Dissertation committee:
Αναπλ. Καθηγήτρια Μ. Μαυρή (επιβλέπουσα), Αναπλ. Καθηγήτρια Ν. Γαλανοπούλου, Ερευνήτρια Β' ΕΚΕΦΕ Δημόκριτος Α. Χρόνη
Original Title:
Μελέτη του ρόλου διαφόρων πρωτεϊνών (αποΑ-Ι, μεταφορείς χοληστερόλης, ένζυμα) του μονοπατιού της HDL
Summary:
Although low levels of high-density lipoprotein (HDL) -cholesterol have been
associated with increased risk factor for cardiovascular disease, recent
studies suggested that HDL functions are determined by the quality rather than
by the quantity of HDL. HDL exists in multiple subpopulations that differ in
size, shape, and composition. The main protein constituent of HDL is
apolipoprotein A-I (apoA-I) that confers many of HDL functions. HDL
antiatherogenic properties include its ability to remove cholesterol from
cells, such as macrophages in the artery wall, as well as anti-inflammatory,
anti-oxidant, vasodilatory, and antithrombotic properties. The aim of the
current study was to characterize the HDL properties under pathologic
conditions, as well as understand the pathways that affect the HDL properties.
Analysis of HDL in families with monogenic low HDL disorders showed that
mutations in apoA-I, ABCA1 or LCAT, three proteins that are involved in the HDL
biogenesis pathway, affect HDL composition that leads to reduced
antioxidant/anti-inflammatory capacity of HDL and result to distinctly
different apoA-I-containing HDL subpopulation profiles. These types of analyses
could prove valuable in differential diagnosis of familial low HDL syndromes.
In addition, we studied the role of apoA-I in the ability of HDL to promote
cellular cholesterol efflux mediated by ABCG1, a cholesterol transporter
associated with the prevention of cholesterol accumulation in macrophages
within multiple tissues. Our findings showed that ABCG1-mediated efflux of
cholesterol and to a much lesser effect of 7-ketocholesterol is decreased by
deletion of the carboxyl-terminal domain from full-length apoA-I bound to
reconstituted HDL (rHDL). The capacity of rHDL containing wild-type apoA-I to
promote ABCG1-dependent cholesterol efflux was also significantly reduced
following limited proteolysis of rHDL by plasmin, a protease found in the
arterial intima. Therefore, our findings may have physiological significance
since increased proteolysis, under pathologic conditions, of HDL-associated
apoA-I in vivo may affect the capacity of HDL to promote cholesterol efflux
from macrophages. Our results, taken as whole, provide new knowledge on how HDL
properties can be affected under pathologic conditions. An improved
understanding of HDL function and dysfunction will help us identify new targets
for diagnosis, prognosis, therapy and prevention of low HDL cholesterol and
atherosclerosis.
Keywords:
HDL, ApoA-I, Antioxidant/anti-inflammatory properties of HDL, HDL subpopulations, ABCG1-mediated cholesterol and 7-keto-cholesterol efflux
