High-density lipoprotein (HDL) levels in plasma are inversely related to the risk of atherosclerotic coronary vascular disease and stroke. This is believed to be due to the role of components such as apolipoprotein A-I (apoA-I) in reverse cholesterol transport (RCT), the process in which excess cholesterol is taken-up from peripheral tissues and delivered to the liver for excretion or recycling. ApoA-I stimulates the activity of lecithin-cholesterol acyltransferase (LCAT) which catalyzes the conversion of cholesterol to cholesteryl esters. This results in the accumulation of esterified cholesterol in the core of the HDL particle, and a morphological change from an immature discoidal shape to the mature spheroidal shape. The maturation of HDL particles is therefore characterized by changes in size and morphology of the particle and these changes reflect cholesterol accumulation within the particle. We will use a novel form of internal reflection infrared spectroscopy, and sophisticated """"""""isotope editing"""""""" strategies to investigate how lipid and protein components of HDL particles regulate the processing and maturation of the particle.
Our aim i s to investigate how the maturation of HDL particles is regulated by the nature and composition of specific lipid and apoprotein components under conditions in which we can measure LCAT activity and particle maturation directly and simultaneously. We also aim to focus our investigation on the effect of oxidatively damaged lipids and acute phase response proteins (injury specific apolipoproteins) on reverse cholesterol transport, both of which play a role in the pathogenesis of coronary artery disease. This knowledge is vital to our understanding of lipid transport and cholesterol homeostasis. Determining the factors responsible for regulation of HDL- mediated cholesterol efflux and RCT therefore represents a logical approach to our understanding the pathogenesis of atherosclerotic coronary vascular disease and stroke.
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