Apolipoprotein E (apoE) is synthesized and secreted by a wide variety of mammalian cells and a number of hypotheses have been developed regarding the potential functions of apoE synthesized in extrahepatic tissues. The macrophage was the first extrahepatic cell type in which apoE synthesis was reported and a great deal of information has been developed characterizing the regulation of apoE synthesis in these cells. We have been primarily interested in further exploring the mechanisms for the regulation of macrophage apoE production. In this application, we propose experiments designed to a) define the molecular mechanism for the induction of apoE gene transcription which i) accompanies cholesterol loading of macrophages; ii) accompanies differentiation of monocytes to macrophages; and b) examine post-transcriptional and post-translational regulation of apoE in macrophages and specifically, to determine how this step is modulated in response to differentiation and extracellular lipids. Our laboratory has been involved in making important basic observations for each of the experimental directions outlined above. Macrophages are a major source of apoE in extrahepatic tissues. A role for apoE has been established in participating in tissue lipid transport as well as modulating the growth, phenotype and differentiated function of a diverse group of extrahepatic cells (e.g. lymphocytes, steroidogenic cells, and mesenchymal cells). Understanding the regulation of apoE production in macrophages could provide major insights into understanding the pathophysiology of disease processes in which macrophages play a key role, for example, atherosclerosis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL039653-04A1
Application #
3356445
Study Section
Metabolism Study Section (MET)
Project Start
1988-07-01
Project End
1996-12-31
Budget Start
1993-01-01
Budget End
1993-12-31
Support Year
4
Fiscal Year
1993
Total Cost
Indirect Cost
Name
Rush University Medical Center
Department
Type
DUNS #
City
Chicago
State
IL
Country
United States
Zip Code
60612
Mazzone, Theodore (2010) Intensive glucose lowering and cardiovascular disease prevention in diabetes: reconciling the recent clinical trial data. Circulation 122:2201-11
Mazzone, Theodore; Chait, Alan; Plutzky, Jorge (2008) Cardiovascular disease risk in type 2 diabetes mellitus: insights from mechanistic studies. Lancet 371:1800-9
Lucic, Danijela; Huang, Zhi Hua; Gu, DeSheng et al. (2007) Cellular sphingolipids regulate macrophage apolipoprotein E secretion. Biochemistry 46:11196-204
Lucic, Danijela; Huang, Zhi Hua; Gu, De Sheng et al. (2007) Regulation of macrophage apoE secretion and sterol efflux by the LDL receptor. J Lipid Res 48:366-72
Fantuzzi, Giamila; Mazzone, Theodore (2007) Adipose tissue and atherosclerosis: exploring the connection. Arterioscler Thromb Vasc Biol 27:996-1003
Huang, Zhi H; Fitzgerald, Michael L; Mazzone, Theodore (2006) Distinct cellular loci for the ABCA1-dependent and ABCA1-independent lipid efflux mediated by endogenous apolipoprotein E expression. Arterioscler Thromb Vasc Biol 26:157-62
Huang, Zhi Hua; Gu, DeSheng; Mazzone, Theodore (2004) Oleic acid modulates the post-translational glycosylation of macrophage ApoE to increase its secretion. J Biol Chem 279:29195-201
Yue, Lili; Rasouli, Neda; Ranganathan, Gouri et al. (2004) Divergent effects of peroxisome proliferator-activated receptor gamma agonists and tumor necrosis factor alpha on adipocyte ApoE expression. J Biol Chem 279:47626-32
Huang, Z Hua; Gu, DeSheng; Lange, Yvonne et al. (2003) Expression of scavenger receptor BI facilitates sterol movement between the plasma membrane and the endoplasmic reticulum in macrophages. Biochemistry 42:3949-55
Zhao, Yuwei; Yue, Lili; Gu, DeSheng et al. (2002) Regulation of macrophage ApoE expression and processing by extracellular matrix. J Biol Chem 277:29477-83

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