Sterols and Bile Acids

465 Pages·1985·12.2 MB·English

by  Henry Danielsson and Jan Sjövall (Eds.)

STEROLS AND BILE ACIDS
New Comprehensive Biochemistry
Volume 12
General Editors
A. NEUBERGER
London
L.L.M. van DEENEN
Urrecht
ELSEVIER
AMSTERDAM NEW YORK OXFORD
* *
Sterols and Bile Acids
Editors
HENRY DANIELSSON and JAN SJOVALL
a
a Department of Pharmaceutical Biochemistiy, University of Uppsala, Uppsala
(Sweden) and Department of Physiological Chemistiy, Karolinska Institutet,
Stockholm (Sweden)
1985
ELSEVIER
-
Amsterdam New York Oxford
*
1985. Elsecier Science Publishers B.V (Biomedical Division)
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ISBN for the series: 0-444-80303-3
ISBN for the volume: 0-444-80670-9
Published by :
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Library of Congress Cataloging-in-Publication Data
Main entry under title.
Sterols and bile acids
(New comprehensive biochemistry: v. 12)
Includes bibliographies and index.
1. Sterols--1Metabolism.2 . Bile acids-Metabolism.
I. Danielsson. Henry. 11. Sjovall. Jan. 111. Series.
[DNLM: 1. Bile Acids and Salts--metabolism. 2. Sterols
--metabolism. W1 NE372F v.12 / QU 95 S8391
QD415.N48 VOI.1 2 574.19’2 s 1574.19’24311 85-20620
/QB752.S75]
ISBN 0-444-80670-9 (U.S.)
Printed in The Netherlands
Preface
Sterols are essential components of all eukaryotic cells. Their function is struc-
tural, and by being precursors of hormones and bile acids they exert a regulatory
function on metabolic processes. Cholesterol and its metabolism are of importance
in human disease. Although the mechanisms are largely unknown, it can be surmised
that abnormalities in the metabolism of sterols and bile acids are associated with
cardiovascular disease and gallstone formation. Steroid hormones are vital for man,
animals and plants. Disturbances in their production can have deleterious conse-
quences.
Ths volume of New Comprehensive Biochemistry is entitled Sterols and Bile
Acids. It includes fourteen chapters written by prominent scientists in the field. The
large volume of material in the field of sterols and bile acids has necessitated a
limitation of the areas covered. Chapters on steroid hormones have been excluded
since this field requires a volume of its own. In spite of this it has not been possible
to produce a book of some few hundred pages. Efforts have been made to condense
the contributions of the individual authors, but the wealth of important information
is such that a further reduction in size would seriously affect the value of the
chapters to the reader.
It may be argued that there are important gaps in the contents of this volume. For
instance, full discussions of the role of compartmentation of sterols and their
metabolism, of the dynamics of cholesterol balance, etc. are lacking. We as editors
take full responsibility for ths. Our only excuse is that the material contained in the
volume is already at the limit of what can be accommodated in a volume of New
Comprehensive Biochemistry.
Although we have tried to make terminology, abbreviations, etc. reasonably
uniform it will be apparent that there are differences between chapters, but hope-
fully not within a chapter. We have felt it more important to let the individualities of
the authors be expressed.
It is our conviction that the eminent contributions in this volume, for which we
are very grateful to our colleagues, will be of the value they deserve for all scientists
in the field of sterol and bile acid research.
Uppsala and Stockholm Henry Danielsson
September 1985 Jan Sjovall
This Page Intentionally Left Blank
H. Danielsson and J. Sjovall (Eds.), Sterols and Bile Acids
0 1985 Elsevier Science Publishers B.V. (Biomedical Division)
Contents
Preface .......................................... ........ v
Chapter I
Biosynthesis of cholesterol
H- ans C. filling and Liliane T. Chayet (Salt Lake City and Santiago) ..... 1
I. ................ 1
11.
111. Acetyl-CoA acetyl transferase (EC 2.3.1.9)
1. Cellular location ................ ..... 3
2. Enzymology ........................... ..... 4
..... 4
IV.
2. Enzymology ......................................
V. ................ 8
2. Mechanism .................................
................ 11
VI.
VII. Phosphomevalonate kinase (EC 2.7.4.2) ........................... 12
VIII. ........ ..... 13
IX.
1. Enzymology ........................... ..... 14
X.
3. Mechanism .......................................
................................................. 20
5. Termination ........................... ..... 21
XI. Squalene synthetase .... ......................
............................ 24
XII.
1. Enzymology .....
2. Mechanism .......................................... ..... 28
XIII. The conversion of lanosterol to cholesterol . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
1. Sterol function. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2. General aspects of enzymology . . . . . . . . . . . . . . . . . . . . . . 31
3. The pathway . . . . . . . . ....................................... 32
4. Decarbonylation at (2-14 ....................................... 32
5. Decarboxylation at C-4 . . . . . ........................ 34
6. Introduction of As . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
Acknowledgement .................................................. 37
References ....................................................... 37
Chapter 2
Control mechanisms in steroi uptake and biosynthesis
John F. Gill Jr., Peter J. Kennelly and Victor W. Rodwell (West tafayette) . 41
1. Control of sterol uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
~
1. Plasma lipoproteins , . . . . , , , . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
a. Normal plasma lipoproteins, 41 - b. Abnormal plasma lipoproteins,
Chemically modified lipoproteins, 44 -
2. Cellular mechanisms of cholesterol uptake . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
a. The LDL receptor and receptor-mediated endocytosis, 45 - b. Other receptor-media-
ted lipoprotein uptake mechanisms, 48 - c. Receptor ndent cholesterol uptake, 51
3. Regulation of receptor-mediated sterol uptake . . . . . .................... 52
4. Diseases related to receptor-mediated cholesterol upta ____..._.......__5_4 _.
a. Homozygous FH, receptor-negative and receptor-defective, 54 - b. Heterozygous
FH. 56 - c. Homozygous FH. internalization-defective, 56 - d. Wolman syndrome, 56
.- e. Cholesterol ester storage disease, 56 -
11. Control of sterol biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
1. Mammalian HMG-CoA reductase .......................... 57
a. Rate-limiting step in sterol bi b. Distribution, 57 - c. Diurnal
rhythm and developmental pattern, 58 - d. Regulation of HMG-CoA reductase protein
level. 59 - e. Modulation of HMG-CoA reductase activity, 62 -
2. Other sites of control . . .......................... 65
a. Early sites of control. 65 - b. Later sites of control, 66 -
67
61
Chapier 3
Participution of sterol carrier proteins in cholesterol biosynthesis, utilization and
intracellulur transfer
Terence J. Scallen and George V. Vahouny (Albuquerque and Washington) 73
I. Introduction ........................................................ 13
11. Sterol carrier protein, (SCP,) 74
1. Purification and characteri 1 .................................. 74
2. Substratespecificity . . . ....................... 74
3. Participation of SCP, in
squalene to sterol . . . . . ................................. 75
4. Properties of SCP, . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
ix
111. Sterol carrier protein, (SCP,) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
1. Participation of SCP, in cholesterol biosynthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 77
a. General remarks, 77 - b. Purification and characterization of SCP,, 77 - c.
Substrate specificity, 78 - d. Kinetic studies, 78 - e. Anti-SCP, IgG, 79-
2. Participation of SCP, in cholesterol utilization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
a. Cholesterol esterification, 80 - b. Cholesterol 7a-hydroxylase, 81 -
3. Participation of SCP, in intracellular cholesterol transfer . . . . . . . . . . . . . . . . . . . . . . . 82
a. SCP, is required for cholesterol transport from adrenal lipid droplets to mitochondria,
82 - b. Identification of adrenal SCP,, 84 - c. SCP, facilitates the translocation of
cholesterol from the outer to the inner mitochondrial membrane, 85 -
4. Comparisoqof SCP, with other low molecular weight proteins . . . . . . . . . . . . . . . . . . . 87
a. Fatty-acid-binding protein (FABP), 87 - b. Nonspecific phospholipid exchange
protein, 90 -
IV. The participation of sterol carrier proteins in intracellular cholesterol metabolism . . . . . . . . 91
Acknowledgements ................................................. 91
References ....................................................... 91
Chapter 4
Biosynthesis, function and metabolism of sterol esters
Alan Jones and John Glomset (Seattle) . . . . . . . . . . . . . . . . . . . . . . . . . . 95
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95
11. Distribution and physical properties of cholesterol esters . 95
111. Enzymes and proteins that mediate the formation, transp
esters . . . . . . . . . . . 98
1. Acyl-CoA :c holesterol acyltransferase( EC 2.3.1.26) . . . . . . . . . . . . . . . . . . . . . . . . . . 98
2. Cholesterol ester hydrolase (EC 3.1.1.13) . . 101
a. Acid CEH, 101 - b. Neutral CEH, 102 -
3. Lecithin : cholesterol acyltransferase( EC 2.3.1.43) 103
4. Plasma cholesterol ester transfer protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
IV. Physiology of choles ............. 107
1. Plasma lipoprotein cholesterol esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
2. Tissue cholesterol esters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110
a. Fibroblasts, 111 - b. Cells that form steroid hormones, 112 - c. Macrophages, 112
- d. Hepatocytes, 113 -
V. Cholesterol sulfate . . . . . . . . . . . . 113
VI. Cholesterol esters and disease . . . . . . . . . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . 114
VII. Conclusion . . . . . . . . . . . . . . . . . . 116
References ....................................................... 116
Chapter 5
Cholesterol absorption and metabolism by the intestinal epithelium
Eduard F. Stange and John M. Dietschy (Dallas) . . . . . . . . . . . . . . . . . . . 121
I. Introduction ........................................................ 121
11. Absorption of cholesterol . . . . ............. 123
111. Intestinal cholesterol synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
1. Methodology.. . . . . . . . . . . ... 125
2. Localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126