| Abstract |
Several studies have shown an inverse correlation between HDL cholesterol levels
and the risk of developing coronary artery disease. HDL is capable of modifying
cardiovascular disease risk or outcome not only by its participation in RCT but also by direct
and indirect actions on endothelial cells and other cell types that influence cardiovascular and
metabolic health. Large clinical and intervention studies have shown the beneficial effects of
raising HDL cholesterol levels. Among the currently available drugs, statins, niacin and
fibrates have been used extensively for raising HDL levels. However, due to the large number
of side-effects, a residual risk remains, promoting the search for additional therapies for
atherosclerosis management. The new therapies aim not only in increased HDL levels but
also in improved HDL functionality. The studies of Attie et al in 2001 and Koukos et al in
2007 demonstrated also that the induction of key enzymes implicated in HDL metabolism
could have important consequences for the therapy of patients with CAD.
Since the expression of lipoprotein-related genes is regulated mainly at the
transcriptional level, our aim was to identify novel transcription factors that are implicated in
the expression of HDL genes in hepatic cells. Specifically, we studied the role of FoxO1
transcription factor a member of the Forkhead superfamily and a key transcription factor in
the liver. We found that FoxO1 overexpression in HepG2 cells decreased the activity of
ABCA1, ABCG5, CETP and PLTP promoters while it did not affect significantly the activity
of ABCG1, ABCG8, LPL and LIPC promoters. By utilizing overexpression and gene
silencing techniques we expect to find in the future new FoxO1 target genes that involved in
HDL metabolic pathway.
FoxO proteins have been shown to interact in a DNA-binding independent manner
with multiple members of the nuclear hormone receptor superfamily (NR) leading in changes
in the transcriptional activity of both proteins. For this purpose, we studied the effect of
FoxO1 protein on HNF-4α transcriptional activity. Specifically, we attempted to identify
novel genes that are regulated by the interplay between FoxO1 and HNF-4α. We found that
FoxO1 and HNF-4α transcription factors are associated with the human ABCG5/8 intergenic
promote. In addition, we demonstrated that HNF-4α regulated ABCG5 but not ABCG8 gene
expression in hepatic cells and FoxO1 was capable of suppressing ABCG5 gene expression
indirectly by inhibiting HNF-4α transcriptional activity. In the future we attempt to elucidate
the mechanism by which FoxO1 inhibits the activity of HNF-4α transcription factor.
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Investigation of molecular mechanisms regulating HDL genes in hepatic cells
