Apolipoprotein E (apoE) is an important protein of the cholesterol transport system. ApoE is responsible for the clearance of lipoprotein remnants from the circulation via lipoprotein receptors, contributes to cholesterol homeostasis, and protects from atherosclerosis. ApoE has also been shown to have other functions which contribute to cholesterol and triglyceride homeostasis, including VLDL triglyceride secretion and VLDL lipolysis, two processes which may affect plasma triglyceride levels. It is our hypothesis, which is supported by preliminary data, that the carboxy terminal domain of apoE is responsible for the hypertriglyceridemia which is induced by overexpression of apoE. We also hypothesize that overexpression of carboxy terminal apoE variants may protect from atherosclerosis.
Our specific aims are: 1) To use adenovirus-mediated gene transfer as well as transgenic mice to elucidate the role of apoE in triglyceride homeostasis and establish the mechanism of apoE-induced hypertriglyceridemia in vivo. 2) To use adenovirus-mediated gene transfer of different apoE forms (in appropriate receptor-deficient mouse models) to elucidate the role of apoE receptors in cholesterol clearance in vivo and in vitro. The mouse models that will be utilized for gene transfer are apoE-/-, LDLR-/-, liver-specific LRP-/- mice as well as crosses among these The gene transfer and receptor binding studies will define the ligand speciflcities for different receptors. 3) To express long-term apoE forms that do not induce hypertriglyceridemia using adenoassociated viral vectors (AAV-apoE) and transgenic mice in order to correct the hypercholesterolemic and atherogenic profile of apoE-deficient mice.
This specific aim will explore the ability of selected truncated and mutant forms of apoE that do not induce hypertriglyceridemia to protect from atherosclerosis. We expect that apoE forms that can clear cholesterol and triglycerides and protect from atherosclerosis may provide new therapeutic tools in the near future for the correction of remnant removal disorders.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL068216-01
Application #
6368426
Study Section
Medical Biochemistry Study Section (MEDB)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2001-09-01
Project End
2005-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
1
Fiscal Year
2001
Total Cost
$285,250
Indirect Cost
Name
Boston University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118
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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