Doctoral theses
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Identifier |
000366128 |
Title |
Μοριακοί Μηχανισμοί μεταγραφικής ρύθμισης του γονιδίου του μεμβρανικού μεταφορέα λιπιδίων ΑΒCA1 στο ήπαρ |
Alternative Title |
Mechanisms of transcriptional regulation of the human ABCA1 gene in the liver. |
Author
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Θυμιακού, Ευσταθία
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Thesis advisor
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Καρδάσης, Δημήτρης
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Reviewer
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Ζαννής, Βασίλειος
Γραβάνης, Αχιλλέας
Στουρνάρα, Χρήστος
Μπούμπας, Δημήτριος
Ηλιόπουλος
Παπακωνσταντή
|
Abstract |
Low levels of plasma HDL cholesterol are an independent risk factor for
cardiovascular disease. The membrane ABCA1 transporter plays a key role in the
biogenesis of HDL by promoting the efflux of cellular cholesterol and phospholipids to
lipid-poor apolipoprotein A-I. Mutations in the ABCA1 gene lead to Tangier disease
which is characterized by near absent plasma HDL levels, accumulation of foam cells
in various tissues and a moderate increase in the incidence of atherosclerosis.
Hepatic ABCA1 protein is the major source of plasma HDL while macrophage
ABCA1 protects against foam cell formation and atherosclerosis. Thus, the induction
of ABCA1 gene expression has been associated with the increase in functional
plasma HDL levels and the protection from atherosclerosis.
The best characterized and most significant mechanism of ABCA1 gene
regulation is via the activation of the nuclear receptors LXRα/RXRα in response to
cholesterol loading. The purpose of the present thesis was the study of the molecular
mechanisms that affect the induction of the ABCA1 gene via the above-mentioned
pathway as well as the identification of new regulatory elements and factors.
Initially, we investigated the role of the transcription factor Sp1 which binds to
the proximal ABCA1 gene promoter and is necessary for its basal activity in hepatic
cells. We showed that, physical and functional interactions between Sp1 and the
nuclear receptors LXRα/RXRα were required for the optimal induction of ABCA1
gene transcription in response to their ligands, oxysterols and retinoids. Next, we
identified, for the first time, binding sites for the hepatic transcription factor
FOXA2/HNF-3β in the ABCA1 gene promoter. Binding of FOXA2 to these sites
repressed the basal ABCA1 gene transcription. Furthermore, we showed that binding
of FOXA2 to the TATA-box of the ABCA1 gene promoter inhibited the induction by
oxysterols and retinoids possibly via competition with the transcription initiation
machinery which is assembled to this site. Finally, we investigated the functional
promoter that is present in the first intron of the ABCA1 gene. We showed the
transcription factor SREBP-1, which is activated by LXRα/RXRα heterodimers in
response to oxysterols and retinoids, binds to multiple sites in the proximal intron 1
promoter region. One of these sites overlaps with an AP1 binding site which binds to
the transcription factor JunB during monocyte differentiation to macrophages.
The ABCG1 transporter, similarly to ABCA1, plays a key role in cholesterol
efflux to mature HDL particles and in the protection against atherosclerosis. We
investigated the role of a natural mutation in the ABCG1 gene promoter which was
identified in the general population in the City of Copenhagen and is associated with
increased incidence of ischemic heart disease, myocardial infarction and dyspnea.
We showed that this mutation abolishes a binding site for the transcription factor Sp1
and inhibits the induction of the ABCG1 gene promoter by this factor.
Understanding in depth the molecular mechanisms that regulate ABCA1 gene
expression in the liver and the role of specific transcription factors in these processes
is anticipated to lead to the development of new substances that will increase ABCA1
gene expression and as a result, plasma HDL levels, providing protection against
atherosclerosis and cardiovascular disease.
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Language |
Greek |
Subject |
Atherosclerosis |
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Biochemistry |
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Coronary heart disease |
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HDL |
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Hepatic transcription factors |
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Nuclear receptors |
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Reverse cholesterol transport |
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Αθηροσκλήρωση , |
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Αντίστροφη μεταφορά χοληστερόλης |
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Βιοχημεία |
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Ηπατικοί μεταγραφικοί παράγοντες |
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Λιποπρωτείνες υψηλής πυκνότητας |
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Πυρηνικοί υποδοχείς |
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Στεφανιαία νόσος |
Issue date |
2009-04-07 |
Collection
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School/Department--School of Medicine--Department of Medicine--Doctoral theses
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Type of Work--Doctoral theses
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Permanent Link |
https://elocus.lib.uoc.gr//dlib/b/9/2/metadata-dlib-5475bbbe1000e24f7a2dd7492eefdb5c_1305798069.tkl
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Views |
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