Advances in Lipid Research

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 LIST OF CONTRIBUTORS

Numbers in parentheses indicate the pages on which the authors' contributions begin.

PIERO P. FOA, Department of Research, Sinai Hospital of Detroit, Detroit,

Michigan (227)
BEATRIX FOURCANS, Department of Chemistry, Indiana University,
Bloomington, Indiana (147)
BARBARA V. HOWARD,* Department of Biochemistry, School of Dental
Medicine, Department of Microbiology, School of Medicine, University
of Pennsylvania and the Clinical Research Center, Philadelphia
General Hospital, Philadelphia, Pennsylvania (51)
WILLIAM J. HOWARD, Department of Medicine, School of Medicine,
University of Pennsylvania and the Clinical Research Center,
Philadelphia General Hospital, Philadelphia, Pennsylvania (51)
MAHENDRA KUMAR JAIN,! Department of Chemistry, Indiana University,
Bloomington, Indiana and Department of Chemistry and Health
Sciences, University of Delaware, Newark, Delaware (147)
GILBERT A. LEVEILLE, Department of Food Science and Human
Nutrition, Michigan State University, East Lansing, Michigan (97)
LEON A. LIPSHAW, Department of Research, Sinai Hospital of Detroit,
Detroit, Michigan (227)
SERGIO MUNTONI, Department of Pharmacology and Chemotherapy,
University of Cagliari; Second Division of Medicine, and Center for
Metabolic Diseases and Arteriosclerosis, SS. Trinita Hospital of
Cagliari, Cagliari, Italy (311)

* Present address: Clinical Research Center, Philadelphia General Hospital, Phila­

delphia, Pennsylvania 19104.
f Present address: Department of Chemistry and Health Sciences, University of
Delaware, Newark, Delaware, 19711.
rx
X LIST O F CONTRIBUTORS

DALE R. ROMSOS, Department of Food Science and Human Nutrition,

Michigan State University, East Lansing, Michigan (97)
P. S. SASTRY, Department of Biochemistry, Indian Institute of Science,
Bangalore, India (251)
ELSPETH B. SMITH, Department of Chemical Pathology, University of
Aberdeen, Aberdeen, Scotland (1)
 PREFACE

The current volume of Advances in Lipid Research brings together

topics which range across the field of lipid metabolism. As in the past,
the chapters in this book represent the most advanced knowledge in the
specific areas represented.
The opening review is devoted to a discussion of the relationships
between plasma and tissue lipids and atherosclerosis. Understanding the
dynamics of exchange of plasma lipoproteins with aortic tissue is the
basis of understanding the etiology of this disease and, hopefully, the
approaches to therapy. A relatively recent research tool, but one which
has already shown great utility, is the study of metabolism using
cultured cells.
The second paper of this book is devoted to a discussion of lipid
metabolism in cultured cells. Cell systems hold promise of understanding
mechanisms of lipidoses and may aid in their diagnosis. All phases of
lipid metabolism are discussed in this review. Research on dietary effects
on lipid metabolism has progressed beyond descriptions of the lipid
content of blood and tissues. The "what" of various regimens is known
and we are now asking "how?" The third article describes the influences
of various dietary components on the specific enzymes of fatty acid and
cholesterol biogenesis. This discussion includes enzyme induction, syn­
thesis, and degradation. Membrane function, especially the metabolic
behavior of one important membrane component, is discussed in the
fourth paper. This article is devoted to an exposition of the role of
phospholipids in transport and enzymic reactions. This discussion in­
cludes membrane fluidity and aspects of lipid-protein interactions.
Thyroid hormone exerts specific effects on cholesterol and bile acid
metabolism. It has been implicated, via these effects on lipids, in the
etiology of atherosclerosis. The lipids of the thyroid gland, however, have
never been fully investigated. The fifth review is devoted to a discussion
of thyroid lipids and their physiologic role. Thyroid lipids are primarily
triglycerides; their synthesis and hydrolysis may aid in the regulation
of glucose metabolism by this gland. The designation "glycolipid" covers
xi
Xll PREFACE

a variety of structures. A newcomer to this area is the class of glycolipids

known as glycosyl glycerides. These compounds are found in plants,
bacteria, and in animal tissues. The chemistry and biological function
of glycosyl glycerides is discussed in the sixth article. The last paper is
devoted to the physiopathology of the biguanidines, a class of oral hypo-
glycemic agents whose relationship to carbohydrate and lipid metabolism
is only now being established.

RODOLFO PAOLETTI
DAVID KRITCHEVSKY
 CONTENTS OF PREVIOUS VOLUMES
Volume 1
The Structural Investigation of Natural Fats
M. H. Coleman
Physical Structure and Behavior of Lipids and Lipid Enzymes
A. D. Bangham
Recent Developments in the Mechanism of Fat Absorption
John M. Johnston
The Clearing Factor Lipase and Its Action in the Transport of Fatty
Acids between the Blood and Tissues
D. S. Robinson
Vitamin E and Lipid Metabolism
Roslyn B. Alfin-Slater and Rosemary Shull Morris
Atherosclerosis—Spontaneous and Induced
Thomas B. Clarkson
Chromatographic Investigations in Fatty Acid Biosynthesis
M. Pascaud
Carnitine and Its Role in Fatty Acid Metabolism
Jrving B. Fritz
Present Status of Research on Catabolism and Excretion of Cholesterol
Henry Danielsson
The Plant Sulfolipid
A. A. Benson
AUTHOR I N D E X — S U B J E C T INDEX

Volume 2
Triglyceride Structure
R. J. VanderWal
xm
Xiv CONTENTS OF PREVIOUS VOLUMES

Bacterial Lipids
M. Kates

Phosphatidylglycerols and Lipoamino Acids

Marjorie G. Macfarlane

The Brain Phosphoinositides

/. N. Hawthorne and P. Kemp

The Synthesis of Phosphoglycerides and Some Biochemical Applications

L. L. M. van Deenen and G. H. deHaas

The Lipolytic and Esterolytic Activity of Blood and Tissues and

Problems of Atherosclerosis
T. Zemplenyi

Evaluation of Drugs Active against Experimental Atherosclerosis

Robert Hess

Comparative Evaluation of Lipid Biosynthesis in Vitro and in Vivo

P. Favarger

AUTHOR I N D E X — S U B J E C T INDEX

Volume 3

The Metabolism of Polyenoic Fatty Acids

E. Klenk
The Analysis of Human Serum Lipoprotein Distributions
Alicia M. Eicing, Norman K. Freeman, and Frank T. Lindgren

Factors Affecting Lipoprotein Metabolism

Angelo M. Scanu
The Action of Drugs on Phospholipid Metabolism
G. B. Ansell

Brain Sterol Metabolism

A. N. Davison

Lipases
E. D. Wills
AUTHOR I N D E X — S U B J E C T INDEX
CONTENTS O F PREVIOUS VOLUMES XV

Volume 4

The Role of Lipids in Blood Coagulation

Aaron J. Marcus

Lipid Responses to Dietary Carbohydrates

I. Macdonald

Effects of Catecholamines on Lipid Mobilization

Max Wenke

The Polyunsaturated Fatty Acids of Microorganisms

Robert Shaw

Lipid Metabolism in the Bacteria

W. J. Lennarz

Quantitative Methods for the Study of Vitamin D

Padmanabhan P. Nair

Labeling and Radiopurity of Lipids

Fred Snyder and Claude Piantadosi
AUTHOR I N D E X — S U B J E C T INDEX

Volume 5

Fatty Acid Biosynthesis and the Role of the Acyl Carrier Protein
Philip W. Majerus and P. Roy Vagelos
Comparative Studies on the Physiology of Adipose Tissue
Daniel Rudman and Mario Di Girolamo

Ethionine Fatty Liver

Emmanuel Farber
Lipid Metabolism by Macrophages and Its Relationship to Atherosclerosis
Allan J. Day
Dynamics of Cholesterol in Rats, Studied by the Isotopic Equilibrium
Methods
F. Chevallier
The Metabolism of Myelin Lipids
Marion Edmonds Smith
XVi CONTENTS O F PREVIOUS VOLUMES

Brain Cholesterol: The Effect of Chemical and Physical Agents

Jon J. Kabara
The Analysis of Individual Molecular Species of Polar Lipids
Ossi Renkonen
Phase Diagrams of Triglyceride Systems
/. B. Rossell
AUTHOR I N D E X — S U B J E C T INDEX

Volume 6
Practical Methods for Plasma Lipoprotein Analysis
Frederick T. Hatch and Robert S. Lees
The Lipids of Mycoplasma
Paul F. Smith

Lipid Quinones
T. Ramasarma

Comparative Pathogenetic Patterns in Atherosclerosis

Robert W. Wissler and Dragoslava Vesselinovitch

Chemistry and Metabolism of Bile Alcohols and Higher Bile Acids

Takahiko Hoshita and Taro Kazuno
Hydroxy Fatty Acid Metabolism in Brain
David M. Rowen and Norman S. Radin

Gas Phase Analytical Methods for the Study of Steroids

E. C. Horning, C. J. W. Rrooks, and W. J. A. Vanden Heuvel
AUTHOR INDEX S U B J E C T INDEX

Volume 7
Lipid Histochemistry
C. W. M. Adams

Control of Plasma and Liver Triglyceride Kinetics by Carbohydrate

Metabolism and Insulin
Esko A. Nikkila
CONTENTS O F PREVIOUS VOLUMES xvii

Lipid Metabolism in Tissue Culture Cells

George H. Rothblat
Carcinogenic Effects of Steroids
Fritz Bischoff
The Chemical and Biological Properties of Heated and Oxidized Fats
Neil R. Artman
AUTHOR I N D E X — S U B J E C T INDEX

Volume 8
Cholesterol Turnover in Man
Paul J. Nestel
Arterial Composition and Metabolism: Esterified Fatty Acids and
Cholesterol
Oscar W. Portman
The Essential Fatty Acids
Michael Guarnieri and Ralph M. Johnson
Lipids in Membrane Development
Godfrey S. Getz
Plant Phospholipids and Glycolipids
M. Kates
Metabolism of Long-Chain Fatty Acids in the Rumen
Romano Viviani
Surface Chemistry of Lipids
Dinesh O. Shah
AUTHOR I N D E X — S U B J E C T INDEX

Volume 9
Light and Electron Microscopic Radioautography of Lipids: Techniques
and Biological Applications
O. Stein and Y. Stein
The Origin of Hydrogen in Fatty Synthesis
Simonne Rous
XV111 CONTENTS O F PREVIOUS VOLUMES

Fatty Acid Biosynthesis in Aorta and Heart

Arthur F. Whereat
Structure of Membranes and Role of Lipids Therein
Frantz A. Vandenheuvel
Glycosphingolipids
Herbert Weigandt
Biosynthesis of Pregnane Derivatives
Shlomo Burstein and Marcel Gut
Lipid Composition of Vegetable Oils
Enzo Fedeli and Giovanni Jacini
AUTHOR I N D E X — S U B J E C T INDEX

Volume 10
Application of Electron Microscopy to the Study of Plasma Lipoprotein
Structure
Trudy Forte and Alex V. Nichols

Employment of Lipids in the Measurement and Modification of Cellular,

Humoral, and Immune Responses
Nicholas R. Di Luzio

Microsomal Enzymes of Sterol Biosynthesis

James L. Gaylor

Brain Lipids
Robert B. Ramsey and Harold J. Nicholas
Enzymatic Systems That Synthesize and Degrade Glycerolipids Possessing
Ether Bonds
Fred Snyder

Lipids in the Nervous System of Different Species as a Function of Age:

Brain, Spinal Cord, Peripheral Nerve, Purified Whole Cell Preparations,
and Subcellular Particulates: Regulatory Mechanisms and Membrane
Structure
George Rouser, Gene Kritchevsky, Akira Yamamoto, and Claude F.
Baxter

AUTHOR INDEX SUBJECT INDEX

CONTENTS O F PREVIOUS VOLUMES xix

Volume 11
The Metabolic Role of Lecithin: Cholesterol Acyltransf erase:
Perspectives from Pathology
John A. Glomset and Kaare B. Norum
Lipoprotein-Polyanion-Metal Interactions
M. Burstein and H. R. Scholnick
Uptake and Transport of Fatty Acids into the Brain and the Role of the
Blood—Brain Barrier System
Govind A. Dhopeshtoarkar and James F. Mead
Microbiological Transformation of Bile Acids
Shohei Hayakaica
Phytosterols
George A. Bean
Metabolism of Steroids in Insects
M. J. Thompson, J. N. Kaplanis, W. E. Robbins, and J. A. Svoboda
Lipids in Viruses
Herbert A. Blough and John M. Tiffany
AUTHOR INDEX SUBJECT INDEX
 The Relationship Between Plasma and
Tissue Lipids in Human Atherosclerosis

ELSPETH B. SMITH
Department of Chemical Pathology, University of Aberdeen,
Aberdeen, Scotland

I. Introduction 1
II. Relationship Between the Chemical and Morphological
Characteristics of Lipid in Human Aortic Intima 2
A. Morphology of Normal Intima and Atherosclerotic
Lesions 2
B. Concentration and Composition of the Lipids 5
III. Concentration of Plasma LD-Lipoprotein in Normal Intima
and Lesions 22
A. Concentration of LD-Lipoprotein in Normal Intima 23
B. Distribution of LD-Lipoprotein in Lesions 27
IV. Quantitative Relationship Between Plasma Constituents
in Intima 31
A. LD-Lipoprotein, Albumin, and Fibrinogen in Normal
Intima and Lesions 32
B. Ratios of Constituents in Plasma and Intima and
Mechanisms of Entry and Retention 33
V. Relationship Between LD-Lipoprotein and the Lipid
"Deposited" in Intima 37
A. Comparison of Lipoprotein and Intimal Lipids 37
B. Lipoprotein Concentration and Dynamic Studies on
Influx and Efflux 42
VI. Conclusions 45
References 46

I. Introduction

A high level of plasma cholesterol has emerged as an important risk

factor in all epidemiological studies on the incidence and prevalence of
ischemic heart disease. However, in man the relationship between plasma
cholesterol levels and the extent and severity of atherosclerosis and the
cholesterol content of the arterial wall has not emerged clearly. This
probably arises from at least two causes. First, it is difficult to obtain
information on plasma cholesterol levels during life in subjects coming
1
2 E L S P E T H B. S M I T H

to autopsy; consequently, the few studies that are published are based
on institutionalized patients of advanced age (Paterson et al, 1956,
1963); second, the atherosclerotic lesions found in arteries of middle-
aged or older humans are extremely heterogeneous, ranging from ac­
cumulation of lipid, particularly cholesterol ester, with very little in­
crease in connective tissue components to a massive hyperplasia of
collagen and smooth muscle cells with only slight accumulation of lipid.
The balance between the different types of lesion is clearly influenced
by many factors including age, sex, and race (McGill, 1968), but the
influence of plasma lipid levels is not clear.
There is, however, a close correspondence between the detailed lipid
composition of the Sf 0-12 (LD) lipoprotein of plasma and the composi­
tion of extracellular lipid in samples of intima with defined histological
characteristics (Smith et al, 1967, 1968; Smith and Slater, 1972a). There
is also a substantial amount of electrophoretically and immunologically
intact LD-lipoprotein in the human aortic intima, and its concentration
in normal intima is highly correlated with the level of the subject's
plasma cholesterol during the week before death (Smith and Slater,
1972b, 1973a,b). From the analysis of the cholesterol esters in topo­
graphically and morphologically defined fractions isolated by microdis-
section, Smith and Slater (1972a) concluded that most of the cholesterol
in the main "atheroma" lipid pool of large plaques in human aorta is
derived directly from plasma LD-lipoprotein and not from disintegra­
tion of fat-filled cells. This suggests that in humans, the entry of LD-
lipoprotein, its retention within the intima and the precipitation of lipid
from it may be key factors in atherogenesis.
This is the aspect of the problem which will be discussed in this paper;
several reviews on other aspects of arterial lipids have already appeared
in Advances in Lipid Research (Clarkson, 1963; Zemplenyi, 1964; Day,
1967; Wissler and Vesselinovitch, 1968; Adams, 1969; Whereat, 1971),
and in particular Portman (1970) has published a most comprehensive
review on esterified fatty acids and cholesterol. No attempt will be
made to cover the same ground as these papers or to emulate their
completeness.

II. Relationship Between the Chemical and Morphological

Characteristics of Lipid in Human Aortic Intima

A. MORPHOLOGY OF NORMAL INTIMA AND ATHEROSCLEROTIC LESIONS

Much of the confusion and apparent disagreement in atherosclerosis

research has undoubtedly arisen either from failure to differentiate be-