Interventions to Increase Apolipoprotein A-I Transcription in Hepg2 Cells
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Interventions to increase apolipoprotein A-I transcription in HepG2 cells Citation for published version (APA): van der Krieken, S. E. (2017). Interventions to increase apolipoprotein A-I transcription in HepG2 cells. Uitgeverij BOXPress. https://doi.org/10.26481/dis.20170330svdk Document status and date: Published: 01/01/2017 DOI: 10.26481/dis.20170330svdk Document Version: Publisher's PDF, also known as Version of record Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. 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If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.umlib.nl/taverne-license Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 27 Sep. 2021 1 2 3 4 5 Interventions to increase apolipoprotein A-I 6 transcription in HepG2 cells 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 This research was supported by the Dutch Technology Foundation STW, which is 48 part of the Netherlands Organisation for Scientific Research (NWO), and which is 49 partly funded by the Ministry of Economic Affairs (project number 11349). The 50 research was performed within NUTRIM School of Nutrition and Translational 51 Research in Metabolism, which participates in the Graduate School VLAG (Food 52 Technology, Agrobiotechnology, Nutrition and Health Sciences), accredited by the 53 Royal Netherlands Academy of Arts and Sciences. 54 55 56 Cover design: ProefschriftMaken 57 Layout: Sophie. E. van der Krieken 58 Printed by: Proefschriftmaken II Uitgeverij BOXPress 59 60 61 © Copyright Sophie E. van der Krieken, Maastricht 2017 62 63 ISBN 978 94 6295 568 4 64 65 66 67 68 69 70 Interventions to increase apolipoprotein A-I 71 transcription in HepG2 cells 72 73 74 75 76 77 78 79 PROEFSCHRIFT 80 81 ter verkrijging van de graad van doctor 82 aan de Universiteit Maastricht 83 op gezag van de Rector Magnificus, 84 Prof. dr. Rianne M. Letschert 85 volgens het besluit van het College van Decanen, 86 in het openbaar te verdedigen 87 op donderdag 30 maart 2017 om 16:00 uur 88 89 90 91 92 93 94 door 95 96 97 98 99 100 101 Sophie Elise van der Krieken 102 103 geboren te Eindhoven op 8 april 1989 104 105 106 107 108 Promotores 109 110 Prof. dr. J. Plat 111 Prof. dr. ir. R. P. Mensink 112 113 Co-promotor 114 115 Dr. H.E. Popeijus 116 117 118 Beoordelingscommissie 119 120 Prof. dr. E.C.M. Mariman (voorzitter) 121 Prof. dr. A.K. Groen (Academisch Medisch Centrum, Amsterdam) 122 Prof. dr. S.A.H. Kersten (Wageningen UR, Wageningen) 123 Dr. S. Rensen 124 Prof. dr. R. Shiri-Sverdlov 125 126 Table of Contents 127 128 129 Chapter 1 General introduction 7 130 131 132 Chapter 2 CCAAT/enhancer binding protein 훽 in relation to ER-stress, 133 inflammation, and metabolic disturbances 23 134 135 136 Chapter 3 C/EBP-β is differentially affected by PPARα agonists 137 Fenofibric acid and GW7647, but does not change 45 138 apolipoprotein A-I production during ER-stress and 139 inflammation 140 141 Chapter 4 Identification of natural PPARα transactivating compounds 142 and their effects on apolipoprotein A-I transcription 85 143 in HepG2 cells 144 145 Chapter 5 Link between ER-stress, PPARα activation and 146 BET inhibition in relation to apolipoprotein A-I transcription 105 147 in HepG2 cells 148 149 Chapter 6 Fatty acid chain length and saturation influences 150 PPARα transcriptional activation and repression 123 151 in HepG2 cells 152 153 Chapter 7 Structure similarity search for natural compounds 154 that increase apolipoprotein A-I transcription in HepG2 cells: 155 a focus on BRD4 inhibition 139 156 157 158 Chapter 8 General discussion 177 159 160 Summary 197 161 Samenvatting 201 162 Valorisation 205 163 164 Dankwoord 209 165 Curriculum vitae 213 166 List of publications 215 167 168 169 170 171 CHAPTER 1 172 173 174 General introduction 175 176 CHAPTER 1 General introduction Despite remarkable improvements in prevention and treatment, cardiovascular diseases (CVDs) are still the leading cause of mortality worldwide [1]. Besides genetic factors, particularly behavioral risk factors such as an unhealthy diet, physical inactivity, cigarette smoking, obesity and excessive use of alcohol, contribute to CVD development [2]. CVDs can be classified as coronary heart diseases (CHDs), cerebrovascular diseases and peripheral arterial diseases and are all strongly related to dyslipidemia. Dyslipidemia is characterized by aberrant plasma lipid and lipoprotein concentrations and the unfavorable distribution of lipids over the different lipoprotein classes, and is defined by a Low Density Lipoprotein cholesterol (LDL-C) concentration above 2.6 mmol/l (or 100 mg/dl) and/or a High Density Lipoprotein cholesterol (HDL-C) concentration under 1 mmol/l (or 40 mg/dl), and circulating triacylglycerol (TGs) of more than 1.7 mmol/l (150 mg/dl). This disturbed lipid and lipoprotein profile, often seen in the metabolic syndrome, is highly associated with the development of atherosclerotic lesions in the artery walls (figure 1). Figure 1. The development of atherosclerotic lesions, a process that is driven by inflammation. This figure was adapted from Fulmer et al. [3]. The development of atherosclerosis is a process that is already initiated during infancy. The onset of atherosclerosis may involve a response to injury of the endothelial wall [4] and the retention of small dense LDL particles from the circulation into the vessel wall [5] and is an inflammatory induced process. When LDL becomes trapped in the sub- endothelial space, it may undergo oxidative modification, forming oxy-LDL. The presence of oxy-LDL triggers the production of adhesion molecules (A) and recruitment of monocytes (B) into the artery wall, where they differentiate into macrophages (C). Oxidized LDL is then engulfed by the macrophages in such high amounts that they form lipid laden foam cells (D). Eventually, the accumulation of foam cells, smooth muscle cells and cell debris, covered by a fibrous cap, will give rise to a mature atherosclerotic plaque (E) [6]. At this stage the plaque is prone to rupture, thereby causing myocardial infarction or stroke. 8 GENERAL INTRODUCTION The most successful example of a therapy to improve dyslipidemia is the use of statins that lower the atherogenic LDL-C concentrations. Statin treatment inhibits the enzyme HMG-CoA reductase, thereby lowering the production of cholesterol in virtually every single cell in the body. Particularly the inhibition of endogenous cholesterol synthesis in the liver contributes to a reduction in circulating LDL-C concentrations. In response to this lower endogenous cholesterol production, the hepatocytes increase their expression of the LDL-receptor, and as such enhance plasma cholesterol uptake. Currently, also the effects of PCSK9 inhibitors are tested in human studies [7]. PCSK9 inhibition decreased plasma LDL-C concentrations even further as it prevents degradation of the LDL-receptor, which further increases the uptake of LDL particles in the liver. Although the use of statins has clearly led to a reduction in CVD events [8], CVDs still occurred in a large portion of patients who already received statin treatment. Thus, in order to further reduce the CVD-related economic and societal burden, it is of major importance to discover additional interventions to further decrease this risk for CVD development. A promising strategy to decrease the detrimental effects of dyslipidemia related to atherosclerosis development is increasing the cholesterol efflux capacity, via increased transcription of apolipoprotein A-I (apoA-I), leading to the production of more functional HDL particles. HDL metabolism After transcription in the human hepatocytes or the small intestinal cells, apoA-I is produced as a pre-pro-protein, which is cleaved in the endoplasmic reticulum by the action of a signal peptidase [9]. This cleavage results in the formation of intracellular pro-apoA-I, which is secreted by the cell into the extracellular space. Subsequently, the pro-segment is removed by the action of Bone Morphogenetic Protein-1 (BMP-1) and Procollagen C-proteinase Enhancer-2 Protein (PCPE2) [10,11]. At this stage, the C-terminal domain of the lipid free or lipid poor apoA-I particle can interact with the adenosine triphosphate-binding cassette A1 (ABCA1) transporter on the surface of macrophages, endothelial cells, hepatocytes and small intestinal cells, facilitating cholesterol, sphingomyelin and phospholipid uptake [12,13].