Metabolism and Functions of Bioactive Ether Lipids in the Brain

269 Pages·2008·2.97 MB·English

by  Akhlaq A. Farooqui, Tahira Farooqui

Metabolism and Functions of Bioactive
Ether Lipids in the Brain
Akhlaq A. Farooqui • Tahira Farooqui
Lloyd A. Horrocks
Metabolism and Functions
of Bioactive Ether Lipids
in the Brain
Akhlaq A. Farooqui Tahira Farooqui
The Ohio State University The Ohio State University
Department of Molecular and Department of Molecular and
Cellular Biochemistry Cellular Biochemistry
Columbus, OH Columbus, OH
USA USA
Lloyd A. Horrocks (1932-2007); A mentor, colleague, and friend.
We dedicate this monograph to the memory
of Professor Lloyd A. Horrocks, an outstanding
neurochemist and a world-renowned authority
on plasmalogens metabolism and
phospholipases A in brain.
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Akhlaq A. Farooqui
Tahira Farooqui
Preface
Neurochemical importance of ether lipids is becoming increasingly evident. These
lipids include plasmalogen and platelet activating factor. They play crucial roles in
membrane fusion, ion transport, inflammation, oxidative stress, and learning and
m emory. Significant advances have been made in our understanding of structure
and functions of plasmalogens and platelet activating factor in neural and non-neu-
ral tissues. Increased degradation of plasmalogens is associated with neurochemical
and neuropathological changes associated with acute neural trauma (stroke, spi-
nal cord trauma, and head injury) and neurodegenerative diseases (such as
Alzheimer disease). The decrease in activity of plasmalogen-synthesizing enzymes
is involved in peroxisomal disorders (such as Zellweger syndrome and Rhizomelic
chondrodysplasia punctata). The increase in platelet activating factor levels has
been reported to occur in ischemic injury, bacterial meningitis, AIDS, prion dis-
eases, and multiple sclerosis. Miller-Dieker lissencephaly is caused by a mutation
in PAF-acetyl hydrolase. In the past decade, there has been considerable develop-
ment not only in our knowledge of the biochemistry of ether lipids but also in our
understanding of signal transduction processes associated with their metabolism in
the brain. The molecular mechanism that governs the transfer of the death signal
from neural cell surface to the nucleus depends upon levels of lipid mediators gen-
erated by the degradation of ether lipids and crosstalk among ether lipid, diacyl
glycerophospholipid, and glycosphingolipid-derived lipid mediators. This cross-
talk modulates the intensity of oxidative stress and neuroinflammation. Thus, inter-
actions among ether lipid, diacyl glycerophospholipid, and glycosphingolipid-derived
lipid mediators play a major role in neuronal cell injury and death following acute
neural trauma and neurodegenerative diseases. At present, it is unclear whether
these processes are primary initiating points in neurodegeneration, or if they are
the end result of the neurodegenerative process itself. In recent years, we have
been empowered by technological advances in lipidomics, proteomics, and genom-
ics. Investigators are using these techniques not only to identify and determine lev-
els of lipid mediators but also for developing diagnostic test for neurodegenerative
diseases associated with altered ether lipid metabolism.
The purpose of this monograph is to present the readers with a coherent overview
and cutting edge information in a manner that is useful not only to students and
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viii Preface
teachers but also to researchers and physicians. This monograph has 12 chapters.
The first chapter describes the occurrence and importance of ether lipids in brain.
Chapters 2 and 3 cover cutting-edge information on the biosynthesis and degradation
of plasmalogens in the central nervous system. Chapter 4 describes the determina-
tion and purification of plasmalogen-selective phospholipase A and lysoplasmalo-
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genase from brain. Chapters 5 and 6 are devoted to roles and involvement of
plasmalogens in neurological disorders. Chapters 7 and 8 describe the biosynthesis
and degradation of platelet- activating factor in the central nervous system. Chapters
9 and 10 describe the functions and association of platelet activating factors with
neurological disorders. Chapter 11 deals with neurochemical effects of antitumor
ether lipids. Finally, Chapter 12 provides readers and researchers with perspective
that will be important for future research work on bioactive ether lipids. Our writing
style and demonstrated ability to present complicated material on bioactive ether
lipid metabolism makes this book particularly accessible to neuroscience graduate
students, teachers, and fellow researchers. It can be used as a supplement for a
range of neuroscience courses. This monograph is essential reading for the busy
physician or pathologist who wants to be up to date with the latest developments on
plasmalogens and platelet-activating factor metabolism.
Clinicians will find this book useful for understanding the molecular aspects of
neurodegeneration in stroke and Alzheimer disease that are mediated by plasmalogen-
selective phospholipase A and PAF acetyl hydrolase. To our knowledge, no one
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has written a monograph on bioactive ether lipids and so this monograph is the first
to provide students, teachers, researchers, and clinicians a comprehensive description
of metabolism and role of plasmalogen and platelet-activating factor along with
abnormal signal transduction processes in neurological disorders.
The choices of topics presented in this monograph are personal. They are not
only based on our interest in ether lipid metabolism in neurological disorders, but also
in an area where major progress has been made. We have tried to ensure uniformity
in mode of presentation as well as a logical progression from one topic to another, and
have provided extensive referencing. For the sake of simplicity and uniformity, a
large number of figures and line diagrams of signal transduction pathways are also
included. We hope that our attempt to integrate and consolidate the knowledge of
signal transduction processes associated with ether lipid metabolism in brain will
provide the basis of more dramatic advances and developments on the involvement
of bioactive ether lipids in neurological disorders.
Akhlaq A. Farooqui
Tahira Farooqui
Acknowledgments
We thank Sage Science Press, USA, and Portland Press Ltd., UK, for granting
permission to reproduce figures from our earlier papers published by them. We also
thank Siraj A. Farooqui for drawing chemical structures and signal transduction
pathways associated with the synthesis and degradation of bioactive ether lipids.
We would also like to express our gratitude to Ann H. Avouris of Springer,
New York for her able and professional handing of the manuscript.
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Contents
1 Occurrence and Importance of Ether Lipids in Brain ........................... 1
1.1 Introduction ......................................................................................... 1
1.2 Classification of Ether Lipids Found in Brain .................................... 2
1.3 Physicochemical Properties of Ether Lipids ....................................... 3
1.4 Fecapentaenes: The Novel Plasmalogens ........................................... 4
1.5 Other Ether Lipids Found in Mammalian Tissues .............................. 6
1.6 Lipid Metabolism in Ether Lipid-Deficient Mice ............................... 10
1.7 Conclusion .......................................................................................... 12
References .................................................................................................... 13
2 Biosynthesis of Plasmalogens in Brain ..................................................... 17
2.1 General Considerations and Distribution of Plasmalogens in Brain ... 17
2.2 Biosynthesis of Plasmalogens ............................................................. 18
2.2.1 Dihydroxyacetone Phosphate Acyltransferase ........................ 20
2.2.2 Alkyl Dihydroxyacetone Phosphate Synthase ........................ 23
2.2.3 Acyl/alkyl Dihydroxyacetone Phosphate Reductase............... 25
2.2.4 Alkylglycerophosphate Acyltransferase .................................. 26
2.2.5 Alkylacyl Glycerophosphate Phosphohydrolase ..................... 26
2.2.6 CDP-Ethanolamine: Diacylglycerol
Ethanolaminephosphotransferase ............................................ 27
2.3 Plasmalogen Synthesizing Enzymes During Brain Development ...... 28
2.4 Topology and Distribution of Plasmalogens and Enzymes
Synthesizing Plasmalogens ................................................................. 29
2.5 Plasmalogens in Lipid Rafts................................................................ 30
2.6 Plasmalogens in the Nucleus ............................................................... 30
2.7 Factors Affecting Plasmalogen Biosynthesis in Brain ........................ 31
2.8 Conclusion........................................................................................... 32
References .................................................................................................... 33
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xii Contents
3 Catabolism of Plasmalogens in Brain ...................................................... 39
3.1 Introduction ....................................................................................... 39
3.2 Plasmalogen-Selective Phospholipase A (PlsEtn-PLA ) ................. 39
2 2
3.3 Receptor-Mediated Degradation of Plasmalogens ........................... 44
3.4 Regulation of PlsEtn-PLA ............................................................... 48
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3.5 Turnover of Plasmalogen in Brain .................................................... 49
3.6 Remodeling of Plasmalogens (Reacylation/
Deacylation Reactions) ..................................................................... 50
3.7 Degradation of Plasmalogens by Phospholipase C .......................... 51
3.8 Nonenzymic Oxidation of Plasmalogens in Brain ............................ 51
3.9 Plasmalogen-Derived Lipid Mediators and Their
Importance in Brain .......................................................................... 54
3.10 Lysoplasmalogens in Brain ............................................................... 58
3.11 Conclusion ........................................................................................ 59
References .................................................................................................... 59
4 Assay and Purification of Plasmalogen-Selective Phospholipase
A and Lysoplasmalogenase Activities ..................................................... 67
2
4.1 Introduction ......................................................................................... 67
4.2 Determination of PlsEtn and PlsCho-PLA by Radiochemical
2
Procedures ........................................................................................... 68
3
4.2.1 Preparation of Radiolabled [ H] Plasmenylcholine
(Choline Plasmalogen) ............................................................ 68
4.2.2 Labeling of Lysoplasmenylcholine at the Sn-2 Position ......... 70
4.2.3 Determination of PlsCho-PLA Activity ................................. 70
2
4.2.4 Determination of PlsEtn-PLA by Fluorometric Assay .......... 71
2
4.2.5 Purification of Ethanolamine Plasmalogen ............................. 72
4.2.6 Labeling of Ethanolamine Plasmalogen with
Pyrenesulfonyl Chloride .......................................................... 72
4.2.7 Determination of PlsEtn-PLA Activity with
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Pyrene-Labeled Plasmalogen .................................................. 73
4.2.8 Continuous Spectrophotometric Determination
of PlsEtn-PLA ........................................................................ 74
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4.2.9 Determination of Lysoplasmalogenase ................................... 74
4.2.9.1 Continuous Spectrophotometric Procedure for
Lysoplasmalogenase . 75
4.2.9.2 Continuous Spectrofluorometric Procedure for
Lysoplasmalogenase . 76
4.3 Activities of Plasmalogen-Selective PLA in Brains of Various
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Animal Species and Cultured Cells of Neuronal
and Glial Origin................................................................................... 78
4.4 Determination of Lysoplasmalogenase Activity in Rat Liver
and Brain Microsomes ........................................................................ 78
4.5 Purification of Plasmalogen-Selective PLA from Brain .................... 80
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4.6 Purification of Lysoplasmalogenase from Liver ................................. 80