Principles and Treatment of Lipoprotein Disorders

513 Pages·1994·15.14 MB·English

by  J. R. Patsch (auth.)

Handbook of
Experimental Pharmacology
Volume 109
Editorial Board
G.V.R.Born,London
P. Cuatrecasas, Ann Arbor, MI
D. Ganten, Berlin
H. Herken, Berlin
K.L. Melmon, Stanford, CA
Principles and
Treatment of
Lipoprotein Disorders
Contributors
D.H. Blankenhorn, H.B. Brewer, G.A. Coetzee, S.L. Connor
W.E. Connor, J. Davignon, A. Gaw, A.J.R. Habenicht
E. von Hodenberg, H.N. Hodis, D.R. Illingworth
U. JanBen-Timmen, D. Kritchevsky, K.J. Lackner, H.J. Menzel
G. Olivecrona, T. Olivecrona, A.G. Olsson, C.J. Packard
J.R. Patsch, W.O. Richter, P.B. Salbach, E.B. Schmidt
P. Schwandt, D. Seidel, J. Shepherd, G. Utermann
W.J.S. de Villiers, D.R. van der Westhuyzen
Editors
Gotthard Schettler and Andreas J .R. Habenicht
Springer-Verlag
Berlin Heidelberg New York London Paris
Tokyo Hong Kong Barcelona Budapest
Professor Dr. Dr. Dres.h.c. GOTIHARD SCHETILER
University of Heidelberg
Klinisches Institut fur Herzinfarktforschung
an der Medizinischen Universitatsklinik
Bergheimer StraBe 58
D-69115 Heidelberg
Germany
Professor Dr. ANDREAS J.R. HABENICHT
University of Heidelberg
School of Medicine, Department of Medicine
Division of Endocrinology and Metabolism
Bergheimer StraBe 58
D-69115 Heidelberg
Germany
With 75 Figures and 68 Tables
ISBN-13:978-3-642-78428-6 e-ISBN-13:978-3-642-78426-2
DOl: 10.1007/978-3-642-78426-2
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List of Contributors
BLANKENHORN, D.H., Atherosclerosis Research Institute, University of
Southern California, CSC-132, 2250 Alcazar St., Los Angeles, CA
90033, USA
BREWER, H.B., National Institutes of Health, National Heart, Lung, and
Blood Institute, Molecular Disease Branch, Building 10, Room 7N117 ,
9000 Rockville Pike, Bethesda, MD 20982, USA
COETZEE, G.A., MCRIUCT Unit for the Cell Biology of Atherosclerosis,
Department of Medical Biochemistry, University of Cape Town Medical
School, Observatory, Cape Town 7925, South Africa
CONNOR, S.L., The Division of Endocrinology, Diabetes and Clinical
Nutrition, Oregon Health Sciences University, 3181 SW S. Jackson Park
Road, L465, Portland, OR 97201-3098, USA
CONNOR, W.E., The Division of Endocrinology, Diabetes and Clinical
Nutrition, Oregon Health Sciences University, 3181 SW S. Jackson Park
Road, L465, Portland, OR 97201-3098, USA
DAVIGNON, J., Hyperlipidemia and Atherosclerosis Research Group, Clinical
Research Institute of Montreal, 110 Pine Avenue, West, Montreal,
Quebec, Canada H2W 1R7
GAW, A., Department of Molecular Genetics, University of Texas, South
western Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75235,
USA
HABENICHT, A.J.R., University of Heidelberg, School of Medicine, De
partment of Medicine, Division of Endocrinology and Metabolism,
Bergheimerstr. 58, D-69115 Heidelberg, Germany
HODENBERG, E. VON, University of Heidelberg, School of Medicine, De
partment of Medicine Division of Cardiology, Bergheimerstr. 58,
D-69115 Heidelberg, Germany
Homs, H.N., Atherosclerosis Research Institute, University of Southern
California, CSC-132, 2250 Alcazar St., Los Angeles, CA 90033, USA
VI List of Contributors
ILLINGWORTH, D.R., Division of Endocrinology, Diabetes and Clinical
Nutrition, Department of Medicine, L465 , Oregon Health Sciences
University, 3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098,
USA
JANSSEN-TIMMEN, U., University of Heidelberg, School of Medicine, De
partment of Medicine, Division of Endocrinology and Metabolism,
Bergheimerstr. 58, D-69115 Heidelberg, Germany
KRITCHEVSKY, D., The Wistar Institute of Anatomy and Biology, 3601 Spruce
Street, Philadelphia, PA 19104-4268, USA
LACKNER, K.J., Institute of Clinical Chemistry, University of Regensburg,
Franz-Josef-StrauB Allee 11, D-93053 Regensburg, Germany
MENZEL, H.J., Institute for Medical Biology and Human Genetics, Univer
sity of Innsbruck, Sch6pfstr. 41, A-6020 Innsbruck, Austria
OLIVECRONA, G., Department of Medical Biochemistry and Biophysics,
University of Umea, S-90187 Umea, Sweden
OLIVECRONA, T., Department of Medical Biochemistry and Biophysics,
University of Umea, S-90187 Umea, Sweden
OLSSON, A.G., Department of Internal Medicine, University of Link6ping,
Faculty of Health Science, S-581 85 Link6ping, Sweden
PACKARD, c.J., Institute of Biochemistry, Royal Infirmary, Glasgow G4
OSF, Great Britain
PATSCH, J.R., Medical Clinic, AnichstraBe, A-6020 Innsbruck, Austria
RICHTER, W.O., Medical Clinic III, Ludwig Maximilians-Universitat,
Marchioninistr. 15, D-81377 Munchen, Germany
SALBACH, P.B., University of Heidelberg, School of Medicine, Department
of Medicine, Division of Cardiology, Bergheimerstr. 58, D-69115
Heidelberg, Germany
SCHMIDT, E.B., Division of Endocrinology, Diabetes and Clinical Nutrition,
Department of Medicine, L465 , Oregon Health Sciences University,
3181 SW Sam Jackson Park Rd., Portland, OR 97201-3098, USA
SCHWANDT, P., Medical Clinic III, Ludwig Maximilians-Universitat,
Marchioninistr. 15, D-81377 Munchen, Germany
SEIDEL, D., Institute of Clinical Chemistry, Ludwig Maximilians-U niversitat,
Marchioninistr. 15, D-81377 Munchen, Germany
SHEPHERD, J., Institute of Biochemistry, Royal Infirmary, Glasgow G4
OSF, Great Britain
UTERMANN, G., Institute for Medical Biology and Human Genetics, Uni
versity of Innsbruck, Sch6pfstr. 41, A-6020 Innsbruck, Austria
List of Contributors VII
VILLIERS, W.J.S. DE, MRCIUCf Unit for the Cell Biology of Athero
sclerosis, Deparatment of Medical Biochemistry, University of Cape
Town Medical School, Observatory, Cape Town 7925, South Africa
WESTHUYZEN, D.R. VAN DER, MRCIUCT Unit for the Cell Biology of
Atherosclerosis, Department of Medical Biochemistry, University of
Cape Town Medical School, Observatory, Cape Town 7925, South
Africa
Preface
Recent advances in research on the molecular mechanisms underlying pri
mary and secondary hyperlipidemias, the development of effective dietary
treatment regimens, and the discovery of new classes of lipid-lowering drugs
have allowed both investigators and physicians to gain new insights into
the pathogenesis and clinical management of cardiovascular disease. This
volume provides a selection of chapters dealing with three central areas: (1)
the physiology and pathophysiology of lipid metabolism; (2) lipid-lowering
therapy with emphasis on the rationale to treat and dietary strategies of
treatment; and (3) major lipid-lowering drugs that are presently being used
clinically.
Section A of the book is introduced by two chapters: in the first,
J. Patsch provides the reader with an update on the principles of the
biochemistry and biology of blood lipids and plasma lipoproteins, and
in the second, H.B. Brewer covers the ongoing research on lipoprotein
metabolism with a focus on potential roles of plasma lipoprotein sub
populations in carrying out specific tasks related to lipid transport and
metabolism. Since most plasma lipoproteins can interact with and/or are
catabolized through specific cell surface receptors, W.J.S. de Villiers et al.
review the advances in this important field with a focus on the classical
low-density lipoprotein receptor. The progress in molecular mechanisms of
lipoprotein disorders, which has the potential to relate molecular events in
cells to epidemiologically defined risks for large populations, is discussed
by G. Utermann and H.J. Menzel, followed by A.J.R. Habenicht et aI.,
who review the evidence that lipoproteins can directly interact with arterial
wall cells to trigger the disease. T. Olivecrona and G. Olivecrona then
portray recent aspects of lipoprotein and hepatic lipases, some of which are
apparently not related to their enzymatic activities. Section A concludes
with a description by D. Kritchevsky of how animal models can be used to
search for molecular mechanisms of lipoprotein disorders and what can be
learned from them to study the human disease.
Section B begins with two chapters dealing with the important issue
of "to treat or not to treat" hyperlipidemia. The first of these, by D.H.
Blankenhorn and H.N. Hodis, discusses the rationale to treat hyperlipi
demias while the second, by W.E. Connor and S.L. Connor, examines the
important role that dietary intervention plays in lowering high lipid levels
x Preface
in patients at risk of developing cardiovascular disease, D. Seidel then
describes the recently developed technique of "lipid apheresis," which
directly removes plasma lipoproteins from the circulation, and discusses
what is presently known about the clinical feasability, safety, and metabolic
sequelae of this technique.
Section C begins with a chapter by E. Illingworth and E. Berg Schmidt,
who report the recent progress in the field of the mechanisms of action and
clinical safety of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA)
reductase inhibitors, which have increasingly been used alone or in com
bination with ion exchange resins in patients with various types of hyper
cholesterolemia. The latter group of substances is dealt with in a separate
chapter by P. Schwandt and W.O. Richter. A. Gaw et a1. follow by covering
one of the widely used lipid-lowering drugs in hyperlipidemia, the family of
fibrates. A.G. Olsson describes recent aspects of the use of nicotinic acid
derivatives, and J. Davignon summarizes the pharmacology of probucol,
which appears to be effective in animal models of hypercholesterolemia
without displaying major lipid-lowering effects, but appears to owe its anti
atherogenic effects in animals to its antioxidant properties. Finally, K.J.
Lackner and E. von Hodenberg review what is known about lipid-lowering
drugs whose use is limited to small numbers of patients or whose side effects
prevent their use in larger populations.
We wish to point out that the basis of any clinical intervention and
management of hyperlipidemic patients should consist in reducing high lipid
levels through dietary means or, in the case of secondary hyperlipidemias, in
treating the underlying disease. Only if these attempts fail should drug
treatment be considered. While there are several million patients around the
world presently being treated with various types or combinations of lipid
lowering drugs, our understanding of whom and when to treat and which
drug for which type of hyperlipidemia and at which dose is still rather
limited. It is, therefore, another objective of this volume to increase the
reader's awareness of such unsolved questions in order to avoid false ideas
and the erroneous interpretation of epidemiological data. Only carefully
controlled prospective trials of large groups of patients and the analysis of
separate patient subgroups that have been treated for prolonged periods of
time will provide the basis for answers to these questions.
It is the environment of uncertainty that needs to be recognized and in
which this book could serve as one source of information to stimulate
discussions on the principles and management of hyperlipidemia.
Heidelberg, GOITHARD SCHEITLER
January 1994 ANDREAS J .R. HABENICHT
Contents
Section A: Physiology and Pathophysiology of Lipid Metabolism
CHAPTER 1
An Introduction to the Biochemistry and Biology of Blood Lipids and
Lipoproteins
J.R. PATSCH. With 1 Figure .................................... 3
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
B. Blood Lipid Transport: Historical Aspects. . . . . . . . . . . . . . .. . . . . 4
C. Blood Lipids, Apolipoproteins, and Lipoproteins . . . . . . . . . . . . . . 6
I. Lipids................................................ 6
II. Apolipoproteins....................................... 9
III. Lipoproteins.......................................... 12
D. Enzymes and Transfer Factors Involved in the Biochemistry of
Blood Lipid Regulation .................................... 13
E. Lipoprotein Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
I. Transport of Exogenous Lipids . . . . . . . . . . . . . . . . . . . . . . . . . . 15
II. Transport of Endogenous Lipids. . . . . . . . . . . . . . . . . . . . . . . . . 17
F. Cholesterol and Atherosclerosis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
G. High-Density Lipoprotein Cholesterol and Reverse Cholesterol
Transport. . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . .. . . . . 19
H. Triglycerides, High-Density Lipoprotein Cholesterol, and
Coronary Artery Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
I. Conclusion............................................... 22
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
CHAPTER 2
Lipoprotein Metabolism
H.B. BREWER. With 9 Figures 29
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
B. Plasma Apolipoproteins .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 30
XII Contents
C. Cellular Receptors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
I. Low-Density Lipoprotein Receptor. . . . . . . . . . . .. . . . .. . . . . 33
II. Scavenger Receptor(s) ................................. 34
III. Chylomicron Remnant Receptor. . . . . . . . . . . . . . . . . . . . . . . . . 34
IV. High-Density Lipoprotein Receptor .......... , .. . . . . .. . . . 36
D. Lipoprotein Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
I. ApoB Metabolic Cascade. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
II. High-Density Lipoprotein Metabolism. . . . . . . . . . . . . . . . . . . . 38
III. Lp(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42
E. Major Plasma Atherogenic and Antiatherogenic Lipoproteins ... 43
I. Low-Density Lipoproteins. . . . .. . . . . . . . . . . . . . . . . . . .. . . . . 44
II. pVery Low Density Lipoproteins................. ....... 45
III. Lp(a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
IV. High-Density Lipoproteins. . . . . . . .. . . . .. . . . . . . . . . . .. .. . . 46
F. Summary................................................. 46
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
CHAPTER 3
Lipoprotein Receptors
W.J.S. DE VILLIERS, G.A. COETZEE, and D.R. VAN DER WESTHUYZEN.
With 6 Figures ................................................ 53
A. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
B. The Low-Density Lipoprotein Receptor. . . . . . . . . . . . . . . . .. . . . . 53
I. Functions of the Low-Density Lipoprotein Receptor in the
Body................................................ 54
II. Structure of the Low-Density Lipoprotein Receptor. . . . . . .. 55
1. Domains........................................... 55
2. Evolution.......................................... 57
3. Low-Density Lipoprotein Receptor Polymorphisms. . . . . . 58
III. Low-Density Lipoprotein Receptor Endocytosis, Recycling
and Turnover . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
IV. Low-Density Lipoprotein Receptor Mutations and Familial
Hypercholesterolaemia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
1. Classes of Low-Density Lipoprotein Receptor Mutations 60
a) Class I Mutations (Null Alleles) . . . . . . . . . . . . . . . . . . . . 61
b) Class II Mutations (Transport-Defective Alleles) .. . . . 62
c) Class III Mutations (Binding-Defective Alleles) ..... . 62
d) Class IV Mutations (Internalization-Defective
Alleles) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 62
e) Class V Mutations (Recycling-Defective Alleles) ..... 62
2. Clinical Variability in Familial Hypercholesterolaemia ... 63
V. Low-Density Lipoprotein Receptor Regulation. . . .. . . . . . .. 63
1. Low-Density Lipoprotein Receptor Promoter. . . . . . . . . . . 63