Obesity is a major health problem in the United States, imparting significant metabolic and cardiovascular risk. The prevalence of obesity is predicted to continue to increase over the next several decades, and there is an urgent need to better understand adipocyte and adipose tissue physiology. Recently, my laboratory has accumulated provocative preliminary information regarding an important role for apoprotein E in adipocyte differentiated function. Our proposal is based on these preliminary data, and takes advantage of our substantial experience in the study of macrophage apoE. The goals of the current application are encompassed in three Specific Aims.
In Specific Aim # 1, we propose to analyze the molecular mechanism for the regulation of apoE gene expression by PPARgamma agonists and TNFalpha that we have already demonstrated. We will also evaluate post-translational regulation of adipocyte apoE expression.
In Specific Aim # 2, we will further expand on our preliminary data that shows expression of apoE has a significant impact on adipocyte lipid metabolism. For these studies, apoE expression will be manipulated by stable transfection, adenoviruses or interfering RNA's. We will also evaluate adipocytes isolated from apoE knockout mice and control mice. We also plan to extend our observations to an in vivo model by transplanting adipose tissue from apoE knockout mice to wild-type mice in order to evaluate parameters of gene expression and lipid metabolism in transplanted tissue.
In Specific Aim # 3, we will investigate potential heterogeneity for regulation of apoE expression, or for the effect of apoE expression on adipocyte lipid metabolism, based on the source of adipose tissue. For these studies, adipose tissue will be collected from the gluteal and abdominal subcutaneous regions, and from the intraperitoneal visceral region, of patients undergoing bariatric surgery; and utilized for isolation of adipocytes. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK071711-02
Application #
7269369
Study Section
Cellular Aspects of Diabetes and Obesity Study Section (CADO)
Program Officer
Haft, Carol R
Project Start
2006-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$308,535
Indirect Cost
Name
University of Illinois at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
Huang, Zhi H; Reardon, Catherine A; Subbaiah, Papasani V et al. (2013) ApoE derived from adipose tissue does not suppress atherosclerosis or correct hyperlipidemia in apoE knockout mice. J Lipid Res 54:202-13
Yue, Lili; Bian, Jing-Tan; Grizelj, Ivana et al. (2012) Apolipoprotein E enhances endothelial-NO production by modulating caveolin 1 interaction with endothelial NO synthase. Hypertension 60:1040-6
Huang, Zhi H; Maeda, Nobuyo; Mazzone, Theodore (2011) Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis. J Lipid Res 52:1733-41
Yue, Lili; Mazzone, Theodore (2011) Endogenous adipocyte apolipoprotein E is colocalized with caveolin at the adipocyte plasma membrane. J Lipid Res 52:489-98
Huang, Zhi H; Espiritu, Doris J; Uy, Arlene et al. (2011) Adipose tissue depot-specific differences in adipocyte apolipoprotein E expression. Metabolism 60:1692-701
Mazzone, Theodore (2010) Intensive glucose lowering and cardiovascular disease prevention in diabetes: reconciling the recent clinical trial data. Circulation 122:2201-11
Espiritu, Doris Joy; Huang, Zhi Hua; Zhao, Yong et al. (2010) Hyperglycemia and advanced glycosylation end products suppress adipocyte apoE expression: implications for adipocyte triglyceride metabolism. Am J Physiol Endocrinol Metab 299:E615-23
Yue, Lili; Mazzone, Theodore (2009) Peroxisome proliferator-activated receptor {gamma} stimulation of adipocyte ApoE gene transcription mediated by the liver receptor X pathway. J Biol Chem 284:10453-61
Sam, Susan; Haffner, Steven; Davidson, Michael H et al. (2009) Hypertriglyceridemic waist phenotype predicts increased visceral fat in subjects with type 2 diabetes. Diabetes Care 32:1916-20
Huang, Zhi Hua; Minshall, Richard D; Mazzone, Theodore (2009) Mechanism for endogenously expressed ApoE modulation of adipocyte very low density lipoprotein metabolism: role in endocytic and lipase-mediated metabolic pathways. J Biol Chem 284:31512-22

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