Abstract (English)
Monocyte-derived macrophage gene regulation plays an important role not only in pathogenesis of atherosclerosis but also in many other inflammatory diseases, such as, cirrhosis, rheumatoid arthritis, glomerulosclerosis, pulmonary fibrosis and chronic pancreatitis. In addition, bioactive lipids as derivatives of lysophospholipids have been remarkably evidenced to contribute to many ...
Abstract (English)
Monocyte-derived macrophage gene regulation plays an important role not only in pathogenesis of atherosclerosis but also in many other inflammatory diseases, such as, cirrhosis, rheumatoid arthritis, glomerulosclerosis, pulmonary fibrosis and chronic pancreatitis. In addition, bioactive lipids as derivatives of lysophospholipids have been remarkably evidenced to contribute to many pathophysiological stages of these diseases. Therefore, the aim of this thesis work is to analyze global gene expression of monocyte-derived macrophages under the modulation of selected of bioactive lipids, including ceramide, S1P, SPC, LPA and LPA, and modified low-density lipoprotein as the source of the these bioactive lipids. Results archived from CD36 and Cla-1 analysis in phagocytic differentiation and foam cell formation was further confirmed the higher atherogenic properties of enzymatically modifification LDL, compared to other type of modifications (acetylation, oxidation). Furthermore, these results also supported the hypothesis of an autoregulatory loop for enhanced cholesterol uptake and provide a link between this modified LDL and the HDL metabolism. In addition, analyses of adipophilin and ABCA2 were also revealed that adipophilin could be considered as a new sensitive marker for lipid loading of human monocytes/macrophages as well as ABCA2 could play a role in intracellular LDL-derived free cholesterol trafficking and lipid homeostasis. Expression of the 13 up-to-date G-protein-coupled receptors for bioactive lipid derivatives; S1P, LPA, LPC, SPC in human monocytes/macrophages was also investigated. The serum-free phagocytic differentiation model was able to eliminate the discrepancy arrived from other studies. Since these bioactive lipid derivatives are products of platelets and involve in many cellular processes, these results suggested the importance of further study on cross-talk between platelets and monocytes/ macrophages. DNA chip analysis provided an overview of cellular effects of the above-mentioned bioactive lipids and cholesterol loading on macrophages global genes expression. The effects of cholesterol loading (E-LDL) on cholesterol metabolism pathways and homeostasis were investigated in-details. Interestingly, exogenous free cholesterol loading of human macrophages could lead to a complete blockage of cellular cholesterol metabolism pathway triggered by SREBP-2, while triacylglycerides and fatty acids metabolism pathways triggered by SREBP-1c were not influenced. The study also reported the expression of ABC transporter A2, A3, A8, B4, C9, D2, G1 and G4 in human macrophages and suggested the roles of ABCA2, ABCB4 and ABCG1 in macrophages cellular lipid rheostat.
Translation of the abstract (German)
Genregulation in Makrophagen spielt eine grosse Rolle in der Pathogenese der Atherosklerose und weiteren inflamatorischen Erkrankungen wie Zirrhose, Rheumatoider Arthritis, Glomerulosklerose, Lungenfibrose und chronischer Pankreatitis. Lysophospholipid-Derivate und andere bioaktive Lipide scheinen verschiedene Schritte dieser Erkrankungen zu modulieren. Ein Ziel dieser Arbeit war deshalb die ...
Translation of the abstract (German)
Genregulation in Makrophagen spielt eine grosse Rolle in der Pathogenese der Atherosklerose und weiteren inflamatorischen Erkrankungen wie Zirrhose, Rheumatoider Arthritis, Glomerulosklerose, Lungenfibrose und chronischer Pankreatitis. Lysophospholipid-Derivate und andere bioaktive Lipide scheinen verschiedene Schritte dieser Erkrankungen zu modulieren. Ein Ziel dieser Arbeit war deshalb die globale Analyse der Genexpression von Makrophagen unter den Einfluß bioaktiver Lipide einschließlich Ceramiden, S1P, SPC, LPA und LPA, und modifizierten LDL-Lipoproteinen.
Die durchgeführten DNA Chip Analysen zeigten einen dominanten Einfluss von bioaktive Lipiden auf die globale Genexpression der Cholesterinaufnahme. Expressionsanalysen von CD36 und Cla-1 bei der phagozytären Differenzierung und Schaumzell-Bildung bestätigen die hohe atherogene Eigenschaft von enzymatisch modifiziertem LDL gegenüber acetyliertem und oxydiertem LDL. Ausserdem unterstützen diese Ergebnisse die Hypothese einer autoregulatorischen Schleife der Cholesterin-Aufnahme mit dem HDL-Metabolismus.
Weitere Analyse zeigten, dass Adipopholin ein Marker der Aufnahme von Lipiden in humane Monozyten/Makrophagen ist und, dass ABCA2 eine Rolle im intrazellulären Cholesterintransport spielt.
Abschliessend wurde in dieser Arbeit die Expression von 13 G-Protein-gekoppelten Rezeptoren für bioaktive Lipid Derivate (S1P, LPA, LPC, SPC) in humanen Monozyten/Makrophagen untersucht.
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