Apolipoprotein E is an important protein of the cholesterol transport system which has three common isoforms, apoE2, apoE3, and apoE4 in the general population. ApoE promotes receptor-mediated clearance of lipoprotein remnants from the circulation, contributes to lipid homeostasis, and protects from atherosclerosis. Deficiency or specific point mutations in apoE that interfere with receptor binding impede the clearance of atherogenic lipoproteins from the circulation, and result in type III hyperlipoproteinemia which is associated with premature atherosclerosis in humans and experimental animals. The apoE4 isoforms of apoE has been also implicated as a risk factor in late-onset familial Alzheimer's disease. Whereas expression of apoE within a physiological range clears lipoprotein remnants, high levels of expression of apoE2, apoES, or apoE4 causes hypertriglyceridemia. We have established recently that the hypertriglyceridemia is mediated to a large extent by hydrophobic residues located between amino acids 261 to 269 of the carboxy terminal region. These residues also influence the formation of apoE-containing HDL particles. Deficiency of the LDL receptor or mutations in the receptor binding domain of apoE decreases the threshold of apoE required for induction of hypertriglyceridemia in mice. In vitro and in vivo experiments have shown that apoE interacts functionally with ABCA1 and promotes the biogenesis of apoE-containing HDL. In addition, apoE interacts functionally with SR-BI and promotes lipid efflux. In this application, we propose to capitalize on the new knowledge we have acquired during the last four years to address three important questions pertinent to the functions of apoE and its role in dyslipidemia, in atherogenesis and the biogenesis of HDL-like apoE-containing lipoproteins.
Our specific aims are: 1: To investigate the contribution of individual apoE residues L261, W264, F265, L268, V269 in the in vivo functions of apoE, including the development ofhypertriglyceridemia, protection from atherogenesis, and formation of HDL. The ultimate goal is to generate recombinant apoE forms that are atheroprotective and have improved biological functions. 2: To investigate the relative contribution of the carboxy terminal domain of apoE in receptor recognition, sensitivity to hypertriglyceridemia and susceptibility to atherosclerosis in apoE mutants that are associated with dominant forms of type III hyperlipoproteinemia. These studies may identify apoE functions different from the LDL receptor binding that contribute to its anti-atherogenic properties. 3: To elucidate how functional interactions between apoE and ABCA1 contribute to the de novo biogenesis of HDL-like apoE- containing lipoprotein particles, the maturation of these particles by subsequent interactions with LCAT and SR-BI, and their role in the overall cholesterol homeostasis. Gene transfer in single or double knockout mice for apoA-l, apoE, SR-BI and biochemical analyses will be employed in these studies. ? ? ?

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Wassef, Momtaz K
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Boston University
Internal Medicine/Medicine
Schools of Medicine
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Fotakis, Panagiotis; Vezeridis, Alexander; Dafnis, Ioannis et al. (2014) apoE3[K146N/R147W] acts as a dominant negative apoE form that prevents remnant clearance and inhibits the biogenesis of HDL. J Lipid Res 55:1310-23
Georgiadou, Dimitra; Chroni, Angeliki; Drosatos, Konstantinos et al. (2013) Allele-dependent thermodynamic and structural perturbations in ApoE variants associated with the correction of dyslipidemia and formation of spherical ApoE-containing HDL particles. Atherosclerosis 226:385-91
Dafnis, I; Tzinia, A K; Tsilibary, E C et al. (2012) An apolipoprotein E4 fragment affects matrix metalloproteinase 9, tissue inhibitor of metalloproteinase 1 and cytokine levels in brain cell lines. Neuroscience 210:21-32
Koupenova, Milka; Johnston-Cox, Hillary; Vezeridis, Alexander et al. (2012) A2b adenosine receptor regulates hyperlipidemia and atherosclerosis. Circulation 125:354-63
Vezeridis, Alexander M; Drosatos, Konstantinos; Zannis, Vassilis I (2011) Molecular etiology of a dominant form of type III hyperlipoproteinemia caused by R142C substitution in apoE4. J Lipid Res 52:45-56
Georgiadou, Dimitra; Chroni, Angeliki; Vezeridis, Alexander et al. (2011) Biophysical analysis of apolipoprotein E3 variants linked with development of type III hyperlipoproteinemia. PLoS One 6:e27037
Vezeridis, Alexander M; Chroni, Angeliki; Zannis, Vassilis I (2011) Domains of apoE4 required for the biogenesis of apoE-containing HDL. Ann Med 43:302-11
Sanoudou, D; Duka, A; Drosatos, K et al. (2010) Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice. Pharmacogenomics J 10:165-79
Iliopoulos, Dimitrios; Drosatos, Konstantinos; Hiyama, Yaeko et al. (2010) MicroRNA-370 controls the expression of microRNA-122 and Cpt1alpha and affects lipid metabolism. J Lipid Res 51:1513-23
Dafnis, Ioannis; Stratikos, Efstratios; Tzinia, Athina et al. (2010) An apolipoprotein E4 fragment can promote intracellular accumulation of amyloid peptide beta 42. J Neurochem 115:873-84

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