Genetics of Dyslipidemia

323 Pages·2001·11.628 MB·English

by  Pascale Benlian (auth.)

OF
GENETICS DYSLIPIDEMIA
BASIC SCIENCE FOR THE CARDIOLOGIST
1. B. Swynghedauw (ed.): Molecular Cardiology for the Cardiologist. Second
Edition. 1998 ISBN: 0-7923-8323-0
2. B. Levy, A. Tedgui (eds.): Biology of the Arterial Wall. 1999
ISBN 0-7923-8458-X
3. M.R. Sanders, I.B. Kostis (eds): Molecular Cardiology in Clinical
Practice. 1999. ISBN 0-7923-8602-7
4. B. Ostadal, F. Kolar (eds.): Cardiac Ischemia: From Injury to Protection. 1999
ISBN 0-7923-8642-6
5. H. Schunkert, G.A.I. Riegger (eds.): Apoptosis in Cardiac Biology. 1999
ISBN 0-7923-8648-5
6. A. Malliani, (ed.): Principles of Cardiovascular Neural Regulation in Health
and Disease. 2000 ISBN 0-7923-7775-3
7. P. Benlian: Genetics ofDyslipidemia. 2001
ISBN 0-7923-7362-6
8. D. Young: Role of Potassium in Preventive Cardiovascular Medicine. 2001
ISBN 0-7923-7376-6
KLUWER ACADEMIC PUBLISHERS - DORDRECHTIBOSTON/LONDON
Library of Congress Cataloging-in-Publication Data
Benlian, Pascale.
Genetics of dyslipidemia / by Pascale Benlian.
p. ; cm. - (Basic science for the cardiologist ; 7)
Includes bibliographical references and index.
ISBN 978-1-4613-5593-9 ISBN 978-1-4615-1517-3 (eBook)
DOI 10.1007/978-1-4615-1517-3
1. Lipids-Metabolism-Disorders. I. Title II. Series.
[DNLM: 1. Hyperlipidemia-genetics. 2. Lipoproteins-metabolism. WD 200.5.H8
B468g2001]
RC632.L54 B46 2001
616.3'997042-dc21
2001037593
Copyright © 2001 by Springer Science+Business Media New York
Originally published by Kluwer Academic Publishers in 2001
Softcover reprint ofthe hardcover Ist edition 2001
AII rights reserved. No part of this publication may be reproduced, stored in a
retrieval system or transmitted in any form or by any means, mechanical, photo
copying, recording, or otherwise, without the prior written permission of the
publisher, Springer Science+Business Media, LLC.
Printed on acid-free paper.
OF
GENETICS DYSLIPIDEMIA
by
Pascale Benlian
St. Antoine Hospital, France
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
GENETICS OF DYSLIPIDEMIA
PREFACE xi
1- THE METABOLISM OF LIPOPROTEINS 1
1.1- Historical Landmarks 2
1.1.1- Cholesterol: a « Janus-Faced» molecule 2
1.1.2- The pathological descriptions of the 19th century 5
1.1.3- From Iipido-proteinic « cenapses » to apolipoproteins 6
1.1.4- The concept of molecular disease 7
1.2-Lipids are essential components for living cells 9
1.2.1- Fatty acids derivatives 9
1.2.2- Isoprenoid derivatives 10
1.3-Lipoproteins: soluble carriers of lipids in extracellular spaces 14
1.3 .1-Structure and functions of lipoproteins 14
1.3 .2-Lipoproteins accross the evolution of living species 16
1.4-The Metabolism of Lipoproteins 21
1.4.1-The general architecture of lipoprotein metabolism 23
+ The Exogenous Pathway 23
+ The Endogenous Pathway 24
+ The Reverse Pathway 25
1.4.2-Regulations of Lipoprotein Metabolism 26
+ By exogenous sources of energy 26
+ By endogenous sensors of energy 27
1.5-Lipids and Atherosclerosis: The Causal Link 29
+ Pathological and biological evidence 29
+ Epidemiological and clinical evidence 31
vi
1.6-Heterogeneity of Dyslipidemia 34
1.6.1-The phenotypic heterogeneity of dyslipoproteinemia 34
1.6.2-Genetic heterogeneity of dyslipidemia 38
11- GENES OF LIPOPROTEIN METABOLISM 41
2.1- Genes of the endogenous pathway 41
2.1.1- The LDL receptor: a gene for familial hypercholesterolemia 41
2.1.2- Apolipoprotein B: a single locus for opposite diseases 54
2.1.3- Microsomal-triglyceride Transfer Protein (MTP), a locus for
abetalipoproteinemia 66
2.1.4- Lipoprotein Lp(a), a mysterious candidate for atherosclerosis 69
2.1.5- HMGCoA reductase, the rate limiting enzyme of the mevalonate
pathway 77
2.1.6- Scavenger receptors 78
2.1.6.1- Scavenger receptors class A: molecular flypapers for modified
lipoproteins 78
2.1.6.2-CD36, a multifunctional receptor for fatty acids and thrombospondin,
scavenging oxidized lipoproteins 81
2.2- Genes controlling Triglyceride-rich lipoprotein metabolism 84
2.2.1- Lipases 84
2.2.11- Lipoprotein Lipase, the rate limiting enzyme for triglyceride-rich
lipoproteins 84
2.2.12- Hepatic Lipase, a lipase for lipoprotein remodeling 94
2.2.13- Other Lipases 97
2.2.2- Apolipoproteins 100
2.2.21- Apolipoprotein C-II, an activator of lipoprotein lipase 100
2.2.22- Apoliprotein C-I, a modulator of lipoprotein catabolism 103
vii
2.2.23- Apolipoprotein E, the major apolipoprotein for intermediate
lipoproteins 106
2.2.3- Receptors 116
2.2.31- LRP, a multifunctional receptor for intermediate lipoproteins 116
2.2.32- Megalin, an ancient member of the LDL receptor gene family
expressed in the kidney 120
2.2.33- VLDL Receptor (LR8), a multifunctional receptor with
species-dependent requirements 122
2.3- Genes of the Reverse Pathway of lipoprotein metabolism 125
2.3.1- Apolipoproteins 125
2.3.11- Apolipoprotein A-I, a major component ofHDL 125
2.3.12- Apoliprotein C-III, a modulator for triglyceride-rich lipoprotein
catabolism 132
2.3.13- Apolipoprotein A-IV, a component of intestinal lipoproteins 136
2.3.14- Apolipoprotein A-II, a modulator of HDL metabolism 139
2.3.2- Circulating Enzymes and Transfer Proteins for
Lipoprotein Remodeling 141
2.3.21- Lecithin Cholesterol Acyl transferase (LCAT), a rate limiting
enzyme for HDL metabolism 141
2.3.22- Cholesteryl Ester Transfer Protein (CETP),
a « points man» of lipoprotein metabolism 145
2.3.23- Phospholipid Transfer Protein (PL TP),
a major component of HDL formation in plasma 151
2.3.3- Receptors 152
2.3.31- ABC-I, or cholesterol efflux regulatory protein,
a gene for Tangier Disease and Familial hypoalphalipoproteinemia 152
2.3.32- Scavenger Receptor class B-1 (SR-BI),
a multifunctional receptor for the selective uptake of cholesterol 156
viii
2.3.33- Cubilin, a receptor for HDL in the kidney 158
2.4- Other Regulatory Pathways of Lipoprotein Metabolism 160
2.4.1- The Traffic ofIntracellular Lipids 160
2.4.11- Lipid tafficking in cellular compartments 160
+ Niemann Pick Disease type C 161
+ Lysosomal Acid Lipase 163
+ Acyl-CoA: Cholesterol acyl transferases (ACAT) 164
+ Intracellular fatty acid trafficking 165
2.4.12-Nuclear coordinators of intracellular energy resources 169
+ SREBPs (Sterol Responsive Element Binding Proteins) 169
+ PPARs (Peroxisome Proliferator Activated Receptors) 171
+ LXR (Liver X Receptor), FXR (Famesoid X Receptor) 173
+ Lamins A/C 174
2.4.2- The Biosynthesis of Bile Acids 174
2.4.3- Other Apolipoproteins 178
2.4.4- Anti-toxic and Anti-oxidative Protection 180
111- THE GENETIC BASIS OF DYSLIPIDEMIAS 183
3.1- The Genetic Architecture of Lipoprotein Metabolism 183
3.1.1- The functionality of candidate genes 184
3.1.11- Levels of functional significance of candidate genes 184
3.1.12- The redundancy of candidate genes 187
3.1.13- The multifunctionality of candidate genes 189
3.1.2- The driving forces of lipoprotein metabolism 190
3.2- The Candidate Gene Approach 194
3.2.1- In human disorders of lipoprotein metabolism 194
3.2.11- Identifying the disease causing mutation in inherited dyslipidemia 195
ix
3.2.12- A redefinition of inherited dyslipidemia 199
3.2.13- The evidence of genetic interactions 201
3.2.14- Identifying risk alleles for complex diseases in populations 202
3.2.15- Genetic determinants of dyslipidemia in populations 206
3.2.2- The candidate gene approach in experimental models
of dyslipidemia 209
3.2.21- In vitro studies and cell cultures 209
3.2.22- In vivo studies and animal models 210
3.2.3- Clinical issues of the candidate gene approach 212
3.2.31- Applications in current clinical care 212
3.2.32- Corrective gene therapy 213
3.2.4- Present limitations to the candidate gene approach 215
3.3- Novel Genes, Novel Approaches 215
3.3.1- Identifying novel genes of lipoprotein metabolism 216
3.3.11- Positional cloning of novel genes 216
3.3.12- Expression cloning of novel genes 218
3.3.13- In silico cloning of novel genes 218
3.3.2- Novel approaches to identify novel mechanisms
of human dyslipidemia 219
CONCLUSION 221
REFERENCES 223
INDEX 311
PREFACE
Cardiovascular diseases represent a heavy morbidity and mortality burden
worldwide. They generally result form the late complications of a silent and
chronic arterial disease: atherosclerosis. The patient often experiences the
disease by a sudden event as brutal as unexpected (myocardial infarction, stroke
etc.). In other cases, the level of individual awareness on cardiovascular risk
factors brings one to adopt a somewhat constraining preventive lifestyle towards
a disease, which remains unfelt. For the expert or the practitioner, it is thus a
question of adapted diagnostic and therapeutic responses to prevent a disease as
much common as it is complex. Dyslipidemia or lipid disorders are major
cardiovascular risk factors and are themselves multifactorial diseases, resulting
from interactions between genetic and environmental factors. If environmental
factors may be uneasy to handle in humans, the study of genetic factors has
recently made a decisive turn as the consequence of dramatic technological
advances in the study and manipulation of DNA, as an experimental object. The
cloning of the first genes of lipoprotein metabolism led to explore their
variations and their contribution to the pathogenesis of human dyslipidemia.
More than fifty genes have been identified not only in sequence but also most
importantly in their physiological or pathological actions. The richness and the
diversity of observations, which rose from these studies, have greatly refined our
knowledge on the control of lipid metabolism in living organisms. They gave
place to a true upheaval of former phenotypic classifications (based on plasma
lipid measurements), distinguishing new clinical entities and defining new
therapeutic strategies, targeted on authentic molecular causes or genetic risk
factors.
At the tum of the millennium, with the recent release of the human genome
sequence, an analysis in retrospect of the past progress, of novel areas opened by
the study of the genetic component of these complex and common disorders
might be welcome. This work aims at exploring the genetic basis of dyslipidemia
by illustrative examples taken from the extraordinary advances of the past two
decades. The objectives were to guide the non-familiar or non-expert reader
through this extremely rich domain of science and medicine. The abundance of
the related literature could not hold in this volume, due to a rapid and permanent
expansion that largely exceeds the limits of cardiovascular disease. Therefore,
we hope that the expert reader will forgive several omissions or schematic
descriptions, and that one might find some information useful for his education,
his scientific research or his medical practice.