High levels of high density lipoprotein-cholesterol (HDL-C) are associated with lowered risk for cardiovascular disease (CVD) in epidemiological studies. However, recent genetic and drug studies have shown that HDL-C itself is probably not causal in reducing CVD risk. Instead, a consensus is building that HDL functions may protect against CVD, and that treating for the biomarker of HDL-C may not always coincide with increased HDL function. One of the functions of HDL that may play a role in its protective effect is its role in the reverse cholesterol transport (RCT) pathway, in which cholesterol is removed from peripheral tissues and transferred to the liver for excretion. HDL and its major protein constituent, apolipoprotein A-I (apoA-I), are critical components of this process. In the first ste of the RCT pathway, lipid-poor apoA-I acts as an acceptor for cell cholesterol and phospholipids via the cell membrane protein ABCA1, generating nascent HDL through a mechanism which is not understood at the molecular level. ABCA1 has two well characterized activities, the outward translocation of phosphatidylserine, and the cell surface binding of its ligand apoA-I. We recently characterized a third activity of ABCA1, the ability to unfold apoA-I's N-terminal helical hairpin.
In Aim 1, we explore our novel finding that phosphatidylinositol phosphates (PIPs) play a role in nascent HDL biogenesis.
In Aim 2, we explore the mechanism by which ABCA1 helps partially unfold apoA-I on the cell surface, including the role of our novel finding of ABCA1 mediated acidification of apoA-I on the cell surface. Successful completion of the proposed studies will increase our knowledge of the mechanism of de novo HDL production, which may yield insights into new strategies to increase HDL biogenesis and HDL function, and aid in the prevention of CVD.
Although HDL-cholesterol is associated with decreased risk for coronary heart disease (CHD), recent genetic and drug studies have shown that HDL-cholesterol may not itself be protective. Instead the consensus is that HDL function may be protective, particularly the ability of apoA-I, the major HDL protein, to accept cholesterol from cells in the arterial wall. Nascent HDL is formed when apoA-I is lipidated in a reaction mediated by the plasma membrane protein ABCA1; however, the mechanism for ABCA1 lipidation of apoA-I is not understood. The proposed studies will test novel hypotheses for the mechanism of ABCA1's lipidation of apoA-I. These studies may lead to a better understanding of HDL biogenesis and provide the basis for future therapeutic strategies to increase prevent CHD.
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