In human plasma, the composition and concentration of circulating lipoproteins is strongly influenced by cholesteryl ester transfer protein (CETP). Given its importance in lipoprotein metabolism and potential influence on atherosclerosis, the regulation of CETP activity has been the subject of extensive study. We have identified a plasma protein, lipid transfer inhibitor protein (LTIP), that regulates CETP activity. Recently, we purified, cloned and expressed LTIP and demonstrated its identity with apolipoprotein F, a protein with no known function. We propose that LTIP is a lipid flux switch that regulates CETP, not by suppressing CETP activity generally, but by selectively interfering with lipid transfer events to and from LDL. This selectivity toward LDL appears to be mediated by the preferential association of LTIP with LDL in plasma. Several lines of evidence from in vitro and in vivo studies strongly suggest that LTIP is a physiological modulator of lipoprotein concentration and composition. Our long-term objective is to define the role of LTIP in regulating lipoprotein metabolism and to define its impact on atherogenesis. In this proposal we further define the role of LTIP in vivo, identify its mechanism of action, and characterize mechanisms regulating its synthesis and secretion. In vitro and in vivo studies test the hypothesis that remnants of VLDL catabolism acquire LTIP as they near LDL in size, which alters their CETP-substrate status and determines the nature of the end- products of VLDL catabolism (Aim 1). Kinetic and lipid monolayer studies with recombinant LTIP, and lipoprotein modification and LTIP mutagenesis studies will determine the mechanism of LTIP's action and define the properties of lipoproteins and the structural features of LTIP that are required for activity (Aim 2). Finally, biochemical and molecular studies with cultured cells and tissue-specific expression analyses will be used to test the hypothesis that LTIP and CETP are co-expressed and co- regulated in response to cellular cholesterol homeostasis (Aim 3). Overall, these studies will provide novel insights into a poorly characterized modulator of cholesterol flux in human plasma.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Metabolism Study Section (MET)
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Cleveland Clinic Lerner
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Izem, Lahoucine; Greene, Diane J; Bialkowska, Katarzyna et al. (2015) Overexpression of full-length cholesteryl ester transfer protein in SW872 cells reduces lipid accumulation. J Lipid Res 56:515-25
Greene, Diane J; Izem, Lahoucine; Morton, Richard E (2015) Defective triglyceride biosynthesis in CETP-deficient SW872 cells. J Lipid Res 56:1669-78
Morton, Richard E; Izem, Lahoucine (2015) Modification of CETP function by changing its substrate preference: a new paradigm for CETP drug design. J Lipid Res 56:612-9
Morton, Richard E; Izem, Lahoucine (2014) Cholesteryl ester transfer proteins from different species do not have equivalent activities. J Lipid Res 55:258-65
Morton, Richard E; Greene, Diane J (2011) Conversion of lipid transfer inhibitor protein (apolipoprotein F) to its active form depends on LDL composition. J Lipid Res 52:2262-71
Izem, Lahoucine; Morton, Richard E (2009) Molecular cloning of hamster lipid transfer inhibitor protein (apolipoprotein F) and regulation of its expression by hyperlipidemia. J Lipid Res 50:676-84
He, Yubin; Greene, Diane J; Kinter, Michael et al. (2008) Control of cholesteryl ester transfer protein activity by sequestration of lipid transfer inhibitor protein in an inactive complex. J Lipid Res 49:1529-37
Morton, Richard E; Gnizak, Hannah M; Greene, Diane J et al. (2008) Lipid transfer inhibitor protein (apolipoprotein F) concentration in normolipidemic and hyperlipidemic subjects. J Lipid Res 49:127-35
Izem, Lahoucine; Morton, Richard E (2007) Possible role for intracellular cholesteryl ester transfer protein in adipocyte lipid metabolism and storage. J Biol Chem 282:21856-65
Morton, Richard E; Greene, Diane J (2007) Partial suppression of CETP activity beneficially modifies the lipid transfer profile of plasma. Atherosclerosis 192:100-7

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