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Identifier

000379057

Title

Ο ρόλος της φλεγμονής στην έκφραση γονιδίων που συμμετέχουν στο μεταβολισμό της λιποπρωτείνης υψηλής πυκνότητας(HDL)

Alternative Title

The role of inflammation on the expression of genes involved in high density lipoprotein metabolism

Author

Θεοφιλάτος, Δημήτρης

Thesis advisor

Καρδάσης, Δημήτριος

Reviewer

Μπούμπας, Δ.
Γουλιέλμος, Γ.

Abstract

3 Abstract Atherosclerosis is the underlying cause of cardiovascular disease (CVD) which accounts for 50% of deaths in the western world. Various factors contribute to the development of atherosclerosis including dyslipidemia, lipid accumulation on the artery wall and chronic inflammation. High density lipoprotein (HDL) is a known atheroprotective factor, since it stimulates the reverse cholesterol transport RCT) and it also exerts both anti-inflammatory and anti-oxidative properties. Both proteins and lipds of HDL determine its atheroprotective functions. Dysfunctional, proinflammatory HDL, has been reported in patients with coronary artery disease (CAD), as well as in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Therefore, in Part I of this thesis we examined the concentration of HDL and the plasma levels of apolipoproteins A-I and M in patients with SLE or RA. ApoM is a novel HDL binding protein with atheroprotective and anti-oxidative properties, which is downregulated by inflammatory stimuli such as tumor necrosis factor a (TNFα). We performed western blot analysis in serum from healthy controls and from patients with SLE or RA and we observed that apoM levels were decreased by approximately 20-65% in patients, while both HDL cholesterol and apolipoprotein A-I (apoA-I) levels remained unchanged. These findings suggest that the lack of apoM in HDL from RA and SLE patients could cause HDL dysfunction and loss of atheroprotection thus leading to accelerated atherosclerosis. Liver X receptor α (LXRα) is a transcription factor that plays key roles in atheroprotection, since it controls the regulation of HDL genes participating in the reverse cholesterol transport pathway and it inhibits the expression of pro-inflammatory genes in macrophages. The mechanisms that regulate the expression of LXRα in macrophages, hepatocytes and other cell types are still not clear. Thus, in Part II of this thesis we focused on the regulation of the LXRα promoter in hepatic cells by inflammatory or metabolic stimuli. To identify regulatory elements in hLXRa promoter that are involved in these processes, we performed transient transfection assays both in human hepatoblastoma (HepG2) and human embryonic kidney (HEK) cells utilizing a series of luciferase reporter plasmids containing consecutive 5΄ deletions of the hLXRα promoter along with inflammatory stimuli such as Toll Like Receptor 4 (TLR4) which is the natural receptor of LPS or metabolic stimuli such as Hepatocyte Nuclear Factor 4 (HNF-4). We observed that overexpression of TLR4 inhibited hLXRa promoter activity through the activation of Nuclear Factor κappa B (NF-κΒ) in an IKKβ (inhibitor of nuclear factor kappa-B kinase b)-independent pathway On the contrary we observed that overexpression of HNF4 in HepG2 cells 4 induced hLXRα promoter activity through the -111/-45 region of the promoter, indicating an antagonism between NF-κB and HNF4 in hLXRa promoter activity.

Language

Greek

Subject

Apolipoprotein

Biochemistry

HDL

HNF4

Inflammation

TLR4

Απολυποπρωτείνη

Φλεγμονή

Issue date