115. Cellular Lipid Metabolism

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115. Cellular Lipid Metabolism

 

 

CATEGORY: Diet Nutrition Supplementation – 500 Courses

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Syllabus

1 The Lipid Droplet: a Dynamic Organelle, not only
Involved in the Storage and Turnover of Lipids……………………………….. 1
Sven-Olof Olofsson, Pontus Boström, Jens Lagerstedt,
Linda Andersson, Martin Adiels, Jeanna Perman,
Mikael Rutberg, Lu Li, and Jan Borén
1.1 Introduction …………………………………………………………………………….. 2
1.2 Lipid Droplets Form as Primordial Structures
at Microsomal Membranes ………………………………………………………… 3
1.2.1 Microsomal Membrane Proteins Involved
in Lipid Droplet Formation……………………………………………… 3
1.2.2 Model for the Assembly of Lipid Droplets ……………………….. 4
1.3 Lipid Droplet Size Increases by Fusion ………………………………………. 5
1.3.1 SNAREs are Involved in Lipid Droplet Fusion ………………….. 5
1.3.2 Model for the Fusion Between Lipid Droplets …………………… 6
1.4 Lipid Droplets and the Development of Insulin Resistance ……………. 7
1.5 Lipid Droplet-Associated Proteins ……………………………………………… 8
1.5.1 PAT Proteins …………………………………………………………………. 8
1.5.2 Other Lipid Droplet-Associated Proteins ………………………….. 11
1.6 Lipid Droplets and the Secretion of Triglycerides from the Cell …….. 11
1.6.1 The Assembly and Secretion of Milk Globules………………….. 12
1.6.2 ApoB100: the Structural Protein of VLDL ……………………….. 13
1.6.3 ApoB100 and the Secretory Pathway ……………………………….. 14
1.6.4 The Assembly of VLDL …………………………………………………. 14
1.6.5 Regulation of VLDL Assembly ……………………………………….. 17
1.6.6 Clinical Implications of VLDL1 Production ……………………… 18
1.7 Conclusions …………………………………………………………………………….. 19
References ………………………………………………………………………………………. 19
2 Oxysterols and Oxysterol-Binding Proteins
in Cellular Lipid Metabolism ………………………………………………………….. 27
Vesa M. Olkkonen
2.1 Oxysterols, Their Synthesis and Catabolism ………………………………… 27
2.1.1 Oxysterols that Arise Through Enzymatic
Cholesterol Oxidation …………………………………………………….. 28

2.1.2 Oxysterols Generated via Non-Enzymatic
Oxidative Events ………………………………………………………….. 31
2.1.3 Oxysterols in the Circulation …………………………………………. 31
2.1.4 Catabolism of Oxysterols ……………………………………………… 33
2.2 Biological Activities of Oxysterols …………………………………………….. 34
2.2.1 Effects of Oxysterol Administration on Cells in Vitro ………. 34
2.2.2 Oxysterols in Atherosclerotic Lesions …………………………….. 35
2.2.3 Oxysterols as Regulators of Cellular Lipid Metabolism ……. 36
2.2.4 Oxysterols Regulate Hedgehog Signaling ……………………….. 40
2.3 Cytoplasmic Oxysterol-Binding Proteins …………………………………….. 41
2.3.1 Indentifi cation of Oxysterol-Binding
Protein-Related Proteins ……………………………………………….. 41
2.3.2 Structure and Ligands of ORPs ……………………………………… 42
2.3.3 Subcellular Distribution of ORPs …………………………………… 45
2.3.4 Function of OSBP in Lipid Metabolism ………………………….. 47
2.3.5 Evidence for the Involvement of Mammalian
OSBP Homologues in Lipid Metabolism ………………………… 48
2.3.6 Functional Interplay of ORPs with the Transcriptional
Regulators of Lipid Metabolism …………………………………….. 50
2.3.7 Function of Yeast Osh Proteins in Sterol Metabolism……….. 50
2.3.8 Osh4p Regulates Secretory Vesicle Transport ………………….. 52
2.3.9 Mammalian ORPs and Intracellular Vesicle Transport ……… 53
2.3.10 ORPs – Integrating Lipid Cues with Cell
Signaling Cascades ………………………………………………………. 54
2.4 Future Perspectives …………………………………………………………………… 55
References ………………………………………………………………………………………. 58
3 Cellular Lipid Traffi c and Lipid Transporters:
Regulation of Effl ux and HDL Formation ……………………………………….. 73
Yves L. Marcel, Mireille Ouimet, and Ming-Dong Wang
3.1 Introduction …………………………………………………………………………….. 73
3.2 Regulation of apoA-I Synthesis, Lipidation and Secretion
in Hepatocytes: Genesis of apoA-I-Containing
Lipoproteins and HDL ………………………………………………………………. 74
3.3 Cell Specifi city of ABCA1 Expression and HDL
Formation in Vivo: Insight from Genetically Modifi ed Mice………….. 75
3.4 Transcriptional and Posttranscriptional Regulation of ABCA1 ………. 76
3.5 Cellular Traffi c of ABCA1 ………………………………………………………… 78
3.5.1 Syntrophin and the Regulation of Lipid
Effl ux Activity …………………………………………………………….. 78
3.5.2 Sorting of ABCA1 Between Golgi, Plasma
Membrane and LE-Lysosomes: Contribution of Sortilin …… 81
3.6 Integrated Models of Lipid Effl ux and Lipoprotein Assembly:
Nascent HDL Formation …………………………………………………………… 82
3.6.1 Interaction of apoA-I with Cell Surface ABCA1 ……………… 83

3.6.2 Contribution of Retroendocytosis …………………………………… 84
3.7 Complementarities of ABCA1, ABCG1 and SR-BI
in Lipid Effl ux and HDL Formation and Their Combined
Role in Reverse Cholesterol Transport in Vivo …………………………….. 85
3.7.1 HDL Genesis in Various Types of Cells ………………………… 85
3.7.2 Cholesterol Effl ux to apoA-I in Macrophages ………………… 86
3.7.3 In Vivo Cholesterol Effl ux from Macrophages
and Reverse Cholesterol Transport ……………………………….. 87
3.8 Cellular Lipid Traffi c Through the Late Endosomes …………………….. 88
3.8.1 Egress of Cholesterol From LE ……………………………………. 88
3.8.2 Regulation of Cholesterol Traffi c in LE ………………………… 89
3.9 Cholesterol Traffi c Through the Lipid Droplet …………………………….. 91
3.9.1 Regulation of Cholesterol Traffi c in the Adipocyte LD …… 92
3.9.2 Regulation of Cholesterol Traffi c in the Macrophage LD … 92
3.9.3 Regulation of Cholesterol Traffi c in the Hepatocyte LD ….. 93
3.10 Caveolin and Cellular Cholesterol Transport ……………………………… 94
3.11 Mobilization of LD Lipids for Effl ux ………………………………………… 95
3.11.1 The LD is the Major Source of Cholesterol for Effl ux …….. 95
3.11.2 Hydrolysis and Mobilization of LD Cholesteryl
Esters for Effl ux …………………………………………………………. 96
3.11.3 Is ABCA1 Involved in the Mobilization and Traffi c
of LD Cholesterol for Effl ux? ………………………………………. 97
3.12 Conclusions …………………………………………………………………………… 97
References ………………………………………………………………………………………. 98
4 Bile Acids and Their Role in Cholesterol Homeostasis …………………….. 107
Nora Bijl, Astrid van der Velde, and Albert K. Groen
4.1 Introduction …………………………………………………………………………….. 107
4.2 Bile Acid Synthesis ………………………………………………………………….. 108
4.2.1 Regulation of Synthesis by Nuclear Receptors ………………. 109
4.2.2 Oxysterol Feed-Forward Regulation of Bile Synthesis ……. 110
4.2.3 Bile Acid Feedback Regulation of Bile Synthesis ………….. 110
4.2.4 FGF-Regulated Feedback of Bile Synthesis …………………… 111
4.2.5 Other Pathways ………………………………………………………….. 113
4.3 Regulation of the Enterohepatic Circulation ………………………………… 115
4.3.1 Liver …………………………………………………………………………. 115
4.3.2 Intestine ……………………………………………………………………. 117
4.4 Cholesterol in the Enterohepatic Circulation ……………………………….. 117
4.4.1 Cholesterol Absorption in the Intestine …………………………. 118
4.4.2 Intestinal Cholesterol Secretion ……………………………………. 119
4.4.3 Novel Pathways for Cholesterol Excretion …………………….. 120
4.5 Role of the Enterohepatic Cycle in the Control
of Cholesterol Homeostasis……………………………………………………….. 123
4.6 Concluding Remarks ………………………………………………………………… 124
References ………………………………………………………………………………………. 124

5 Cholesterol Traffi cking in the Brain ………………………………………………… 131
Dieter Lütjohann, Tim Vanmierlo, and Monique Mulder
5.1 Introduction …………………………………………………………………………… 131
5.2 Cholesterol Turnover in the Brain …………………………………………….. 132
5.3 Release of 24(S)-Hydroxycholesterol from the Brain
into the Circulation ………………………………………………………………… 135
5.4 Lipoproteins in the Cerebrospinal Fluid …………………………………….. 136
5.5 Astrocytes Supply Neurons with Cholesterol …………………………….. 137
5.6 How do Neurons Regulate Their Cholesterol Supply? ………………… 139
5.7 Alternative Pathway for Cholesterol Release from Neurons? ……….. 142
5.8 Role for cAMP Responsive Element Binding Protein
in the Regulation of Neuronal Cholesterol Homeostasis ……………… 143
5.9 Internalization of Cholesterol by Neurons …………………………………. 143
5.10 The Choroid Plexus as an Alternative Source of HDL ………………… 144
5.11 Disturbances in Cholesterol Traffi cking Between Astrocytes
and Neurons in Alzheimer’s Disease? ………………………………………. 145
5.12 Do Alterations in Systemic Sterol Metabolism Alter Brain
Sterol Metabolism? ………………………………………………………………… 147
References ………………………………………………………………………………………. 148
6 Intracellular Cholesterol Transport ………………………………………………… 157
Daniel Wüstner
6.1 Biophysical Properties of Cholesterol in Model Membranes ……….. 157
6.2 Molecular Organization and Function of Cholesterol
in the Plasma Membrane ………………………………………………………… 161
6.3 Overview of Membrane Traffi c Along the Endocytic
and Secretory Pathways and its Dependence on Cholesterol ……….. 165
6.4 Function of Various Organelles in Cellular
Cholesterol Metabolism and Transport ……………………………………… 168
6.5 Vesicular and Non-Vesicular Transport of Cholesterol:
Targets, Kinetics and Regulation ……………………………………………… 171
6.6 Alterations in Intracellular Cholesterol Traffi cking
in Atherosclerosis and Lipid Storage Diseases …………………………… 176
6.7 Future Prospects …………………………………………………………………….. 180
References …………………………………………………………………………………….. 181
7 Role of the Endothelium in Lipoprotein Metabolism ……………………….. 191
Arnold von Eckardstein and Lucia Rohrer
7.1 Introduction …………………………………………………………………………… 191
7.2 Expression of Proteins Involved in Lipoprotein Metabolism ………… 192
7.2.1 Lipoprotein Lipase and GPIHBP1 ………………………………….. 193
7.2.2 Hepatic Lipase …………………………………………………………….. 193
7.2.3 Endothelial Lipase ……………………………………………………….. 194
7.3 Lipoprotein Transport Through the Endothelium ……………………….. 195

7.3.1 General Aspects of Transendothelial
Lipoprotein Transport …………………………………………………….. 195
7.3.2 Paracellular (Lipo)protein Transport ………………………………… 196
7.3.3 Transendothelial (Lipo)protein Transport …………………………. 198
7.4 Target for Physiological and Pathological Effects
of Lipoproteins ………………………………………………………………………… 200
7.4.1 Regulation of the Vascular Tone ………………………………………. 200
7.4.2 Leukocyte Adhesion and Extravasation ……………………………. 202
7.4.3 Platelet Aggregation, Coagulation, and Fibrinolysis …………… 203
7.4.4 Endothelial Survival and Repair ………………………………………. 204
References ………………………………………………………………………………. 206
8 Receptor-Mediated Endocytosis and Intracellular
Traffi cking of Lipoproteins …………………………………………………………… 213
Joerg Heeren and Ulrike Beisiegel
8.1 Lipoproteins and Their Receptors ………………………………………………. 213
8.1.1 Metabolism of LDL ……………………………………………………….. 214
8.1.2 Metabolism of Triglyceride-Rich Lipoproteins ………………….. 215
8.2 Receptor-Mediated Endocytosis of LDL……………………………………… 216
8.2.1 Structure and Function of the LDL Receptor …………………….. 217
8.2.2 Ligands of the LDL Receptor ………………………………………….. 219
8.2.3 Intracellular Processing of LDL ………………………………………. 220
8.2.4 Regulation of LDL Receptor Function ……………………………… 221
8.3 Receptor-Mediated Endocytosis of Chylomicron Remnants ………….. 223
8.3.1 Structure and Function of LRP1 ………………………………………. 223
8.3.2 Ligands of LRP1 ……………………………………………………………. 224
8.3.3 Intracellular Processing of Chylomicron Remnants ……………. 225
8.3.4 Regulation of LRP1 Function ………………………………………….. 229
References ………………………………………………………………………………. 230
9 Angiopoietin-Like Proteins and Lipid Metabolism ………………………….. 237
Sander Kersten
9.1 Introduction …………………………………………………………………………….. 237
9.2 Angpt14 and Lipid Metabolism …………………………………………………. 238
9.2.1 Discovery and Structure of Angpt14 ………………………………… 238
9.2.2 Regulation of Angptl4 Expression …………………………………… 239
9.2.3 Role of Angptl4 in Lipid Metabolism ………………………………. 240
9.2.4 Role of Angptl4 in Human ……………………………………………… 243
9.3 Angpt13 and Lipid Metabolism …………………………………………………. 243
9.3.1 Discovery and Structure of Angptl3 …………………………………. 243
9.3.2 Regulation of Angptl3 Expression …………………………………… 244
9.3.3 Role of Angpt13 in Lipid Metabolism ……………………………… 244
9.3.4 Role of Angpt13 in Human …………………………………………….. 246
9.5 Conclusion ………………………………………………………………………………. 246
References ………………………………………………………………………………………. 246

10 Thyroid Hormones and Lipid Metabolism:
Thyromimetics as Anti-Atherosclerotic Agents? ……………………………. 251
Bernhard Föger, Andreas Wehinger, Josef R. Patsch,
Ivan Tancevski, and Andreas Ritsch
10.1 Thyroid Hormones, Thyroid Hormone-Receptors
and Lipoprotein Metabolism ………………………………………………….. 252
10.1.1 Thyroid Hormone Signalling ……………………………………… 252
10.1.2 Thyroid Function and Lipoprotein Metabolism ……………. 253
10.2 Thyromimetics and Thyromimetic Compounds………………………… 268
10.2.1 Background ……………………………………………………………… 268
10.2.2 Selective Thyromimetic Compounds ………………………….. 270
10.2.3 Selective Thyromimetics as Hypolipidemic Drugs ……….. 271
10.2.4 Potential Additional Applications ………………………………. 273
10.2.5 Off-Target Toxicity of Selective Thyromimetics …………… 274
References …………………………………………………………………………… 276
11 Adipokines: Regulators of Lipid Metabolism ………………………………… 283
Oreste Gualillo and Francisca Lago
11.1 Introduction …………………………………………………………………………. 283
11.2 Regulation of Lipid Metabolism by Adipokines ………………………. 284
11.2.1 Leptin ……………………………………………………………………… 284
11.2.2 Adiponectin …………………………………………………………….. 290
11.2.3 Other Relevant Adipokines Contributing
to Lipid Metabolism …………………………………………………. 291
11.3 Conclusions …………………………………………………………………………. 294
References …………………………………………………………………………………….. 295
12 Cellular Cholesterol Transport – Microdomains,
Molecular Acceptors and Mechanisms ………………………………………….. 301
Christopher J. Fielding
12.1 Overview …………………………………………………………………………….. 301
12.2 Structure and Properties of the Cell Surface …………………………….. 304
12.3 Role of Cell-Surface Lipid Transporters in RCT ………………………. 305
12.4 Cholesterol Effl ux and the LCAT Reaction ……………………………… 306
12.5 Signifi cance of ABCG1 ………………………………………………………… 308
12.6 Recycling of apo-A-I ……………………………………………………………. 308
12.7 RCT from Activated Macrophages …………………………………………. 309
References …………………………………………………………………………………….. 311

13 The Ins and Outs of Adipose Tissue ………………………………………………. 315
Thomas Olivecrona and Gunilla Olivecrona
13.1 Introduction …………………………………………………………………………. 316
13.2 Sources of Lipids for Deposition in Adipose Tissue …………………. 317
13.3 Lipoprotein Lipase ……………………………………………………………….. 321
13.3.1 Molecular Properties ………………………………………………… 321
13.3.2 Synthesis, Maturation and Transport of LPL ……………….. 329
13.3.3 LPL at the Endothelium …………………………………………….. 336
13.3.4 Regulation/Modulation of Tissue LPL Activity ……………. 343
13.4 Intracellular Lipases ……………………………………………………………… 347
13.4.1 Adipose Triglyceride Lipase………………………………………. 347
13.4.2 Hormone-Sensitive Lipase…………………………………………. 348
13.4.3 Monoacylglycerol Hydrolase …………………………………….. 349
13.4.4 Perilipin and the Orchestration of Lipolysis …………………. 350
13.5 Triglyceride Synthesis …………………………………………………………… 350
13.5.1 A Triglyceride–Diglyceride Cycle? …………………………….. 351
13.5.2 Reacylation of Monoglycerides ………………………………….. 351
13.5.3 De Novo Synthesis of Triglycerides ……………………………. 352
13.5.4 Acylation-Stimulating Protein ……………………………………. 352
13.6 Conclusion: an Integrated View of the Lipase Systems
in Adipose Tissue …………………………………………………………………. 353
References …………………………………………………………………………………….. 354
Index …………………………………………………………………………………………………… 371

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