Cellular Proteins and Their Fatty Acids in Health and Disease

483 Pages·2003·8.77 MB·English

by  Asim K. Duttaroy

AsimK. DuttaroyandFriedrich Spener
(Eds.)
CellularProteins and TheirFatty Acids
in Health and Disease

Asim K. Duttaroy and Friedrich Spener (Eds.)
Cellular Proteins and Their Fatty Acids
in Health and Disease
Editors: (cid:2) This book was carefully produced. Nevertheless,
authorsandpublisherdonotwarranttheinfor-
ProfessorDr.AsimK.Duttaroy mationcontainedthereintobefreeoferrors.
InstituteforNutritionResearch Readersareadvisedtokeepinmindthatstate-
UniversityofOslo ments,data,illustrations,proceduraldetailsor
POB1046Blindern otheritemsmayinadvertentlybeinaccurate.
N-0316Oslo
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V
Preface
Long-chain fatty acids, in addition to providing the cell with energy, are substrates
for membrane biogenesis and act as signalling molecules. These fatty acids and
theirderivativesdirectlyorindirectlyregulatecellularprocessessuchasdifferentia-
tion, development and gene expression as well as the activities of enzymes, mem-
branereceptorsandionchannels.Dietaryfatshaveprofoundeffectsongeneexpres-
sionandfattyacid-activatedtranscriptionfactors(nuclearreceptors)mayhaveafun-
damentalroleinregulatingenergybalancethroughtheirsensingoffattyacidfluxin
metabolicallyactivetissues.Becauseofthefunctionalrolesofthesefattyacidsandof
their structural features and physico-chemical properties, it is important to under-
stand the mechanisms that evolved for uptake and retention of these molecules.
The picture emerging is that the cell has multiple binding proteins in the mem-
branesaswellasintheaqueouscompartmentsthatassureadequateuptakeandin-
tracellular movementoflong-chain fatty acidsand their regulatory action.
This book covers the various aspects of intracellular binding proteins (FABPs,
ACBP, SCP-2), such as structure-function, ligand specificity, delivery of ligands by
membrane-protein and protein-protein interaction, as well as their expression and
roles pertaining to nutrition, health, and disease. Regulation and expression of
membrane fatty acid transporters such as FABPpm, FAT, FATP, and ABC trans-
porters are treated in further chapters. In addition, transcription factors PPARs,
RXRs, RARs, LXR, and HNF4 which bind fatty acids or their derivatives are also
dealt with in depth. They play a central role in regulating the storage and catabo-
lism of dietary fats and essentially all major metabolic paths of lipids appear to be
under control of one or more genes regulated by these transcription factors.Their
roles in inflammatory disorders, obesity, cancers, and atherosclerosis are also dis-
cussed. Since these transcription factors require fatty acids or their derivatives as
ligands, FABPs may play important rolesin transporting these ligands.
Many leading investigators have contributed their most recent developments to
this book. We believe that it will prove to be an invaluable reference text for both
those familiar with and those new to the exciting, and ever changing world of cel-
lular proteins whosecommondenominator isbinding of fatty acids.
VI Preface
Finally, we would like to express our thanks to all contributors to this book and
to the reviewers for their competent advice. The untiring support and patience of
Ines Chyla and the staff at Wiley-VCHisgratefully acknowledged.
Osloand Münster, February 2003 Asim K. Duttaroy, Oslo
FriedrichSpener, Münster
VII
Contents
Preface V
ListofContributors XIX
Part1 TheMolecularBasisofProtein-LipidInteraction
andFunctionalConsequences 1
1 Structure-FunctionofCD36andEvidenceforitsRole
inFacilitating MembraneFatty AcidTransport 3
ChrisT. Coburn and Nada A. Abumrad
1.1 Introduction 3
1.2 Primary Structure 4
1.3 Ligand Binding Domains 6
1.4 MembraneLocalization and Role in Cell Signaling 6
1.5 CD36 GeneStructure and Regulation 8
1.6 CD36 Deficiency 10
1.7 CD36 and Platelet Function 11
1.8 CD36 and Atherosclerosis 12
1.9 CD36 and Phagocytosis 13
1.10 CD36 and Angiogenesis 14
1.11 CD36 and Malaria 14
1.12 CD36 and Fatty AcidTransport 15
1.12.1 CD36 isIdentified as a MediatorofFAUptake 15
1.12.2 CD36, SHR, and Insulin Resistance 17
1.12.3 CD36 Transgenic and Knockout MiceModels 18
1.12.4 CD36-null Mice– the FedPhenotype 18
1.12.5 CD36-null Mice– the Fasting Phenotype 22
1.12.6 CD36 and Insulin Responsivenessin the Mouse 23
1.13 Perspectivesand Future Directions 24
1.14 References 25
VIII Contents
2 RoleandFunctionofFATPsinFatty AcidUptake 31
Jean E. Schaffer
2.1 Introduction 31
2.2 Identification ofFatty AcidTransporterProteins 32
2.3 Structure ofFATPs 32
2.4 Function of FATPs 34
2.5 Regulation ofFATPexpression 35
2.6 Significance ofFATPs 36
2.7 References 37
3 Function,Expression,andRegulationofHumanABCTransporters 39
Gerd Schmitz and Thomas Langmann
3.1 Introduction 39
3.2 Structural Featuresof ATP Binding Cassette(ABC) Transporters 40
3.3 OverviewofHuman ABC GeneSubfamilies 41
3.3.1 The ABCA (ABC1) Subfamily 45
3.3.2 The ABCB (MDR/TAP) Subfamily 46
3.3.3 The ABCC (CFTR/MRP) Subfamily 48
3.3.4 The ABCD (ALD) Subfamily 50
3.3.5 The ABCE (OABP) and ABCF (GCN20) Subfamilies 51
3.3.6 The ABCG (White) Subfamily 51
3.4 Diseasesand Phenotypes Caused by ABC Transporters 52
3.4.1 Familial HDL-deficiency and ABCA1 52
3.4.2 Retinal Degenerationand ABCA4 (ABCR) 54
3.4.3 Cystic Fibrosis(ABCC7/CFTR) 56
3.4.4 Multidrug Resistance(ABCB1/MDR1, ABCC1/MRP1, ABCG2) 57
3.4.5 Adrenoleukodystrophy (ABCD1/ALD) 58
3.4.6 Sulfonylurea Receptor(ABCC8/SUR) 59
3.5 Function and Regulation ofABC Transportersin Lipid Transport 60
3.5.1 ABCA1 in Macrophage Lipid Transport 61
3.5.2 ABCG1 and Other ABCG membersin Sterol Homeostasis 64
3.5.3 ABC Transportersinvolvedin Hepatobiliary Transport 67
3.6 Conclusionsand Perspectives 70
3.7 References 70
4 AlbuminReceptors–StructureandFunction 79
NigelJ. Brunskill
4.1 Introduction 79
4.2 The Search foran Albumin Receptor 80
4.2.1 The Endothelium–Albumin Relationship: Early Concepts 80
4.2.2 Identification ofReceptorsforNative
and ModifiedAlbumin in Endothelial Cells 81
4.3 Albumin Receptorsin the Kidney 83
4.3.1 Glomerular Handling of Albumin 83
4.3.2 Binding and Uptake ofAlbumin in the Kidney Proximal Tubule 83
Contents IX
4.4 Megalin and Cubilin as Proximal TubuleAlbumin Receptors 84
4.4.1 Megalin 84
4.4.2 Cubilin 86
4.5 Albumin as a Signaling Molecule–
Implications forAlbumin ReceptorFunction 87
4.5.1 LDLR Family as Signaling Receptors 88
4.5.2 Megalin as a Signaling Receptor 89
4.6 Summary 90
4.7 References 90
5 IntracellularLipid BindingProteins:
Evolution,Structure,andLigandBinding 95
Christian Lücke,LuisH. Gutiérrez-González,and JamesA.Hamilton
5.1 Introduction 95
5.2 The Evolution ofLipid Binding Proteins 95
5.2.1 The Calycin Superfamily 95
5.2.2 The Intracellular Lipid Binding Proteins 96
5.2.3 The Phylogeny ofiLBPs 98
5.3 Structural CharacteristicsofiLBPs 99
5.3.1 The CommonThree-dimensionalFold 101
5.3.2 The iLBP Subfamilies 103
5.3.2.1 Subfamily I 103
5.3.2.2 Subfamily II 105
5.3.2.3 Subfamily III 106
5.3.2.4 Subfamily IV 106
5.3.3 Dynamic PropertiesofiLBPs 107
5.3.4 Mutagenesis Studies 108
5.4 Ligand Binding Assays 109
5.4.1 Microcalorimetry 109
5.4.2 The Lipidex Assay 110
5.4.3 Fluorescence-basedBinding Assays 111
5.4.4 The ADIFAB Assay 111
5.4.4.1 Thermodynamic Analysis 112
5.4.4.2 Kinetic Analysis 112
5.4.5 Lipid Binding Preferences 113
5.5 Concluding Remarks 113
5.6 References 114
6 Fatty AcidBindingProteinsandFatty AcidTransport 119
JudithStorch and Lindsay McDermott
6.1 Introduction 119
6.2 Equilibrium Binding ofFatty Acidsto FABPs 119
6.3 In vitro Fatty AcidTransferPropertiesof FABPs 122
6.4 TransfectionStudiesof FABP Function 125
6.5 Cellular Fatty AcidTransport via FABP-Protein Interactions 126