLTP activity in type 2 diabetes (Dallinga-Thie et al., 2006 and Tan et al., 2006). The relationship of elevated PLTP activity to human atherosclerosis needs to be clarified.

    Conclusion

    Numerous studies in humans, animals and in vitro have addressed the importance of RCT and cholesterol efflux in atherogenesis. It is possible that augmentation of RCT and cholesterol efflux could be therapeutically useful. Potential major strategies include accelerating RCT and cholesterol efflux, which may be achieved by increasing HDL and apoA-I levels, or by stimulating PLTP or CETP. However, uncertainties remain about the impact of PLTP on RCT, cholesterol efflux and cardiovascular disease. Elevated activities in subjects with diabetes mellitus and CAD may result from partly elevated rates of VLDL turnover, inhibition of VLDL synthesis and increase of HDL catabolism. The regulation of PLTP and lipolytic enzyme levels, and their impacts on atherosclerosis, are not clear. Since the function of PLTP may influence both pro-atherogenic and anti-atherogenic factors, the net effect of these on plasma lipoproteins and atherosclerosis is not predictable in the current state of knowledge, and further investigations are warranted.

    References

    J.J. Albers, J.H. Tollefson, C.H. Chen, A. Steinmetz, Isolation and characterization of human plasma lipid transfer proteins, Atherosclerosis4 (1984) 49–58.

    J.J. Albers, A.Y. Tu, G. Wolfbauer, M.C. Cheung, S.M. Marcovina, Molecular biology of phospholipid transfer protein, Curr Opin Lipidol7 (1996) 88–93.

    J.J. Albers, G. Wolfbauer, M.C. Cheung, J.R. Day, A.F. Ching, A.Y. Tu, Functional expression of human and mouse phospholipid transfer protein: effect of recombinant and plasma PLTP on HDL subspecies, Biochim Biophys Acta1258 (1995) 27–34.

    N. Attia, A. Nakbi, M. Smaoui, et al., Increased phospholipid transfer protein activity associated with the impaired cellular cholesterol efflux in type 2 diabetic subjects with coronary artery disease, Tohoku J Exp Med213 (2007) 129–137.

    G.R. Castro, C.J. Fielding, Early incorporation of cell-derived cholesterol into pre-beta-migrating high-density lipoprotein, Biochemistry27 (1988) 25–29.

    M.C. Cheung, B.G. Brown, E.K. Marino Larsen, A.D. Frutkin, K.D. O'Brien, J.J. Albers, Phospholipid transfer protein activity is associated with inflammatory markers in patients with cardiovascular disease, Biochim Biophys Acta1762 (2006) 131–137.

    H.M. Colholm, L.M. Scheek, M.B. Rubens, et al., Lipid transfer protein activities in type I diabetic patients without renal failure and nondiabetic control subjects and their association with coronary artery calcification, Diabetes50 (2001) 652–659.

    L.K. Curtiss, D.J. Bonnet, K.A. Rye, The conformation of apolipoprotein A-I in high-density lipoproteins is influenced by core lipid composition and particle size: a surface plasmon resonance study, Biochemistry39 (2000) 5712–5721.

    L.K. Curtiss, D.T. Velenta, N.J. Hime, K.A. Rye, What is so special about apolipoprotein AI in reverse cholesterol transport?Arteroscler Thromb Vasc Biol26 (2006) 12–19.

    G.M. Dallinga-Thie, A. van Tol, H. Hattori, P.C. Rensen, E.J. Sijbrands, Plasma phospholipid transfer protein activity is decreased in type 2 diabetes during treatment with atrovastatin: a role for apolipoprotein E?Diabetes55 (2006) 1491–1496.

    J.R. Day, J.J. Albers, C.E. Lofton-Day, et al., Complete cDNA encoding human phospholipid transfer protein from human endotherial cells, J Biol Chem269 (1994) 9388–9391.

    R. de Vries, G.M. Dallinga-Thie, A.J. Smit, B.H. Wolffenbuttel, A. van Tol, R.P. Dullaart, Elevated plasma phospholipid transfer protein activity is a determinant of carotid intima-media thickness in type 2 diabetes mellitus, Diabetologia49 (2006) 398–404.

    C. Desrumaux, V. Deckert, A. Athias, et al., Plasma phospholipid transfer protein prevents vascular endothelium dysfunction by delivering alpha-tocopherol to endothelial cells, FASEB J13 (1999) 883–892.

    C.M. Desrumaux, P.A. Mak, W.A. Boisvert, et al., Phospholipid transfer protein is present in human atherosclerotic lesions and is expressed by macrophages and foam cells, J Lipid Res44 (2003) 1453–1461.

    R.P. Dullaart, K. Hoogenberg, B.D. Dikkeschei, A. van Tol, Higher plasma lipid transfer protein activities and unfavorable lipoprotein changes in cigarette-smoking men, Arterioscler Thromb14 (1994) 1581–1585.

    R.P. Dullaart, W.J. Sluiter, L.D. Dikkeschei, K. Hoogenberg, A. van Tol, Effect of adiposity on plasma lipid transfer protein activities: a possible link between insulin resistance and high density lipoprotein metabolism, Eur J Clin Invest24 (1994) 188–194.

    E. Dusserre, P. Moulin, H. Vidal, Differences in mRNA expression of the proteins secreted by adipocytes in human subcutaneous and visceral adipose tissues, Biochim Biophys Acta1500 (2000) 88–96.

    S. Eisenberg, High density lipoprotein metabolism, J Lipid Res25 (1984) 1017–1058.

    D.J. Gordon, B.M. Rifkind, High-density lipoprotein – the clinical implications of recent studies, N Engl J Med321 (1989) 1311–1316.

    P.W. Gray, G. Flaggs, S.R. Leong, et al., Cloning of the cDNA of a human neutrophil bacterial protein. Structure and functional correlations, J Biol Chem264 (1989) 9505–9509.

    J. Huuskonen, M. Ekstrom, E. Tahvanainen, et al., Quantification of human plasma phospholipid transfer protein (PLTP): relationship between PLTP mass and phospholipid transfer activity, Atherosclerosis151 (2000) 451–461.

    J. Huuskonen, M. Jauhiainen, C. Ehnholm, V.M. Olkkonen, Biosynthesis and secretion of human plasma phospholipid transfer protein, J Lipid Res39 (1998) 2021–2030.

    J. Huuskonen, V.M. Olkkonen, C. Ehnholm, J. Metso, I. Julkunen, M. Jauhiainen, Phospholipid transfer is a prerequisite for

    Enjoying the preview?
    Page 1 of 1