Advances in lipid research. Vol. 23, 1989 PDF
Preview Advances in lipid research. Vol. 23, 1989
EDITORIAL ADVISORY BOARD B. LEWIS G. SCHLIERF A. V. NICHOLS C. SlRTORI G. H. ROTHBLAT R. W. WiSSLER Advances in Lipid Research Volume 23 Edited by Rodolfo Paoletti Institute di Farmacologia et di Farmacognosia Universita di Milano Milano, Italy David Kritchevsky The Wistar Institute Philadelphia, Pennsylvania ACADEMIC PRESS, INC. Harcourt Brace Jovanovich, Publishers San Diego New York Berkeley Boston London Sydney Tokyo Toronto This book is printed on acid-free paper. @ COPYRIGHT © 1989 BY ACADEMIC PRESS, INC. All Rights Reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. ACADEMIC PRESS, INC. San Diego, California 92101 United Kingdom Edition published by ACADEMIC PRESS LIMITED 24-28 Oval Road, London NW1 7DX LIBRARY OF CONGRESS CATALOG CARD NUMBER: 63-22330 ISBN 0-12-024923-5 (alk. paper) PRINTED IN THE UNITED STATES OF AMERICA 89 90 91 92 9 X 7 6 5 4 3 21 PREFACE This volume of Advances in Lipid Research touches on areas of importance in mammalian as well as plant metabolism. Emerging data suggest that the apoproteins which may be recognized by receptors, namely apoB and apoE, may offer a foothold for further probes of the genetics underlying increased susceptibility to ischemic heart disease. The first article in this volume ad- dresses the molecular biology of human apolipoproteins B and E. The next essay is concerned with the lipid metabolism of dermatophytes and discusses their lipid composition and how it may be modulated. It also touches on the biosynthesis and turnover of dermatophyte lipids. The distribution, function, and biosynthesis of the sterols of fungi is the subject of the third article. Influ- ences of fungal sterols on membrane fluidity are also discussed. The last four articles are devoted to two specific topics. We felt the data were such that they deserved to be reviewed in succeeding essays. The fourth and fifth are devoted to eicosanoids, an important new player on the lipid stage. The influence of dietary polyunsaturated fatty acids on eicosanoid for- mation in humans is the theme of the fourth. The fifth is a review of the analysis of eicosanoid formation. Platelet-activating factor (PAF) is 1-O-alkyl- 2-acetyl-sft-glycero-3-phosphocholine, and it has been implicated in a number of physiological processes including allergy, asthma, and thrombosis. The sixth article presents a review of the biosynthesis and degradation of PAF as well as its physiological function. The final essay concentrates on one specific area of PAF activity, namely, renal processes. This volume is a good example of the diversity of the lipid research area. RODOLFO PAOLETTI DAVID KRITCHEVSKY ix ADVANCES IN LIPID RESEARCH, VOL. 23 Molecular Biology of Human Apolipoproteins B and E and Associated Diseases of Lipoprotein Metabolism VASSILIS I. ZANNIS Departments of Medicine and Biochemistry Boston University Medical Center Boston, Massachusetts 02118 I. General Introduction II. Apolipoprotein B A. Introduction B. Derivation of the Primary Sequence of Human apoB-100 from the Corresponding cDNA and Gene Sequences C. Distribution of Cysteines and N-Glycosylation Sites of the apoB-100 Sequence D. The Receptor and Heparin Binding Domains of Human apoB-100 E. The Lipid Binding Domains of Human apoB-100 F. Synthesis, Assembly, and Flotation Properties of Nascent apoB-100 and apoB-48 Containing Lipoprotein Forms G. Relationship between apoB-100 and apoB-48 Forms H. Lipoprotein Receptors Recognizing apoB-100 I. Genetic Variation in Human apoB-100 J. Conclusions III. Apolipoprotein E A. Introduction B. Primary Structure of Human apoE Protein, mRNA, and Gene C. Synthesis, Modifications, and Flotation Properties of Nascent apoE D. Lipoprotein Receptors Recognizing apoE E. Receptor and Heparin Binding Domains of apoE F. Genetic Variation and Posttranslational Modification in Human apoE G. apoE Phenotypes Demonstrated to Be the Result of Structural Mutations in the apoE Gene H. Certain apoE Phenotypes and Genotypes Associated with Type III HLP I. Molecular Basis of a Familial apoE Deficiency J. Reduced Binding to Lipoprotein Receptors of apoE Derived from Individuals with the E2/2 Phenotype May Underlie type III HLP K. Factors Affecting Phenotypic Expression of type III HLP L. apoE Alleles Affect Plasma Lipid and Lipoprotein Levels in the General Population M. apoE Functions IV. Conclusions References 1 Copyright © 1989 by Academic Press, Inc. All rights of reproduction in any form reserved. 2 VASSILIS I. ZANNIS I. General Introduction Lipoproteins are macromolecular complexes of lipids and proteins that are synthesized mainly by the liver and the intestine and catabolized by hepatic and extrahepatic tissues. Their main, well-defined physiological function is to transport dietary and/or endogenously synthesized lipids (e.g., cholesterol, triglycerides, and phospholipids) from one organ to another (Morrisett etal., 1975), although they may also be involved in the regulation of other impor- tant physiological processes. In normal plasma, there are traditionally con- sidered to be four lipoprotein classes: (1) chylomicrons, (2) very low-density lipoproteins (VLDLs), (3) low-density lipoproteins (LDLs), and (4) high- density lipoproteins (HDLs) (Table I). Several subfractions of VLDLs, LDLs, and HDLs and a lipoprotein class of density intermediate between VLDLs and LDLs (IDLs) have also been described. The plasma lipoproteins are spherical particles with cores of nonpolar neutral lipid consisting of cholesteryl ester and triglycerides and coats of relatively polar materials consisting of phospholipid, free cholesterol, and proteins (Atkinson etal., 1974; Laggner et al., 1981; for reviews see Herbert et al, 1982; Scanu et al, 1982; Smith et al, 1978) (Table I). The protein components of lipoproteins are called apolipo- Table I PROPERTIES AND COMPOSITION OF HUMAN PLASMA LIPOPROTEINS* Lipoprotein class Properties and composition Chylomicrons VLDLs LDLs HDLs Size (A) 750-12,000 300-700 180-300 50-120 Density (g/ml) 0.94 0.94-1.006 1.019-1.063 1.063-1.21 Triglycerides (°/o wt.) 80-95 45-65 4-8 2-7 Phospholipids (°7o wt.) 3-6 15-20 18-24 26-32 Free cholesterol (°/o wt.) 1-3 4-8 6-8 3-5 Esterified cholesterol 2-4 16-22 45-50 15-20 (% wt.) s? 400* 20-400* 0-12* 0-9c Electrophoretic mobility Origin (cathode) Pre-0 P a Proteins (% wt.) 1-2 6-10 18-22 45-55 Major apoproteins A-I, A-IV, B, CI, B, E, CI, B A-I, A-II, CIII, E CII, CIII E Minor apoproteins A-II, CII A-I, A-II, CI, CII, CI, CII, A-IV CIII, E CIII, D, E "Modified from Herbert et al. (1982). ^Corrected flotation rate at a density of 1.063 g/cm3, expressed in svedbergs [10"13cm/(sec dyne g)]. cFj 20 designates corrected flotation at a density of 1.20 g/cm3. Apolipoproteins B and E, Associated Diseases 3 proteins and have been designated apoA-I, apoA-II, apoA-IV, apoB, apoCI, apoCII, apoCIII, apoD and apoE (Alaupovic, 1971). Analysis of the secondary structure of apolipoproteins indicates that they contain extensive regions of amphipathic helices containing nonpolar and polar surfaces. In these structures the nonpolar surface of the helix is presumed to interact with nonpolar lipids, such as cholesteryl ester and triglycerides, and the polar surface supposedly interacts with the polar head group of the phospholipid as well as with the aqueous phase (Sparrow etal, 1975). This is consistent with the role of apolipoproteins in lipoprotein structure and/or lipid transport. Although only partially understood at the present time, lipoprotein metabo- lism is a complex pathway and contains the following steps: (1) apolipoprotein synthesis, (2) intracellular apolipoprotein modification, (3) lipoprotein assembly, (4) lipoprotein secretion, (5) extracellular apolipoprotein modifica- tion, (6) hydrolysis of lipoprotein triglycerides by lipoprotein lipase and hepatic lipase, (7) esterification of lipoprotein cholesterol by lecithin cholesterol acyltransferase, (8) enzyme-catalyzed exchange and/or transfer of cholesteryl esters and phospholipids, (9) exchange and/or transfer of apolipoproteins, (10) reverse transport of cholesterol from cells to lipoproteins, (11) receptor- mediated catabolism of lipoproteins. Schematic representations of this pathway are shown in Fig. 1A and B; for details see Zannis and Breslow (1985a,b). Figure 1A and B indicates that a variety of proteins, including apolipoproteins, plasma proteins, and lipoprotein receptors, participate in this pathway. Research in the last 15 years has provided ample evidence that mutations in these proteins may lead to human diseases (Breckenridge et al, 1978, 1982; Breslow etal, 1982; Cladaras et al, 1987; Davis etal, 1986; Goldstein and Brown, 1982; Karathanasis <##/., 1983a; Lehrman et al, 1985, 1987; Nikkila, 1982; Norum etal, 1982; Rail etal, 1982; Zannis and Breslow, 1985a,b). In addition, research in the last decade has shown that some apolipoproteins are not merely structural components of lipoproteins, but can be cofactors in enzymatic reactions that affect lipoprotein metabolism (Fielding etal, 1972; Fukushimaef a/., 1980; Havel etal, 1970; LaRosaera/., 1970; Nilsson-Ehle, 1980; Soutar etal, 1975; Steinmetz and Utermann, 1985) or can be involved in receptor-mediated catabolism of lipoproteins (Carrela and Cooper, 1979; Goldstein and Brown, 1982; Hui etal, 1981; Innerarity and Mahley, 1978; Innerarity et al, 1983; Weisgraber et al, 1983). Figure 1C shows how a cell, by the action of sets of lipoproteins and lipoprotein receptors, can maintain cholesterol homeostasis. The apolipoprotein composition of the lipoproteins is summarized in Table I. Our current knowledge of apolipoprotein struc- ture, function, and sites of synthesis is summarized in Table II (Albers et al, 1981; Blackharterfl/., 1986; Blum etal, 1980; Boguskief a/., 1986a; Carlson 4 VASSILIS I. ZANNIS and Holmquist, 1982; Cladaras etal, 1986a; Das et al, 1985; Drayna etal, 1986; Green etal. 1980; Havel etal, 1980a; Karathanasisetftf/., 1983b, 1985, 9 1986a,b; Knott etal, 1984, 1985a, 1986; Law etal., 1986; Lenich etal., 1988; Paik etal., 1985; Protter etal., 1984; Schonfeld etal., 1982; Shoulders etal, 1983; Tsao era/., 1985; Wei etal, 1985; Wu and Windmueller, 1979; Yang etal, 1986; Zannis etal, 1985a). A LIPOPROTEIN SYNTHESIS LIPOPROTEIN INTERCONVERSION AND CATABOLISM E + Csfrom HDL A-l All E Receptor-Mediated ~A-IV Catabolism by Liver B 48 B-100 CM A-l, Cs, A-IK?) to HDL cm A-IV to HDL or d 1.21 g/ml E D Extrahepatic Tissues HDL Nascent HDL Nascent PL, TG Synthess i A-l, All, Cs Macrophages ^^" HDL2 from VLDL and chylomicrons Extrahepatic ^ Tissues LHDL,,HDLC CE to VLDL, IDL, LDL E + Csfrom HDL -LDL- -B/E Receptor-Mediated /l Catabolism by Hepatic and Extrahepatic Tissues \\ B/E and E Receptor- UMedi ated Catabolism ►M Aecdyial tLedD LC aRtaebcoelpistomr- by Macrophages ^-VLDL- •0-VLDL Receptor-Mediated Catabolism by Macrophages FIG. 1. (A) Schematic representation of the pathway of lipoprotein metabolism. The pathway is based on the information reviewed by Zannis and Breslow (1985a,b). LCAT, Lecithin-cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; LPL, lipoprotein lipase; HTL, hepatic triglyceride lipase; C, cholesterol; TG, triglyceride; PL, phospholipid; A-I, apoA-I, etc.; d, density. (B and C) Simplified representation of the pathway of lipoprotein metabolism and its role in cellular cholesterol chemeostasis. Apolipoproteins B and E, Associated Diseases 5 B LIPOPROTEIN METABOLISM CELL COMPARTMENT • PLASMA COMPARTMENT LJPIDS NASCENT CELL LIPOPROTEINS ENZYMES AND OTHER PLASMA PROTEINS MODIFYING APO X LIPIDS AND APOPROTEINS MATURE lOODI LIPOPROTEINS FICATIONS APO x' CELL RECEPTORS ~ CELLULAR CHOLESTEROL HOMEOSTASIS HDL receptor cholesterol / removal CELL cholesterol delivery F"* LDL receptor Fig. 1. {Continued.). Utilization of molecular biology approaches has greatly advanced our knowledge of the structure of normal apolipoproteins and apolipoprotein genes and has contributed to our understanding of human diseases caused by structural apolipoprotein gene mutations. At the present time the combined efforts by several laboratories have con- tributed to the elucidation of the sequences of the gene and/or the complemen- tary mRNA (cDNA) for all of the human apolipoproteins (Blackhart etai, Table II APOPROTEINS AND THEIR ASSOCIATION WITH HUMAN DISEASES Plasma Amino acid Association with concentration sequenceMolecular of Sites of 6 fl Function(mg/ml)clinical disorders mature protein weight Apoprotein synthesis ApoA-I-apoCIII defi-A-I Activates LCAT AA 24328,000 Liver/intestine, minor 1.0-1.2 c ciency sites77 AA 8500 Liver 0.3-0.5 A-II 376 AA Activates LCAT 45,000 A-IV Liver/intestine 0.16 Abetalipoproteinemia, Receptor-mediated 513,000 0.7-1.0 4536 AA Liver/intestine B-100 normotriglyceridemic catabolism of LDLs abetalipoproteinemia (B-100 deficiency) Similar to amino-243,000 B-48 Liver/intestine terminal portion (residues 1-2152) of B-100 Liver/adrenal 57 AA Activates LCAT CI 6500 0.04-0.06 (moderately) Activates lipoprotein CII 9000 Familial typeLiver/intestine 0.03-0.05 79 AA I hyperlipoproteinemia lipase 79 AA cm 9000 Inhibits catabolism of ApoA-I-apoCIII Liver/intestine 0.12-0.14 apoE containing deficiency lipoproteins 19,500 Adrenal gland, kidney, 0.06-0.07 AA D 169pancreas, placenta, minor sites^ E 0.025-0.05 299 AA Liver/peripheral 34,200 Receptor-mediated III Familial typetissues catabolism of apoE hyperlipoproteinemia containing lipoproteins °The plasma concentrations of apolipoproteins are based on information from Albers et al. (1981), Blum et al. (1980), Carlson and Holmquist (1982), Green et al. (1980), Havel et al. (1980a), and Schonfeld et al. (1982). Information on the major sites of synthesis was obtained from Lenich et al. (1988), al., (1985a). Wu and Windmueller (1979), and Zannis etb LCAT, Lecithin-cholesterol acyltransferase. cMinor sites of apoA-I mRNA synthesis in fetal human tissues are the adrenal gland, kidney, gonads, ovaries, heart, and stomach, whereas apoE mRNA is present in every tissue analyzed (Zannie et al., 1985a). ^Minor sites of apoD mRNA synthesis are the intestine, liver, spleen, and brain (Drayna et al., 1986).
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