High-Density Lipoproteins as Biomarkers and Therapeutic Tools: Volume 1. Impacts of Lifestyle, Diseases, and Environmental Stressors on HDL

402 Pages·2019·18.352 MB·English

by  Kyung-Hyun Cho

Kyung-Hyun Cho
High-Density
Lipoproteins as
Biomarkers and
Therapeutic Tools
Volume 1. Impacts of Lifestyle,
Diseases, and Environmental Stressors
on HDL
High-Density Lipoproteins as Biomarkers
and Therapeutic Tools
Kyung-Hyun Cho
High-Density Lipoproteins
as Biomarkers
and Therapeutic Tools
Volume 1. Impacts of Lifestyle, Diseases,
and Environmental Stressors on HDL
Kyung-Hyun Cho
LipoLab, Yeungnam University
Gyeongsan-si, Gyeongsangbuk-do
South Korea
ISBN 978-981-13-7386-2 ISBN 978-981-13-7387-9 (eBook)
https://doi.org/10.1007/978-981-13-7387-9
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Preface
This book is designed to demonstrate many aspects of high-density lipoprotein
(HDL) in human growth, human disease, and aging process under different environ-
mental changes. Because HDL is dynamic and reversible, it can be changed upon
various health statuses, such as exercise, dietary patterns, exposure of infections,
and environmental pollutions. HDL can be a good biomarker to diagnose many
diseases and its progression via the monitoring of changes in its antioxidant and
anti-inflammation abilities.
HDL can be used for therapeutic tools and vehicle for drug delivery. HDL is a
potent antioxidant, anti-inflammatory macromolecule in body fluids to maintain
human health. Advantageous activities of HDL are well known as anti- atherosclerotic
and antidiabetic activity and recently expand to antiaging activities. The advanta-
geous virtues of HDL are highly dependent on its lipids, proteins, apolipoproteins,
and enzymes, specifically their compositions and ratios. In normal state, the HDL
particle is constituted with cholesterol, triacylglyceride (TG), and several HDL-
associated enzymes and apolipoproteins, including paraoxonase, lecithin/choles-
terol acyltransferase, and cholesteryl ester transfer protein (CETP).
HDL cholesterol (HDL-C) level should be more than 40 and 50 mg/dL for men
and women, respectively, to maintain healthy state. Lower HDL-C levels (<40 mg/
dL) have been recognized as an independent risk factor for coronary artery disease,
as well as a known component of metabolic syndrome. In addition to HDL-C, func-
tional and structural changes of HDL have also been recognized as factors pivotal to
the evaluation of HDL quality. HDL are susceptible to structural modifications
induced via several mechanisms, including oxidation, glycation, nitration, or pro-
tein degradation upon external stress such as infection of virus and bacteria, inflam-
mation, and pollutant exposure. The modification resulted in severe loss of
advantageous functions of HDL regarding anti-senescence and antidiabetic and
anti-atherosclerosis activity due to functional and structural modification with
increased protein degradation. In order to replace the dysfunctional HDL, blood
infusion of reconstituted HDL (rHDL) caused reduction of plasma glucose levels by
increasing plasma insulin in pancreatic beta cells, which raised the feasibility of a
wider clinical application of rHDL from cardiovascular disease to diabetes.
v
vi Preface
In this book, I have elected to focus on functional and structural correlations of
HDL and apoA-I in various health statuses and the roles of HDL-associated apoli-
poproteins and enzymes as therapeutic tools. Interestingly, HDL and apoA-I can be
found in many important body fluids in all age, including breast milk, cord blood,
vessel blood, lymph, and cerebrospinal fluid. Several clinical applications of HDL
have also been reviewed herein, particularly the therapeutic targeting of HDL
metabolism and reconstituted HDL, as these techniques represent promising emerg-
ing strategies for the treatment of diabetes and cardiovascular disease and for drug-
delivery. Herein are many aspects of HDL in diseases and environmental stresses to
change quantity and quality of HDL as shown in the illustration below. A reconsti-
tuted HDL can be synthesized with many other ingredients to test functionality or
drug delivery as shown in the left side. Many HDL from various subjects and
patients were characterized to compare native HDL and dysfunctional HDL as
shown in the right side.

Actually, HDL is a dynamic macrocomplex, which is not fixed in certain struc-
ture and functions. It has energetic structural and functional features of HDL
depends on health status and environmental circumstances, as well as change of
HDL by lifestyle and various diseases, we will see impairment of HDL by environ-
Preface vii
mental pollutant and food ingredient to produce dysfunctional HDL, which can
exacerbate pre-existed diseases. However, HDL functionality can be enhanced by
consumption of functional food, such as vitamin C and policosanol. The enhanced
HDL functionality is accompanied with reducing aortic stiffness and blood
pressure.
Finally, we would take a look about HDL quality and quantity to maintain our
healthy life and longevity. I do believe this book provides new aspects of HDL in
healthy aging and unique insight of HDL field.
Gyeongsan-si, Gyeongsangbuk-do Kyung-Hyun Cho
South Korea
Contents
1 Understanding HDL: Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 HDL and Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1.1 Dysfunctional HDL and Diseases . . . . . . . . . . . . . . . . . . . . 2
1.2 HDL Functions and Clinical Applications . . . . . . . . . . . . . . . . . . . . 4
1.2.1 Functional and Structural Correlations of HDL. . . . . . . . . . 6
1.2.2 Anti-atherosclerotic Function of HDL . . . . . . . . . . . . . . . . . 7
1.2.3 Antioxidant Properties of HDL . . . . . . . . . . . . . . . . . . . . . . 7
1.2.4 Anti-inflammatory Function of HDL . . . . . . . . . . . . . . . . . . 8
1.3 HDL Composition: Apolipoproteins and Enzymes . . . . . . . . . . . . . 8
1.3.1 Apolipoprotein A-I . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.3.2 Apolipoprotein A-II . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
1.3.3 Apolipoprotein C-I, C-II and C-III . . . . . . . . . . . . . . . . . . . 10
1.3.4 Cholesteryl Ester Transfer Protein (CETP) . . . . . . . . . . . . . 11
1.3.5 Lecithin:Cholesterol Acyltransferase (LCAT) . . . . . . . . . . . 11
1.3.6 Paraoxonase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.3.7 Platelet Activating Factor-Acetyl Hydrolase
(PAF-AH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
1.4 Maturation of HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
1.5 HDL and Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
2 Change of HDL by Life Style . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.1 Exercise and HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
2.1.1 Serum Parameters . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.1.2 Particle Distribution of VLDL, LDL, and HDL. . . . . . . . . . 24
2.1.3 Ferric Reducing Ability (FRA) as Antioxidant Ability . . . . 26
2.1.4 LCAT Ability and Protein Expression in HDL . . . . . . . . . . 27
3
2.1.5 Paraoxonase Ability and Protein Expression . . . . . . . . . . . . 28
2.1.6 CETP Activity and Protein Expression . . . . . . . . . . . . . . . . 28
2.1.7 Expressional Level of apoA-I and A-II in HDL
Species . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
ix
x Contents
2.1.8 Runners and Wrestlers Had the Biggest HDL Size . . . . . . 30
2
2.2 Smoking and HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
2.2.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
2.2.2 Blood Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.2.3 Serum Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 34
2.2.4 Lipoprotein Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
2.2.5 Lipoproteins from Smokers Are More Oxidized . . . . . . . . . 36
2.2.6 Glycated Species and Modification of Electrophoretic
Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36
2.2.7 CETP Activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
2.2.8 Cellular Uptake of LDL into Macrophages . . . . . . . . . . . . . 40
2.3 Elderly’s HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
2.3.1 Recruitment of Elderly Subjects . . . . . . . . . . . . . . . . . . . . . 44
2.3.2 Serum Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
2.3.3 Reduced Antioxidant Ability in the Elderly Group . . . . . . . 45
2.3.4 PON Activity Was Reduced in the Elderly Group . . . . . . . . 46
2.3.5 CE-Transfer Ability Was Increased in the Elderly
Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
2.3.6 Expression of apoA-I in HDL and LPDS . . . . . . . . . . . . . . 48
2.3.7 The Elderly Group Showed Truncation
of the C-Terminal of A-I in HDL . . . . . . . . . . . . . . . . . . . . 50
3
2.3.8 The Elderly Group Showed Increased Glycated
Levels of apoA-I in HDL . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3
2.3.9 HDL Particle Size Was Decreased in the Elderly . . . . . . . . 52
2
2.3.10 The Level of Expression of SAA and apoC-III . . . . . . . . . . 52
2.4 HDL Depends on Body Weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . 55
2.4.1 Subjects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
2.4.2 BMI and Serum HDL-C. . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2.4.3 Serum Lipid Level and Body Weight . . . . . . . . . . . . . . . . . . 57
2.4.4 CETP Mass and Ability . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
2.4.5 Correlation of HDL-C and Body Shape. . . . . . . . . . . . . . . . 58
2.4.6 Correlation of HDL-C and Blood Pressure . . . . . . . . . . . . . 60
2.4.7 Antioxidant Ability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
2.4.8 Compositions of Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . 61
2.4.9 Modification of Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . 62
2.4.10 Expression Level of apoA-I in HDL . . . . . . . . . . . . . . . . . . 63
2.4.11 HDL Particle Size and Cholesterol Efflux . . . . . . . . . . . . . 64
2
2.5 HDL from Obese but Healthy Subject . . . . . . . . . . . . . . . . . . . . . . . 67
2.5.1 Blood Sampling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
2.5.2 Ultracentrifugation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69
2.5.3 Serum Profiles of the Hypolipidemic Obese Patient . . . . . . 69
2.5.4 Different Apolipoprotein Expression Levels
in HDL and HDL . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
2 3
2.5.5 Particle Size Distribution of Lipoproteins . . . . . . . . . . . . . . 71
2.5.6 Composition of apoA-I and A-II in HDL Subtypes . . . . . . . 71
Contents xi
2.5.7 LCAT Ability and Protein Levels in HDL-Subspecies . . . . 73
2.5.8 The Obese Patient Lacked CETP Activity . . . . . . . . . . . . . . 74
2.5.9 The Obese Subject Had Larger HDL and HDL
2 3
Particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
2.6 HDL and apoA-I in Smokers’ Breast Milk . . . . . . . . . . . . . . . . . . . 76
2.6.1 Recruiting of Breast Milk Donor . . . . . . . . . . . . . . . . . . . . . 78
2.6.2 Microinjection of Zebrafish Embryos . . . . . . . . . . . . . . . . . 78
2.6.3 Higher Body Fat in Smokers . . . . . . . . . . . . . . . . . . . . . . . . 79
2.6.4 Compositional Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 80
2.6.5 Embryo Survivability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 81
2.6.6 Developmental Speed and ROS Production . . . . . . . . . . . . 81
2.6.7 Electrophoretic Analysis of Protein Composition . . . . . . . . 82
2.6.8 Expressional Level of apoA-I . . . . . . . . . . . . . . . . . . . . . . . 82
2.6.9 Influential Factors for Embryo Survivability . . . . . . . . . . . . 84
2.7 Breast Milk from Frequent Trans-fatty Acid Consumers . . . . . . . . 88
2.7.1 Recruiting of Breast Milk Donor . . . . . . . . . . . . . . . . . . . . . 89
2.7.2 Composition Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
2.7.3 Embryo Survivability and Developmental Speed . . . . . . . . 90
2.7.4 Electrophoretic Analysis of Protein Composition . . . . . . . . 91
2.7.5 Expression Level of apoA-I . . . . . . . . . . . . . . . . . . . . . . . . . 92
2.7.6 Influential Factors for Embryo Survivability . . . . . . . . . . . . 92
2.8 HDL in Cord Blood from Small Neonates . . . . . . . . . . . . . . . . . . . 95
2.8.1 Collection of Umbilical Cord Blood . . . . . . . . . . . . . . . . . . 96
2.8.2 Lipid Parameters in Cord Serum . . . . . . . . . . . . . . . . . . . . . 97
2.8.3 Lipoprotein Profile in Cord Blood . . . . . . . . . . . . . . . . . . . . 99
2.8.4 SGA Shows Lower Antioxidant Ability . . . . . . . . . . . . . . . . 100
2.8.5 Expression Level of Growth Hormones and IL-6
in Cord Serum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 100
2.8.6 Expression of apoA-I, Apo-B, and apoC-III
in Lipoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101
2.8.7 Glycation and Oxidation Extent of HDL . . . . . . . . . . . . . . . 103
2.8.8 Antioxidant Ability of Lipoproteins . . . . . . . . . . . . . . . . . . 103
2.8.9 Higher Atherogenic Properties . . . . . . . . . . . . . . . . . . . . . . . 104
2.8.10 Diminished apoA-I Expressional in Amniotic
Fluid of SGA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 107
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
3 Change of HDL in Various Diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119
3.1 HDL from Patients with Myocardial Infarction . . . . . . . . . . . . . . . . 119
3.1.1 Patients and Controls . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3.1.2 Plasma and Lipoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . 120
3.1.3 Serum Lipid Profile and Inflammatory Markers . . . . . . . . . 121
3.1.4 TG and apoC-III Were Elevated in Lipoproteins
from MI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123
3.1.5 Increase of CETP Protein and Ability . . . . . . . . . . . . . . . . . 123