Study of the effect of the olive constituent oleuropein in lipid homeostasis (Doctoral thesis)

Μάλλιου, Φωτεινή Β.

Oleuropein (OLE), the main polyphenolic constituent of the olive tree, has demonstrated antioxidant and hypolipidemic properties. It is well established that upon activation, Peroxisome proliferator activated receptor type α (PPARα), plays a key role in the regulation of lipid metabolism, as well as the energy homeostasis of the cell. This study focuses on the mechanisms underlying the Oleuropein’s hypolipidemic properties and specifically, on its role on PPARα activation. For this purpose, we initially evaluated using in silico approaches, the Oleuropein’s binding capacity to PPARα. These in silico studies, employing theoretic binding models at the PPARα’s crystal structure along with Molecular Docking simulation, confirmed our hypothesis that OLE is a PPARα agonist. Furthermore, we investigated in vitro, using the Luciferase reporter gene assay, Oleuropein’s ability to bind to the LBD of PPARα. Both, in silico and in vitro studies, clearly showed that OLE is a ligand of PPARα. In vivo studies also confirmed that OLE is a PPARα agonist that induces PPARα activation. Specifically, treatment of male wild-type mice with OLE (100mg/kg, p.o.) followed the regular rodent diet for 6 weeks, resulted in the up-regulation of both, PPARα and several target genes in the liver, potentially via activation of the PI3K/AKT/p70S6K signaling pathway. This effect was correlated with a significant reduction of serum triglycerides (TGs) and total cholesterol levels. In contrast, OLE had no effect in these lipid markers in Ppara-null mice indicating a direct involvement of PPARα in the OLE-mediated suppression of serum TG and total cholesterol levels. The assessment of the effect of OLE on hepatic and W.A.T regulatory factors playing determinant roles in TG homeostasis indicated the following: 1) the activation of HSL (Hormone Sensitive Lipase) in the W.A.T of wild type mice, 2) the upregulation of several hepatic factors involved in TG uptake, transport, metabolism and clearance. It is very likely that both, HSL activation in the W.A.T. and activation of several hepatic factors may also contribute in the OLE- mediated reduction of TGs and total cholesterol levels. In summary, it appears that OLE reduces serum TGs and total cholesterol levels in mice via PPARα activation. The data of this study, also indicated that HSL activation in the W.A.T. and upregulation of various hepatic genes (most of them are PPARα target genes) may contribute in the mechanism mediating the Oleuropein’s hypolipidemic effects. In conclusion, this study has demonstrated in mice the Oleuropein’s hypolipidemic effects and has clarified to a certain point the underlying mechanisms indicating mainly, the catalytic role of PPARα activation. Given that lipid homeostasis is regulated by complex cellular mechanisms, involving a plethora of factors, we consider that potentially other mechanisms also mediate the Oleuropein’s hypolipidemic effects, and that their thorough investigation is a subject of future studies.
Alternative title / Subtitle: διερεύνηση του ρόλου των πυρηνικών πρωτεϊνών PPARs
investigation of the role of nuclear receptors PPARs
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Subject classification: Λιπίδια -- Μεταβολισμός
Keywords: Ελευρωπαΐνη,PPARα,Τριγλυκερίδια,Μεταβολισμός λιπιδίων,Oleuropein,Triglycerides,Lipid metabolism
Appears in Collections:Διδακτορικές Διατριβές

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