Epidemiological studies indicate that reduced levels of HDL are an important risk factor for the development of atherosclerosis. A major theory to explain this relationship is that low levels of HDL are a metabolic marker for a tendency to accumulate atherogenic remnants of triglyceride-rich lipoproteins in plasma. The plasma cholesteryl ester transfer protein (CETP) mediates the transfer of CE from HDL to the triglyceride-rich lipoproteins. This pathway represents a major route for the catabolism of HDL CE in humans, and has the potential to increase the atherogenicity of remnant lipoproteins in subjects who accumulate these particles in plasma. The objective of this proposal is to understand on a molecular level the structure and function of plasma CETP and its role in HDL metabolism, as a means of furthering the understanding of the regulation and significance of HDL levels.
The specific aims of the proposal are 1) to determine the three dimensional structure of CETP, by crystallization of the recombinant molecule; 2) to perform site-directed mutagenesis on the CETP molecule in order to elucidate amino acids that are necessary for lipid transfer or which mediate binding of CETP to specific lipoproteins; 3) to employ lipoprotein reconstitution and other techniques to define the molecular features of particular subclasses of HDL which permit specific recognition by CETP; 4) to use available CETP transgenic mice in order to determine in vivo the effects of hypertriglyceridemia and hepatic lipase on the expression of CETP activity; and 5) to examine the relationship between plasma CETP, lipoprotein levels and atherogenesis in an ongoing case-control study of the relationship of post-prandial lipoprotein changes to coronary artery atherosclerosis. The proposed studies will increase the understanding of the structure and mechanism of action of CETP, and will help to clarify the relationship between triglyceride-rich lipoproteins, HDL and coronary artery disease.
|Jung, Un Ju; Millman, Peri N; Tall, Alan R et al. (2011) n-3 fatty acids ameliorate hepatic steatosis and dysfunction after LXR agonist ingestion in mice. Biochim Biophys Acta 1811:491-7|
|Ishibashi, Minako; Masson, David; Westerterp, Marit et al. (2010) Reduced VLDL clearance in Apoe(-/-)Npc1(-/-) mice is associated with increased Pcsk9 and Idol expression and decreased hepatic LDL-receptor levels. J Lipid Res 51:2655-63|
|Yvan-Charvet, Laurent; Kling, Jelena; Pagler, Tamara et al. (2010) Cholesterol efflux potential and antiinflammatory properties of high-density lipoprotein after treatment with niacin or anacetrapib. Arterioscler Thromb Vasc Biol 30:1430-8|
|Tall, Alan R (2010) Functions of cholesterol ester transfer protein and relationship to coronary artery disease risk. J Clin Lipidol 4:389-93|
|Masson, David; Koseki, Masahiro; Ishibashi, Minako et al. (2009) Increased HDL cholesterol and apoA-I in humans and mice treated with a novel SR-BI inhibitor. Arterioscler Thromb Vasc Biol 29:2054-60|
|Sun, Yu; Ishibashi, Minako; Seimon, Tracie et al. (2009) Free cholesterol accumulation in macrophage membranes activates Toll-like receptors and p38 mitogen-activated protein kinase and induces cathepsin K. Circ Res 104:455-65|
|Yvan-Charvet, Laurent; Pagler, Tamara A; Wang, Nan et al. (2008) SR-BI inhibits ABCG1-stimulated net cholesterol efflux from cells to plasma HDL. J Lipid Res 49:107-14|
|Welch, Carrie L; Sun, Yu; Arey, Brian J et al. (2007) Spontaneous atherothrombosis and medial degradation in Apoe-/-, Npc1-/- mice. Circulation 116:2444-52|
|Liang, Chien-Ping; Han, Seongah; Senokuchi, Takafumi et al. (2007) The macrophage at the crossroads of insulin resistance and atherosclerosis. Circ Res 100:1546-55|
|Yvan-Charvet, Laurent; Matsuura, Fumihiko; Wang, Nan et al. (2007) Inhibition of cholesteryl ester transfer protein by torcetrapib modestly increases macrophage cholesterol efflux to HDL. Arterioscler Thromb Vasc Biol 27:1132-8|
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