Abstract

The long term goal of this research is to understand the functional basis for the expression of apolipoprotein (apo) E in peripheral tissues. The proposal consists of 4 aims that are focused on activities of apoE that influence cellular cholesterol metabolism in adrenal cells and activities that are anti-atherogenic within the vascular wall. Experiments in Aim 1 will test the hypothesis that low levels of systemic apoE act within the vascular wall to block an early step in atherosclerotic lesion development.
Aim 2 will explicitly test the hypothesis that low levels of apoE provide protection against atherogenesis initiated by apoB48 lipoproteins but do not protect against atherogenesis due to apoB100 lipoproteins.
Aim 3 will test the hypothesis that adrenal gland apoE expression increases adrenal cholesteryl ester storage and diminishes steroid production.
Aim 4 will test the physiological importance of a newly discovered apoE-stimulated pathway for the selective uptake of low density lipoprotein cholesteryl ester.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL032868-17
Application #
6388946
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Applebaum-Bowden, Deborah
Project Start
1984-06-01
Project End
2004-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
17
Fiscal Year
2001
Total Cost
$433,478
Indirect Cost

  Institution

Name
State University New York Stony Brook
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804878247
City
Stony Brook
State
NY
Country
United States
Zip Code
11794

  Publications

Ma, Yanqing; Malbon, Craig C; Williams, David L et al. (2008) Altered gene expression in early atherosclerosis is blocked by low level apolipoprotein E. PLoS One 3:e2503
Zhao, Yue; Thorngate, Fayanne E; Weisgraber, Karl H et al. (2005) Apolipoprotein E is the major physiological activator of lecithin-cholesterol acyltransferase (LCAT) on apolipoprotein B lipoproteins. Biochemistry 44:1013-25
Mann, Karen M; Thorngate, Fayanne E; Katoh-Fukui, Yuko et al. (2004) Independent effects of APOE on cholesterol metabolism and brain Abeta levels in an Alzheimer disease mouse model. Hum Mol Genet 13:1959-68
Wientgen, Hilke; Thorngate, Fayanne E; Omerhodzic, Sabina et al. (2004) Subphysiologic apolipoprotein E (ApoE) plasma levels inhibit neointimal formation after arterial injury in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 24:1460-5
Thorngate, Fayanne E; Yancey, Patricia G; Kellner-Weibel, Ginny et al. (2003) Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression. J Lipid Res 44:2331-8
Temel, Ryan E; Parks, John S; Williams, David L (2003) Enhancement of scavenger receptor class B type I-mediated selective cholesteryl ester uptake from apoA-I(-/-) high density lipoprotein (HDL) by apolipoprotein A-I requires HDL reorganization by lecithin cholesterol acyltransferase. J Biol Chem 278:4792-9
Thorngate, Fayanne E; Strockbine, Penelope A; Erickson, Sandra K et al. (2002) Altered adrenal gland cholesterol metabolism in the apoE-deficient mouse. J Lipid Res 43:1920-6
Swarnakar, S; Beers, J; Strickland, D K et al. (2001) The apolipoprotein E-dependent low density lipoprotein cholesteryl ester selective uptake pathway in murine adrenocortical cells involves chondroitin sulfate proteoglycans and an alpha 2-macroglobulin receptor. J Biol Chem 276:21121-8
DeMattos, R B; Rudel, L L; Williams, D L (2001) Biochemical analysis of cell-derived apoE3 particles active in stimulating neurite outgrowth. J Lipid Res 42:976-87
Thorngate, F E; Rudel, L L; Walzem, R L et al. (2000) Low levels of extrahepatic nonmacrophage ApoE inhibit atherosclerosis without correcting hypercholesterolemia in ApoE-deficient mice. Arterioscler Thromb Vasc Biol 20:1939-45

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